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Circulation on the Run

Each 15-minute podcast begins with an overview of the issue’s contents and main take-home messages for busy clinicians on the run.

438 avsnitt • Längd: 25 min • Veckovis: Måndag

Hälsa och motion • Life Science • Medicin • Vetenskap

Om podden

Each 15-minute podcast begins with an overview of the issue’s contents and main take-home messages for busy clinicians on the run. This is followed by a deep dive into a featured article of particular clinical significance: views will be heard from both author and editor teams for a “behind the scenes” look at the publication. Expect a fun, highly conversational and clinically-focused session each week!

The podcast Circulation on the Run is created by Greg Hundley, MD and Peder Myhre, MD, PhD. The podcast and the artwork on this page are embedded on this page using the public podcast feed (RSS).

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Circulation April 18, 2023 Issue

17 april 2023 | 22 min

This week, please join authors Marc Sabatine and Prakriti Gaba, as well as Associate Editor Amit Khera, as they discuss the article "Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE."

Dr Greg Hundley:

Welcome listeners, to this April 18th issue of Circulation on the Run and I am Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo.

Dr Greg Hundley:

Peder, today's feature discussion, very interesting. We're going to evaluate the association between what's achieved with LDL cholesterol lowering, and then also long-term cardiovascular and safety outcomes. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first?

Dr Peder Myhre:

Yes, Greg. I would love to. And the first paper is from the World of Preclinical Science and it comes to us from corresponding author, Jan Magnus Aronsen from University of Oslo in Norway. And perhaps, as you know, Greg, cardiomyocyte contraction and relaxation depend on the activity of the sarcoplasmic reticulum CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced activity of SERCA2, as seen in chronic heart failure, weakens contractile force and delays relaxation and no available therapy involves direct manipulation of the SERCA2 activity. And Greg, phosphodiesterase 3A is proposed to be present in the SERCA2 interactome limit SERCA2 activity and disruption of phosphodiesterase 3A from SERCA2 might thus be a strategy to develop SERCA2 activators. And in this study, the authors investigated and mapped SERCA2 and phosphodiesterase 3A and assessed this in experiments assessing the binding between these two in cardiomyocytes and in vesicles.

Dr Greg Hundley:

Wow Peder, sounds very interesting. So what did they find and how about the clinical implications of the findings?

Dr Peder Myhre:

So Greg phosphodiesterase 3A bounded directly to SERCA2 in the cardiomyocyte. So that's the first finding. Second, they demonstrated that SERCA2 phosphodiesterase 3A disruption increased SERCA2 activity independently of the catalytic activity of phosphodiesterase 3A in both normal and failing cardiomyocytes. And third, SERCA2 activity by the optimized SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced mortality and improved contractility after aortic binding in mice. So the clinical implication is that direct targeting of phosphodiesterase 3A binding to SERCA2 could be a novel approach to increase SERCA2 activity and thus cardiac contractility in patients with heart failure.

Dr Greg Hundley:

Very nice Peder. What a great new finding in the world of preclinical science. Well my paper is going to delve into the world of clinical science and involves patients with stroke. So Peder in this study led by corresponding author, Dr. Dileep Yavagal from University of Miami Miller School of Medicine performed a survey in 75 countries through the Mission Thrombectomy 2020+ Global Network between November of 2020 and February of 2021 to determine the availability of mechanical thrombectomy for large vessel occlusion in patients with stroke. Now Peder, the primary endpoints were the current annual mechanical thrombectomy availability, the mechanical thrombectomy operator availability and the mechanical thrombectomy center availability. All of these availabilities were defined as the proportion of estimated large vessel occlusion for patients receiving mechanical thrombectomy in a given region annually.

Dr Peder Myhre:

Okay, Greg, so this is really an access question. So in essence, what is the availability of mechanical thrombectomy worldwide? So what did they find?

Dr Greg Hundley:

Right, great Peder. So what they found, the authors received 887 responses from 67 countries and low-income countries had 88% lower mechanical thrombectomy availability compared to high-income countries. The global mechanical thrombectomy operator availability was 16.5% of optimal, and the mechanical thrombectomy center availability was only 20.8% optimal. And with these results, the authors indicate that global cooperation and targeted region-specific public health interventions, including all stakeholders involved in stroke care delivery, are really needed to rapidly increase access to this brain-saving and disability-sparing treatment with mechanical thrombectomy really worldwide.

Dr Peder Myhre:

Oh wow. What a beautiful summary, Greg. Thank you so much. And we also have some other interesting papers in the mailbag today. We have an exchange of letters between Dr. Yang and Dr. O'Donoghue regarding the article “Long Term evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease.”

Dr Greg Hundley:

Great Peder, and also Professor Perera has a Frontiers article entitled “Unloading the Left Ventricle in Venoarterial ECMO in Who, When and How?” and then finally there's a Research Letter from Professor Verma entitled “Prevalence of Diabetes and Cardiovascular Risk in the Middle East and Africa: The Primary results of the PACT-MEA Study.” Well Peder, how about we jump to that feature discussion?

Dr Peder Myhre:

Can't wait.

Dr Greg Hundley:

Welcome listeners to this feature discussion on April 18th and we have with us today Prakriti Gaba and Marc Sabatine from Brigham and Women's Hospital and our own associate editor, Dr. Amit Khera. Welcome everyone. Well Marc, we'll start with you. Can you describe for us some of the background information that really helps constitute the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Marc Sabatine:

Yeah, thanks Greg and thanks for having us. So we've seen in a variety of epidemiologic cohorts the association between LDL cholesterol and the risk of adverse cardiovascular events like in Framingham Heart Study and UK Biobank. But in those cohorts, in these industrial societies, we don't have the benefit of lots of data in individuals with very low levels of LDL cholesterol and so we had the opportunity with the FOURIER study that was the randomized comparison of evolocumab PCSK9 inhibitor versus placebo to get patients down to extremely low levels of LDL cholesterol and evolocumab. We were able to get individuals down to about 30 mg/dL. And so in addition to all the studies we've done showing the comparison of evolocumab to placebo, we also then had the chance to use FOURIER, and as you'll hear from PK, FOURIER-OLE, the open-label extension, as a cohort to then examine patients' new baseline, if you will, their new achieved LDL cholesterol and then it's association not only with cardiovascular events but safety events.

And so the hypothesis is that there would be a relationship with the lower the LDL cholesterol, the lower the risk of cardiovascular events and we wanted to explore how far down that went. And then the second one for safety would be that there wouldn't be any association between low levels of LDL cholesterol and a variety of safety outcomes that rightly or wrongly people have ascribed to low levels of LDL cholesterol.

Dr Greg Hundley:

Thanks so much, Marc. Well listeners, now we're going to turn to PK, the first author, on this very interesting paper and PK, Marc mentioned to us the FOURIER-OLE study. Maybe describe for us here your study design and then what specifically was your study population?

Dr. Prakriti Gaba (PK):

Yeah, definitely. Thanks so much for the introduction. So the study population included 27,564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels that were greater than or equal to 70 mg/dL or non-HDL cholesterol greater than or equal to a 100 mg/dL on statin therapy. The patients who then went on to the FOURIER-OLE or the open-label extension part of the trial consisted of about 6,635 patients. And so in this study we essentially evaluated the combination of those populations in 2 separate analyses. We then categorized patients according to 6 pre-specified bins based on their achieved LDL cholesterol levels at designated time points and those ranged from LDL levels of less than 20 mg/dL all the way up to 100 mg/dL. And then we looked at their baseline characteristics and evaluated the cardiovascular and safety outcomes that Dr. Sabatine mentioned earlier.

Dr Greg Hundley:

Very nice PK. Well we've got a great listening audience today and they're anxious to hear your study results, so can you share those with us please?

Dr. Prakriti Gaba (PK):

Definitely. So over the course of more than 77,000 patient years of follow-up, we found that there was a monotonic relationship between achieving lower LDL cholesterol levels down to very low levels of less than 20 mg/dL and a lower annualized risk of the primary efficacy endpoint, which was a composite of 5 individual endpoints. We also found that there was a similar relationship observed between lower LDL achieved, LDL cholesterol levels and a lower annualized risk of the secondary efficacy endpoint, and then when we looked at safety, there were actually no clear monotonic trends between lower achieved LDL levels and the risk of any of the 8 adverse events and these included things like serious adverse events, hemorrhagic stroke or muscle related events.

Dr Greg Hundley:

Very nice PK and I'm sure our listeners are wanting to know, did you find any discrepancy in your results based on either age or gender?

Dr. Prakriti Gaba (PK):

That's an excellent question, and we did look at age and gender throughout. I think across the board the results were pretty consistent, but additional subanalyses will further address this question.

Dr Greg Hundley:

Very good. Well listeners now we're going to turn to one of our associate editors, Dr. Amit Khera, who has helped move this article through the process of evaluation with the editorial team. Amit, you have many papers come across your desk, what attracted you to this paper and then how do we put this study's results really in the context of other studies that have sought to dramatically lower LDL cholesterol?

Dr. Amit Khera:

Well first thanks a lot Greg for allowing me to participate today. I want to congratulate Drs. Gaba and Sabatine on a fantastic paper and the minute I saw it, and you know can tell when you've done this for a while what's a great paper, and this one certainly is and we work closely with them to try to make it better and enhance the analyses and as a group, I think we achieved that. I was fortunate to write an accompanying editorial that you'll see.

So I got to take a pretty deep dive in this paper and I want to just talk about sort of what's important here, why is this important, and I think as Dr. Gaba mentioned, there's two sides to this. There's the efficacy side where you talk about LDL lowering and getting to very low levels. Now mind you, they got to, what I call, ultra low levels, even explored for a down to a median of 7 mg/dL, so really, really low. And first I think what our listeners need to know when we look at guidelines, these numbers of 70 or 55, these are completely arbitrary and they're based on what was observed in clinical trials, what was achieved in high intensity versus moderate intensity statins in IMPROVE-IT.

There's no biology behind that, and I think what this study does is reminds us there is no biology behind how low we need to go. This group previously published their shorter-term data approximately 2 years with this construct of lower is better and I think that's fine, but people worry, particularly on the safety side about extension, and we'll get to that in a minute, so where this fits is it gives us even more reassurance that lower is better, reminds us there's no biologic basis of that even down to very low levels. And so what does that mean? I think that comes back to guidelines. We have some discrepancy between European, ACC, Multisociety Guidelines that are around 55 and so from a guideline perspective, I think we'll see a little bit more enthusiasm about lower cut points or lower thresholds. And from a clinical standpoint, as a clinician it reminds me that when I see someone that's very high risk, there's no magic to achieving a number that if the risk is high, we need to be quite intensive and get their LDL down as low as possible and as safely as possible.

I do want to also acknowledge, there's not, to your point about context, the IMPROVE-IT study also showed very low levels show additional efficacy and there's also a lot of other data, genetics and ecologic data supporting this. So this is... we look at Bayesian analysis that this is consistent that we're seeing across different platforms.

I do want to talk about safety too, Greg. That's really important because honestly this is when it comes to patient level, the safety part of it. We as clinicians may have comfort with very low levels, but the safety is important. I also want to, just from a steady design, this is post-hoc, so those that achieve very low levels are different. You can see that in their table 1, but these investigators did lots of things. They did pretty extensive multi-variable analysis, they looked at time-dependent LDLs, they looked at it multiple different ways, but as mentioned, there really did not seem to be a safety signal. And this is where time matters.

Safety in two years, interesting, but safety 5 to 8 years really offers us much more reassurance. So I think that's where this really comes in about that safety piece with the extended analysis. So again, I think from a guideline perspective, from a clinical perspective, there's so many implications from this paper and I really hope people take the time to take a deep dive and also put it in context, like you said, to the other literature where this is not standalone, but it's corroborating what we're seeing.

Dr Greg Hundley:

Very nice, amit. Marc, I want to come back to you, just two quick questions thinking about the preparation of your study. One, did you sample cognition? One thing we hear about frequently in dramatic lowering of LDL cholesterol are questions around cognition, particularly in the elderly?

Dr. Marc Sabatine:

Yeah, it's a great question Greg. So first of all, in the FOURIER study itself, there was an embedded study called EBBINGHAUS that Bob Giugliano from our group led that actually did formal neurocognitive testing in individuals using basically a iPad-like test. We also collected the usual neurocognitive adverse events as part of safety collecting. So 2 ways, the general asking about any adverse events and then the specific neurocognitive testing. We had previously reported out the results of EBBINGHAUS that there wasn't any relationship between evolocumab and the low LDL cholesterol and the risk of any neurocognitive AEs. We just were able to recently do this OLE analysis over time for the major adverse cardiovascular events and for the general safety events including cognition, so all that looked good. As PK indicated, we're now digging into the EBBINGHAUS formal neurocognitive testing, which was also extended out. So stay tuned for those results.

Dr Greg Hundley:

Very nice. And then eligibility, maybe just walk us through that really quickly. Patients that are going to be randomized to this form of therapy, were they already on high-dose statins? Who exactly did we randomize in this trial?

Dr. Marc Sabatine:

Yeah, so at the get-go, as PK indicated, these are patients with atherosclerotic cardiovascular disease, so they had a prior MI, prior stroke, symptomatic PAD. They were to be on an optimized lipid-lowering regimen, optimized statin therapy, so for close to 70%, that was a high-intensity statin. We had a small percentage on ezetimibe, but that's because we hadn't yet published the results of the IMPROVE-IT trial that Amit mentioned when we were enrolling in FOURIER, but it was a well-treated population on statin therapy. So these results would apply to your typical patient with ASCVD who's on a good statin regimen.

Dr Greg Hundley:

Very nice. Well, listeners now we're going to go back to both of our authors and investigators, as well as Dr. Khera. PK we'll start with you. What do you see as the next study to really be performed in this sphere of research?

Dr. Prakriti Gaba (PK):

I think that's an excellent question. I think with the data presented here now we know that the lower the LDL, the lower the risk of adverse cardiovascular events and that having a low LDL is safe in the long term. I think moving forward, as Dr. Khera mentioned, there needs to be a shift of these recommendations into the guidelines. So I think additional studies confirming these findings is what we need, but we do have the evidence available.

Dr Greg Hundley:

Very nice. And Marc?

Dr. Marc Sabatine:

Yeah, and I agree with PK of course. I think there's a couple things that we want to look at. We had looked in the parent FOURIER trial and found some groups who were higher risk, who seemed to have a bigger benefit early on, and those by and large were people who had a lot of athero. But as Amit indicated that the parent FOURIER trial was relatively short at about in two and a quarter years median follow up, and so now we have the benefit of an additional half decade of follow up in a subset of people and so now we're starting to look through and see the subgroups where we saw some differential benefit and this was a paper we published in circulation soon after we published the primary results of FOURIER.

Now we have the ability to go through and look at those same subgroups and see what happens now with an additional 5 years. And so that'll be quite interesting, I think, to see how those groups play out now over time. I think as Amit indicated, time is critical. We know the benefit of lipid lowering really tends to grow with time. We saw that in FOURIER, we saw that in FOURIER-OLE and then as Amit indicated, I think for safety also it's now very reassuring, being able to go out to not two and a half years, but 5, 6, 7, 8 years of safety follow up.

Dr Greg Hundley:

Very nice. Well, listeners we're next going to turn to Dr. Khera. I'm going to put him on the spot a little bit. I don't know if many of you know he's a cardiologist with expertise in primary prevention. So here we've really focused today, I think, on a very unique set of results in secondary prevention. Amit, as you think about studies to be performed in the future, is there a role for really lowering LDL cholesterol as a primary prevention target?

Dr. Amit Khera:

The short answer is absolutely. I think, to be fair, you can't necessarily directly extrapolate these results 'cause it's a secondary prevention population, but I think if we step back for a second, is there any reason I think this wouldn't work in primary prevention, there's not, and I think there's tons of genetic data, tons of other long-term data that suggests that lower is better than primary prevention. I think the challenge, as you know, is just from primary prevention is it's just about the number that you need to treat and primary prevention is pretty profound in terms of to lower events. So this is where the trade-off comes.

I think even in their study, we do have to appreciate while lower is better, when you have very low levels and you're going to even lower, let's say when you go from in secondary prevention from 50 to 40, as much as that sounds valuable, that delta's pretty small and then the absolute risk reduction is still going to be pretty small for those individuals and that's only magnified in primary prevention. So the short answer is I have no reason to believe that lower is better is not applicable in primary prevention, but I do know that the cost and what entails to get there, you don't get as much return on investment.

I do want to say one last thing though. We're talking about lower is better, and I know these investigators know this well, but it's not only just how low but how long and I think that's where primary prevention about to go to clinic and I play the long game for primary prevention that we know we've magnified these benefits over the long term and even a little bit early in life can pay off long dividends. So that's how I look at it.

Dr Greg Hundley:

Very nice. Well, listeners we want to thank Dr. Prakriti Gaba, Dr. Marc Sabatine, both from Brigham and Women's Hospital and also our own associate editor, Dr. Amit Khera from University of Texas Southwestern Medical Center for bringing us this study involving patients with arteriosclerotic cardiovascular disease indicating that long-term achievement of lower LDL cholesterol levels down to values less than 20 mg/dL was associated with a lower risk of cardiovascular outcomes and not and not an increase in the risk of significant safety related events.

Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation April 11, 2023 Issue

10 april 2023 | 28 min

This week, please join author Kavita Sharma and Associate Editor Svati Shah as they discuss the article "Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction."

Dr. Greg Hundley:

Welcome listeners, to this April 11th issue of Circulation on the Run. And I am one of your cohosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am Dr. Peder Myhre from Akershus University Hospital, and the University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, wow. This week's feature discussion, very interesting. We spend a lot of time, especially with our colleague, Dr. Carolyn Lam, on heart failure preserved ejection fraction. But this week's feature discussion, it's going to focus on some of the myocardial metabolomics in this condition. But before we get to that, how about we grab a cup of coffee, and jump into some of the other articles in the issue? How about if I go first?

Dr. Peder Myhre:

Let's go, Greg.

Dr. Greg Hundley:

Okay. So Peder, some believe that cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. And so, the American Heart Association, as you know, recently released an updated algorithm for evaluating cardiovascular health. Life's Essential 8, and it has a very nice score. So these authors, led by Dr. Lu Qi, from Tulane University, aimed to quantify the associations of the Life Essential 8 scores with life expectancy in a nationally representative sample of US adults. And the team included 23,000 non-pregnant non- institutionalized participants who were age 20 to 79 years, who participated in the National Health and Nutrition Examination survey, or NHANES, from 2005 to 2018. And whose mortality was identified through linkage to the National Death Index, from the period extending through December of 2019.

Dr. Peder Myhre:

Oh wow. So really, a validation of the Life's Essential 8. Greg, that's so interesting. What did they find?

Dr. Greg Hundley:

Right Peder, as you say, very interesting. So here are some of the data, and let's itemize them. So, during a median of 7.8 years of follow up, 1,359 total deaths occurred. Now, the estimated life expectancy at age 50 was 27.3 years, 32.9 years, and 36.2 years, in participants with low Life's Essential 8 scores, less than 50. Moderate, so Life's Essential 8 scores of greater than or equal to 50, but less than 80. And then, high scores, greater than 80. Okay? So equivalently, participants with high Life's Essential 8 scores had an average of 8.9 more years of life expectancy at age 50, compared to those with low scores.

Next, on average, 42.6% of the gained life expectancy at age 50, from adhering to sort of that cardiovascular health, those recommendations, was attributable to reduced cardiovascular death.

Next, significant associations with the Life's Essential 8 score and life expectancy were observed in both men and women.

Next, similarly significant associations of cardiovascular health, Life's Essential 8, with life expectancy were observed in non-Hispanic Whites and non-Hispanic Blacks, but not in those originating from the country of Mexico.

So Peder, finally, in summarizing all of this, adhering to the cardiovascular health lifestyle, defined by the Life's Essential 8 score, it was related to a considerably increased life expectancy. However, because of the findings from the individuals from the country of Mexico, more research is needed to be done in some of these minority groups, and particularly, those of Hispanic ethnicity, and perhaps other races.

Dr. Peder Myhre:

Oh, wow. Very interesting. And I would love to learn more about this subgroup analysis in future studies.

So Greg, the next paper is about the hospitalization for heart failure measures. Because contemporary measures of hospital performance for heart failure hospitalization, the 30-day risk standardized readmission and mortality rate, are estimated using the same risk adjusted model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial ethnic groups, and may not adequately represent the hospital performance for patients of Black or other races. And in this study, led by co-corresponding authors, Mentias from Cleveland Clinic and Pandey from University of Texas Southwestern Medical Center, the authors used fee for service Medicare beneficiaries from 2014 to 2019 hospitalized with heart failure, in hospital level 30 day risk standardized remission and mortality rates were estimated using traditional race agnostic models and the race specific approach, with measures derived separately for each race ethnicity group.

Dr. Greg Hundley:

Ah, very interesting, Peder. So what did they find from this study?

Dr. Peder Myhre:

So the study included more than 1.9 million patients, comprising of 75% White patients, 15% Black patients, and 10% patients of other races, with heart failure from 1,860 hospitals. And compared with the race agnostic model, composite race-specific metrics for all patients demonstrated stronger correlation with 30 days readmissions. And that is correlation coefficient 0.78 versus 0.63, and 30 day mortality rate 0.52 versus 0.29 for Black patients. In concordance in hospital performance was for all patients and patients of Black race was also higher with race specific as compared to race agnostic metrics.

So Greg, the authors conclude that among patients hospitalized with heart failure race specific 30 day risk standardized remission and mortality rates are more equitable in representing hospital performance for patients of Black and other races.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful summary in a very elegant study. Peder, myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlining molecular mechanisms for this relationship remain unclear. Now, recent studies demonstrate, that the diabetic heart is resistant to several cardioprotective interventions, including adiponectin and pre-conditioning. The universal quote, unquote, resistance to multiple therapeutic interventions suggest, impairment of the requisite molecule, or molecules, involved in broad pro survival signaling cascades. Now caveolin is a scaffolding protein coordinating trans-membrane signaling transduction. However, the role of caveolin-3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. And so these investigators, led by Dr. Xinliang Ma, from Thomas Jefferson University, studied mice fed a normal diet or high fat diet for two to 12 weeks, and subjected them to myocardial ischemia and reperfusion.

Dr. Peder Myhre:

Oh wow. What an interesting preclinical science paper, Greg. What did they find?

Dr. Greg Hundley:

Right. So the authors found that nitration of caveolin-3 at tyrosine 73 and resulted signal complex dissociation was responsible for cardiac insulin adiponectin resistance in the pre-diabetic heart. And this contributed to ischemic heart failure progression. Now, early interventions preserving caveolin-3 centered signal zone integrity was found to be an effective novel strategy against diabetic exacerbation of ischemic heart failure. And Peder, I think these very exciting results suggest that this is a new area of research and further experiments are warranted.

And there's a very nice editorial by Professor Heidenreich, entitled “Pursuing Equity in Performance Measurement.

Well Peder, there's some other articles in this issue, and we'll dip in this week to the mail bag, for a Research Letter from Professor Hibbert, entitled “Utility of a Smartphone Application in Assessing Palmar Circulation Prior to Radial Artery Harvesting for Coronary Artery Bypass Grafting.”

Dr. Peder Myhre:

That is so cool. And we also have a Letter from Dr. Kim, regarding the article entitled, “Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study.”

Dr. Greg Hundley:

Very nice. Well, how about we get along to one of Carolyn's favorite topics, heart failure with preserved ejection fraction, and learn more about myocardial metabolomics?

Dr. Peder Myhre:

Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is on my favorite topic, heart failure with preserved ejection fraction, or HFpEF. But today, what we're focusing on is truly novel. We are looking at the myocardial metabolomics of human HFpEF, very, very valuable data and insights. We're so pleased to have with us the corresponding author of today's feature paper, Dr. Kavita Sharma, who's from the Johns Hopkins University School of Medicine, and our associate editor, Dr. Svati Shah, who's, of course, from Duke University School of Medicine.

So welcome Kavita and Svati. Kavita, if I could start by, please put us and bring us all to the same level of knowledge, by perhaps explaining in simple terms, what is metabolomics? And what is normal versus perhaps abnormal metabolomics, in a known condition, like systolic heart failure or heart failure with reduced ejection fraction?

Dr. Kavita Sharma:

Sure. Well thank you, Carolyn, for the opportunity to chat around this topic. And it's great to be with you and Svati this morning. Metabolomics is a broad general study of essentially, all the chemical processes involving metabolites, or small molecule substrates, their intermediates, and even the products of cellular metabolism. This can be studied in really, any organ system, in any organ. What is really unique, I think, to this particular paper in our project is that, it has yet to have been defined or described in human HFpEF from the myocardial tissue. We call this heart failure with preserved ejection fraction, and inherent to that name in this complicated syndrome is that, there is something probably wrong with the heart, yet we have not really had much insight to what that might be from direct myocardial tissue.

We are also still learning about what metabolomics looks like in, for example, the heart failure with reduced ejection fraction state. Though, there is more published in this space than in HFpEF. From the limited knowledge that we have, it does appear that heart failure with reduced ejection fraction hearts, and this is certainly seen in the plasma, which is where most of metabolomic studies have generated from, those hearts tend to utilize various forms of energy banks, if you will. Whether that's fatty acid oxidation, whether that is glucose utilization or intermediates and so on. And our primary interest was to understand, how do the preserved EF parts in patients fare in comparison?

Dr. Carolyn Lam:

Oh, thank you so much, Kavita. That was beautifully explained. And indeed, what's so special about your paper is, it's not just circulating metabolites but myocardial metabolites. And you have the control groups that are so important to study at the same time. So patients with HFpEF, but also those with HFrEF and versus controls. And thank you for establishing too, that if I'm not wrong, fatty acid metabolism accounts for the majority of ATP generation in the normal heart. Whereas, this declines a little in the HFrEF heart. And now, I think we're about to find out what happens in the HFpEF heart. So if you could explain what you did and what you find.

Dr. Kavita Sharma:

Yes, absolutely. So we examined, again, tissue and plasma metabolomics from 38 subjects with HFpEF. These are patients referred to the Hopkins HFpEF Clinic. And so they have been essentially, clinically evaluated, and have what we define as HFpEF, based on hemodynamic testing. So a right heart catheterization, often with exercise, that meets criteria for diagnosis of the syndrome.

As you stated, we compared our HFpEF patient tissue and plasma samples to samples coming from patients with HFrEF, dilated cardiomyopathy, and non-failing controls. And the latter two sources were a tissue bank from the University of Pennsylvania, that is long-standing, where patients with endstage dilated cardiomyopathy are able to have tissue banked at the University of Pennsylvania at the time of explant prior to transplant. So albeit, we are comparing to fairly advanced end stage dilated cardiomyopathy, and control tissue comes from unused donor hearts, essentially. So presumably, normal heart function patients, likely in a brain death state, who for whatever reason, the hearts were not utilized for transplantation. Again, not an entirely perfect controlled state, but again, given the nature of the work, the fact that it's myocardial tissue, the closest that we have found we've been able to come to for a control comparison.

We started out performing what we call quantitative targeted metabolomics. We measured organic acids, amino acids, and acylcarnitines in the myocardium. And that was totaling around 72 metabolites. And we did the same in plasma, so close to 69 metabolites. And our metabolomics work was actually completed at the University of Pennsylvania. And so, I wish to credit Dr. Zoltan Arany and Dr. Dan Kelly for their great collaboration in this study.

Dr. Carolyn Lam:

That's wonderful. Kavita, if you could tell us a little bit more about the patients with HFpEF. We understand it was end stage dilated cardiomyopathy, HFrEF, and donor hearts as the controls, but the patients with HFpEF, in relation to obesity, diabetes, and how that may impact the interpretation of the results.

Dr. Kavita Sharma:

Sure. So these are HFpEF patients that are in an ambulatory state outpatient setting. They have many of the comorbidities we know are intrinsic today to HFpEF. Out of our HFpEF population, the majority were women. So 71%, that's 27 out of the 38 we serve. And we're very fortunate to serve a African-American enriched population in Baltimore that's intrinsic to our center. And so, over half of our patients were Black. The remaining Caucasian, one non-Caucasian. Over half had been hospitalized, for example, in the prior one year. So these are certainly symptomatic patients. And all had NYHA II or greater symptoms.

We do have a rather obese cohort at Hopkins. And so, our median BMI, for example, was 39, our mean is very similar. And the majority have, as we see often in HFpEF, the majority with hypertension, over half with diabetes. In fact, it was actually 70% or so. Rather few with coronary disease, and this is a trend we're seeing in general in HFpEF in the present day kind of common phenotypes, and about a third with atrial fibrillation. So really, representative, I think, of this kind of cardiometabolic as we call it, phenotype of HFpEF, that is the predominant phenotype we're seeing, at least in North America.

Dr. Carolyn Lam:

Oh, that's perfect. And then, maybe just a few words about the results before I bring Svati in for her thoughts. Thanks.

Dr. Kavita Sharma:

Sure, absolutely. So we conducted this study in a couple different stages. We first started with performing a principal component analysis and hierarchical clustering analysis, to see whether the myocardial metabolites and the plasma metabolites, respectively, would they distinguish these three patient groups? So HFpEF from HFrEF and controls. And interestingly, in the myocardial tissue, our PCA analysis and our hierarchical clustering analysis show that actually, in fact, as few as 70 metabolites in the myocardium really distinctly differentiate these three subgroups. The top contributors that separated HF from controls, for example, and HFrEF, were mostly related to amino acids, including branched chain amino acids and their catabolites, as well as medium and long chain acylcarnitines, which are byproducts of fatty acid oxidation.

When it came to the plasma metabolome, on the other hand, there was far less distinguishing between the groups, and significant overlap, both in PCA and hierarchal clustering. And really, the take home there is that, the myocardial tissue and the plasma were really quite distinct for the overall metabolite analysis. But then, even as we broke it down by fatty acid oxidation, by glucose metabolism, and even branched chain amino acids, we saw this trend continue, that the plasma was quite distinct from the myocardial tissue.

Now, which of the two is more representative of the disease state? Which is the one that we should be paying more attention to? I think that remains to be fully understood further. And of course, it would be really nice to replicate these findings in another cohort. But that is something that, I think, is a first, that certainly, that we have seen and important for the community.

Dr. Carolyn Lam:

Indeed. Oh, Kavita, we could go on talking forever, but I'd really love Svati's thoughts. Why was this paper so special? What does it tell us clinically with any implications?

Dr. Svati Shah:

Yeah. I just want to commend Dr. Hahn, Dr. Sharma, on this incredible work. If you can just imagine how much painstaking work this took for Dr. Sharma and Dr. Hahn. It's a very careful phenotyping of HFpEF. These are true HFpEF patients. The ability to get tissue, and to pair the tissue to the plasma, so that we can really understand. When we measure things in the circulation, and we think they're telling us about the heart, are they actually telling us about the heart? So I really want to commend this incredible work.

And Carolyn, I love talking about cardiac metabolism, because the heart is an incredible organ, right? The heart is a metabolic omnivore. It'll eat many different kinds of fuels, and a lot of different things determine which fuels it uses. And as you nicely outlined, Carolyn, earlier, in the normal heart, the heart prefers to use fatty acids.

But what we are not completely certain of is, what happens in HFpEF? So in HFrEF, we know that the heart switches to glucose, which is not a great fuel, actually. It's actually, a metabolically inefficient fuel. And so we know in HFrEF, that the heart has this metabolic inflexibility. All of a sudden, it's not an omnivore, and it's kind of stuck with certain fuels, which are not very healthy for it.

But what Dr. Sharma and Dr. Hahn have shown, for the first time really, is what happens in HFpEF? And so, I think it's really cool that, actually, it just highlights how complex HFpEF is as a disease. So they were able to show that in some ways, HFpEF is similar to HFrEF, including that there's impairments in use of these fatty acids, which is what the normal heart does.

But, they also show that HFpEF may be different than HFrEF in many ways, including, because of these branched chain amino acids. And that may be because of some of the clinical differences that we know exist in patients with HFpEF, including the obesity and diabetes, that Dr. Sharma nicely outlined. Although, I want to point out, they were very careful about trying to take these clinical factors into account when they looked at differences in the metabolites.

So really incredible work, highlighting that the HFpEF heart also has this metabolic inflexibility. It also is not a metabolic omnivore like the normal heart is, but highlighting important differences, potentially, between HFpEF and HFrEF.

Dr. Carolyn Lam:

Oh, Svati, thank you for putting that so clearly.

Dr. Kavita Sharma:

No, I think that was a really elegant summary of the findings, Svati. And thank you for your kind words and support in allowing us to share our work through Circulation. I really couldn't say it better, but that's exactly what we seem to find is that, when we look at various sort of stores or banks of energy resource, what we really found is that these HFpEF hearts are energy inflexible, as Svati said, that begins with fatty acid metabolism. And so, when we look at, for example, medium and launching acylcarnitines, what we find is that these are markedly reduced in HFpEF myocardial tissue, quite similar to HFrEF. Again, both of them reduced compared to controls. And again, these are byproducts of fatty acid oxidation, and that is really responsible for almost 80% of generally what we think of energy metabolism in the normal state.

In the plasma, however, again, back to that theme where we don't see that reproduced in the plasma, we find that HFpEF is actually not too dissimilar from controls for certain medium and long chain acylcarnitines, and then closer to HFrEF in some cases. And interestingly, we compared our metabolomics study to our prior report of our RNA sequencing paper, that was also published in Circulation now two years ago. And what we found is that, there is reduced gene expression of many of the proteins involved with fatty acid uptake and oxidation, when we compare them to control states. So the story is sort of, fits with what we have seen previously, and when we focus in on this group of genes.

Our analysis of glucose metabolism though, did not include glycolysis or glucose oxidation intermediates. We still found that, majority of the TCA cycle intermediate, so succinate, for example, fumarate, malate, were all reduced in HFpEF versus control. It was really only pyruvate in isolation that was increased in HFpEF myocardium, compared to controls. And again, a number of genes implicated in glucose metabolism in general, we found to be lower in HFpEF versus control, including gluten 1, or SLC2A1, which is involved in glucose uptake.

So again, this theme of, we have patients with significant obesity, many in the diabetic state, we would think that these hearts would utilize these energy stores, but they don't seem to be. And finally, we see distinct differences in the tissue and branched chain amino acid pathways as well. There appears to be some sort of a block between the branched chain amino acids, and then sort of byproducts, as you continue down through ketoacids and further. And we don't fully understand where those blocks are, but that was certainly notable.

And then lastly, I'll say, one interest that we've had, and really, what led to much of this work in the tissue, is to pursue what we call deep phenotyping. Can these molecular signatures, whether it's gene expression, or metabolomics, or what we're working on now, which is proteomics, can these really help us identify unique subgroups within HFpEF? And so, we've tried to do that with the metabolomics, and we found that, using various sort of clustering analytical methods, in fact, there is significant overlap, as it turns out, within HFpEF, when it comes to the metabolomic signatures. And we only found, really, two subgroups within HFpEF. And even these two really did not have much that distinguished them, beyond branched chain amino acids.

And so, this is the first time, at least that our group has seen, at a tissue level, that there is actually a fair bit of homogeneity now in the metabolomic signatures, compared to our RNA sequencing work. And that may be reflective of now, this increasingly cardiometabolic phenotype of HFpEF. And now, we may be seeing signs of that at the clinical and at the treatment level, where we have therapies like SGLT2 inhibitors, that are showing benefit to what seems to be a much broader spectrum of HFpEF, compared to prior therapies. So a lot of questions that have been generated from the work, and we're looking forward to exploring much of this in more detail.

Dr. Carolyn Lam:

And Svati, may I give you the last word? Where do you think this field is headed next?

Dr. Svati Shah:

I think there's so much to do, and I think Dr. Sharma and Dr. Hahn have highlighted how much work there is to do in this space. We're brushing the surface and understanding cardiac metabolism with this really important paper. But Carolyn, as you pointed out, we really need to understand what happens to these patients over time? What happens to, not just cardiac metabolism, but molecular biology more broadly, in patients with HFpEF with these various treatments? Including now, thank goodness, we have SGLT2 inhibitors as a therapeutic intervention for patients with HFpEF. And in fact, we published in Circulation a few months ago, a paper led by a very talented junior faculty, Senthil Selvaraj, where we actually showed that these acetylcarnitine levels that reflect fatty acid oxidation actually are changed by SGLT2 inhibitors, and are associated with changes in clinical outcomes in HFpEF. So we really need larger sample sizes, being able to look at these patients in a longitudinal fashion. But really, doing what Dr. Sharma and Dr Hahn have done, which is careful, careful phenotyping and multidisciplinary teams, so that we can understand the molecular biology, as well as the clinical implications.

Dr. Carolyn Lam:

Oh, wow. Thank you so much, Kavita and Svati, for this incredible interview. I learned so much, and enjoyed it so thoroughly, as I'm sure our listeners did as well.

Well, listeners, you've been listening to Circulation on the Run. Thank you for joining us today, and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is Copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

Circulation April 4, 2023 Issue

3 april 2023 | 27 min

This week, please join authors Tatsuhiko Naito and Kosuke Inoue as well as Associate Editor Wendy Post as they discuss the article "Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Study."

Dr. Greg Hundley:

Welcome listeners, to this April 4th discussion of Circulation on the Run. I am one of your co-hosts, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital and the University of Oslo in Norway. So Greg, today we have the feature paper, discussing the genetic risk of primary aldosteronism and its contribution to hypertension. So this is such an interesting topic and av very important cost on hypertension. And in this paper, they use cross-ancestry meta-analysis from GWAS studies to assess this very interesting discussion.

But first, Greg, I have a paper that comes to us from the DELIVER trial, and it is about dapagliflozin to patients with HFpEF, and assessing the association with the duration of the heart failure.

So Greg, it is important to understand how the effects of new treatments vary by the duration of heart failure. Because on one hand, physicians may think that a patient who has longer standing heart failure represents a stable survivor where new treatment is unnecessary. On the other hand, the view has been expressed that patients with long-standing heart failure may have more advanced disease, and there may come a point where they no longer respond to or tolerate the addition of new therapies, particularly because of hypotension, kidney dysfunctional and electrolyte abnormality. So the investigators from the DELIVER trial, led by corresponding all author John McMurray from University of Glasgow, therefore, aimed to assess the efficacy and safety of the SGLT2 inhibitor dapagliflozin, according to the duration of heart failure with EF above 40%. So that is mildly reduced or preserved.

Dr. Greg Hundley:

Wow, Peder, very timely, very timely article. So what did they find?

Dr. Peder Myhre:

So Greg, the authors categorized patients by duration of heart failure, one category less than six months, and then six to 12 months, and then one to two years, two to five years, and finally, more than five years. And longer duration heart failure patients were older, and more comorbid with worse symptoms, and the rate of the primary outcome increased with heart failure duration. And so, the benefit of dapagliflozin was consistent across heart failure duration categories with hazard ratios 0.67, 0.78, 0.81, 0.97, and 0.78. And that gives a P4 interaction of 0.41. So the absolute benefit was therefore since there was no P4 interaction, greatest among those with highest risk, and that it was the longest duration heart failure. So there was a number needed to create for heart failure above five years of 24, versus 32 for those with the shortest duration of heart failure. And the authors therefore conclude, that even in patients with long-standing heart failure and generally mild symptoms cannot be considered stable, and it is not too late for such patients to benefit from an SGLT2 inhibitor.

Dr. Greg Hundley:

Ah, very practical information, Peder, beautiful description. Well Peder, this next paper comes to us evaluating low density lipoprotein cholesterol. And as you know, low density lipoprotein cholesterol is an important causal risk factor for atherosclerotic cardiovascular disease. However, a sizable proportion of middle-aged individuals have not developed coronary atherosclerosis as assessed by the presence of coronary artery calcification. Now whether the presence of coronary artery calcification modifies the association of LDL cholesterol with atherosclerotic cardiovascular disease risk, well, that's unknown. So these authors, led by the corresponding author of Martin Mortensen from Aarhus University Hospital, evaluated the association of LDL cholesterol with future atherosclerotic cardiovascular disease events, in patients with and without coronary artery calcium, from 23,132 consecutive symptomatic patients evaluated for coronary artery disease, using coronary commuted tomography angiography, or CTA, that were included in the Western Denmark Heart Registry, which is a semi-national multi-center based registry with longitudinal registration of both patient and procedural data.

Dr. Peder Myhre:

Oh, that is so important, Greg. So we're looking at LDL cholesterol and the association with ASCVD in patients with and without coronary artery calcification. So what did they find?

Dr. Greg Hundley:

Right, Peder. So during a median follow up of 4.3 years, 552 patients experienced a first cardiovascular disease event. In the overall population, LDL cholesterol per 38.7 milligrams per deciliter increase, was associated with cardiovascular disease events during the follow-up period. Now, when stratified by the presence or absence of a baseline coronary artery calcium score, LDL cholesterol was only associated with a cardiovascular disease event in the 47% of patients with a coronary CAC score greater than zero. While no association was observed in the 53% of individuals with a coronary artery calcium score equal to zero.

Now similarly, very high LDL cholesterol, so greater than 193 milligrams per deciliter, versus an LDL cholesterol of less than 116 milligrams per deciliter, was associated with a cardiovascular disease event in patients with a CAC score greater than zero, but not in those without coronary artery calcium. Next, Peder, in patients with coronary artery calcium equal to zero, diabetes, current smoking, and low HDL cholesterol levels, were associated with future cardiovascular disease events. This principle finding was replicated in the multiethnic study of atherosclerosis.

And so, Peder, LDL cholesterol appears almost exclusively associated with a cardiovascular disease event over the ensuing five years of follow-up in middle-aged patients with versus without evidence of coronary atherosclerosis, as identified by coronary artery calcium scores. This information is quite valuable for individualized risk assessment among middle-aged patients.

Dr. Peder Myhre:

Oh, that is so important, Greg. So really, LDL seems to be more predictive of atherosclerotic cardiovascular disease than those with calcium in their coronaries, while there was no association in those with no calcium in their coronaries. Very interesting.

Dr. Greg Hundley:

Absolutely. And there's a very nice editorial by Professor Sniderman entitled, “Cholesterol Coronary Calcification and Cardiovascular Prevention: Lessons We Can Learn from the Western Denmark Heart Registry.”

Dr. Peder Myhre:

Thank you, Greg, that was a beautiful summary. And we are going to stay in clinical science, but we're going to move to aortic disease and look at gut microbiota. Now, Greg, large scale human and mechanistic mouse studies indicate a strong relationship between the microbiome dependent metabolyte, Trimethylamine-N-oxide, abbreviated TMAO, and several cardiometabolic diseases. And in this study, which comes to us from corresponding author Philip Owens from University of Cincinnati, the investigators aim to assess TMAO's role in the pathogenesis of AAA and targeting its parent microbes as a potential pharmacologic intervention.

Dr. Greg Hundley:

Ah, very interesting, Peder. So what methodology did they use?

Dr. Peder Myhre:

So Greg, this is one of those fantastic studies combining clinical and preclinical science. And the investigator measured TMAO in two independent patient cohorts, with a total of 2,129. And in addition, they used the murine AAA model, and fed the mice a high choline diet, which is a diet that markedly augment plasma levels of TMAO. And these mice were then treated with broad spectrum antibiotics, targeted inhibition of a gut microbial enzyme with fluorometer chloroquine, called FMC, or utilizing mice genetically deficient of Fmo3.

Dr. Greg Hundley:

Very nice. So what did they find, Peder?

Dr. Peder Myhre:

So the authors found that elevated TMAO was associated with increased AAA incidence and growth in both patient cohort studies. And dietary colon supplementations augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad spectrum antibiotics. In treatment with FMC ablated TMAO production attenuated colon augmented aneurysm in the initiation, and halted progression of an established aneurysm model. And additionally, the Fmo3 knockout mice had reduced plasma TMAO, aortic diameters, and were protected from AAA rupture compared to wild type mice.

So Greg, in conclusion, this study defined a role for gut microbiota generated TMAO in AAA formation, and additionally, increased microbiome derived TMAO may serve as a novel therapeutic approach for AAA treatment where non currently exists.

Dr. Greg Hundley:

Beautifully described, Peder. And another one of their articles in Circulation that, as you indicated, very nicely complying the world of preclinical and clinical science.

Well, we've got some other articles in the issue, and how about we jump into some of those? So first, there's a very nice Letter to the Editor from Professor Wong entitled, “Frailty and Age Correlation in Clinical Trials.” And there is another reply to a prior Letter to the Editor from Professor McMurray entitled, “Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure, a Pre-specified Analysis of the DELIVER Trial.” And then next, Peder, Michelle A. Albert has a very nice synopsis of the American Heart Association Presidential Address, entitled, “Economic Adversity and Healthcare.”

Dr. Peder Myhre:

Nice. And finally, there's a Research Letter from Dr. Baggish entitled, “Association Between Concussion Burden During Professional American-style Football and Post-career Hypertension.”

Dr. Greg Hundley:

Very good, Peder. Well, what a packed issue we have this week, and how about we jump next to that feature discussion with our colleague Carolyn? Ah.

Dr. Peder Myhre:

Let's go.

Dr. Carolyn Lam:

Primary aldosteronism, or, we're going to say PA for this discussion, is one of the most common causes of secondary hypertension, and it is also a particularly morbid form of secondary hypertension. So identifying this subgroup of hypertensive patients with primary aldosteronism, again PA, would allow us to perhaps, direct more aggressive management to their cardiometabolic risk. Now, is a genetic approach the way to do it? Well, we're about to find out in today's very special paper.

We're very honored to have the first author, Dr. Tatsuhiko Naito, from Osaka University Graduate School of Medicine, and his second and co-author Dr. Kosuke Inoue, from the Graduate School of Medicine in Kyoto University, as well as our associate editor, Dr. Wendy Post, from Johns Hopkins University School of Medicine, here to discuss this very important paper. Perhaps I could start with you, Dr. Tatsuhiko. Could you please, perhaps, tell us a little bit about what made you do this study, what you did, and what you found?

Dr. Tatsuhiko Naito:

I would like to thank you for inviting us to present the information from our paper. In terms of genetic, germline genetic factors behind the development of PA has not been isolated. And in addition, the PA is the cause of hypertension, but the genetic relationship between hypertension and PA has not been discussed previously. That is why we conducted a genome-wide association study, GWAS, of PA here. Our GWAS consisted of three defined cohorts of our Japanese cohort, UK Biobank, and FinnGen. In our Japanese cohort, we collected samples in Hiroshima University, and we used controls from Biobank Japan, which is the largest Japanese biobank. And we also used two publicly available biobanks, UK Biobank and FinnGen. So they can be used upon registration. By utilizing these resources, we conducted a cross-ancestry, meta-analysis of GWAS.

Dr. Carolyn Lam:

Thank you. And the results, please?

Dr. Tatsuhiko Naito:

In the meta-analysis, we identified five genetic loci that were significantly associated with the risk of PA satisfied in the genome world significant threshold. The strongest association was observed at WNT2B, which is located in chromosome 1. And in addition, we identified one near the genome-wide association locus CYP11B1 and B2, which is located on chromosome 8. So CYP11B2 is the key enzyme that acts in producing aldosterone in the adrenal gland, thus, we consider that resource. This locus would be also our PA risk associated locus with a high probability.

Of interest, these loci were reported to be associated with hypertension, but we thought this results is resemble, because PA occupies around five to 10% of causes of hypertension. Does the PA associated loci could be reported as hypertension associated loci in previous GWAS with large sample size?

So to support our assumption, we compared the risk effect of these genetic loci between PA and hypertension. So if there are risk effects who are coming from PA, these loci should present higher effect on PA than on hypertension. And expectedly, these loci presented significantly higher effect on PA here.

And lastly, inspired by these results, we hypothesized that some of other loci, that had been reported to be associated with hypertension, might come from the primary effects on PA. To investigate this, we picked up blood pressure rated genetic loci from previous GWAS of blood pressure, and compared their risk effects between PA and hypertension. The result was that, 66.7% presented a higher risk effect for PA than for hypertension. And two strictly demonstrates the result. We also performed the adjustment of blood pressure values, and even in this adjustment, 61.9% showed a higher effect on PA than on hypertension. So considering the prevalence of PA among hypertensive individuals, this result is little bit surprising, we think. So PA may explain an unexpectedly large amount of genetic background of hypertension, we think.

Dr. Carolyn Lam:

Wow, thank you so much, Tatsuhiko. So first, genome-wide evidence for genetic predisposition to PA susceptibility, and then, revealing that two thirds of previously established BP associated variants were in fact a higher risk effect for PA than for hypertension. Wow. So Wendy, could you help us put these findings into perspective, please?

Dr. Wendy Post:

Thank you, Carolyn. Congratulations to the authors. This was a really interesting paper that we enjoyed discussing in our meetings. We were especially interested in the clinical potential, clinical implications of your study. We all see patients with hypertension, whether we're cardiologists, or endocrinologists, or primary care physicians. And so, trying to understand more about what is potentially the underlying causes for hypertension, from a biological standpoint, that might help us to identify and treat our patients appropriately, is really so important. And so, I was wondering, Kosuke, if you could tell us, from your perspective as an endocrinologist and a researcher, how you interpret these studies in a way that our readers might be able to use these results to think about the next patient we're seeing in our clinic with hypertension?

Dr. Kosuke Inoue:

Yeah. Thank you very much for asking this important point, Wendy. We're, first of all, I'm very pleased that our research is published in Circulation, and thank you very much for your consideration. And I think there are two major implications of our findings, treatment and a diagnosis.

First of all, for treatment, well, our findings advance our current state of knowledge about PA pathogenesis. Like Wendy said, what is the causes? And what is the genetic causes of primary aldosteronism ? And particularly, it'll be helpful for better precision medicine in the future. And therapy involving genetic information, this may not be the clinical practice tomorrow, but this would advance our clinical practice in the future.

And the second point is diagnosis. Well, primary aldosteronism is really important to diagnose, because treating only blood pressure, or hypertension, is not enough for patients with primary aldosteronism. Like Tatsu said, aldosteronism itself has a direct effect on organ damage beyond blood pressure, elevated blood pressure. So diagnosis of primary aldosteronism is critical, and our findings showed 10%, the current percentage of 10% primary aldosteronism, may not be fully diagnosed patients, given that 67% of PA associated variants presented higher alteration for the PA. So I think, we needed to be more careful about diagnosing primary aldosteronism. So for those who have a resistant hypertension, or who are suspected to have primary aldosteronism, we needed to screen more for such patients.

Dr. Wendy Post:

Thank you, that was really helpful. Can I ask you a little bit more about what you recommend in clinical practice? I've been asking around, we actually just had our American College of Cardiology meeting in New Orleans, and I knew this paper had just been published online, and the editorial is about to come out. And so, I noticed that there's a lot of variability in practice, as to whether we screen for PA, or just treat with aldosterone blocking medications, such as spironalactone. So can you tell me a little bit more about what you recommend? And maybe your practice is different as an endocrinologist, but should we just presume people have primary aldo, and aldosteronism, and treat them for that? Or should we be searching for aldosterone producing adenomas, and surgically removing them? If you could, tell us a little bit more about what you recommend.

Dr. Kosuke Inoue:

Thank you very much for asking this, Wendy. So to be honest, I don't think we can conclude something only from our result, of course. But what I can recommend is, from our findings, it is better to always thinking about primary aldosteronism when treating patients with hypertension. So those may have and those may not have that. I think thinking about primary aldosteronism is important, and if there's a possibility they have, or if their clinicians have trouble treating hypertension, then I would recommend screening for such patients about primary aldosteronism.

Dr. Wendy Post:

In order to find an adenoma, is that the purpose of the screening?

Dr. Kosuke Inoue:

I think, whether they have an adenoma or, there are two types of primary aldosteronism, aldosteronism producing adenoma, and BAH bilateral adrenal hypocardia. And rather does not have adenoma itself, but they have a hyper aldosteronism in their blood. So we cannot tell whether they have a PA or BAH. But anyway, we needed to think about whether they have excess level of aldosterone, and if they have, we needed to think about the proper treatment, such as medication therapy or surgical treatment.

Dr. Wendy Post:

Thank you. So if they have bilateral adrenal hyperplasia, then medical therapy.

Dr. Kosuke Inoue:

Yes.

Dr. Wendy Post:

If they had an adenoma, you might consider surgical excision.

Dr. Kosuke Inoue:

Generally, yes.

Dr. Wendy Post:

Thank you.

Dr. Carolyn Lam:

Wendy, I love that clinical focus, because much as PA is a highly morbid cause of secondary hypertension, it's also sometimes seen as potentially curable, or at least targetable with specific medical therapy. And thank you for inviting that beautiful editorial, I'd love to quote from it. Because the final sentence of it really does say that this paper really reminds everyone treating hypertension, to maintain a high clinical suspicion for PA, and hopefully, such a high clinical suspicion will lower the threshold for biochemical testing. Will motivate the pursuit of localization studies, to determine if a surgical cure is possible. And at minimum, allow for early initiation of mineralocorticoid-receptor blockade. How beautifully put, huh?

So thank you for inviting that editorial. And if I may, are there any final take home messages from anyone? May I start with Dr. Tatsuhiko? Any take home messages or next steps you'd like to mention?

Dr. Tatsuhiko Naito:

Okay. Yeah. I think the future advances in this study first, as Kosuke said, of PA is mainly classified into aldosterone producing adenoma and bilateral adrenal hyperplasia. However, we couldn't identify subtype specific risk associated loci, due to the lack of statistical power. And specifically, we know that histopathological features of aldosterone producing adenoma are reported, vary depending on the causative somatic mutations. So further insights may be obtained by investigating the genetic risk of aldosterone producing adenoma, according to the causative somatic mutations. But anyways, we are happy to present the genome-wide association genetic loci that associated with PA in the cross-ancestry cohort for the first time. Thank you.

Dr. Carolyn Lam:

Thank you. Kosuke?

Kosuke Inoue:

Sure. So I totally agree with what Tatshu said, and also, aldosterone is a nasty hormone. So as a clinician, I would recommend, for all clinicians who treat patients with hypertension, please always consider aldosterone, and whether their aldosterone should be treated or not. And thank you.

Dr. Carolyn Lam:

Wendy?

Dr. Wendy Post:

I also wanted to get back to your statements, Kosuke, about precision medicine. And this was a genetic study, and you did mention how this could potentially lead to precision medicine, practical approaches to identifying patients who might be treated with specific therapies, based on their genetics. And of course, we're not there yet, but thanks for helping us to get closer to that vision in the future.

Dr. Carolyn Lam:

Indeed, thank you so much for publishing this very important paper in Circulation, and for coming online to discuss it today.

You've been listening to Circulation on the Run. Thank you listeners for joining us today, and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

Circulation March 28, 2023 Issue

27 mars 2023 | 29 min

This week, please join author Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study."

Dr. Gregory Hundley:

Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion.

Dr. Gregory Hundley:

Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966.

Dr. Peder Myhre:

Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find?

Dr. Gregory Hundley:

Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery.

Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race.

So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients.

Dr. Peder Myhre:

Well, that is really interesting, Greg. Are you ready for the next paper?

Dr. Gregory Hundley:

Absolutely.

Dr. Peder Myhre:

So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events.

Dr. Gregory Hundley:

Interesting, Peder. So what did they find?

Dr. Peder Myhre:

So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits.

Dr. Gregory Hundley:

Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses.

Dr. Peder Myhre:

Oh, this is really interesting, Greg. So what did they find?

Dr. Gregory Hundley:

Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction.

So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.

Dr. Peder Myhre:

Oh wow. That was really impressive.

Dr. Gregory Hundley:

Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled “A Mouse Model of Atrial Fibrillation in Sepsis.” And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled “Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure.” And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled “Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes.” And that particular paper is published in Nature.

Dr. Peder Myhre:

That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.” And finally we have On My Mind by Bertram Pitt entitled “Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension.” Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes.

Dr. Gregory Hundley:

Very good. Let's go.

Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Vincent Aengevaeren:

So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis.

And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density.

Dr. Gregory Hundley:

Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here?

Dr. Vincent Aengevaeren:

The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics.

So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise.

Dr. Gregory Hundley:

Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here.

Dr. Vincent Aengevaeren:

So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes.

Dr. Gregory Hundley:

Very nice. So Vince, describe for us your study results.

Dr. Vincent Aengevaeren:

During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings.

Dr. Gregory Hundley:

And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples.

Dr. Vincent Aengevaeren:

So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher intensity, for example spinning on a spinning bike, it's traditionally at a higher exercise intensity. So that was counted as a very vigorous intensity exercise. And I have to say this was based on questionnaire data, so I did not have six-year or lifelong heart rate data. So it is based on questionnaire data, the categorization of exercise intensity. That's a good example. Other things of [inaudible 00:19:03] intensives, for example, soccer, hockey, I don't know how popular those sports are in America, but those are pretty popular in Netherlands as well.

Dr. Gregory Hundley:

When you mean very vigorous for some of our runners out there, I mean for the casual runner that might run two or three miles a day, is that very vigorous or are you talking about someone that's training periodically for marathons and running three or four marathons a year?

Dr. Vincent Aengevaeren:

That is really more, I guess, about volume. So if people do a lot of marathons, that can actually be at a lower intensity. Like, with intensity, we really, really mean the heart rate intensity and not the intensity of the volume. So I have to specify that. It's really exercise intensity such as for oxygen consumption or heart rate and not the volume in the hours per week. So typically the runners that we had were mostly very vigorous runners. So couple hours per week traditionally they did like trainings of one and a half hour, which is usually at a higher intensity.

Dr. Gregory Hundley:

Very nice. Well listeners, now we're going to turn to one of our associate editors, Dr. Jarett Berry, who really has some expertise in this area. And Jarett, you see many papers in circulation. What do you find is unique about this particular study and then how do you put its results really in the context of other studies that have focused on exercise both in duration as well as intensity?

Dr. Jarett Berry:

Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege to be able to visit with both of you today about this important paper. I think if you take a step back here, challenges I think we all have as physicians is dealing with these uncertain questions that arise clinically where you encounter patients who are exercising at these extreme levels. And although it's not super common, we do encounter these scenarios clinically. And what we need in context like this is we need some data and understanding of what's happening clinically to be able to provide guidance. And so we're really in a context like this in a scenario where we have the common clinical problem of incomplete information. And I think it's studies like this that really help us move the needle to help us understand how to think about those patients of ours that exercise at very high levels.

I do think it's important to put it into context, about 10% of the participants in this study exercised below 1,000 minutes per week. And so for those of you taking notes at home, that's the guidelines in 500 and 1,000 minutes per week would be, I mean you'd be hitting the guidelines. And two-thirds of these individuals were exercising at 2,000 minutes per week. So I think it's important to put it into context when we think about applying and understanding the question about toxicity of exercise, putting that into context that most of the patients that we encounter are not exercising at these high levels. However, as I mentioned, we do encounter this and we have to know what to do with it.

The key here I think is... The other context is with a point that's been raised already in some of the questions and discussion is the heterogeneity that we see in individuals who exercise at these high levels. When you're trying to think about dose of exercise, we have to think about not just intensity but volume. And I think what the study's done here has done a really nice job of trying to parse that out because we can achieve the dose of exercise that's recommended or the dose of exercise that we want to achieve for personal reasons, but we can get there through different ways. We can get there through more hours or we can get there through a higher intensity. And then of course, obviously combinations of the two.

And I think this study here does two things for us. Number one, it gives us a delta question. We've seen this before with just looking cross-sectionally and we have all the challenges that come with that with regard to recall of exercise. Here we have a prospective cohort that we're following or that events followed. And secondly, the ability to parse out both volume and intensity over time. And I think that for me, the finding that really sticks out is that in addition to all the complexities that are right here, we see that the story with regard the components of the dose may not be uniform. That intensity or exercising at very high intensity may be a different part of the equation beyond just volume.

And I think that as we think about counseling our patients as they are engaging in this type of high level of exercise, I think it's one additional component of our way of interpreting this and providing counsel to these patients about how to think about volume and intensity. And maybe these data suggests the hypothesis that the volume part of the dose equation may be safer or maybe something that's more palatable for the heart perhaps over time than the intensity. I think the big elephant in the room, of course, is the fundamental question is that we're dealing with an intermediate phenotype and we know lots of observational data showing that more atheros bad. We all recognize that, but you can get to athero through different mechanisms here.

And I think that these data and others suggest that exercise is one mechanism perhaps that though you can get athero, the question is what is the true clinical significance from a [inaudible 00:24:32] standpoint down the road as we try to extrapolate the intermediate phenotype into the future. And I think there's controversy, I think agreement about what the intermediate phenotype means in these high volume exercisers. And I think that question remains unknown, I think.

But in the interim, as I said in the beginning, that as we think about putting all this into context, we don't have perfect information and we do have to take the information that we do have to provide the counsel that we need to provide if these patients. And I think I take away from this that when providing counsel, maybe I lean more towards volume and less towards this really high volume, sorry, this really high intensity for those individuals whose coronary calcium or their athero burden is particularly high. But a fantastic study. Another step in the road and it's really trying to understand an incredibly complex story and one that will continue to unfold.

Dr. Gregory Hundley:

Very nice, Jarett. And listeners, we're going to turn back to both Vince and Jarett here each in 30 seconds. Vince, what do you see as the next study that your group or others might want to be considering in this sphere of research?

Dr. Vincent Aengevaeren:

For me personally, the next big thing that we should do is really cardiovascular risk. So what's the clinical relevance of this finding? So coronary calcification is strongly associated with cardiovascular risk, but how that is in these athletes in which we see increased coronary calcification, that's still pretty much the question. I mean, any plaque is worse than no plaque, but how is this for the very vigorous exercisers who may show some more calcification and whether that risk is different. I mean, that's the question that all the athletes that email me after this type of publication have the question. And also the mechanisms. Like, what are the underlying mechanisms? That's also a next lead study for me.

Dr. Gregory Hundley:

Very nice. And Jarett?

Dr. Jarett Berry:

Yeah, I think the ultimate question is, I completely agree, is what is the clinical significance. I think that's going to be... That's a challenging question to answer just because of the on average these individuals are more rare. And so following these individuals over time to really tease out the clinical significance of this type of athero in these athletes, I think, is a challenge. I think for me the next step would be more studies like this where we can get more granular with regard to measured exercise intensity. I think wearable devices, things that Vince alluded to with regard to heart rate, really trying to get more quantitative to try to parse out the contribution of more objectively measured exercise intensities, I think would probably, for me, represents kind of probably the next step, is digging a little deeper into the phenotype and being a little bit more precise perhaps with studies like this to help us begin to understand the significance of these findings.

Dr. Gregory Hundley:

Very nice. Well, listeners, we want to thank Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands, and our own associated editor, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas for bringing us this study highlighting that exercise intensity but not volume was associated with progression of coronary atherosclerosis during a six-year follow-up of this cohort of really trained athletes and intriguingly the very vigorous. So we want to distinguish that. The very vigorous intensity exercise was associated with greater coronary artery calcium calcified plaque progression, whereas simply just vigorous intensity exercise, casual riding of the bike, casual running, et cetera, was associated with less coronary artery calcium progression.

Well, on behalf of Peder and Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation March 21, 2023 Issue

20 mars 2023 | 26 min

This week, please join author Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age."

Dr. Greg Hundley:

Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?

Dr. Peder Myhre:

I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts.

Dr. Greg Hundley:

Wow, Peder, so a very large gene-wide association study. So what did they find?

Dr. Peder Myhre:

So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease.

Dr. Greg Hundley:

Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development.

Dr. Peder Myhre:

Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find?

Dr. Greg Hundley:

Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.

So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects.

Dr. Peder Myhre:

Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first?

Dr. Greg Hundley:

Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study."

Dr. Peder Myhre:

And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions.

And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century."

And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that?

Dr. Greg Hundley:

Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion?

Dr. Peder Myhre:

Let's go.

Dr. Mercedes Carnethon:

Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found.

Professor Mikael Dellborg:

Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor.

Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD.

Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline.

So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed.

Dr. Mercedes Carnethon:

Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you?

Professor Mikael Dellborg:

What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age.

Dr. Mercedes Carnethon:

Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation?

Dr. Gerald Greil:

Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future?

Professor Mikael Dellborg:

Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years.

The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet.

It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers.

We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper.

Dr. Gerald Greil:

Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients?

Professor Mikael Dellborg:

I think they relate to our paper in a nice way, because one of the things we also could show was that the morbidities of patients with adult congenital heart disease are significant. The risk of heart failure, atrial fibrillation, stroke, nonfatal MI, diabetes, and so on, is much larger in that group. And the cumulative risk of having any such adverse event is about 75% at age 68 after 50 years of follow-up. The letter by Bergh et al. focuses on, as you say, heart failure. And during a follow-up or 25 years, there was an overall, like you said, 8.7 times higher risk for patients with CHD to develop heart failure. The most, I think, important factor from this is not only that the risk is increased, it has been described before and it's obvious and quite intuitive, but there was a dramatic difference in the age of onset of heart failure, which was about 40 years in patients with CHD compared to 66 years of age for the controls who developed heart failure.

And again, it was obvious that it was highest among the most complex CHD. The risk was 20 to 40 times higher. But also among non-complex CHD, the atrial receptor defects, the ventricular receptor defects, the risk was significantly higher, five to 10 times. One thing we saw there was that... That could be seen there was that the risk was particularly high in the youngest age group, the youngest patients, as compared to controls. And not so much, although still significant, it increased also in the higher age groups. We could also see that the risk of heart failure seemed to increase. It was higher among those born after 1970 as compared to those before 1930 to '69.

And I have two explanations for that. One is that a lot of patients born in 1930 and so on were not captured by our registers, because they have died before that. But it also reflects that the most complex patients, the most likely to develop heart failure, they survive these days. They did not survive in their thirties, forties, fifties, sixties and early seventies and so on, so that's why. So things haven't been worse, but we do have a much sicker group of patients with congenital heart disease that are alive today.

Dr. Mercedes Carnethon:

That's very hopeful. When I hear that and I think about the impact that treatment and therapy has had on these improvements in survival, it's really exciting to hear. We were really enthusiastic because our colleagues, Dr. Rosenthal and Qureshi from London, submitted an editorial to discuss your piece as well as Dr. Bergh's piece. And they're discussing in it some of the complexity in providing this care and what it has taken to get us to this point where survival is better. Can you tell us a little bit based on the findings from your study and what you know of the field, how do you envision the future care of adults with congenital heart disease?

Professor Mikael Dellborg:

Yes, Mercedes, thank you. I think this is a very nice editorial. It summarizes very well where we are today, and I think they see the future very much along the same lines as I do and as we do. But the large number of patients with CHD living into their sixties, seventies, and eighties, they will not only live longer, they will also have more comorbidities. And I think that's what our data shown and what the editorial is discussing. This will require some changes to be made to the care of adults with congenital heart disease. We will clearly, as pointed out, need large, highly specialized, very competent ACHD centers located close to, or at least in close corporation with pediatric centers. There's no doubt about that building such centers need to continue and you need roughly one large complete such center with outpatient clinic, surgical interventions, structured transfer, specialized physicians, physiotherapists, nurses, education research, et cetera.

You need about one such center per 5 million people. But over time the need of ACHD patients will also change and this will have impact also on the large specialized centers. For instance, if you have an adult patient with say, tetrology of Fallot, fairly common disease in this setting, well operated on a early childhood, well-functioning, modest right ventricular dysfunction, modest pulmonary valve insufficiency, and it's followed by a large centralized ACHD unit. You will keep track of the right ventricle size waiting for the proper time to intervene and replace the right ventricular outflow tract by surgery or catheter. This waiting is probably 10, 15, maybe 20 years before anything needs to be done. But during that time the patient develops hypertension, type 2 diabetes, AFib, and the chances of this happening at some time are fairly substantial. So either the ACHD unit needs to take care of also these comorbidities and that's not always the case today.

And I think it's unrealistic to expect primary care GPs to do this. I mean, would you as primary... As a GP start the SGLT2 treatment? Is that okay for a patient with Fallot? Or the indications for anticoagulation the same as... And that's not easy patients to handle. So on the other hand, if the ACHD unit will take care also of all these comorbidities, they will, I think, have too much to do and I think they will find it difficult to completely cope with this. So as in increasing role for cardiologists who are knowledgeable on ACHD care, but who perhaps spend most of the time caring for the usual patients with heart failure and AFib, post-MI, type 2 diabetes and who are confident in using novel anti-diabetic medications, but at the same time they know about Fallot. They know enough to understand the do's and don'ts, and they can interact on a regular basis with the local ACHD units. So patients will see their general cardiologist twice a year perhaps, and the ACHD center every two years, something like that. I think there's a great need for that.

Dr. Mercedes Carnethon:

I really appreciate having your insights on that. Do you have anything, Gerald, that you'd like to follow up with? I think the feedback that you've shared with us, Mikael, about where you see the treatment field going for adults has been very comprehensive and it's fantastic to be able to have these conversations with you, because obviously these discussions go beyond what you can share in the original research article, which is why we really enjoy this opportunity with the podcast. So Gerald, I'd really like to turn it to you for a final wrap up, given your expertise in this area.

Dr. Gerald Greil:

Yeah, I mean, Mikael, thank you so much to you and your colleagues just giving us this great overview, and even more importantly giving us the perspective how this field is going. I think we are getting more and more aware that there are more patients with and adults with congenital heart disease we need to take care of. We need to find new strategies, as you correctly pointed out, to cope with the enormous burden of disease and providing these patients good quality of life and excellent outcome after sometimes a very difficult start in their lives. And we need to be aware of the pediatricians and adult cardiologists and other subspecialties are forming a team and working together and not working as separate entities. So thank you so much for giving us this perspective. And I would hand over to Mercedes to wrap up the whole discussion please.

Dr. Mercedes Carnethon:

Well, yes, I just really want to thank our listeners for tuning in with us today. It was such a delight to have you here with us, Dr. Dellborg, and thank you as well for sharing your insights.

Thank you for joining us again for this episode of Circulation on the Run Podcast. It's meant to whet your appetite and turn you towards the journal so that you can read more. So thank you very much.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation March 14, 2023 Issue

13 mars 2023 | 21 min

This week, please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first.

I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs.

Dr. Greg Hundley:

Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study.

Dr. Carolyn Lam:

Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination.

Dr. Carolyn Lam:

Wow. Wow. Important question. Everyone's interested in the results. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis.

Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science.

Dr. Carolyn Lam:

Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, “Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction.” That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we?

Dr. Greg Hundley:

Absolutely.

Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address?

Dr. Milind Desai:

Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers.

So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today.

Dr. Greg Hundley:

Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll?

Dr. Milind Desai:

Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients.

Dr. Greg Hundley:

Very nice. So Milind, what were your study results?

Dr. Milind Desai:

Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers.

But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT.

Dr. Greg Hundley:

And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex?

Dr. Milind Desai:

No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders.

Dr. Greg Hundley:

And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there?

Dr. Milind Desai:

There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity.

Dr. Greg Hundley:

And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles?

Dr. Milind Desai:

The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy?

Dr. Mark Link:

Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper.

Dr. Greg Hundley:

Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research?

Dr. Milind Desai:

Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out.

Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging.

Dr. Greg Hundley:

Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about?

Dr. Milind Desai:

So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very careful about over inhibition of the cardiac myosin and a drop in ejection fraction and its downstream ramifications including heart failure. The other aspect is drug-drug interaction because of its pathway of metabolism. So these are the two key things we have to be on the careful about.

Now you asked my clinical experience. So we have been prescribing this for almost six, seven months, and we have dozens of patients on this using the REMS strategy, careful echocardiographic monitoring and clinical decision making. So far, we have been very successfully able to navigate these patients without any major adverse events. And the vast majority of the patients, true to form as we have shown in the clinical trial, are doing very, very well in terms of their symptoms, their need for SRT, as well as their markers, including outflow tract gradient.

Dr. Greg Hundley:

Very nice. And Mark, turning to you from the perspective of an electrophysiologist, what potential future studies do you see forming in this space?

Dr. Mark Link:

Yeah, very similar to Milind. And I think the long term efficacy and safety really has to be looked at. There's a signal for potential harm in that the EF can drop, and Milind mentioned that too, that we have to learn how to deal with that. The way to prescribe it now, you have to be in a special program. You have to be trained, you have to agree to get echoes every three months, I believe it is, essentially for the rest of their life. So we need to see what happens long term with these drugs and we need to know how to dose them and how to do it safely.

Dr. Greg Hundley:

Very nice. So for our listeners, really a class of drugs that is emerging and at this time only under really strictly supervise protocols. Well, from the perspective of our listeners, we want to thank Dr. Milind Desai and our own associate editor, Dr. Mark Link, for bringing us this informative new early randomized trial study results indicating that in severely symptomatic patients with obstructive hypertrophic cardiomyopathy, 32 weeks of mavacampten treatment showed sustained reduction in the proportion proceeding to septal reduction therapy.

Well, on behalf of Petter, Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation March 7, 2023 Issue

6 mars 2023 | 22 min

This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume.

Dr. Greg Hundley:

Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform?

Dr. Carolyn Lam:

So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment.

Dr. Greg Hundley:

Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative.

Dr. Carolyn Lam:

Oh wow. So a new gene variant. So what was the relationship?

Dr. Greg Hundley:

Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials.

And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling.

Dr. Carolyn Lam:

Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go.

So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes.

Dr. Greg Hundley:

Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find?

Dr. Carolyn Lam:

They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar.

In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration.

So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more.

Dr. Greg Hundley:

Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals."

Dr. Carolyn Lam:

There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare.

Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion?

Dr. Greg Hundley:

You bet.

Dr. Mercedes Carnethon:

Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine.

I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us.

Dr. Xuerong Wen:

Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone.

Dr. Mercedes Carnethon:

Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth.

Dr. Sandeep Das:

Thanks Mercedes. It's great to be with you.

Dr. Mercedes Carnethon:

Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found?

Dr. Xuerong Wen:

So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population.

So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results.

Dr. Mercedes Carnethon:

Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team?

Dr. Xuerong Wen:

That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population.

Dr. Mercedes Carnethon:

Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation?

Dr. Sandeep Das:

Yeah, absolutely. Thanks for the question.

So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question.

Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello.

Dr. Mercedes Carnethon:

Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well.

Dr. Sandeep Das:

Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients?

Dr. Xuerong Wen:

I would say yes. Okay.

Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced.

And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist.

And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease.

Dr. Sandeep Das:

Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice.

Dr. Mercedes Carnethon:

I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular?

Dr. Xuerong Wen:

That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that.

Dr. Mercedes Carnethon:

Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions?

Dr. Sandeep Das:

No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing.

Dr. Mercedes Carnethon:

Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work?

Dr. Xuerong Wen:

Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical.

Dr. Mercedes Carnethon:

Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen.

Dr. Xuerong Wen:

Thanks for this great opportunity to disseminate my study with us, thank you.

Dr. Sandeep Das:

Thanks Mercedes.

Dr. Mercedes Carnethon:

Thank you for joining us for this episode of Circulation on the Run.

Dr. Greg Hundley:

Circulation February 28, 2023 Issue

27 februari 2023 | 21 min

This week, please join author Jennifer Conway as she discusses the article "The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Carolyn, wow. We're closing out the month of February, this is February 28th. And the feature discussion today, very interesting. So in patients with hypertrophic cardiomyopathy, we often see them as adults, and guidelines are very clear on how to manage them. What about patients' children that present with hypertrophic cardiomyopathy? How do we manage them? Should we do exercise testing? Well, to get the answers to some of those questions, you'll have to wait listeners to our feature discussion today. But first we're going to grab a cup of coffee and jump into some of the other articles in the issue. Carolyn, would you like to start?

Dr. Carolyn Lam:

I would love to. With this first paper, which is a preclinical study revealing a novel signaling axis in cardiorenal interaction.

Dr. Greg Hundley:

Wow. Pray tell.

Dr. Carolyn Lam:

I will. So this paper is from Dr. Molkentin and colleagues from University of Cincinnati. And using mouse models of ischemia reperfusion acute kidney injury and unilateral ureteral obstruction, these authors found that interleukin 33 release from the kidney endothelium during acute kidney injury communicates with the heart through the suppression of tumorigenicity 2 or ST2L receptor on cardiomyocytes. And that's where it causes hypertrophy, fibrosis, and loss of cardiac function. Mice lacking interleukin 33 or mice lacking the gene encoding this ST2L receptor on cardiomyocytes, but not endothelial cells or fibroblasts, were protected from acute kidney injury induced hypertrophy and cardiomyopathy. Indeed, inhibition of acute interleukin 33 release from the kidney after acute kidney injury with a monoclonal antibody prevented cardiomyopathy. So the interleukin 33 ST2L signaling axis is a novel potential therapeutic target to protect the heart during kidney injury.

Dr. Greg Hundley:

Wow, Carolyn, really interesting preclinical science relating acute kidney industry and cardiomyopathy. Well, I have another paper from the World of Preclinical Science. And, Carolyn, this pertains to the metalloprotease ADAMTS7, and it is a novel locus associated with human coronary atherosclerosis. ADAMTS7 deletion protects against atherosclerosis and vascular restenosis in rodents. Carolyn, these authors led by Professor Wei Kong from Peking University designed three potential vaccines consisting of distinct B-cell epitopic peptides derived from ADAMTS7 and conjugated with the carrier protein KLH as well as aluminum hydroxide as an adjuvant. And they tested the efficacy of the vaccines to evaluate coronary intimal hyperplasia in mirroring wire models and after stent implantation in porcine models.

Dr. Carolyn Lam:

Oh, wow. So a vaccine against atherosclerosis? Cool.

Dr. Greg Hundley:

Yeah, it is really a vaccine concept against restenosis. Carolyn, this peptide vaccine against metalloproteinase ADAMTS7 efficiently mitigated atherosclerosis in vaccinated hyperlipidemic mice without lowering lipid levels and impeded intimal hyperplasia in both the murine wired injured arteries and the swine stented coronary arteries without any significant immune related organ injuries. Carolyn, the clinical implications are that the vaccine against the metalloproteinase ADAMTS7 is a novel atherosclerosis vaccine, mainly targeting vascular remodeling, thereby also alleviating instent restenosis. And perhaps in the future the application of this vaccine would be a complimentary therapeutic avenue to current lipid loading strategies for atherosclerotic disease. And this is nicely followed by an editorial from Professors Heribert Schunkert and Thorsten Kessler.

Dr. Carolyn Lam:

Cool, thanks, Greg. Well, this next paper asks the question that if coronary artery calcium can be identified on non-gated chest CTs, can this finding be effectively incorporated into care with the help of AI? So the Notify One was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease or a prior statin prescription were screened for coronary arterial calcium on a prior nongated chest CT from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental coronary artery calcium were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient specific image of coronary artery calcium and guideline recommendations regarding statin use. And the primary outcome was statin prescription within six months.

Dr. Greg Hundley:

Really interesting, Carolyn. So coronary artery calcium observed when a patient might happen to come in for another chest CT scan or actually randomizing a patient population to being notified and maybe doctors act on it versus not. So what did they find?

Dr. Carolyn Lam:

Yep, beautifully summarized. And this is from Dr. Sandhu and colleagues from Stanford University. And what they found was among more than 2000 patients who met initial and clinical inclusion criteria, coronary artery calcium was identified by the algorithm in 424 patients and confirmed by a radiologist in 89% who were randomized to notification or usual care. At six months, the statin prescription rate was 51% in the notification arm versus 7% with usual care. Thus, opportunistic coronary artery calcium screening of prior nongated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is of course needed to determine whether this approach can actually reduce atherosclerotic cardiovascular disease events. This is discussed in an editorial by Doctors Joshi, Nasser, and Navar.

Dr. Greg Hundley:

Wow, Carolyn, you know, this all fits with behavioral science. When we see something, then often we change our behavior much more readily. And so, gosh, boy, just a perfect example of that in this last paper. Well, there's some other articles in the issue, and I see again, just as it was last week, you've got a whole list here to describe.

Dr. Carolyn Lam:

Oh, you bet Greg. First, there's an exchange of letters between Doctors Du and Lee on physical activity has no significant association with stroke. There's a primer by Dr. Leyva on “Declining Risk of Sudden Cardiac Death in Heart Failures, Is that a Fact or a Myth?” There's a Research Letter by Dr. Soehnlein on “Time Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice.” There's also Highlights from the Circulation Family of Journals by Molly Robbins. The characteristics of patients with recurrent sudden cardiac death are described in circulation arrhythmia and electrophysiology. A proof of principle gene therapy for correction of long QT two and short QT one syndromes is presented in circulation, genomic and precision medicine.

The impact of food insecurity on heart failure mortality is reported in circulation heart failure. The associations of hypertension and hypertension treatment with differences in sexual identities are presented in circulation, cardiovascular quality and outcomes. A multi-modality imaging and biomarker strategy to detect early decompensation with chronic aortic regurgitation is reported in circulation cardiovascular imaging, and an analysis of revascularization at the time of TAVR on cardiovascular outcomes is reported in circulation cardiovascular interventions. Finally, that's a Perspective piece by Dr. Turer on cardiac myosin inhibitors unlocking potential to improve treatment in hypertrophic cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, just another issue that's so rich with both preclinical and clinical science. Well, how about we get off to that feature discussion and learn more about management of children and young adults with hypertrophic cardiomyopathy?

Dr. Carolyn Lam:

So important. Let's go.

Dr. Greg Hundley:

Welcome listeners to this February 28th feature discussion where we're going to work into the world of hypertrophic cardiomyopathy in children. And we have with us today Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta. Welcome Jennifer. And maybe Jennifer, let's start off, could you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Jennifer Conway:

Sure. And I would just like to start by thank you for inviting us to really present the information from our paper. We think it's a very exciting paper and are excited to share our results. When you think about hypertrophic cardiomyopathy in children, a lot of the information in the past has really been extrapolated from adults. And we know from the recent 2020 guidelines that exercise testing is really no longer part of risk stratification for adults. It's mostly used to look at functional outcomes and really when assessing patients more for heart failure related symptoms. So we wanted to see whether or not exercise testing in children had a different role because we know the recent risk stratifying calculators such as the primacy calculator that's come from this cohort of patients or HCM risk kids, has different risk factors that have been identified for sudden events, for instance, than in the adult population. And that's really kind of sparked us to see, well, maybe exercise has a different role in children than it does in adults.

Dr. Greg Hundley:

And so we wanted to investigate the role of exercise testing in children with hypertrophic cardiomyopathy. So how did you arrange your study design, and what was your study population?

Dr. Jennifer Conway:

This is an international cohort of 20 centers from the US, Canada, and Australia. And it's an observational cohort, and there is over 724 patients' information that has been collected within this cohort of patients. And for this particular study, 630 of them had an exercise test and therefore were included in the study to look at.

Dr. Greg Hundley:

And in the study population, I know it's a pediatric population, what was the age range?

Dr. Jennifer Conway:

The average range was about 13 years old with probably the youngest being around eight because that's really where you can do an exercise test with and that's up to 18 years of age. So that's kind of the general age range of patients.

Dr. Greg Hundley:

And of these pediatric populations, what percentage were, I guess, boys versus girls?

Dr. Jennifer Conway:

Yeah, so just over 75% were males within this study population.

Dr. Greg Hundley:

Okay. And then now Jennifer, can you describe for us your study results?

Dr. Jennifer Conway:

Sure. I think the first main result is that we can really think about what we defined as an abnormal exercise test so maybe we'll start with that and kind of explain our findings there. So abnormal exercise test in this study was really a threefold one if you had an abnormal blood pressure response. The other one is if you had ventricular ectopy or if you had ST-T wave changes, which we described as ischemia. And so taking those three together, about 28% of our pediatric patients had an abnormal finding on their exercise test. So that's kind of the first main finding. So then we took those abnormal exercise patients and compared those with a normal exercise test to try to look for outcomes. And the two outcomes that we mainly focused on all cause mortality and transplantation is one outcome and the other one was sudden cardiac death events.

So when we looked at the five-year freedom for all cause mortality and transplant, we found that those who had an abnormal exercise test had a lower five-year freedom from all cause mortality and transplantation. And when we sub-analyzed the different abnormalities in the exercise test, we found that ischemia and an abnormal blood pressure response were both associated with kind of a higher risk of mortality and transplantation. And then when we went on to look at sudden cardiac death events, there was really no difference seen between those with an abnormal or normal exercise test in terms of sudden cardiac death events. But when we looked at the individual factors once again exercise induced ischemia was associated with a lower freedom from a sudden cardiac death event.

Dr. Greg Hundley:

Jennifer, frequently in adults we're often examining with exercise how the intracavitary or left ventricular outflow tract gradient may change with exercise. What did you find in children in regards to that parameter?

Dr. Jennifer Conway:

Yeah, so we couldn't actually study that because this was a compilation of different types of exercise tests. So not everybody at each institution did the same form of exercise tests. So some patients had an exercise echo, some had a CPET test, and some had an exercise stress test. And so we took the common parameters from all of those to study, so we weren't specifically able to look at LV outflow tract gradients for instance.

Dr. Greg Hundley:

Jennifer, as a pediatrician managing a patient with hypertrophic cardiomyopathy, how do we use the results of your study to influence how we might manage patients moving forward?

Dr. Jennifer Conway:

I think this is an excellent question, and there's probably really two things that we can think about. The first is, what is the role of exercise testing in pediatrics? And just as we're starting to discover what our risk factors are for sudden cardiac death events, I think we have to do a little bit more to discover what our role is truly going to be with exercise test. So one of the things that we're doing as part of the primacy group is trying to decide is if we add exercise testing abnormalities to the already developed primacy calculator, does it change its power at all? That's one of the things kind of for the future to see with the current kind of sudden death risk factor calculators, can exercise, add to them? The second thing is I think that there is probably a role in exercise testing in general with patients that you see in your clinic to look at these predictive outcomes, and that is not standard across centers.

We know that because not everybody in this cohort had an exercise test. I think there are some higher risk patients that likely are not suitable for exercise tests, but I think a majority of the patients that we see likely can undergo exercise testing. And although it's not published in this paper, of the 630 patients, there's only one patient who had a kind of aborted arrest during the exercise test. And that patient was a higher risk patient who had a previous reported aborted arrest. And this actually corresponds with two other papers in the literature, one from CHOP in Boston where it's a very low event rate when exercise testing is done in a controlled environment with professionals around and have a lab set up to specifically do that. The other aspect of this I think is that as we're starting to understand hypertrophic cardiomyopathy in general better, I think using exercise tests to try to help design exercise interventions is going to be important.

Another study that I'm doing that's not part of this is looking at the cardiovascular health of children with hypertrophic cardiomyopathy across Canada. And we are finding that there's a high level of obesity, sedentary lifestyle, high lipid profiles for instance, all of which put people at risk for cardiovascular disease as adults. And so I think as we're getting more comfortable potentially with looking at exercise prescriptions for hypertrophic cardiomyopathy patients and understanding risks a bit better, then exercise testings going to be a key in trying to design maybe some of that programming for patients.

Dr. Greg Hundley:

Wow, Jennifer, just a beautiful explanation of where we need to move with your research results in the future. One thing that kind of caught my attention as you were speaking, really safety. So for all our listeners, in terms of exercising children with this condition or young adults, would you recommend a specialized center or what would you describe in that, at least in terms of safety precautions?

Dr. Jennifer Conway:

Well, if you look at all the... There's not a lot of studies that have been published, but the ones that have, they're in a lab that commonly exercises children. They have protocols of who they will exercise and who they won't and when you would stop an exercise test. For instance, the paper from CHOP nicely describes how they approach the exercise in hypertrophic cardiomyopathy, and they have clear guidelines of when they stop testing. So in their 140 patients, for instance, they stop testing in two patients, one who had, I think ST segment changes and the other one who developed some ventricular ectopy. I think it needs to be in a controlled environment where you have safety measures in place and you have guidelines to direct you in terms of if this happens, this is the response to that. I think that's all very important when you're kind of thinking about exercising what has been deemed as higher risk patients.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta for sharing with us these really interesting results, highlighting that exercise abnormalities are common in childhood hypertrophic cardiomyopathy, and an abnormal exercise test was independently associated with lower transplant free survival especially in those with ischemic or abnormal blood pressure responses during that exercise testing.

Well, on behalf of Peter, Carolyn and myself, we want to wish you a great week, and we will catch you next week on The Run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation February 21, 2023 Issue

20 februari 2023 | 25 min

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis?

Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion.

Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address?

Dr. Carolyn Lam:

Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine.

And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan.

However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials.

Dr. Greg Hundley:

Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find?

Dr. Carolyn Lam:

In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure.

Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña.

Dr. Greg Hundley:

Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis.

So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition.

And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage.

So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression.

Dr. Carolyn Lam:

Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex.

They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models.

So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression.

Dr. Carolyn Lam:

Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension.

So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence.

Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development.

As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age.

So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results.

Dr. Greg Hundley:

Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models?

Dr. Carolyn Lam:

Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension.

The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration."

So lots of translational implications of this paper.

Dr. Greg Hundley:

Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe.

Dr. Carolyn Lam:

Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants."

There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea."

In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature.

Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity.

There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study.

Dr. Greg Hundley:

Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion?

Dr. Carolyn Lam:

Let's go. Thanks.

Dr. Greg Hundley:

Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen.

Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Amil Shah:

Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today.

So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality.

Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes.

Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation.

Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction.

And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals.

But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults.

And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease.

To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life.

Dr. Greg Hundley:

So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population?

Dr. Amil Shah:

Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota.

Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age.

We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally.

And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion.

Dr. Greg Hundley:

Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results?

Dr. Amil Shah:

So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair.

And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort.

And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes.

Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest.

Dr. Greg Hundley:

Now, did you find similar results for men and for women?

Dr. Amil Shah:

So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar.

Dr. Greg Hundley:

And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions?

Dr. Amil Shah:

Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages.

So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly.

So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings.

For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that.

Dr. Greg Hundley:

Very nice. Well, thank you so much, Amil.

And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper?

Dr. Ntobeko Ntusi:

Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle.

And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms.

We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex.

And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution.

The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease.

And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations.

So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg.

Dr. Greg Hundley:

Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research?

Dr. Amil Shah:

So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life.

And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in.

I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients.

Dr. Greg Hundley:

Very nice. Ntobeko, do you have anything to add?

Dr. Ntobeko Ntusi:

Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward.

The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease.

Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time.

And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events.

Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation February 14, 2023 Issue

13 februari 2023 | 26 min

Please join Circulation Senior Associate Editor Sana Al-Khatib and Associate Editor Mercedes Carnethon as they discuss the seventh Go Red for Women issue of the journal.

Dr. Sana Al-Khatib:

Hello and welcome to the Special Circulation on the Run podcast focused on the seventh Go Red for Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I had the pleasure of co-leading this issue with a colleague and friend, Dr.

Dr. Mercedes Carnethon:

Well, I am so pleased to be with you today, Sana. My name is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine. I'm an associate editor at the journal Circulation and extremely excited to join you this year on the seventh issue, as a guest editor for our Go Red for Women Issue. And we've got so many great pieces today, so let's get going.

Dr. Sana Al-Khatib:

Wonderful. So we're very excited to provide you with some highlights of the issue that covers a broad range of topics related to cardiovascular disease in women. In this particular issue, the content is presented as five original research articles, three research letters, five online articles, and one in-depth review article. And like prior podcasts, this year's podcast will only focus on the original research articles, so let's get to it.

The first original research article is titled Exercise for the Prevention of Anthracycline Induced Functional Disability and Cardiac Dysfunction. This was the breast cancer randomized exercise intervention Brexit study. In this trial, the investigators enrolled 104 women who were between 40 and 75 years old and had stage one to three breast cancer. And these women were scheduled for anthracycline based chemotherapy and they randomized them to three to four days per week of aerobic and resistance exercise training for 12 months and they were randomized in one-to-one ratio to either do the exercise or really usual care. Very interesting study Merci, don't you think?

Dr. Mercedes Carnethon:

Absolutely. This is such an important issue, particularly for survivors of breast cancer.

Dr. Sana Al-Khatib:

Exactly. And in this trial, they focused on looking at the following measures, cardiopulmonary exercise testing to quantify the peak VO2 and functional disability, cardiac reserve, quantified using exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output stock volume, standard-of-care echocardiography-derived resting LVEF and global longitudinal strain.

And exercise training was found to attenuate functional disability at four months, which was really interesting, but not at 12 months. But when they looked at it, Merci, in a per protocol analysis, functional disability was found to be entirely prevented at 12 months among participants who adhered to exercise training.

Dr. Mercedes Carnethon:

That is so exciting to hear, especially with the potential to intervene for better outcomes.

Dr. Sana Al-Khatib:

Exactly. And then listen to this, as compared with usual care at 12 months, exercise training was associated with a net plus 3.5 milliliter per kilogram per minute improvement in the peak VO2 that coincided with improvements in cardiac output, stroke volume, LVEF and RVEF reserve, all of them improved, Merci.

Dr. Mercedes Carnethon:

That is such great news. What did the authors have to say about these findings?

Dr. Sana Al-Khatib:

Well, of course they were really excited about these findings because hopefully this will help a lot of patients. Now, when they looked at the exercise training in relation to resting measures of LV function, there didn't seem to be an effect. So they concluded that in women with early stage breast cancer undergoing anthracycline based chemotherapy, 12 months of exercise training did not attenuate functional disability, but it certainly provided clinically meaningful benefits in relation to the peak VO2 and cardiac reserve. So really interesting findings. Obviously I personally would like to see these findings replicated by other studies, but I think these results are promising.

Dr. Mercedes Carnethon:

I'm so excited to be able to feature that important piece in here, especially as more women are living and being treated for breast cancer.

Dr. Sana Al-Khatib:

Indeed. So Merci, I'll turn it over to you to tell us about a couple of your articles.

Dr. Mercedes Carnethon:

Well, I'd love to do two of mine back to back if that's okay with you because they address similar issues. So in one of the first from Dr. Yuan, Liu, and colleagues, they studied the influence of maternal exposure to particulate matter, small, fine, particular matter, and how that influenced the risk of congenital heart defects. We certainly know that congenital heart disease is a significant problem. And what's even more interesting is that the author's site that more than 80% of congenital heart disease has no known cause.

However, prior research does suggest that particulate matter is a plausible environmental exposure that could damage follicular development, disrupt hormone homeostasis, cause inflammation and glucose intolerance. All of those processes could lead to abnormal placentation and fetal development. And so I thought it was really exciting that they would pull together this very large study. And in fact, this isn't the first study to ask this question, but it is one of the largest. It was carried out in China, which is an area with relatively higher levels of pollution.

And the authors did some really cool things. I can't wait to tell you Sana, because I feel as though I rarely get to say NASA was involved in a study that we're featuring here in Circulation. So let me tell you about it.

Not just cardiologists, not just obstetricians and gynecologists, but environmental scientists were involved here and the mean monthly measures of PM 2.5, which is small fine particulate matter, were made via satellite, NASA satellites, and imputation procedures were used that combined a number of meteorologic variables, land use types, road network information, elevations and emissions to train models using machine learning to make estimates of the burden of PM 2.5. Isn't this cool?

Dr. Sana Al-Khatib:

Wow. How interesting. Absolutely.

Dr. Mercedes Carnethon:

Yes. It's probably not something you do every day in your cardiology practice, but it's particularly important for us to be able to get these precise measures of PM 2.5 exposure and what the authors were doing were matching up these units of exposure with the preconception period three months before pregnancy, the first trimester three months after pregnancy, and the entire window to determine how exposures to PM 2.5 during those critical periods for fetal development influenced congenital heart disease and they studied the major causes of congenital heart disease, the major classes using ICD 10 codes.

Dr. Sana Al-Khatib:

Wow. Well, I can't wait to hear the results.

Dr. Mercedes Carnethon:

So the results suggested that in general, the risk of delivering a baby with a congenital heart defect increased by 2% for each 10 nanogram per meter cubed in maternal exposure to PM 2.5 during the preconception period. And this relationship was even stronger preconception than it was during the first trimester. And when they studied different types of congenital heart diseases, the strongest associations were with septal defects. And this was regardless of the exposure window, this was preconception, the first trimester and the entire peri-conception window. I think another really compelling thing about a study of this size, and did I mention that it was 1.4 million births that were studied here during a period of time between 2014 and 2017? 1.4 million births.

Dr. Sana Al-Khatib:

That's a very large study.

Dr. Mercedes Carnethon:

Yes, and one of the benefits of having a study of that size is that you have the opportunity to look at subgroup effects to determine whether there are other characteristics that modify the relationship of the exposure and the outcome in this case PM 2.5 exposure. And what they found was that the relationship of PM 2.5 exposure with congenital heart disease was even stronger for births that took place in northern China or births that happened in areas with a low per capita disposable income. And even more surprising, and I'm not sure if this surprised you, but the relationships were even stronger in births to mothers who were younger than age 35. And that's particularly telling given that many births are obviously happening when women are below age 35.

So I think these findings are just so compelling. I think they are important certainly for our cardiology community, but I think they're also important for policy makers as they consider the implications of air quality and how that affects our long-term health.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. Very important implications here, Merci. I agree.

Dr. Mercedes Carnethon:

Yes. Well, so I was really pleased to feature that article and then in the same issue, if I can continue to hold the microphone here.

Dr. Sana Al-Khatib:

Yes, please.

Dr. Mercedes Carnethon:

In the same issue, we have another paper led by authors from China, Zhang and colleagues, who carried out a study of what happens when women grow up with congenital heart disease and they have their own pregnancies? And so the goal of this particular paper was to look at the influence of pulmonary hypertension, which is a common complication of women with congenital heart disease when they become pregnant, to see how the severity of pulmonary hypertension influences pregnancy outcomes in these women.

Dr. Sana Al-Khatib:

A very important topic. Yeah, I agree, Merci.

Dr. Mercedes Carnethon:

Yes. And so this was carried out in over 2000 pregnant women with congenital heart disease who had completed pregnancies. This was a retrospective analysis. And of those a significant portions, 729 women, had pulmonary hypertension. And these range from mild to moderate to severe. And unfortunately, maternal mortality was an outcome in this study along with birth outcomes among the babies. And what the authors found, I guess, consistent with what one might hypothesize, is that the severity of pulmonary hypertension was associated with adverse outcomes. Those women who had more severe pulmonary hypertension were more likely to experience maternal mortality. They were more likely to experience heart failure and other cardiac complications.

And unfortunately, those risks were as well passed along to the babies where there were more obstetric complications and other adverse events. So it's an unfortunate finding, but I would say that there were a number of bright spots and a few bright spots to this particular study. And their findings were that those women who had follow-up care with a multidisciplinary team, strict antenatal supervision, tended to have a lower likelihood of these adverse events.

Dr. Sana Al-Khatib:

That is so good to know. Of course, I mean, we have thought of that to be the case, but now to have a study showing that is really impactful.

Dr. Mercedes Carnethon:

It certainly is. And especially such a well done study. These aren't common. And so this team managed to find a relatively large sample size so that they could produce robust estimates that we can use and consider when we consider helping women with congenital heart disease manage their developing families. So I really thank you for letting me talk about two of these studies back to back, but I can't hog the microphone. We have so much good work in this episode.

Dr. Sana Al-Khatib:

Yeah, no problem. But it's so good to see more work being done on the adult congenital heart disease, by the way, because this is a growing patient population, and it's great that we were able to feature it in two articles, Merci. So let me present the second paper that I had the pleasure of handling in many ways, this particular paper. First of all, it is a topic that's near and dear to my heart as I am an electrophysiologist and the paper provides data on the comparative effectiveness of left atrial appendage occlusion versus oral anticoagulation bisects in patients with atrial fibrillation. And not only am I interested in the topic, but I actually was the senior author on this paper, and so I really need to acknowledge that and would like to share some highlights of the paper with you.

So in this particular paper, Merci, we analyzed Medicare claims data from 2015 through 2019, and we really focused on patients who were deemed to be eligible for left atrial appendage occlusion.

And we divided them into sex subgroups. And of course, we had to apply robust statistical methodology first in terms of making sure that patients with left atrial appendage occlusion were well-matched in one-to-one ratio to those receiving anticoagulant therapy. Obviously, a lot of selection bias goes into those assignments in clinical practice, and so we needed to make sure to match those groups, and we did that for women and we did that for men. And we were really interested in looking at the risks of mortality stroke or systemic embolism as well as bleeding between these matched groups, so we wanted to compare those risks.

And so among females, we had 4,085 left atrial appendage occlusion recipients, and those were again matched in one-to-one ratio to women who were receiving anticoagulant therapy. And if you look at the subgroup of males, 5,378 were left atrial appendage occlusion recipients. And again, those were similarly matched to men who received oral anticoagulation.

And so of course, after doing the matching, we applied the further adjustment to take care of remaining differences between the groups. So what did we find? We found that left atrial appendage occlusion was indeed associated with a significant reduction in the risk of mortality as well as stroke or systemic embolism and this was true for females and males. And when we looked at the bleeding risk, we found that that risk was significantly greater in left atrial appendage occlusion recipients early after implantation, because as you know, Merci, those people for the first six weeks have to be treated either with anticoagulation or a combination of aspirin and Plavix, and so it's not surprising that bleeding was actually high early on, but really lower after the six week per procedural period for both females and males.

And so what we concluded in this study, which was a real world study, and that's the significance of this because several trials had been conducted, but many of us always raised the questions of, well do the results of the clinical trials apply to the average patient that we see in clinical practice? So many of us would like to see comparative effectiveness analysis being conducted in real world populations, and here we were able to show that left atrial appendage occlusion was associated with a reduction in the risk of death, stroke, or systemic embolism as well as long-term bleeding both in females and males. So really very interesting results that I think should help inform shared decision making discussions with patients.

Dr. Mercedes Carnethon:

Oh, absolutely. I have to say I'm not biased. It's not because you are the senior author, it's because this is just truly excellent work, really a creative design. And I agree with your assessment that doing this sort of real world work is critically important because sometimes we don't have the representation in clinical trials of a distribution of people who would ordinarily be the targets of these types of therapies. And so I really applaud you and your team for really leading an excellent study that I hope people will find extremely useful.

Dr. Sana Al-Khatib:

Well, thank you very much, and I really want to give a lot of credit to the first author, Dr. Zeitler, who has been mentee of mine for many years and has done a great job and really a lot of credit to the rest of the co-authors.

Dr. Mercedes Carnethon:

Well, that's fantastic. I'm glad that I chose the ordering that I did because the final study that I'd like to talk about is in fact a randomized trial. And I think similar to the one that you just described, this is another study that's comparing sex differences. So this particular study led by Coughlan and colleagues describes sex differences in 10-year outcomes after percutaneous coronary intervention with drug-eluting stents. And given the positive impact that drug-eluting stents have had on improving coronary artery disease, I think it's critically important for us to find out whether or not there are any disparities by sex and the types of outcomes that occur following percutaneous coronary intervention. And so in order to address this question, what the authors did was to carry out a pooled analysis of five individual patient data from trials of drug-eluting stints that had at least 10 years of follow up.

And the objective here was to really address the controversy in the field about whether the outcomes were worse for women, which was observed in some studies versus in other studies where there was no difference. And the benefit of using this pool design, again, this sample size, I'm an epidemiologist, I love big samples for what can be done. And in the 9,700 patients that were included in this trial, 24% of them were women. So really it required this type of a meta analytic design in order to have enough women to answer these questions. So the outcomes of interest here included death from all causes, death from cardiovascular disease, MI, stent thrombosis, and revascularization of the target lesion, the target vessel, and the non-target vessel.

So one of the challenges in interpreting findings from prior studies of this question are the concerns that the clinical characteristics of men versus women who underwent PCI were different.

And in fact, in this particular pooled analysis, men were more likely than women to have three vessel disease, and they had a lower, lower mean ejection fraction coming in the characteristics following angiogram and the procedure also showed some differences by sex groups, namely that women had smaller vessel reference diameters before PCI and a smaller minimal luminal diameter after PCI. But men had a longer total stinted length as compared with women. So I'm sure you want to know what ended up happening.

Dr. Sana Al-Khatib:

Please.

Dr. Mercedes Carnethon:

Yes. So when the authors tested their primary hypothesis of sex differences in tenure outcomes, they found that some of the very minor differences in the proportion of women versus men who experience the outcomes of interest were eliminated following adjustment for relevant characteristics, or in fact that women were slightly less likely to experience the outcomes of interest. Specifically women were less likely to experience death from any cause over 10 years, but there was no difference in cardiovascular death as compared with men.

Women though were significantly less likely than men to require repeat revascularization of the target legion, the target vessel, and the non-target vessels over 10 years. But unfortunately, the findings weren't all good. A notable exception was that when the offers examined the one-year event rates, women had a significantly increased likelihood of MI in the first 30 days after PCI. And I'm not sure why this is, but the authors did advance numerous hypotheses to explain their findings. One was that baseline and procedural characteristics varied markedly between men and women, and that the age was a primary confounder of these findings. And this was because they carried out a series of sensitivity analyses where they didn't account for age and when they didn't account for age, women had an increased risk of cardiovascular death through the entire 10 years of follow up. And it's curious why this would happen.

And the observation was thought to be attributable either to women developing CAD later than men in life, or because they're diagnosed later because of decreased physician awareness among women. And that's shocking to hear since we all know that cardiovascular disease is the leading cause of death among women. So I really think that the observations in this large pooled analysis do warrant further study and investigation. And a point that I think we discussed earlier is that the representation of women in clinical trials, we have to have more women in these trials and this was an argument that the authors advanced because then without more women in these trials, we don't have adequate power to investigate these sex differences and to explore reasons behind these sex differences. And so I hope that investigators will really heed these calls so that we can generate the best possible science to inform treatment options for women so that we can maximize our health outcomes.

Dr. Sana Al-Khatib:

No, absolutely. Those are excellent points, Merci, that you make. And we certainly need to make sure that we have more women participating in clinical trials and that to the extent that we can, that patients enrolled in clinical trials are representative of patients that we see in clinical practice. You bring up excellent points. Thank you for that great summary.

Dr. Mercedes Carnethon:

Thank you so much, and thank you really for letting me join you in this special issue. I'm so excited about all of our pieces, not just these original research pieces, but as well our research letters and the rest of our content. I think there's just a lot for our readers to dig into here.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. Merci, it's been a pleasure for me to co-lead this issue with you and I agree while we focus this podcast on the original research articles, the other articles are equally interesting and impactful. So a lot for our readers to enjoy here. So in closing, we want to wholeheartedly thank Dr. Joe Hill, the editor-in-chief for Circulation, Dr. James De Lemos, the executive editor of the Journal and all authors who submitted the research for this issue. We also want to thank the Circulation associate editors and staff who worked so hard to deliver what you are about to experience. We're very excited about this issue and know you will find it very informative and interesting.

This concludes our Go Red for Women issue Circulation on the Run podcast. Thank you so much for listening.

Dr. Mercedes Carnethon:

Thank you.

Dr. Greg Hundley:

Circulation February 7, 2023 Issue

6 februari 2023 | 23 min

Please join author Petr Ostadal and Associate Editor Dharam Kumbhani as they discuss the article "Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial."

Dr. Carolyn Lam:

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today Carolyn will have such an interesting feature discussion. We are going to look into the use of ECMO to treat patients with cardiogenic shock, the results of the ECMO-CS randomized clinical trial. Isn't that interesting?

Dr. Carolyn Lam:

Awesome. Can't wait. But I suppose you're going to tell us about some papers in the issue first. I'm getting my coffee.

Dr. Peder Myhre:

Yeah, go ahead. Because first we're going to talk about a very interesting paper that relates to diabetes and the progression of coronary artery disease. So as you know, Carolyn, diabetes remains associated with an increased risk of cardiovascular morbidity and mortality. And although the absolute risk difference between patients with and without diabetes have declined over the past 20 years, we still don't know what is the diabetes associated differences in coronary plaque morphology and lipid content.

Dr. Carolyn Lam:

It's true. That's a very interesting question. And will you tell us more?

Dr. Peder Myhre:

Yeah. So the investigators in the prospect two study who enrolled patients exclusively from Denmark, Norway in Sweden who presented with biomarker positive MI and assessed both culprit lesions and untreated non-culprit lesions in these patients. And then they stratified the patients by diabetes status and examined with three vessel quantitative coronary angiography and near infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention.

Dr. Carolyn Lam:

Okay, that's deep investigation. And what did they find?

Dr. Peder Myhre:

So diabetes was present in about 12% of patients and during a median or 3.7 year follow up, MACE occurred almost twice as free frequently in patients with versus without diabetes. And that was primarily due to an increased risk of MI related to culprit lesion stenosis and non-culprit relation related spontaneous MI. However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes, concerning culprit and the non-culprit lesions and in multi-variable models, diabetes was associated with MACE in lesions but not with prevalence of high-risk plaque characteristics. So Carolyn, the authors conclude that diabetes related plaque characteristics that might underlie the increased risk were not identified by multimodal imaging.

Dr. Carolyn Lam:

Oh, I just love studies like that so elegant with just a really, really intriguing results that make us ask more important questions. Love it. Thank you. Well, the next paper is also about myocardial infarction, but this time looking at the fibrotic remodeling after myocardial infarction because we know that MI induces a repair response that ultimately generates a stable fibrotic scar. And although the scar is important to prevent cardiac rupture, excessive pro-fibrotic response impairs optimal recovery because it promotes a development of non-contractual fibrotic areas. So would it be possible to regulate the expansion of cardiac fibroblast after MI through a paracrine action on the cardiac stromal cells? So the authors led by corresponding author Dr. Hulot from University of Paris performed a bioinformatic secretome analysis of cardiac stromal PW1 positive cells isolated from normal and post MI mouse hearts to identify novel secreted proteins.

And they found that first cardiac PW1 positive stromal cells responded to myocardial infarction by secreting factors that promoted the proliferation and activation of resident fibroblasts and one such factor growth differentiation factor three or GDF3 was highly upregulated in the ischemic hearts and promoted a high induction of fibroblast proliferation via interaction with TGF beta receptors and activation of SMAD1/5 and SMAD2/3 signaling cascades. The upregulation of GDF3 was detected in the plasma of mice and humans following MI and high levels of plasma GDF3 in the days following MI predicted adverse outcomes measured six months later including cardiac dilation and limited recovery of contractile function in humans.

Dr. Peder Myhre:

Oh, that's so interesting. We already know GDF15 were very well, but now we hear about GDF3 in predicting fibrotic remodeling post myocardial infarction. So Carolyn, what are the clinical implications of these findings?

Dr. Carolyn Lam:

Exactly, Peder, in fact you said it. So the detection of high circulating GDF3 in plasma may serve as a novel biomarker of adverse fibrotic remodeling in heart tissue. That's one. And next the measurement of GDF3 plasma levels in the early post MI phase may allow for the identification of patients within an increased risk of severe myocardial fibrosis and heart failure and therefore could guide specific disease management.

Dr. Peder Myhre:

Thank you. That was an excellent summary of the paper, Carolyn. And now I'm going to look into a paper that relates to the important issue of arteriosclerosis following heart transplantation because as you know, transplant arteriosclerosis characterized by concentric and diffuse narrowing of vastly lumen is a major complication in long-term survivors of heart transplant patients. And increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis. But how lymphangiogenesis affects this process is unknown. The authors of this paper, which comes to us from corresponding author Sue from Sejong University, transplanted vascular allografts between various combinations of mice including mice with severe combined immune deficiency and studied the lymphatic vessels within the grafted arteries.

Dr. Carolyn Lam:

Wow, that is really cool. Studying lymphatics and lymphangiogenesis in atherosclerosis. Interesting. What did they find, and what are the clinical implications?

Dr. Peder Myhre:

So Carolyn, lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 were associated with these immune structures. Fibroblasts in the vascular allografts released VEGFC, which stimulated lymphangiogenesis into the grafts and inhibition of VEGFC signaling inhibited lymphangiogenesis, neointima formation and adventitial fibrosis of vascular allografts. And these studies identified VEGFC released from fibroblasts as signal stimulating lymphangiogenesis extending from the host into the vascular allografts. So, Carolyn, the authors conclude that the formation of lymphatic vessels play a key role in the immune response to vascular transplantation and inhibition of lymphangiogenesis may be a novel approach to prevent transplant atherosclerosis.

Dr. Carolyn Lam:

Wow, that is super interesting. Thanks, Peder. While also in this issue, there's an exchange of letters between Drs. Tanaka and Schulze regarding SGLT2 inhibitor treatment in acute decompensated heart failure. Why do we initiate it early? There's also a really nice On My Mind paper by Dr. Schiattarella on Cardiometabolic HFpEF. Is it the NASH of the heart?

Dr. Peder Myhre:

Oh, that's interesting. We also have some cardiology news by our own ‪Bridget Kuehn entitled “No Benefit Seen for Nighttime Dosing Over Morning Dosing for Antihypertensive Medications.” And this is a summary of the time trial, which was presented at European Society of Cardiology Congress in 2022. And finally, Carolyn, we have a Research Letter entitled “Stepwise Generation of Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to Model Coronary Microvascular Dysfunction” by Dr. Joseph Wu from Stanford University School of Medicine.

Dr. Carolyn Lam:

While cool, Peder. But now I'm so excited to hear about the ECMO-CS randomized trial. Let's go.

Dr. Greg Hundley:

Welcome listeners to this February 7th feature discussion and we have with us today Dr. Petr Ostadal from Na Homolce Hospital in Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome, gentlemen. Well, Petr, we'll start with you. Can you describe for us some of the background information that really led you to perform this study, and what was the hypothesis that you wanted to address?

Dr. Petr Ostadal:

According to the current guidelines from the management for the management of cariogenic shock, it should be considered administration of inotropes and vasopressor for hemodynamic stabilization, or it may be considered administration of inotropes and vasopressors and it should be considered the use of short-term mechanical circulatory support. And the aim of the ECMO-CS trial was to compare early conservative therapy with inotropes and vasopressors and immediate implementation of ECMO in patients with the rapidly deteriorating or severe cardiogenic shock. The hypothesis of the ECMO-CS trial was that immediate implantation of ECMO in patients with cardiogenic shock and critical hemodynamic condition will be associated with improved outcomes.

Dr. Greg Hundley:

Very nice. Can you describe for us this study population and then also what study design did you use to address your hypothesis?

Dr. Petr Ostadal:

We try to select patients who can really profit from the early ECMO implantation, and we define two categories of patients. First category where the patients with rapidly deteriorating cardiogenic shock corresponding to current sky stage D or E. This patient should have evidence of left ventricle pump failure as left ventricle ejection fraction below 35% or ejection fraction 35 to 55 in case of severe mitral regurgitation or aortic stenosis. And this patient also should require a repeated both of vasopressors to maintain mean arterial pressure about 50 millimeters of mercury. The second category where the patients with severe cardiogenic shock corresponding to current sky stage D and this patient should have the criterion of a hemodynamic conditions which was cardiac index less than 2.2 or systemic blood pressure below 100 millimeters of mercury in both situation with higher doses of inotropes and vasopressors. And in case of a low systolic blood pressure, also the evidence of left ventricle pump failure based on ejection fractional below 35 or ejection fraction 35 to 55 in case of severe mitral regurgitation of aortic stenosis.

The second criteria for the metabolic criteria, that was the evidence of tissue hypoperfusion and this was defined as a higher lactate above three millimeters per litter or low ScvO2 below 50%. And the third criterion was exclusion of hypovolemia, and this was based on central venous pressure or pulmonary artery wedge pressure. So this was the major inclusion criteria in the ECMO trial. The study population was not defined based on theology of cardiogenic shock, but just on severity of cardiogenic shock.

Dr. Greg Hundley:

Very nice. And so your design, did you have a one-to-one randomization, or how did that work? And then also how many subjects did you include in this important trial?

Dr. Petr Ostadal:

The patients were randomized in one-to-one ratio to immediate implementation of ECMO or to early conservative therapy. But it is important to point out that in the early conservative therapy downstream use of ECMO was allowed in case of further hemodynamic worsening defined as increase of what lactate by three millimeters per litter. We enrolled 122 patients, 61 were randomized to early ECMO and 61 to early conservative strategy. Five patients were excluded due to absence of informed consent and finally 58 patients were analyzed in the early ECMO or immediate ECMO arm and 59 patients were analyzed in the early conservative arm.

Dr. Greg Hundley:

Sounds great Petr. And then tell us and describe your study results.

Dr. Petr Ostadal:

The primary endpoint was composite of death from any cause, resuscitated circulatory RS and implementation of another mechanical circulatory support including ECMO in the early conservative arm at 30 days. And there was no difference in the primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95% confidence in interval 0.46 to 1.12. There was also no difference in the incidence of death from any cause. 50% in the immediate ECMO arm and 28%, 47.5% in the early conservative arm. There was no difference in the incidence of resuscitated circulatory arrest, 10.3 in the immediate ECMO arm and 13.6 in the early conservative arm. Less patient required another mechanical circulatory support in the early ECMO arm through 17.2 in comparison with 42.4% in the early conservative arm and downstream ECMO was used in 39% of patients in the early conservative arm.

Dr. Greg Hundley:

Very nice. So similar results both immediately and then 30 days later for both arms. And I think that last point that you make is very interesting. 39% of the individuals randomized to the conservative arm went on to receive VA-ECMO. Well, listeners next, we're going to turn to one of our associate editors and Dharam, you have many papers that you see. How do we put the results that Petr has just described really in the context of management of shock and results that have been published previously?

Dr. Dharam Kumbhani:

Yeah, Greg, thank you. And Petr, thank you for this important paper and again, I'm really honored to be here on behalf of Circulation on the Run. So again, want to congratulate the authors for really an important study. I think in terms of context, what is really interesting is the use of ECMO, particularly VA-ECMO for patients with shock has really skyrocketed. And it is interesting that this expansion has occurred in the absence despite, I guess high quality clinical trials, this trial certainly fills an important void. Although it is a small patient population, it is randomized, it is a largest randomized trial to date on this important population. And so I think most of the studies that have been done so far have been done using observational data sets which have sort of inherent limitations. So I certainly want to congratulate you on trying to study this very challenging population because in sort of that acute setting, it's frequently very hard to get patients randomized.

So just broadly in that context, I think at the same time this study does sort of pose some important questions and sort of perhaps leads, just given the limitations of the sample size does sort of leave a few unanswered questions. So one question I have is, Petr, in addition to the 40% crossover rate is obviously important as Greg pointed out. The other thing is it appears that the use of other mechanical support during the conduct of this trial was also close to 40%, about 42%. So pretty much everybody in the conservative arm ended up with some kind of mechanical support. Now, at least in the last few years, a concept that has gained a lot of traction is a concept of a shock team where a number of providers with particular expertise from different disciplines would get together and sort of decide next steps was a shock team sort of part of the decision-making, especially for the conservative arm.

Dr. Petr Ostadal:

Thank you for this question. The situation is maybe a little bit more simple in the Czech Republic here, the cardiologist are responsible for the acute cardiac care, usually competent and experience not only for the diagnosis and examinations and monitoring of patients in cardiogenic shock, but also experience in insertion and management of the mechanical circulatory support. So here this attending cardiologist competent to manage this patient from different sites from the manage not only the conservative therapy but also the mechanical circulatory support therapy in these patients. So in this respect, this is more simple situation in the Czech Republic.

Dr. Dharam Kumbhani:

I just had a very quick question about, and I don't know if you want to include this, but Petr, I was curious, were patients with cardiac arrest, I know you mentioned sky shocks in were patients with cardiac arrest on the field or in the hospital included?

Dr. Petr Ostadal:

Thank you for this excellent question. And in comparison, with other trials comparing the or focusing on patients with cardiogenic shock in the ECMO-CS trials, cardiac arrest survivors were excluded. And the reason was that the brain damage, which is the major cause of death in these patients cannot be influenced by ECMO insertion. And second, in majority of patients after cardiac arrest, if there is a presence of shock, there is frequently combined shock with important peripheral component. And again, it cannot be assumed that this peripheral component can be reversed by ECMO implantation. So in the ECMO-CS trial, the cardiac arrest survivors were excluded from that enrollment.

Dr. Greg Hundley:

Well, thank you so much Petr. Petr, what do you think is the next study to be performed really in this area of research?

Dr. Petr Ostadal:

I think that we are happy because several other clinical trials focusing on the mechanical circulatory support in patients with cardiogenic shock underway. And there are other trials focused on ECMO and trials a bit focused on combination of ECMO with balloon pump and trials focused on Impella. So I think in the very close time we will be able to see the results of these current running trials1.

Dr. Greg Hundley:

And Dharam, do you have anything to add?

Dr. Dharam Kumbhani:

No, I agree completely with Petr. I think this is a very exciting field. I know there's a lot of interest in doing well conducted clinical trials in this space. And so certainly, I think the future is bright for investigation in this field.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Petr Ostadal from Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from Dallas, Texas for bringing us this study highlighting that immediate implementation of VA-ECMO in patients with rapidly deteriorating, or severe cardiogenic shock did not improve clinical outcomes compared to an early conservative strategy that permitted downstream use of VA-ECMO in the case when the patient's hemodynamic status worsened.

Well, on behalf of Carolyn, and Peder, and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation January 31, 2023 Issue

31 januari 2023 | 44 min

Please join Guest Host Maryjane Farr, authors Sarah Franklin and Stavros G. Drakos, as well as Associate Editor Hesham Sadek as they discuss the article "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo.

Dr. Carolyn Lam:

Peder, today's featured paper is very, very important in the heart failure world. It is such a deep dive into the transcriptomic and proteomic profile that specifies heart failure and the potential of myocardial recovery with mechanical unloading and circulatory support.

Dr. Peder Myhre:

Can't wait for that feature discussion today, Carolyn.

Dr. Carolyn Lam:

But you have to wait because I insist on telling you about yet another really important paper, of course in my favorite subject, heart failure with preserved ejection fraction or HFpEF. Now you know that exercise intolerance is a defining characteristic of HFpEF and a marked rise in pulmonary capillary wedge pressure during exertion is pethepneumonic for HFpEF and it's thought to be a key cause of the exercise intolerance. Now if that is true, acutely lowering the wedge pressure should improve exercise capacity, right? Well, don't assume this because to test this hypothesis, authors led by corresponding author Dr. Ben Levine from UT Southwestern evaluated peak exercise capacity with and without nitroglycerin, which was used to acutely lower pulmonary capillary wedge pressure during exercise in patients with HFpEF.

Dr. Peder Myhre:

Oh, that's so cool. What an amazing research question and Carolyn, you're the best to summarize this. Please tell us what did they find?

Dr. Carolyn Lam:

Well, they studied 30 patients with HFpEF and get this. They underwent two bouts of upright seated cycle exercise dosed with sublingual nitroglycerin or a placebo every 15 minutes in a single blind randomized crossover design. So really well done. Wedge pressure, VO2 and cardiac output were assessed at rest with 20 watts exercise and at peak exercise during both the placebo and nitroglycerin conditions and the principle finding of the study (singing) acutely lowering pulmonary capillary wedge pressure during upright exercise with nitroglycerin in HFpEF did not improve peak exercise performance. So peak VO2 was practically identical with a 1% difference despite a 17% drop in peak wedge pressure. Peak cardiac output and peak peripheral oxygen extraction were unchanged, again, despite the drop in peak wedge pressure suggesting that oxygen delivery and utilization were unaffected. Exercise performance variables including peak wattage, peak ventilation and peak RER were unchanged, suggesting that again, reductions in peak wedge were insufficient to improve exercise tolerance.

All these results suggest acute reductions in wedge pressure are insufficient to improve exercise capacity and provide convincing evidence that a high wedge during exercise by itself is an epiphenomenon perhaps rather than a primary limiting factor for exercise performance in patients with HFpEF. Now of course this is incredibly interesting contrary to hypothesis and so please read the paper. The discussion is very rich.

Dr. Peder Myhre:

Oh wow, Carolyn. That is such a great paper. I can't wait to pick it up and read it from start to finish and now Carolyn, we're going to look into research within cardiovascular disease from COVID-19 and we have learned so much and so quickly about COVID-19 and its effects on the heart and we have really come a long way from the first case reports reported in the beginning of the pandemic and this paper, which comes to us from corresponding author Professor JP Greenwood, really adds important knowledge to this field. The COVID heart study was a prospective longitudinal multi-center observational cohort study of patients hospitalized with COVID-19 and at elevated serum troponin levels across 25 hospitals in the UK and these investigators aim to characterize myocardial injury, its association and sequela in convalescent patients following hospitalization with COVID-19 utilizing appropriately matched contemporary controls.

Dr. Carolyn Lam:

Ooh, important stuff. So what did they find?

Dr. Peder Myhre:

So these authors included in total 519 patients comprising 342 patients with COVID-19 and an elevated troponin, 64 patients with COVID-19 and a normal troponin and 113 age and comorbidity matched controls without COVID-19 and the frequency of any heart abnormality defined as left or right ventricular impairment, scar or pericardial disease was two full greater in patients with COVID positive and troponin positive, so 61% compared to the control groups and that is 36% for COVID positive and troponin negative and 31% for COVID negative and comorbidity positive and the myocardial injury pattern was different for these patients with COVID and an elevated troponin more likely than controls to have infarction and micro infarction. But there was no difference in non-ischemic scar and using the late MRI criteria, the prevalence of probable recent myocarditis was almost 7% for those with COVID and elevated troponin compared to only 2% for the controls without COVID-19 and myocardial scar is but not prior COVID-19 infection or troponin was an independent predictor of MACE.

So Carolyn, these authors discussed their findings in light of previously reported studies and these authors identified a lower prevalence of probable recent myocarditis than previously described and a higher proportion of myocardial infarction and this newly described pattern of micro infarction following COVID-19 and Carolyn, there is a brilliant editorial really summarizing this by Dr. Stuber and Baggish entitled "Acute Myocardial Injury in the COVID Heart Study Emphasizing Scars While Reassuring Scarce." I really recommend everyone to pick this up and read the editorial as well.

Dr. Carolyn Lam:

Very clever title. Thank you. For the last original paper in today's issue, it focuses on the crosstalk between sterile metabolism and inflammatory pathways, which have been demonstrated to significantly impact the development of atherosclerosis. Authors today are featuring and focusing on 25 hydroxy cholesterol, which is produced as an oxidation product of cholesterol and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. So these authors with co-corresponding authors, Dr. Suárez and Fernández-Hernando from Yale University School of Medicine, they showed beautifully that first, 25 hydroxy cholesterol accumulates in human coronary atherosclerosis. Next, that 25 hydroxy cholesterol produced by macrophages accelerated atherosclerosis progression and promoted plaque instability by promoting the inflammatory response in macrophages and also via paracrine actions on smooth muscle cell migratory responses.

Dr. Peder Myhre:

Wow, that is so interesting, Carolyn. What are the therapeutic implications of these findings?

Dr. Carolyn Lam:

Yes, I'm glad you asked because it was summarizing a lot of work in those findings with the very important implications that inhibition of 25 hydroxy cholesterol production might therefore delay atherosclerosis progression and promote plaque stability. So this study actually opens a door to explore the role of 25 hydroxy cholesterol as a target to control inflammation and plaque stability in human atherosclerosis.

Dr. Peder Myhre:

Oh, that is so important. Thank you so much and there is more in this issue as well, Carolyn. We have another issue of Circulation Global Rounds and this time we're going to France in a paper written by Dr. Danchin and Bouleti. We also have an exchange of letters by Dr. Yang and Dr. Schultze regarding the article, "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation" and an ECG Challenge by Drs. Manickavasagam, Dar and Jacob entitled "Syncope After Transcatheter Aortic Valve Implantation: Pace or Not."

Dr. Carolyn Lam:

Interesting. There's a Frontiers paper also by Dr. Dimopoulos on “Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus,” a Research Letter by Dr. Kimenai on the impact of patient selection on performance of an early rule out pathway for myocardial infarction from research to the real world. Nice. Well let's carry on to that feature discussion on heart failure, transcriptomics and proteomic, shall we?

Dr. Peder Myhre:

Can't wait.

Dr. Maryjane Farr:

Welcome everybody to Circulation on the Run. We are so pleased to be talking with Dr. Stavros Drakos and Dr. Sarah Franklin from the University of Utah. My name is Maryjane Farr and I am the heart failure section chief at UT Southwestern and Digital Strategies editor for circulation. Myself and Hesham Sadek will be talking with them about their new paper and circulation called "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients with Potential of Myocardial Recovery Upon Mechanical Unloading and Circulatory Support." Just briefly, Dr. Stavros Drakos is the director of cardiovascular research for the division of cardiology at Utah and co-director of the Heart Failure Mechanical Circulatory Support and Heart Transplant Program. Dr. Sarah Franklin is associate professor of medicine at the University of Utah whose lab has a specific expertise in the applications of proteomics to heart disease. Welcome, Stavros and Sarah.

Dr. Sarah Franklin:

Thank you.

Dr. Stavros Drakos:

Thank you. Thank you for having us.

Dr. Maryjane Farr:

This paper is exciting for clinicians. It's exciting for translational scientists. Hesham, why don't you start digging into this paper and tell us one or then the other of you tell us what this paper is about, what's the background and let's get into the science. Let's go there and then we'll pull back and look at some of the big picture stuff. Hesham.

Hesham Sadek:

Well, thank you. So I've been fascinated by the field of cardiac recovery for some time now and obviously Stavros is as an expert and one of the leaders of that field and what struck me about this is that we are starting to see some distinct molecular signature of patients that can experience recovery as opposed to patients undergoing the same procedures with the same profile that do not manifest evidence of myocardial recovery and specifically, the study was conducted very rigorously and the signature was very clear in that they saw primarily interest for someone like me who's interested in cardiac regeneration, a signature of cell cycle in the patients that experience recovery as well as ECM signature which could suggest reverse remodeling and also there's some evidence that ECM might impact cardiomyocyte and myocardial regeneration. So my interest in this for selfish reasons is primarily that this supports the hypothesis that perhaps there is a molecular signature of regeneration that occurs in patients that experience myocardial recovery with LVAD.

Dr. Maryjane Farr:

So Stavros, let's start with you. Give us the reason why to do this study. You mentioned some of the background. It'd be great to sort of talk for a moment about re-stage heart failure and then how it brought you to this study.

Dr. Stavros Drakos:

Thank you, Jane. So again, thank you for the opportunity to talk about the findings and the implications of this study. I like the way you are asking us to look a little bit at what led to this study and as you mentioned, the re-stage is a multi-center study that was performed in six US sites which showed in a reproducible fashion now given that we had single center studies from all over the world suggesting that, advanced heart failure is not an irreversible process that has to lead to end stage, an irreversible disease and what a re-stage demonstrated was that there is a subset of patients which if you select them based on clinical characteristics that we derived from other studies that were performed previously, you can achieve reverse remodeling, essentially a bad heart looking much better by every clinical, functional, structural characteristic in up to 50% of the selected patients. That's what re-stage showed.

So having this finding now in a multicenter study, what made this study very timely was to be able to understand what drives this remarkable response. What are some of the mechanisms, as Hesham said, that we can if uncover take advantage of and expand this paradigm and enhance it and achieve reverse remodeling and recovery of even more patients and even go earlier in the disease process. So that's kind of how I would link the clinical findings that preceded this study with the motivation to perform the study and the implications of these findings for the ongoing translational and basic science research.

Hesham Sadek:

I'd like to ask a question here. So Stavros, do you think it's too early to sort of redefine the term reverse remodeling in this context to include perhaps some evidence of regeneration? Is there evidence of regeneration in this field or that's too premature to say?

Dr. Stavros Drakos:

I think the data are directing us towards the direction you just mentioned. I think that we can begin talking about it and planting the seed. We do have other evidence from work that you and others have performed indicating that this indeed is one of the mechanisms that drives this phenomenon and I think that the findings, especially in the cell cycle that we identified add to and contribute even more to that body of work that you and others have done. At this point, I will turn it to Sarah who can talk a little bit more about the findings related to the cell cycle that we identified in our study and I think that these may complete the answer to you, Hesham.

Dr. Sarah Franklin:

Yeah, I would love to comment. I think it's a really interesting phenomenon and really in these patient samples we were trying to understand molecularly what the difference is between individuals that respond positively to therapy and individuals that receive the same exact therapy and do not respond positively. So these are termed responders and non-responders and in our analysis we combined two platforms where we could molecularly interrogate what's different in these two tissues and try to see what is differentiating these populations. So what's consistent and reproducible different in responders and non-responders on a molecular level and in both the transcriptomic data and the phospho proteomic data, we saw clear patterns with cell cycle regulation and extracellular matrix or focal adhesion molecules and the interesting thing about cell cycle is cardiomyocytes have typically been thought to exit the cell cycle not long after birth and we see some interesting phenomenon either in humans or mice where we can have nuclei that have either multiple sets of chromosomes or multiple nuclei and there's some differences that have been observed in the nucleus with regards to disease, so hypertrophy, heart failure.

So the molecules that we've identified, we saw a large difference in proteins involved in cell cycle regulation. Now the interesting thing is not all of those molecules are increasing or decreasing. We see a combination of molecules that are increasing or decreasing. But I think the other thing that's interesting is that these molecules, even though we are seeing changes in expression or changes in phosphorylation, exactly how that contributes to either cell cycle or cell cycle reentry or just nuclear function and transcription of proteins or genes or DNA regions is still what we need to continue to study. So exactly how these changes in proteins or transcripts related to the cell cycle, how they are exactly contributing to the physiological improvements that we're seeing is something that still needs to be investigated but is really important that that is a highlight of this study and as Stavros mentioned of previous work.

Dr. Maryjane Farr:

Stavros, tell us the design of the study.

Dr. Stavros Drakos:

Okay. So this study was performed in 93 patients that were prospectively enrolled in the Utah transplant affiliated hospitals here in Salt Lake City between the University of Utah, Intermountain Medical Center and the VA and these people came from all over the mountain west, the surrounding states of Utah and through our VA, through the state, from all over the west and south, from Alaska and Hawaii to Texas and we think it's a very representative population of our country's patient population and then we followed prospectively these people with serial echocardiograms so we can tell who will respond as Sarah said before, which essentially means which hearts are going to get better by echocardiographic criteria functionally and structurally, the dimensions of the heart shrinking and the ejection fraction improving to more than 40% and the dimension shrinking to normal range and then we compare these people, the subset of patients that have responded to the majority of patients actually that they have not responded. As we know these are advanced end stage patients and there is only a subset of those that they will favor respondents.

As we said earlier, these subset can increase if you go selectively and pick these patients based on baseline characteristics. So then we analyze the tissue we got from these people when the LVAD went in, which is the core of the apex of the heart and compare that to the tissue we receive when the patients got transplanted and we got the whole heart. So in the meantime, as we just discussed, we phenotyped these people so we knew who were responders and non-responders and then we went back in the lab and tried to marry two basic processes, analyzing the transcriptome and the proteome and by doing that we were able to see some overlapping changes between the transcriptome and the proteome and we felt that by doing this overlapping analysis, we will increase the likelihood that what we are seeing, exponential mechanistic drivers will be the real mechanism and not just associations that you can frequently find when you do studies in humans and that's kind of a rough, brief summary of the design. Sarah, would you add something to that?

Dr. Sarah Franklin:

No, I think that's a great overview of it. I think what excites me about it is that this was first clinically observed that these patients were recovering and so I think the exciting part is the hypothesis was that there was some molecular underpinnings that could molecularly define these patients that were responding or not responding and so with that hypothesis we then carried out these analyses hoping that we would see a difference and we're very excited. It's very successful in that we found very clear, molecular differences that are reproducible between these patient populations.

Dr. Maryjane Farr:

So obviously there's lots of implications. Let me start with one very simple clinical one and that is, so based on some of the differences in the signatures and pathways that you saw for the next patient who needs LVAD therapy and you're trying to predict in some way whether they may be a responder or a non-responder, could you look at a biopsy sample and try to make some sort of prediction based on some of your findings so that they can choose a VAD over a transplant? That's a very clinical question and then I guess the second question is would it have to be a left ventricular myocardial sample? So are the differences? What do you think about that question? Or it's just too much too, far beyond? This is obviously a mechanistic study. But I'm just asking.

Dr. Stavros Drakos:

No, that's a great question and I'll start and Sarah can add later. So obviously it will be great if we can have a practical way to predict before the intervention who are the people that they will respond and that's one of the motivations for this study. It was not just to find the mechanism so we can make this phenomenon better and enhance it and find the mechanism, create new therapies. It was also the practical approach that you suggested, Jane, and I think that yes, this adds to the clinical predictors that we have already identified from other studies and yes, we could theoretically take the tissue and do this analysis. Is this the most practical thing we can say to the patient to biopsy the heart, right? It would've been better to be able to identify a biomarker in the plaque and we've done that. We started in other studies, identifying what's going on in the tissue and then going targeted in the blood and that's how we identified two cytokines and a two cytokines model, interferon gamma and TNF alpha being predictive as circulating biome.

In this study we identify changes that can also inform future studies of biomarkers in the blood. But if we had a way to easily get the tissue and analyze the genes, yes, we could have done that as a predictor as well. The practical issue is that asking a patient for a biopsy just to predict the response to therapy may be something that most patients and most clinicians will consider way too advanced and complicated, right?that's why more work should and could be done to identify circulating biomarkers or other modalities that can help us interrogate what's going on in the heart related with these findings. But not that we cannot also do what you said. It's just more complicated. I don't know if Sarah would like to add to this.

Dr. Sarah Franklin:

I'd love to. I think that's a great overview. I think the only thing that I would add is that there are a number of conditions whether in the heart or otherwise in the body that you can use a single biomarker and it can be very predictive of conditions. Heart failure is so complex that often individual biomarkers are not sufficient enough to cover an entire population and all the nuances that can go into heart failure symptoms or syndromes and I think the exciting part about this study is it is one of the largest cohorts of patients that have been examined in this manner, which is exciting, but also that we have a multi-factor panel that is made up of multiple biomarkers that with the number of individuals that we examined is completely predictive of all of these patients.

So these biomarkers are consistent and reproducible across all of these patients between responders and non-responders regardless of some of the nuances in the heart failure that they have and so it's very exciting because it's possible that a multifactorial panel could be much more applicable and last the test of time more so than an individual biomarker. I think the one other thing that is exciting like Stavros mentioned is that we did initially identify these in the left ventricle and it will be really exciting to see how far these biomarkers can be used if they can be used in potentially other aspects of the heart or blood, which obviously is less invasive and so that's not something that we've applied this panel to yet, but I think is a really wonderful extension of now saying, can we also identify some of these biomarkers in the blood which would be less invasive even if it's a fraction of them. That would still be wonderful.

Dr. Maryjane Farr:

I have so many clinical questions. But Hesham, what questions do you have?

Hesham Sadek:

Yeah, so the elephant in the room here obviously is that the variable is that these patients have an unloaded heart and there is evidence that unloading can reverse some of the changes that occur after birth with increasing ventricular load and initiate cascade of molecular events that may allow myocytes to proliferate. So this begs the question, is there a difference in how these ventricles of patients that recover versus those that do not recover see load? Are we able to measure load appropriately and is there a difference in load between these patients and if so, can this be improved or detection or measuring unloading or the degree of unloading clinically, can this be improved?

Dr. Stavros Drakos:

No, that's a great question and it provides the opportunity to talk about some of the things we can do on the clinical arena to further enhance this phenomenon. Yes, there are ways that we can use to tailor the mechanical unloading that we can provide in order to enhance this phenomenon. One way, and that's a study that we are proposing, is to use sensors, pressure sensors that can guide the way you function the machines, the devices, right? The way you remove part of the load and these sensors, some of them are clinically approved like cardioments and then without doing invasive procedures you can follow chronically how these patients are being unloaded and how the heart is responding to this unloading. We know that a lot of LVAD patients, despite doing clinically well, we know this from snapshot evaluations in right-heart cath studies, they are not optimally unloaded. They are feeling pressures left and right are not always optimized and so by doing this kind of prospective assessment of the mechanical unloading, you can tailor what you offer and the hypothesis generated is that by doing that you may be able to recover even more people.

You can do this as we said, with approved sensors like cardioments or with other sensors that they are under investigation. You can also do more invasive stuff like PV loops. Of course these will require cathing these patients, which is a little bit more complicated. But it will provide more accurate assessment and it will also interrogate how the heart is improving and provide to you in-depth investigation and in-depth insights on also how the recovery process and the reverse remodeling process is being, I would say, digested by the heart and translated to functional response instead of just looking at it with an echocardiogram or the findings of a right-heart cath and these are studies that others have performed and have published and we know that they can give you a real good look into the systolic and diastolic function of the heart and how this is changing and improving down the road. So yes, that's the short answer. We can do that and we can tailor the unloading and potentially that's the hypothesis, maximize the effect that we saw here.

Hesham Sadek:

So this begs the question, maybe two questions here. One, is there evidence that patients who recover not from this study only but from other studies, is there evidence that patients who recover are more unloaded than patients that do not recover and the second question is: is it time to standardize assessment of mechanical load in patients with LVAD, especially those that will undergo or would be considered for recovery?

Dr. Stavros Drakos:

Yes. So that's a great opportunity to share with our audience what we know and what we don't know in this field in relation to your question about whether we know what is the optimum degree of unloading and the answer I think is that we need to know and understand more. What do I mean by that? There's this idea that the heart as every other organ after being unloaded and not working for some time may it lazy, may get atrophic and may need some rehab like the skeletal muscle when we put it in the cast and get atrophic and we need to rehab it when we remove the cast. So you can imagine that the LVAD and the unloading that provides, which in many cases may take over a significant part of the function of the heart may need gradual reloading as a second phase after the first phase of unloading and that's something that we've done. We have an ongoing study on this and also others have published that it may be beneficial.

Of course, it needs to be validated and investigated further and to discuss about the degree of unloading in the first phase and what is the optimum degree of unloading, I would say even there, there is room for us to understand better what's going on and I think that we can investigate with ongoing studies right now whether full unloading versus partial unloading and measure the pressures using these sensors can translate to better changes functionally and structurally. I think that's something that is very doable and it would be very beneficial. What was the second part of your question, Hesham?

Hesham Sadek:

I was asking whether it's time to start standardizing some measure of unloading if these patients are planned for recovery?

Dr. Stavros Drakos:

Yes, and that's what we are doing. In all of these people, we report from the get-go what is their recovery score based on the intermixed ICARS derived score and when we have patients that they have high likelihood of recovery, we monitor them very closely and clinically what we do is just looking at the echo and whenever we do a right heart cath for clinical reasons. But in a prospective research study we could do more than just looking at the echo and occasional right heart cath and using the sensors we just discussed previously, you can tailor the unloading and begin prospectively unloading them in a more I would say well monitored wave. Yes.

Hesham Sadek:

So this is unloading or device specific parameters. Now are there patient specific parameters with regards to type of heart failure? So we talked initially about whether there's an element of regeneration specifically when it comes to cell cycle. But many patients with non-ischemic cardiomyopathy for example, don't have large scars and don't have lot of myocytes as the underlying cause of cardiomyopathy. Would you foresee that there is different mechanisms, for example, in these patients that don't have myocyte loss, that perhaps maybe it's not cardio myocyte proliferation and not regeneration?

Dr. Stavros Drakos:

Yes. So I think that the differential responses we get based on the heart failure theology warrant further investigation. Sarah and I have discussed that and actually we are following on our findings with larger number of patients so we can tease out these and I'll let Sarah talk a little bit more about it in a minute. But to answer the clinical part of this question, we don't know yet whether different parts of heart failure should be prescribed different modes of unloading. But the way you described it of course invites the hypothesis that of course different substrates, different injuries of the heart, as you said, it's a completely different failing heart if you have a big scar there versus a patient who has a mode of heart failure, another type of injury and would this be treated better and more effectively in terms of reverse remodeling by applying a different mode of unloading? That's things that we need to investigate further. But Sarah, would you like to comment on the potential on the effect of the different heart failure theologies on some of the findings we saw?

Dr. Sarah Franklin:

Yeah, definitely. So I think it's a really interesting question and in this analysis we included ischemic and non-ischemic samples in the patient populations and really we're just stratifying them based on responders and non-responders. When we start layering additional levels onto that, then we're effectively kind of reducing the potential numbers. So if we have 25 responders and we start breaking that down into ischemic and non-ischemic to see if there's another layer of biomarkers there, we actually did that we did not include it in this study. It's something that we're working on to add that. But we do reduce the number overall of patients in those two populations. So it would be fine to share that we were seeing stratification between ischemic and non-ischemic. But we did not feel like the numbers might be high enough within the responder and non-responder categories that warrant including that in this manuscript. So it's very intriguing that just responders and non-responders alone stratify as well as they do.

They separate based on these biomarkers and it looks like it will also be possible in the future for us to even separate these samples further based on similar or additional biomarkers based on more specific factors in the etiology. So I think that will be another really exciting next step for future research.

Hesham Sadek:

My final question would be maybe a little bit broader than LVAD population, but definitely informed by this study. The term non-ischemic cardiomyopathy, do you think it's too broad and too vague for us to use in this setting because this encompasses many different types of cardiomyopathy that really are not nuanced enough by this definition.

Dr. Stavros Drakos:

Well, Jane was smiling while you were asking this question because we all as heart failure clinicians need to accept that it was not a good idea to name all of these different diseases non-ischemic cardiomyopathy when we did it or when this happened many moons ago. As you said, Hesham, and I couldn't agree more, these are completely different diseases. We need to understand them better and I think that the way we treat nowadays, chronic heart failure, many years down the road when people will look back, they will consider it a little bit, I would say, surprising that we were treating all of these the same way.

We need more studies like the one we just did, that they will have enough numbers and that's when the issue becomes that you need enough numbers to be able to tell the differences between all of these non-ischemic cardiomyopathy types, theologies and if you go upstream, motivated and inspired by findings like this, we hope that we will be able to identify how to go and do a root cause analysis and treat these diseases, not down, down, downstream the same way, but going upstream, finding what really went wrong and treating them earlier in the molecular or other pathophysiological mechanism pathway that led to the heart failure and so yes, it was a bad idea to do that. But of course sometimes we do things because we don't understand it better, right? As one of our keynote speakers here in the recovery symposium said a few years ago, Jay Khan, the founder of Heart Failure Strata of America, some things look complicated until you understand them. Then when you understand them, they look simple.

So here we don't really understand non-ischemic cardiomyopathy and how all these theologies lead there and I think studies like these can help us really inform the field better. But we will need, as Sarah said, more numbers.

Dr. Maryjane Farr:

So that was a great conversation. I wanted to just raise one last thing and that is what's so interesting about this cohort relative to re-stage heart failure is these were older patients and for re-stage heart failure, I think the average age was 35. So you would imagine there might have been one etiology for cardiomyopathy, uncontrolled hypertension or peripartum. But for cohorts in their fifties, there's probably an accumulation of different insults over many years time and so I thought that was particularly interesting from the point of view of that you were probably dealing with, again, a mixed bag of pressure overload, volume overload, maybe a genetic underpinning, whatever the life trajectory of some of these patients were and then lastly, the decision to try to go to recovery rather than to transplant, which would be the real world experience of why this wet pathway than the other. These are people truly in their fifties where they may have one or two surgeries in their lifetime left and so it's the relevant population that you're studying and so I'll leave it at that. That's a comment rather than a question, I think.

But I think for heart failure clinicians, this is why the bench to bedside piece is so relevant to understanding this because it actually does change clinical practice, even if the mechanistic pathways may take still many more years to truly understand. It helps understand what's possible from an accrued clinical decision-making level.

Dr. Sarah Franklin:

Jane, if I might just comment on that, I actually think that's one of the most exciting parts about this dataset is that, as you mentioned, these patients have complex diseases. They are older. But yet we are still able to see consistent and reproducible differences between the patient populations that respond and don't respond and to me that suggests that at the end of the day there are consistent differences or reproducible or consistent molecular changes in cardiac tissue and in response to stress and I think that that gives us hope that we could potentially not only predict who would respond or not respond, but that as we get better at understanding the differences, that there could be potential therapeutic targets or therapies that would still be beneficial regardless of the complexity of the heart failure.

Dr. Maryjane Farr:

Okay. So Sarah, Stavros, thank you so much for spending time with Hesham and myself and look forward to EUCORS--I'm allowed to say that.

Dr. Stavros Drakos:

Of course.

Dr. Maryjane Farr:

Thanks so much. Bye.

Dr. Greg Hundley:

Circulation January 24, 2023 Issue

23 januari 2023 | 30 min

Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway.

Dr. Carolyn Lam:

Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question.

Dr. Peder Myhre:

That is so interesting, Carolyn. I can't wait to hear this discussion.

Dr. Carolyn Lam:

Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis.

Dr. Peder Myhre:

Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn.

Dr. Carolyn Lam:

Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157.

How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis.

Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed.

Dr. Peder Myhre:

Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP.

Dr. Carolyn Lam:

Cool. That's interesting. So how did they do this, and what did they find?

Dr. Peder Myhre:

So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm.

And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies.

Dr. Carolyn Lam:

Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction.

Dr. Peder Myhre:

Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain.

Dr. Carolyn Lam:

I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study.

This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload.

So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh?

Dr. Peder Myhre:

Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury.

Dr. Carolyn Lam:

Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find?

Dr. Peder Myhre:

Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study.

Dr. Carolyn Lam:

Indeed.

Dr. Peder Myhre:

And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury.

Dr. Carolyn Lam:

Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature.

Dr. Peder Myhre:

And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles."

And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy."

Dr. Carolyn Lam:

Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we?

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Subodh Verma:

First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes.

Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described.

Dr. Greg Hundley:

Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population?

Dr. Subodh Verma:

So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity.

Dr. Greg Hundley:

And how many subjects did you randomize?

Dr. Subodh Verma:

So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups.

Dr. Greg Hundley:

Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results?

Dr. Subodh Verma:

So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%.

Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant.

Dr. Greg Hundley:

And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age?

Dr. Subodh Verma:

Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se.

Dr. Greg Hundley:

Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes?

Dr. Christopher Granger:

Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes.

But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure.

And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research?

Dr. Subodh Verma:

Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working.

And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further.

So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards.

Dr. Greg Hundley:

Very nice. And Chris, do you have anything to add?

Dr. Christopher Granger:

Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months.

Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation January 17, 2023 Issue

17 januari 2023 | 26 min

Please join author Pieter Martens and Associate Editor Justin Grodin as they discuss the article "Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial."

Dr. Greg Hundley:

Welcome listeners to this January 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo, in Norway. And today, Greg, we have such an exciting feature paper. It comes to us from the ADVOR trialists. And the ADVOR trial examined the effect of acetazolamide in acute decompensated heart failure. And in this paper we're going to discuss how that treatment effect was across the left ventricular ejection fraction, across the spectrum. Greg, what do you think?

Dr. Greg Hundley:

Oh, wow. Sounds very interesting. But we might have some other articles in the issue. How about we grab a cup of coffee and Peder maybe this week, I'll go first and we'll start with preclinical science. How about that?

Dr. Peder Myhre:

Let's do preclinical science, Greg.

Dr. Greg Hundley:

Well, Peder, this particular paper focuses on the relationship between cardiac fibroblasts and cardiomyocytes. Remember that myocytes sit on a lattice of network of fibroblasts. And when the myocytes die, the fibroblasts then proliferates, secrete collagen and form this thick scar. Now, if we're going to try to regenerate, how are we going to get myocytes to get back into that thick scar when there's really a complete absence?

And so as adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts synthesize extracellular matrix, post myocardial infarction to form fibrosis, leading to cardiac dysfunction and heart failure. And therapies that can regenerate the myocardium and reverse fibrosis in the setting of a chronic myocardial infarction are lacking. Now, these investigators led by Professor Masaki Ieda from University of Tsukuba, were going to evaluate this process. The overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, Han2, all combined as MGTH. They can directly reprogram cardiac fibroblasts into induced cardiomyocytes and improve cardiac function in and under the setting of an acute myocardial infarction. However, the ability of an in vivo cardiac reprogramming to repair chronic myocardial infarction with established scars, well, that is really undetermined.

Dr. Peder Myhre:

Oh, what a wonderful introduction, Greg. And the way you described to us how cardiomyocytes and fibroblasts interact was really fascinating. Thank you. And now let's hear what the authors found and don't forget the clinical implications.

Dr. Greg Hundley:

Thanks, Peder. So these authors developed a novel transgenic mouse system where cardiac reprogramming and fibroblasts lineage tracing could be regulated spatiotemporally with tamoxifen treatment to analyze in vivo cardiac reprogramming in the setting of chronic MI. Then with this new model, the authors found in vivo cardiac reprogramming generates new induced cardiomyocytes from resident cardiac fibroblasts that improves cardiac function and reduces fibrosis in chronic myocardial infarction in mice. Wow.

And additionally, they found that overexpression of cardiac reprogramming factors converts profibrotic cardio fibroblasts to a quiescent state, and that reverses fibrosis in chronic myocardial infarction. And therefore, Peder, direct cardiac reprogramming may be a promising therapy for chronic ischemic cardiomyopathies and heart failure. Really exciting work, converting scar tissue to actual functional cardiomyocytes.

Dr. Peder Myhre:

That was such a fantastic summary, Greg, and a very interesting paper. And I'm now going to take us back to clinical science and epidemiology. Because Greg, we all know that social and psychosocial factors are associated with cardiovascular disease risk. But the relative contributions of these factors to racial and ethnic differences in cardiovascular health has not been quantified. So these authors, led by the corresponding author, Nilay Shah from Northwestern University Feinberg School of Medicine in Chicago, used data from NHANES to examine the contributions of individual level social and psychosocial factors to racial and ethnic differences in population cardiovascular health. And that was measured by something called the cardiovascular health score, CVH score, which ranges from zero to 14, and it counts for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, and blood glucose.

Dr. Greg Hundley:

Wow, really interesting, Peder. So what did they find here?

Dr. Peder Myhre:

So Greg, among males, the mean cardiovascular health score was 7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic black, and 7.6 in non-Hispanic white adults. And the authors found that the education explained the largest component of cardiovascular health differences among males. And now what about females? In females, the mean score was 8.0 in Hispanic, 9.3 in non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in non-Hispanic white adults. And for women, education explained the largest competence of cardiovascular health difference in non-Hispanic black. And place of birth, and that is US born versus born outside the US, explained the largest component of cardiovascular health difference in Hispanic and non-Hispanic Asian females. So Greg, the authors conclude that education and place of birth conferred the largest statistical contributions to the racial and ethnic differences in cardiovascular health among US adults.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful description and outline that so well highlighting the differences in men versus women. Well, now we're going to turn back to the world of preclinical science, listeners. And we will continue with the paper by Dr. Amit Khera from Verve Therapeutics. Now, Peder, VERVE-101, this is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene. And that permanently turns off hepatic protein production and thereby, durably lowers LDL cholesterol. In this study, the investigators tested the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and also in a murine F1 progeny study.

Dr. Peder Myhre:

So more on PCSK9s, and this time CRISPR technology. Very exciting. Greg, what did they find?

Dr. Greg Hundley:

Right, Peder. So VERVE-101 was well tolerated in non-human primates and led to, listen to this, an 83% lower blood PCSK9 protein and 69% lowering of LDL-C with durable effects up to 476 days following the dosing. These results have supported initiation of a first inhuman clinical trial. That's what needs to come next in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Wow.

Dr. Peder Myhre:

Even greater reductions from this therapy on PCSK9 than the previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we go from one fascinating study to another. And this time we actually have the primary results from a large randomized clinical trial, Greg. Isn't that exciting?

Dr. Greg Hundley:

Yes.

Dr. Peder Myhre:

And this paper describes the primary results of a trial testing in Indobufen versus aspirin on top of clopidogrel in patients undergoing PCI with drug-eluting stent DES who did not have elevated troponin. So that is patients without mycardial infarction. And in fact, fact, this is the first large randomized control trial to explore the efficacy and safety of aspirin replacement on top of P2Y12 inhibitor in patients receiving PCI with death. And Greg, I suppose you like I wonder what Indobufen is, and I just learned that that is a reversible inhibitor of platelet Cox-1 activity and it has comparable biochemical and functional effects to dose of aspirin. And previous data indicate that Indobufen could lessen the unwanted side effects of aspirin and that includes allergy intolerance and most importantly, aspirin resistance, while it retains the antithrombotic efficacy.

Dr. Greg Hundley:

Wow, Peder. Really interesting and great explanation. Indobufen. So how did they design this trial and what were the primary results?

Dr. Peder Myhre:

So Greg, the investigators of this trial, called OPTION, led by corresponding authors, Drs. Ge, Quian, and Wu from Fudan University in Shanghai, randomized 4,551 patients from 103 center to either indobufen based DAPT or conventional, and that is aspirin based DAPT for 12 months after DES implementation. And the trial was open label and with a non-inferiority design, which is important to keep in mind. And the primary endpoint was a one year composite of cardiovascular death, non-fatal MI, ischemic stroke, definite or probable stent thrombosis or bleeding, defined as BARC criteria type 2, 3, or 5.

And now Greg, the primary endpoint occurred in 101, that is 4.5% of patients in the indobufen based DAPT group compared to 140, that is 6.1% patients, in the conventional DAPT group. And that yields an absolute difference of 1.6%. And the P for non-inferiority was less than 0.01. And the hazard ratio was 0.73 with confidence intervals ranging from 0.56 to 0.94.

And Greg, the occurrence of bleeding was particularly interesting and that was also lower in the indobufen based DAPT group compared to the conventional DAPT group. And that was 3.0% versus 4.0% with the hazard ratio of 0.63. And that was primarily driven by a decrease in BARC type two bleeding.

So Greg, the authors conclude that in Chinese patients with negative cardiac troponin undergoing DES implementation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of one year net clinical outcomes, which was mainly driven by reduction in bleeding events without an increase in ischemic events.

Dr. Greg Hundley:

Very nice, Peder. So another reversible inhibitor of platelet COX-1 activity, indobufen. And seems to be very, have high utility in individuals of Chinese ethnicity and Asian race. Well, perhaps more to come on that particular drug. Peder, how about we dive into some of the other articles in the issue? And I'll go first. So first, there's a Frontiers article by Professor Beatty entitled “A New Era and Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies and Priorities.” And then there's a Research Letter by Professor Zuurbier entitled, “SGLT-2 inhibitor, Empagliflozin, reduces Infarct Size Independent of SGLT-2.”

Dr. Peder Myhre:

And then Greg, we have a new ECG challenge by Drs. Haghighat, Goldschlager and Oesterle entitled, “AV Block or Something Else?” And then there is a Perspective piece by Dr. Patrick Lawler entitled, “Models for Evidence Generation During the COVID-19 Pandemic: New Opportunities for Clinical Trials in Cardiovascular Medicine.” And Greg, there's definitely so much to learn from all the research that has been done through the pandemic. And finally, we have our own Molly Robbins giving us Highlights from the Circulation Family of Journals. And first, there is a paper describing the characteristics of postoperative heart block in patients undergoing congenital heart surgery described in Circulation: Arrhythmia Electrophysiology. Next, the impact of socioeconomic disadvantages on heart failure outcomes reported in Circulation: Heart Failure. Then there is social and physical barriers to healthy food explored in circulation, cardiovascular quality and outcomes. And then there is the association of culprit-plaque morphology with varying degrees of infarct, myocardial injury size reported in Circulation: Cardiovascular Imaging. And finally, the impact of optical coherence tomography on PCI decisions reported in circulation cardiovascular interventions.

Dr. Greg Hundley:

Fantastic, Peder. Well, how about we get off to that feature discussion?

Dr. Peder Myhre:

Let's go.

Dr. Mercedes Carnethon:

Well, thank you and welcome to this episode of the Circulation on the Run Podcast. I'm really excited today to host this show. My name is Mercedes Carnethon. I'm an associate editor at Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm really excited to learn from the lead author of a new study on decongestion with Acetazolamide and acute decompensated heart failure across the spectrum of LV ejection fraction. And I've got the lead author with me today, Pieter Martens, as well as my colleague and associate editor Justin Grodin, who handled the paper. So I'd love to start off with just welcoming you, Dr. Martens.

Dr. Pieter Martens:

Thank you for having me. It's a pleasure to be here today.

Dr. Mercedes Carnethon:

Yes. And thank you so much for submitting your important work to the journal, Circulation. I'd love to start to hear a little bit about what was your rationale for carrying out this trial and tell us a little bit about what you found.

Dr. Pieter Martens:

So the ADVOR trial was a double blind placebo controlled randomized trial, which was performed in Belgium. And it set out to assess the effect of acetazolamide in acute decompensated heart failure and this on top of standardized loop diuretic therapy and patients with heart failure. And the goal of the current analysis was to assess whether the treatment effect of acetazolamide in acute heart failure differs amongst patients with a different ejection fraction at baseline at randomization. So we looked specifically at patients with heart failure, reduced, mildly reduced and preserved ejection fraction to determine whether acetazolamide works equally well in those patients.

Dr. Mercedes Carnethon:

Well, thank you so much. Tell me a little more. What did you find? Did your findings surprise you?

Dr. Pieter Martens:

All patients that were randomized in the ADVOR trial, we registered a baseline left ventricular ejection fraction at baseline. And what we saw was at the multiple endpoints that we collected in the ADVOR trial, that randomization towards acetazolamide was associated with a pronounced and preserved treatment effect. And different endpoints that we looked at was a primary endpoint which was successful, which is an important endpoint, which we all strive towards in acute decompensated heart failure. And we saw that irrespective of what your baseline ejection fraction was, that randomization towards acetazolamide was associated with a higher odds ratio for having successful decongestion.

And also looking at other endpoints which we find important in the treatment of patients with acute compensated heart failure, such as renal endpoints such as the diuresis, the amount of urine that they make, or the natruresis, the amount of sodium that they excrete, we again saw that randomization towards acetazolamide was associated with a higher treatment effect, so more diuresis, more natruresis, which was not effective, whether you had heart failure, reduced, mildly reduced or preserved eject fraction. We did see a slight increase in the creatinine, which was a little bit more pronounced in patients with heart failure with reduced ejection fraction.

Dr. Mercedes Carnethon:

Thank you so much for that excellent summary. I'm an epidemiologist, so I'm certainly aware that of the cardiovascular diseases and their changes over time, heart failure is one that is going up over time and affecting more of the population. So I know I really enjoyed hearing about an additional therapy that helps to improve quality of life and improve clinical outcomes in individuals who are experiencing heart failure. And I'm really curious as I turn to you, Justin, what attracted you to this particular article and why did you find it to be such a good fit for our audience here at Circulation?

Dr. Justin Grodin:

Well, Mercedes, I mean, I think you hit the nail on the head with your comment. And clearly when we look at Medicare beneficiaries in the United States, hospitalization for decompensated heart failure is the number one or most common cause for hospitalization. And up to this time, we really haven't had any multi-center randomized control clinical trials that have really informed clinical care with a positive result or a novel strategy that says, "Hey, this might be a better way to treat someone in comparison with something else."

And so when we have a clinical trial like ADVOR, one of the crucial things that we want to understand is how does this work and does it work for everybody? And now when we look at the population hospitalized with heart failure, we know that approximately half of them have a weak heart or low ejection fraction, and the other half have a stiff heart, a normal ejection fraction. And so since we've got this 50/50 makeup, it is a crucially important question to understand if we have an important study like ADVOR, does this apply? Are these benefits enjoyed by all these individuals across the spectrum?

Dr. Mercedes Carnethon:

Thank you so much for really putting that in context. And I believe you had some additional questions for Dr. Martens.

Dr. Justin Grodin:

Yes. Yeah, thank you. So Pieter, I mean obviously this was a terrific study. One question I had for you guys is, you and your colleagues and the ADVOR research team is whether you had expected these results. Because we know at least historically, that there might be different cardiorenal implications for individuals that have a weak heart or heart failure with reduced ejection fraction in comparison with a stiff heart or heart failure with preserved ejection fraction.

Dr. Pieter Martens:

Thank you for that comment. And thank you also for the nice feedback on the paper. I think we were not really completely surprised by the results. I think from a pathophysiologic perspective, we do wonder whether heart failure with reduced ejection fraction from a kind of renal perspective is different from heart failure with preserved ejection fraction. Clearly, there are a lot of pathophysiological differences between heart failure with reduced, mildly reduced and preserved ejection fraction. But when it comes to congestion and acute heart failure, they seem to behave, or at least similarly in terms of response to acetazolamide, which was very interesting. We do think there are neurohormonal differences between heart failure reduced ejection fraction, preserved ejection fraction. But at least how acetazolamide works seems relatively unaffected by the ejection fraction.

Dr. Justin Grodin:

And Pieter, another question that comes to mind, and this is getting a little bit technical, but there have been studies that have shown that people that present to the hospital with decompensated heart failure, that have HFpEF, have a very different perhaps congestion phenotype where they might not have as much blood volume expansion. And so I, for one, was pretty curious as to how these results were going to play out. And I wonder what your thoughts are on that, or maybe that's perhaps more niche and less widely applicable than what you observed.

Dr. Pieter Martens:

Now, I can completely agree that when we are thinking about congestion, the congestion itself is a sort of pressure based phenomenon. And the pressure based phenomenon is based on what your volume is and the compliance within your cardiovascular system. But I think one of the important things to remember is that how we enrolled patients in the ADVOR trial was that we enrolled patients who had clear signs of volume overload. Remember, we used a volume score to assess clinical decongestion or actually getting rid of the volume. Volume assessment isn't really necessarily a pressure based assessment. And pressures might be the genesis of elevated pressures might be different amongst heart failure with reduced versus preserved ejection fraction.

But what was really clear was that all these patients were volume overloaded. And when you think about the volume axis, then it's really about getting rid of that additional sodium, water, and that's where really acetazolamide works. So I do think we differ a little bit from historical acute decompensated heart failure trials in which they sometimes use signs and symptoms of more congestion, a pressure based phenomenon, where our endpoint was truly at volume endpoint. And we do believe that diuretics work really on a volume component of heart failure.

Dr. Mercedes Carnethon:

Thank you so much, especially for explaining that in a way that even non-clinicians such as myself can understand the potential implications. A big picture question that I have, and I really enjoy these discussions because they give us an opportunity to speculate beyond what we read in the paper. And that question is we do clinical trials and we identify effective therapies. And one of the bigger challenges we often face is getting those therapies out to the people who need them. Do you perceive any barriers in uptake of the use of acetazolamide in clinical practice?

Dr. Pieter Martens:

That's an excellent question. So one of the, I think beauties about acetazolamide is that this drug has been on the market for about 70 years. So I think everybody has access to it. This is not a novel compound which needs to go through different steps of getting marketing approval and getting a sort of reimbursement before it becomes available in clinical practice. And in theory, everybody should have access to this relatively cheap agent and can use it in its clinical practice. And I think it was very interested when we came out with the initial paper. I think already the day afterwards, we were getting messages from across the world that people have been using acetazolamide. So I think it is an agent which is available in current clinical practice and should not be too many barriers to its current implementation and clinical practice.

Dr. Mercedes Carnethon:

Well, that's fantastic to hear. So I hope Justin, that you will certainly help to ring the bell to get the information out about this wonderful study. I do want to turn to you, Pieter, to find out whether or not there are any final points that you didn't have an opportunity to discuss with us today.

Dr. Pieter Martens:

Think some of the other end points we didn't discuss were the effect, for instance, on length of stay. I think length of stay is a very important endpoint because hospital admissions, like Justin said, heart failure is the number one reason why elderly patients are being admitted. And just shortening the length of stay from a financial perspective might be important. So it was also very interesting to see that the use of acetazolamide in the study also translated into a shorter length of stay, which was also was unaffected, whether you had heart failure, reduced, mildly reduced or preserved ejection fraction,

Dr. Mercedes Carnethon:

Well, I certainly know people appreciate being in their own homes and being able to discharge is certainly a major benefit. So thank you so much for sharing that final point. I really want to thank you so much for a stimulating discussion today. I know that I learned a lot from you, Pieter, and the hard work of your research team as well as from you, Justin, for putting these findings in context and really helping our listeners and the readers of our journal understand why this paper is so important and how it's really moving the field forward for a clinically important problem. So thank you both so much for joining us here today on Circulation on the Run.

Dr. Justin Grodin:

Thank you.

Dr. Pieter Martens:

Thank you for having me.

Dr. Mercedes Carnethon:

I really want to thank our listeners for joining us today for this episode of Circulation on the Run. I hope you will join us again next week for more exciting discussions with our authors.

Dr. Greg Hundley:

Circulation January 10, 2023 Issue

9 januari 2023 | 25 min

Please join authors Loren Field and Sean Reuter, as well as Associate Editor Thomas Eschenhagen as they discuss the article "Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity But Not Cardiomyocyte Proliferation."

Dr. Greg Hundley:

Welcome listeners, to this January 10th issue of Circulation on the Run, and I am Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, listeners, this week's feature discussion delves into the world of preclinical science and evaluates cardiac troponin I and its impact on S phase activity in cardiomyocytes, and does that relate to cardiomyocyte proliferation. But before we get to that, how about we grab a cup of coffee and Peder and I will work through some of the other articles in the issue. Peder, how about this week I go first?

Dr. Peder Myhre:

Go ahead, Greg.

Dr. Greg Hundley:

Right. So Peder, this first study evaluated whether the burden of positive coronary artery calcification on cardiovascular disease differed by multidimensional individual characteristics, and so the investigators led by Dr. Kosuke Inoue from Kyoto University sought to investigate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease. And so Peder, to examine this question, the authors implemented a cohort study design that included adults aged greater than 45 years, free of cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis, or MESA, and after propensity score matching in a one-to-one ratio, they applied a machine learning causal forest model to, first, evaluate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease and then, second, to predict the increase in cardiovascular disease risk at 10 years when the coronary artery calcium score was greater than zero, so versus is it zero at all at the individual level?

Dr. Peder Myhre:

Oh, Greg, that is so cool, so using machine learning for coronary artery calcium and risk prediction, I'm very excited. What did they find?

Dr. Greg Hundley:

Right, Peder, so the expected increases in cardiovascular disease risk when the coronary artery calcium score was greater than zero were heterogeneous across individuals. Moreover, nearly 70% of people with low atherosclerotic cardiovascular disease risk showed a large increase in cardiovascular disease risk when the coronary calcium score was greater than zero, highlighting the need for coronary artery calcium screening among such low-risk individuals. And Peder, future studies are really needed to assess whether targeting individuals for coronary artery calcium measurements based on not only the absolute ASCVD risk, but also the expected increase in CVD risk when a CAC score is greater than zero and whether that improves overall assessment of cardiovascular outcomes.

Dr. Peder Myhre:

Wow, that is so clinically relevant and very interesting. And we're actually going to stay clinically relevant with the next paper which is about anti-platelet therapy after PCI. And this paper describes the long-term results of the HOST-EXAM trial. To remind you, Greg, the HOST-EXAM trial was an investigator-initiated prospective, randomized, open label, multicenter trial done at 37 sites in Korea. They enrolled patients who had undergone PCI with DES and maintained dual anti-platelet therapy without any clinical event for a mean 12 months and then they were randomized one to-one to either clopidogrel, 75 milligrams once daily, or aspirin, 100 milligram once daily. The primary results of this trial was published in Lancet in 2021 and showed superiority of clopidogrel over aspirin in prevention of the composite of MACE and major bleeding during 24 months of followup. And then, through the current paper, this describes the results of the post trial extended followup of about five years.

Dr. Greg Hundley:

Very nice, Peder, so aspirin versus clopidogrel and looking at the maintenance of that monotherapy and cardiovascular outcomes. Wow, so what did they find?

Dr. Peder Myhre:

Yeah, Greg. They, in this extended followup study, had a total of 5.8 years median followup, and the primary endpoint occurred in 12.8% in the clopidogrel group versus 16.9% in the aspirin group, and that has a range of 0.74 with a 95% conference interval ranging from 0.63 to 0.86. So also the clopidogrel group had lower risk of the secondary thrombotic endpoint and the secondary bleeding endpoint while there was no significant difference in the incident on all caused death. So Greg, to conclude, these very interesting results from the primary analysis of the HOST-EXAM trial was consistent through the longer followup, and this support the use of clopidogrel over aspirin monotherapy from 12 months onwards after PCI.

Dr. Greg Hundley:

Very nice Peder, beautiful description and sounds like long-term clopidogrel use over aspirin was quite beneficial. Well, the next study comes to us from the world of preclinical science, and it is from the investigative group led by Dr. Yunzeng Zou from Shanghai Institute of Cardiovascular Diseases and the Zhongshan Hospital and Fudan University. Peder, the study pertains to diabetes. So diabetic heart dysfunction is a common complication of diabetes mellitus and cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise intervening time of particular cell death type remained largely unknown in diabetic hearts. And so, Peder, this study aimed to identify the particular cell death type that is responsible for diabetic heart dysfunction and propose a promising therapeutic strategy by intervening in this cell death pathway.

Dr. Peder Myhre:

Wow, Greg, that is really interesting. Heart dysfunction in diabetes is something that we really have to learn more about and I'm so excited to hear what these authors found, Greg.

Dr. Greg Hundley:

Right. So first, Peder, the authors identified necroptosis as the predominant cell death type at later stages in the diabetic heart. And then second, Peder, the CB2 receptor, and we'll call that CB2-R, recruits transcription factor Bach2 to repress necroptosis and protects against diabetic heart injury while hyperglycemia and MLKL in turn phosphorylates CB2-R to promote ubiquitous dependent degradation of CB2-R, thus forming a CB2-R centric feedback loop of necroptosis. And finally, Peder, cardiac CB2-R or Bach2 expression negatively correlates with both MLKL 10 expression and the extent of diabetic heart injuries in humans. And so the clinical implications of these findings, Peder, are that the CB2-R centric necrotic loop represents a promising target for the clinical treatment of diabetic heart injuries.

Dr. Peder Myhre:

So Greg, this paper that comes to us from corresponding author Amanda Paluch from University of Massachusetts Amherst, is a meta-analysis of eight prospective studies with device measured steps including more than 20,000 adults who were followed for CVD events. And the mean age of participants in this study was 63 years and 52% were women. And the participants were followed for a median of 6.2 years and 1,523 cardiovascular events occurred.

So first, Greg, there was a significant difference in the association of steps per day in cardiovascular disease between older, that is greater or equal to 60 years, and younger, that is less than 60 years adults. So for older adults that has the ratio for cardiovascular disease using Q1 as reference was 0.80 for Q2, 0.62 for Q3, and 0.51 for Q4. And for younger adults that has ratio for cardiovascular disease using Q1 as reference was 0.79 for Q2, 0.90 for Q3, and 0.95 for Q4. And in the paper, Greg, there are some beautiful, restricted cubic lines that really illustrate the association between daily steps and the risk of cardiovascular disease among older adults and in younger adults.

So the authors conclude that for older adults taking more daily steps is associated with a progressively lower risk of cardiovascular disease. And monitoring and promoting steps per day is a simple metric for clinician patient communication and population health to reduce the risk of cardiovascular disease.

Dr. Greg Hundley:

Well, Peder, we've got some other very interesting articles in this issue and how about we dive into that mail bag and discuss a few of those. So I'll go first. The first is a Perspective piece by Professor Powell-Wiley entitled “Centering Patient Voices through Community Engagement in Cardiovascular Research.” A very important topic where can those in the community actually help us design meaningful outcomes for our research initiatives? And next Peder, there is a Research Letter from Professor Evans entitled “Increasing Mononuclear deployed Cardiomyocytes by Loss of E2F7/8, and does that fail to improve cardiac regeneration post myocardial infarction?”

Dr. Peder Myhre:

Thanks, Greg. We also have an ECG Challenge by Dr. Li entitled, “What Is The Truth Behind Abnormal ECG Changes?” And this is describing a very rare and interesting cause of ST segment elevation. I recommend everyone to read that case. We also have our own Nick Murphy who gives us the Highlights from the Circulation Family of Journals where he summarizes five papers from the Circulation subspecialty journals. First, the experience with a novel visually assisted ablation catheter is reported in circulation A and E. The impact of various exercise training approaches on skeletal muscle in heart failure with preserved the F is presented in circulation heart failure. Gaps in heart failure treatment over a decade are reported in circulation cardiovascular quality and outcomes, and the associations of machine learning approaches to plaque morphology from coronary CTA with ischemia are reported in circulation cardiovascular imaging. And finally, Greg, an observational study of left main PCI at sites with and without surgical backup is reported in circulation cardiovascular interventions. Let's go on to the feature paper today describing the cardiac troponin I interacting kinase and the impact on cardiomyocyte S phase activity.

Dr. Greg Hundley:

Great, let's go.

Welcome listeners to this January 10th feature discussion. Very interesting today as we are going to delve into the world of preclinical science. And we have with us today Dr. Loren Field and Dr. Sean Reuter from University of Indiana in Indianapolis, Indiana. And our own associate editor, Dr. Thomas Eschenhagen from University Medical Center of Hamburg in Hamburg, Germany. Welcome gentlemen. Well, Loren, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Loren Field:

Sure. This study actually came about in a rather roundabout fashion. We were doing a study with Kai Wollert in Hanover, Germany, where we were looking at the impact of a CXCR4 antagonist, which is used to mobilize stem cells from the bone marrow. And we had sent our mice over to Kai's lab and we have a mouse model that allows us to track S phase activity in cardiac myocytes, so these are cells are starting to replicate. And Kai crossed them into a different genetic background. And when he sent the mice back to us to analyze the hearts, we observed that we saw things that we never saw before in our experiments here.

His injury model was different than ours and now the mouse also had a genetic background, so we had to spend about a year to figure out if it was the injury model or the background. It turned out to be the genetic background, and the phenotype was these mice had about a 15-fold elevated level of cell cycle reentry. So then it became a relatively simple genetics game where we took the progenitor mice, made F1 animals, looked for the phenotype, did backcross animals, and basically identified the gene responsible for the phenotype.

Dr. Greg Hundley:

Very nice. And so in this study moving forward, what hypothesis did you want to address?

Dr. Loren Field:

Well, the main hypothesis was to figure out what the gene was and then secondarily to figure out the degree of cell cycle progression. When the cell is proliferating, the first task is to replicate its genome, which is S phase activity that's followed by the nuclei dividing and then finally by the cell itself becoming two cells. So our task was to identify, first, the gene and secondly, how far through the cell cycles the cells progressed.

Dr. Greg Hundley:

Very nice. And how did you construct your experiment?

Dr. Loren Field:

It was, again, very straightforward. It was simply setting up the appropriate genetic crosses to produce the animals. For the past 10, 15 years, we've been developing a computer assisted assay that allows us to identify the anatomical position of S phase positive cardiac myocytes in sections of the heart. And basically, we apply that program to the different genetic backgrounds and after that it's a ball of mapping studies, QTL mapping.

Dr. Greg Hundley:

So really mechanistic understanding. Well listeners, we're next going to turn to Sean, and Sean, can you describe for us your study results?

Dr. Sean Reuter:

Yes, as Loren stated, we saw a 15-fold increase in the S phase activity within the remote zone. Now we partition the heart in three different zones after injury, so the scar, the border zone, and then the remote zone or injury. And as Loren stated, we saw a 15-fold increase in the S phase activity, cell cycle activity, in the remote zone. And it's only because we have this system in hand that we can anatomically map the S phase activity within the heart that we were able to detect and also quantify this. And I think that's the reason we discovered this particular phenotype. But in addition to that, we performed RNA-seq or Exome sequencing and discovered that TNNI3K was the responsible gene for elevated S phase activity within the remote zone and border zone, but interestingly not in the scar.

Dr. Greg Hundley:

Very interesting, Sean, and so describe for us the importance of the TNNI3K and its relationship to this S phase.

Dr. Sean Reuter:

Sure. This particular gene was first discovered around 2000, and it's been studied for a while now, but the targets of this kinase specifically expressed in the heart, and it does get elevated after injury, but the actual targets are not well described or well known. It's believed that it phosphorylates some mild filament fibers and structural proteins, but the actual mechanism and the consequence of this is not known. So when we saw this in the remote zone, the elevated S phase, our current theory is that we believe that it's probably increasing oxidative stress that would basically further out from the at-risk zone or the border zone and then it now is in the remote zone. So we think it's just causing the heart, a pathological area of the heart, basically to expand. And so that's our current theory. Other groups have published on the oxidative stress in over expression of TNNI3K as well.

Dr. Greg Hundley:

Very nice. Well listeners, next we are going to turn to our associate editor, Thomas many articles come your way and come across your desk. What attracted you to this particular article, and how do we put its results really in the context of cardiac regeneration?

Dr. Thomas Eschenhagen:

Indeed, there were several arguments. It's a cool paper and the whole field is still very important. As probably most of you know, the field have a rough ride over the last 20 years, went up and down, lots of bad findings. And in the end it turns out that we are there where we have been 20 years ago, the mammalian heart essentially doesn't regenerate. So anything which would improve that would be of very major importance. Why is it a good paper? Because it starts from a very clear finding, one mouse, which looks like strongly regenerating after MI, another mouse line, which doesn't. And so by applying, let's say, classical genetic, very stringent methodology, Loren Field and his group identified this troponin I kinase to be the culprit. And they also proved it, because putting it back in the strain with a low, so-called, regeneration brought it back to the other level. So it's a very clear, nice methodology.

And finally, it's also a bit provocative because others in a very prominent paper, actually, have shown that this kinase... Or they concluded more or less just the opposite. The reason for the discrepancy is not quite clear and I was very happy to learn that the two groups actually discussed about it. So it's not just a bad controversy, but something which brings forward science.

And finally, I think something we didn't talk about yet today, what I particularly liked, maybe the most, on this paper is that this group didn't stop at the point of DNA synthesis. Everybody else would've probably said, "Okay, here we are, one regenerate the other doesn't." But in the very important extra finding of this paper is that this is just increased DNA synthesis and not more myocytes. And this distinction is so critical to the field because people forget that adult mammalian cardiomyocytes often have several nuclei and individual nuclei have more than one set of chromosomes, so this polyploid. And so if you see DNA synthesis like in this paper, it doesn't necessarily mean more myocytes. And actually here it was shown that it is not more myocytes but more polyploidization and making this difference so clear, I think it's a very important contribution to the field.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn back to each of our guests today and we'll start with you Loren. Based on your results, what do you see as the next study moving forward in this sphere of research?

Dr. Loren Field:

I think these results made me appreciate for the first time that the intrinsic level of cell cycle reentry, that's just the S phase, not the cell division, is actually much higher than I had thought previously. And this was because we just fortuitously, or I guess anti-fortuitously, we're using a strain that had low levels of S phase induction. If you calculate the turnover, if every nucleus that it synthesized DNA actually went on to have that cell divide, you could replace a 50% loss of myocytes over the course of about 550 days, give or take. And to me, that's actually telling me that if we could push those cells from just being polypoid, as Thomas was saying, to actually go through cytokinesis, there would be enough intrinsic activity to go forward. So this really tells me that what we should be focusing on is now not trying to induce cell cycle, but to allow the cells that are entering the cell cycle to actually progress through it.

Dr. Greg Hundley:

Very nice. And Sean?

Dr. Sean Reuter:

Yes, well, echoing Loren's point there, it's really not necessarily cell cycle induction, it's cell cycle completion to the cytokinetic fate. And that's the key. If we can get to that point, if we can figure out the mechanism to get to that point, then we have a wonderful discovery. However, we're not quite there yet, but we hope to be.

Dr. Greg Hundley:

And Thomas.

Dr. Thomas Eschenhagen:

Well, nothing to add really from my side, except that I would like to know what this Troponin I kinase does, because that is somehow still a missing link. How does this kinase lead to more DNA synthesis or the initiation of cell cycling? That would be an important finding and I'm sure there will be more research going on. Particularly also, to solve this discrepancy, I mean, there must be something in it and we don't quite yet know how, but I think we are in a good way. I'm sure there will be papers showing that soon. So I think that's, again, a very good start for this discussion.

Dr. Greg Hundley:

Well, listeners, we want to thank Dr. Loren Field, Dr. Sean Reuter and Dr. Thomas Eschenhagen for bringing us this really informative study in mammalian myocellular regeneration, highlighting that the level of cardiomyocyte cell cycle reentry in hearts expressing TNNI3 kinase would lead to significant regenerative growth if each cardiomyocyte exhibiting S phase activity was able to progress through cytokinesis. And this in turn suggests that identification of factors which facilitate cardiomyocyte cell cycle progression beyond S phase will be key to unlocking the intrinsic regenerative capacity of the heart.

Well, on behalf of Carolyn, Peder and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation January 3, 2023 Issue

3 januari 2023 | 27 min

This week, please join author Judith Hochman, Editorialist Steven Bradley, and Guest Host Mercedes Carnethon as they discuss the article " Survival After Invasive or Conservative Management of Stable Coronary Disease" and editorial “If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.”

Dr. Greg Hundley:

Welcome everyone to our new year 2023, and we are here on this January 3rd edition of Circulation on the Run. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I am Dr. Peder Myhre, Social Media Editor and doctor at the Akershus University Hospital and University of Oslo.

Dr. Greg Hundley:

Very nice. Well, welcome listeners and this week's feature, ah, very interesting. You know many times patients with stable coronary artery disease, we're seeing a lot in the literature about an invasive strategy versus a conservative strategy. But what happens long term for these patients? What's their prognosis? Well, more to come in the feature discussion. But first, how about we grab a cup of coffee and we discuss some of the other issues in this session. Peder, would you like to go first?

Dr. Peder Myhre:

Yes, Greg I would love to and the first paper today is very interesting and relates to one of the most important challenges globally, namely climate changes and extreme temperatures. And in this paper, which comes to us from corresponding author, Barrak Alahmad from Harvard Chan School of Public Health in the United States, together with a large international group of authors, investigated the associations between extreme temperatures and cardiovascular cause-specific mortality in 567 cities in 27 countries from 1979 to 2019.

Dr. Greg Hundley:

Wow Peder, that is a really large comprehensive study. So, how did they perform this analysis? What did they find?

Dr. Peder Myhre:

So Greg, the investigators collected city-specific daily ambient temperatures from weather stations and analyzed cause-specific cardiovascular mortality and excess deaths in association with extreme hot and extreme cold temperatures. And in total, the analysis included more than 32 million deaths from any cardiovascular cause, which were subdivided into deaths from ischemic heart disease, stroke, heart failure and arrhythmia and at extreme temperature percentiles. And that is defined as heat above the 99th percentile and as cold below the first percentile were associated with a high risk of dying from any cardiovascular cause, ischemic heart disease, stroke and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality.

And Greg, across a range of extreme temperatures, hot days above the 97.5 percentile and cold days below the 2.5 percentile accounted for more than two and more than nine excess deaths for every thousand cardiovascular death respectively. And heart failure was associated with the highest excess death proportions from extreme hot and cold days. So Greg, it seems like extreme temperatures really impact the cardiovascular mortality across the globe.

Dr. Greg Hundley:

Yeah, beautiful description Peder. And I think what was really exciting about that particular article is you had results from 27 countries. Wow, so really quite a global study and very informative.

Dr. Peder Myhre:

Yes, indeed very impressive.

Dr. Greg Hundley:

Well, Peder my next study comes to us from the world of preclinical science. And Peder, these investigators led by Professor Jose Luis de la Pompa from CNIC, evaluated two structural cardiac diseases, left ventricular non-compaction and bicuspid aortic valve. And they wanted to determine if those two conditions were caused by a set of inherited heterozygous gene mutations affecting the notch ligand regulator, Mind bomb-1 and co-segregating genes.

Dr. Peder Myhre:

Okay Greg, so we are looking at mechanisms for non-compaction and bicuspid aortic valve. What did they find?

Dr. Greg Hundley:

Right Peder, so whole exome sequencing of the left ventricular non-compaction families identified heterozygous missense mutations in five genes co-segregating with E3 ubiquitin protein ligase-1 Mib-1 as well as left ventricular non-compaction. And corresponding mouse models showed that left ventricular non-compaction or bicuspid aortic valve in a notch-sensitized genetic background. Now, also gene profiling showed that increased cardiomyocyte proliferation and defective morphological and metabolic maturation in mouse hearts and human pluripotent stem cell cardiomyopathy. Biochemistry suggested a direct interaction between notch and some of the identified gene products.

And so, these data Peder support a shared genetic basis for left ventricular non-compaction and bicuspid aortic valve with Mib-1 notch playing a crucial role. And thus, identification of heterozygous mutations leading to left ventricular non-compaction or bicuspid aortic valve may allow us to expand the genetic testing panel repertoire for better diagnosis and or risk stratification of both of these conditions, left ventricular non-compaction and bicuspid aortic valve.

Dr. Peder Myhre:

All right, that is really great and novel linking left ventricular non-compaction to bicuspid aortic valve, really great. And now Greg, we're going to go back to clinical science and we're going to talk about lipoprotein(a) or Lp(a). And as you know, elevated Lp(a) is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. And the authors of this next paper coming to us from corresponding author Olli Raitakari from University of Turku in Finland, examined Lp(a)'s potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease, ASCVD. And they did this by measuring Lp(a) in youths nine to 24 years old and linking that to a diagnosis of ASCVD as adults and also linking it to carotid intermediate thickness in the Young Finns Study. And in addition, these results were validated in the Bogalusa Heart Study.

Dr. Greg Hundley:

Oh, very nice Peder. So, what did they find?

Dr. Peder Myhre:

So Greg, those who have been exposed to high Lp(a) levels in youth and that was defined as greater than or equal to 30 milligrams per deciliter, had about two times greater risk of developing adult ASCVD compared to non-exposed individuals. In fact, all the following youth risk factors were independently associated with a higher risk. Lp(a), LD, cholesterol, body mass index and smoking all independently associated with ASCVD. And similar findings were made in the validation cohort who were participants with a high Lp(a) had 2.5 times greater risk of developing adult ASCVD compared to non-exposed individuals. And this also persisted in adjusted models. Now, what about the carotid intermediate thickness? In that analysis, there were no associations detected to youth Lp(a) levels in either of the cohorts.

Dr. Greg Hundley:

Very nice, Peder. So, great description of the utility of lipoprotein(a) measurements in the youth and for predicting future major cardiovascular events. Well, the next paper goes back to the world of preclinical science. And Peder, cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum. Now, these misfolded proteins can be removed via the adaptive retro-translocation, poly-ubiquitylation and a proteasome mediated degradation process. The endoplasmic reticulum-associated degradation, ERAD, which altogether as a biological process and rate has not been studied in vivo.

So, these investigators led by Dr. Christopher Glembotski from University of Arizona College of Medicine, investigated the role of ERAD in a pathophysiological model and they examined the function of the functional initiator of ERAD, VCP-interacting membrane protein and positing that the VCP-interacting membrane protein would be adaptive in pathological cardiac hypertrophy in mice.

Dr. Peder Myhre:

Thanks Greg. So, we're talking about degradation of the endoplasmatic reticulum and the association to hypertrophy. So, what did these investigators find, Greg?

Dr. Greg Hundley:

Right, Peder. So, this was really the first study to demonstrate that endoplasmic reticulum-associated protein degradation or ERAD is responsible for degrading and thus, regulating the levels of a cytosolic non-endoplasmic reticular protein. The results reported here describe a new mechanism mediating the pathological growth of the heart, such that in the healthy heart SGK-1 levels are low due to ERAD-mediated degradation. While in the setting of pathology, ERAD-mediated degradation of SGK-1 is disrupted, allowing the pro-growth kinase to accumulate and contribute to pathological cardiac hypertrophy.

And so Peder, the clinical relevance of these findings is that the investigators found that a variety of proteins that constitute the ERAD machinery were decreased in both mouse and human heart failure samples while SGK-1 was increased, supporting the possibility that SGK-1 is a contributor to the disease phenotype. And this is notable and that these studies could lead to the development of new therapeutic approaches for managing pathological cardiac hypertrophy and heart failure that target the ERAD to restore efficient SGK-1 degradation.

Dr. Peder Myhre:

That was an excellent explanation of a very difficult topic. Thank you, Greg.

Dr. Greg Hundley:

Well, Peder how about we take a look and see what else is in the issue? And now I'll go first. Well, first there's an In Depth by Professor Ntsekhe entitled, "Cardiovascular Disease Among Persons Living with HIV: New Insights into Pathogenesis and Clinical Manifestations within the Global Context." And then, there's a Research Letter by Professor Verma entitled, "Empagliflozin in Black Patients Versus White Patients With Heart Failure: Analysis of EMPEROR results-Pooled."

Dr. Peder Myhre:

Great Greg and there is an On My Mind by Gabriel Steg entitled, "Do We Need Ischemia Testing to Monitor Asymptomatic Patients With Chronic Coronary Syndromes?" Very timely and interesting. And finally, there is an AHA Update from Michelle Albert, the President of the AHA entitled, "Tackling Adversity and Cardiovascular Health: It is About Time."

Dr. Greg Hundley:

All right. Well Peder, how about we get onto that feature discussion looking at survival after invasive or conservative management in stable coronary heart disease?

Dr. Mercedes Carnethon:

Thank you so much for joining us for this episode of Circulation on the Run. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. And I'm very excited today to have as a guest, Dr. Judith Hochman, who is going to be discussing the long-awaited findings from the ISCHEMIA-EXTEND trial that are looking at survival after invasive or conservative management of stable coronary disease. Really pleased to have you with us today, Judy to hear about these findings.

Dr. Judith Hochman:

It's a pleasure to be here.

Dr. Mercedes Carnethon:

Thank you. So, just to start off, can you tell us about this study? What motivated this long-term follow-up of this particular trial?

Dr. Judith Hochman:

Yeah, so as I think the viewers or the listeners will recall, we built on a wealth of data from COURAGE and BARI 2D, some of the landmark trials that looked at revascularization versus optimal medical therapy or guideline-directed medical therapy alone. We tested an invasive strategy versus a conservative strategy dating back already to 2012 is when we started. And we had a five component primary outcome, which included cardiovascular death, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. And at the end of 3.2 median years of follow-up, we saw no difference in the primary outcome in that the curves crossed with some excess risk upfront due to periprocedural MI and decreased risk of spontaneous MI long-term. But the net overall timeframe spent free of event was similar between the groups.

So, we did observe improved quality of life for the invasive strategy, but in terms of clinical outcomes there was no difference. So, cardiovascular death at the end of that time period was no different between the groups, all-cause mortality was no different, non-cardiovascular death, there was actually an increase in the invasive group, which was somewhat of a mystery. We can get into that a little bit later because I think that becomes important. But 3.2 years meeting and follow-up is relatively short. So, everyone was very interested in what would the long-term outcomes be. So, we had another grant from the National Heart, Lung and Blood Institute to follow these patients long-term. And this is an interim report with seven years of follow-up, a median of 5.7 years.

And the bottom line is that all-cause mortality was the same at seven years but for the first time, an invasive strategy resulted in lower cardiovascular mortality, which was very interesting and very exciting except that it was offset, exactly offset by the continued excess that we had previously observed in non-cardiovascular mortality. And that's basically the upshot of what we just reported and why we continue to follow patients and why we're going to continue to follow patients and have a final report in 2026.

Dr. Mercedes Carnethon:

This is really fantastic work. As you point out, the initial follow-up was fairly short and the findings were so critically important demonstrating that there were subtle differences between the two approaches but that overall, things appeared relatively similar. Did it surprise you? Oh, please correct me.

Dr. Judith Hochman:

I should point out that because there were less spontaneous MIs during follow-up and spontaneous MIs are associated with a heightened risk of subsequent death more so than the periprocedural MIs, we did hypothesize and we're very interested in longer term cardiovascular and all-cause mortality thinking that those reduced spontaneous MIs in the invasive group would be associated with reduced cardiovascular death and perhaps reduced mortality. As I did indicate, cardiovascular death mortality was reduced but all-cause mortality was the same with a hazard ratio of 1.0.

Dr. Mercedes Carnethon:

Well, nothing seems more clear than a hazard ratio of 1.0 with those very tight confidence limits so thank you so much. I'm really pleased that our editorialist, Dr. Steve Bradley was also able to join us today because to hear his thoughts about where this fits in the context of what we know can be really insightful. So, I'd really love to turn to you, Dr. Bradley. In your opinion, why was this study question so important and tell us a little bit about how you think the clinical field should use these findings.

Dr. Steven Bradley:

Absolutely and thanks for having me. I think there were some indication that perhaps the farther we follow the patients out from the original ISCHEMIA trial that we might start to see some evidence of benefit for revascularization. I think Dr. Hochman spoke about the evidence of more of these spontaneous myocardial infarctions that were happening in the non-revascularization arm of the study and an association with worse cardiovascular outcomes in patients that experience spontaneous events. And so, the thoughts might be that over time we would see the benefit of that. And certainly if you parse out cardiovascular versus non- cardiovascular outcomes, we do, we see lower rates of cardiovascular death in the patients who undergo revascularization but it's balanced out by non-cardiovascular death. And so, it becomes a zero sum game for a patient. They want to be alive, it doesn't matter by what mechanism.

So, if we have a therapy that doesn't actually prolong their life but it leads to different mechanisms by which they have an outcome, that's important for us to understand. This adds to an already robust evidence-based that ISCHEMIA really did inform and it gives us that long-term trajectory to help us understand for patients what the implications are. I will note that and we've commented in the editorial and this is something that was shown in the original ISCHEMIA trial, that it's not just about mortality for patients, it's important that we help them live better as well. And certainly we know that revascularization is associated with quality of life improvement so that's an important part of the conversation with patients. But again, continuing to refine our understanding of what the implications of revascularization are for mortality is where this study leads us now.

Dr. Mercedes Carnethon:

Thank you so much. One of the things that I find so impressive about clinical trials of this scale are that you incorporate such a broad audience. I note that 36 countries contributed data to this particular trial. I wonder whether, did you have an opportunity to investigate whether these findings were similar in low and middle income countries as compared with higher income countries? And how would you expect clinicians in low and middle income countries to use this information?

Dr. Judith Hochman:

That's a great question and yes, the treatment effect was similar across regions, didn't really have any very low income regions but we did have India was in the study and a number of South American countries. And I think it's incredibly important for those countries where there are very limited resources to reassure them, the practitioners and their patients that just because they can't afford an expensive invasive procedure, stenting or bypass, does not mean it's going to cut their life shorter, it's not going to make them survive for a shorter amount of time. Therefore, they can limit the use of scarce resources to the most severely impaired in terms of quality of life, the patients with the most frequent angina. It also became extremely relevant during COVID.

Dr. Mercedes Carnethon:

Tell me more.

Dr. Judith Hochman:

Well, elective procedures were shut down during COVID and more publications that cited the ISCHEMIA trial to say that they felt comfortable not being able to do elective stenting in patients with stable ischemic heart disease that would've met the ISCHEMIA trial criteria, which by the way we should add was preserved ejection fraction, we excluded ejection fraction less than 35, patients had to be stable. They could not have had two coronary syndrome within the last few months. They could not have had angina refractory to medical therapy and they could not have had left main disease. So, those are key. There are other exclusion criteria but those are the key exclusion criteria.

Dr. Mercedes Carnethon:

Thank you for that. And I can really see a corollary and I appreciate the messaging around similar outcomes and preserving resources. And I think certainly even within our own country where we see vast differences in access to intensive medical therapies or tertiary care medical centers who do these procedures on a higher volume, at least we can feel reassured that outcomes may be quite similar as far as mortality. What do you-

Dr. Judith Hochman:

If they take their guideline-directed medical therapy.

Dr. Mercedes Carnethon:

Thank you for pointing that out.

Dr. Judith Hochman:

It's incredibly important. John Curtis' group looked at adherent patients by the modified Morisky score versus non-adherent patients. Non-adherent patients don't have as good a health status as adherent patients. So, just that also adds to a wealth of literature that you have much better outcomes if you actually take your medications.

Dr. Mercedes Carnethon:

No, I think that's a very good point. What are your thoughts, Steve on what the next steps might be?

Dr. Steven Bradley:

Well, I know that as was pointed out earlier, there's going to be the opportunity to see additional longer term follow-up beyond this interim analysis. So, it'll be interesting to see what that continues to show us in terms of understanding applications on mortality. I'll pose a question that we posed within our editorial around trying to identify non-fatal outcomes to see if there are any opportunity to capture those non-fatal outcomes to give us an understanding of potential mechanisms for why there is this cardiovascular versus non- cardiovascular mortality difference by treatment arm? Certainly, that may be helpful.

Dr. Judith Hochman:

Sorry. We're very, very interested in the excess in non-cardiovascular death. So, we are as a result of this interim analysis, revising our case report form, which was very lean, pragmatic because the funding is relatively limited to include especially collection of data around malignancy. Because as we reported before, the non-cardiovascular deaths were largely malignancy and to some extent infection. And what was driving the difference, the excess in non-cardiovascular death as we published in American Heart Journal in the invasive group was excess malignancy.

Dr. Mercedes Carnethon:

That's really interesting.

Dr. Judith Hochman:

To our deep surprise and shock, it appeared that the only variable associated with that excess risk was the number of tests or procedures you had that involve radiation. And of course, we're talking about medical doses of radiation. And this short timeframe, three and a half to seven years, which is when the curve started to diverge to three and a half, we filed to seven years is not thought to ... it's thought to be too short a timeframe for exposure to radiation to lead to excess malignancy.

So, we have partnered with some radiation experts, we are adding much more details to our case report form, not only in terms of death from malignancy but just the occurrence of malignancy. Did you get malignancy during the course of follow-up? And that's really critically important. We are not adding information about additional myocardial infarctions. We think that the key, if we're going to focus on site burden and how much they can actually collect, is to look at the mechanisms of death and the occurrence of malignancy, whether that leads to death or not, those are our top priorities at this point.

Dr. Mercedes Carnethon:

I could go on and on, I'm learning so much speaking with the two of you. And again, that really is the primary goal of our podcast to really have an opportunity to extend beyond what's written in the paper and really hear directly from the authors who led the study to hear your thoughts as well as those of the editorialists on where this is going. I really want to thank you both for the time you've spent today to share with our audience of the Circulation on the Run podcast.

Dr. Judith Hochman:

You're very welcome.

Dr. Steven Bradley:

My pleasure.

Dr. Mercedes Carnethon:

I just want to thank all of our listeners for joining us on this really stimulating discussion today on this episode of Circulation on the Run.

Please tune in next week where we will have more exciting discussions like this one. Thank you.

Dr. Greg Hundley:

Circulation December 27, 2022 Special

26 december 2022 | 31 min

In this week’s Circulation on the Run podcast, we turn the show over to Circulation’s Social Media Editors Dr. Pishoy Gouda and Dr. Peder Myhre. They interview the 2022 recipients of the Joseph Loscalzo Award for Best Basic Science Article, and the 2022 recipients of the James T. Willerson Award for Best Clinical Article.

Dr. Maryjane Farr:

Welcome everybody to Circulation on the Run. My name is Maryjane Farr, and I'm the digital strategies editor at Circulation. Carolyn and Greg are on break this week. And as part of the Circulation tradition, we turn the stage over to two of our social media editors, Dr. Peder Myhre from Oslo and Dr. Pishoy Gouda from Edmonton. They're going to be interviewing the 2022 winners of the Loscalzo Award and the Willerson Award. Take it away, Peter and Pishoy.

Dr. Peder Myhre:

Today. Pishoy, we have a very exciting issue of Circulation on the Run. We are going-

Dr. Pishoy Gouda:

We certainly do.

Dr. Peder Myhre:

Yeah. We're going to discuss two amazing papers that are award-winning and we're going to talk to the first authors who really know these papers and conducted the amazing work that we're going to display here today.

Dr. Pishoy Gouda:

Yeah, I'm excited.

Peter. And with us today, we'll start talking about the recipients of the Loscalzo Award. So I wanted to start off by introducing Dr. Leo and Dr. Suvorava, who are the very proud recipients of the Loscalzo Award for their paper entitled Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure. So welcome Doctors Leo and Suvorava. How are you guys doing today?

Dr. Francesca Leo:

Hi, thank you for the introduction and pretty well, I'm currently in Italy for my winter Christmas holidays, but I'm really excited and happy to be here today with you.

Dr. Pishoy Gouda:

Excellent.

Dr. Suvorava:

Hello. I'm also very happy to be here today. Thank you for your invitation and for your congratulations. It's a privilege and honor for me to be a recipient of this Dr. Loscalzo Award. Thank you.

Dr. Pishoy Gouda:

Well, I just wanted to start off by taking another second here to congratulate you both on this award. We all know the sheer amount of work and dedications to get these projects going, so congratulations. And I'm going to start off with a really easy question for you guys. When you found out that you were a recipient of the Loscalzo Award, who is the first person that you told?

Dr. Francesca Leo:

As I mentioned, I'm Italian and as a good Italian I need to say that. Of course, the first people I told were my parents because we all know that Italian and parents are just one thing. So they were the first ones. And then all of course, my partner and friends came second, parents first, family first.

Dr. Pishoy Gouda:

Very good. What about yourself, Tatsiana?

Dr. Tatsiana Suvorava:

Hi. Yeah. I had to think back like seven years ago and I very good remember one day when I was really excited about the results, what we found, I was in the lab, I was developing a western blood to check the functional ability of our models and it showed that it was very successful that we couldn't knock out our protein of interest almost completely. And at that day exactly, we had a lab meeting. So I directly pulled this image on my USB stick and then showed it on the lab meeting. So actually these were my colleagues who first hear about this.

Dr. Pishoy Gouda:

That's awesome. That's lovely. Well, after I got married, sometimes my parents get bumped to the second phone call and they weren't very happy about that and they let me know very clearly. But let's switch gears a little bit and tell us a little bit about how you made the decision to pursue academics. It's such a daunting career and a daunting topic sometimes. And how did you get interested in research and how did you find yourself coming into this research project?

Dr. Francesca Leo:

If I can start first. Well, I decided to pursue an academical career at the beginning following my master thesis that I did at the University of Pisa here. And I've always wanted to go abroad and gain experience, get to know different realities apart from Italy. And I was actually really lucky that I got the opportunity to work in the laboratory Professor Cortese-Krott because that gave me the opportunity to grow a lot, both personally and professionally, of course. I learned new techniques and together with our great team, we managed to achieve many goals. In particular, this paper, I must say that was my last satisfaction before my doctoral exam. So I think the feeling that you get after any also small achievement is something that you can really, I cannot find it hard to explain to people that are not in research or not in science in general.

Dr. Pishoy Gouda:

No, I totally agree. When I get a new data set, I get so excited and my wife is telling me, what are you doing is I just got new data and I'm like a little child on Christmas day. She doesn't understand it, but she appreciates that some people like that. What about yourself? What about yourself?

Dr. Tatsiana Suvorava:

Yeah, well my decision to pursue academic career started with as probably for many researchers, started from intense fascination from one discovery. I was at the beginning of my bachelors' science studies and then the Nobel Prize was given for the discovery of nitric oxide as a signaling molecule in a cardiovascular system. And I was so fascinated that the gaseous molecule so simple has so lots of responsibility in the body. And since that time, that was always in the focus of my research and this is for me, a lifelong journey. I'm still on the way.

Dr. Pishoy Gouda:

That's amazing, Tatsiana. And that sort of sets us up nicely. And as you guys know, I'm a interventional cardiologist. Basic science is a little bit farther from my memory. So I'll start off by admitting that my basic science research is not where it should be. But with that in mind, I was wondering if you could just tell our listeners a little bit about your research and why this question is so important and explain it to you like you were lowly clinicians that don't really understand basic science.

Dr. Francesca Leo:

I always take over Tanya, but yes, I have less to say than you. I must admit.

Dr. Tatsiana Suvorava:

Okay so let’s start. No problem.

Dr. Pishoy Gouda:

It's a team effort. It's a team effort.

Dr. Tatsiana Suvorava:

Its a team effort and yeah. Ok.

Dr. Francesca Leo:

It's been a really teamwork, I must say from the really, really, really beginning. So this paper was, as I said, the central focus of my doctoral thesis. I just take two small part of it, of course, in particular, what is really important on the paper, I think that is we use really new mice models that Tanya and my Professor Cortese-Krott really and highly characterized at the really beginning, so developed completely from new, and they are mice that are expressing or not eNOS this protein that is responsible for nitric oxide production in the endothelium or in red blood cells. So the importance of this research was to demonstrate the role or pivotal role of eNOS expressed in the red blood cells in the modulation of blood pressure as well as circulating nitric oxide metabolites. And we actually did it with this paper. And considering that cardiovascular disease are one of the major causes of death nowadays, this results can really have important clinical and therapeutical implications for future research and real life, let's say.

Dr. Tatsiana Suvorava:

Yeah, maybe I could add to Francesca.

Dr. Francesca Leo:

Sure,

Dr. Tatsiana Suvorava:

Yeah.

Dr. Pishoy Gouda:

Of course.

Dr. Tatsiana Suvorava:

I think our research was especially important because it's identified the existence of previously unrecognized and actually non-canonical pathway, how the red blood cells can regulate blood pressure. And it was so exciting about this.

Dr. Pishoy Gouda:

Right. So trying to find out if the red blood cell, nitric oxide synthase can actually regulate blood pressure. And this has obviously lots of clinical implications. So in practice, how did you guys set up your experiments? How did you try to test the significance of the Enos red blood cells effects?

Dr. Francesca Leo:

Just if I can add something, what was really important. So what is known is that Enos expressing the endothelium plays an important role in the modulation of blood pressure. What we actually found out is that the one in the red blood cells also is involved and played a role that seems to be independent from the one played from the eNOS expressed in the endothelium. For answering your question, I also, I need to say I'm not the right candidate because this is a huge project that started about 10 years ago. So I was really, I repeated and I will always repeat it, I was really lucky to take part to this project and to get the opportunity to take part to this journey because it was really a journey and it gave me the opportunity to work with very different people and get in touch with very different realities, academical realities.

And I can say that this project started from my previous boss and Tanya that they had this idea and started this whole project together with, of course Tanya is the one that is involved since the really beginning. So she can definitely better answer to this question.

Dr. Tatsiana Suvorava:

Yeah, thank you, Francesca. It's a long way actually what we did, and actually I started this particular project on the level of postdoc and eNOS and hypertension have been already in a center of my research interest for several years. And in a previous project what I had, I also had a transgenic mice, which were generated by conventional genetic approach by micro injection of D N a. And at that time we observed a significant contribution of external endothelial component into the blood pressure regulated. However, at that time we were not able to identify the exact extracellular allocation of this component. There were several candidates which were suggested, and one of them there were red blood cells. And everyone was kind of skeptical about this because the level of eNOS protein in red blood cells is extremely low. And furthermore, there were a lot of doubts how eNOS activity can be exported from the red blood cells because it's red blood cells are full of heme, which is a scavenger of nitric oxide.

Furthermore, actually it was not clear how they transported and how it is released this activity. But now if we think that red blood cells are the largest component contributor to overall cell number in the body, so maybe then we can more critically think and then think that the total amount of red blood cells maybe compensate for this very low eNOS protein expression. And actually because they have a high density and their shape is erase high, so they provide a very sufficient release of this inactivity from red blood cells. But this idea was doubted for many years, although there it was reported that eNOS is expressed in red blood cells in 2006 was a paper.

Dr. Pishoy Gouda:

Well that's very exciting. So what we really learned is that eNOS system in both red blood cells and endothelial cells contribute to blood pressure regulation. Now I might direct this to you, Francesca. Well what does that mean for the clinicians in our audience? Well, what does that mean for a hypertension patients?

Dr. Francesca Leo:

So for clinicians, so, I must say these findings may have really important pathophysiological implication in the understanding of the interrelationships between hematologic and cardiovascular disease and may reveal the really novel therapeutic approaches to improve tissue perfusion. Moreover, our data and models may also help in understanding how red blood cells eNOS signaling can really affect red blood cells function, the scavenging of nitric oxide, as Tanya had previously said, as well as the crosstalk between nitric oxide and the sulfides that are of highly present in the bloodstream and in the body as well as oxygen transport. And may also enable us to refine the criteria for blood banking transfusion and to also try to develop new strategies or therapies for many diseases and pathologies where red blood cells are involved.

For example, coronary artery disease, chronic kidney disease that normally are pathologists that show a decrease in the expression of eNOS expressed in the red blood cells or hematologic disease hemoglobinopathies, which are normally characterized by a systemic decrease in nitric oxide bioavailability or one of the most common diseases, sickle cell disease. Cause of course the shape of red blood cells is definitely also responsible of their functioning. And it can also determine, of course, an impairment or more alteration in the release of nitric oxide in the body.

Dr. Tatsiana Suvorava:

Yeah, maybe I'll just add few words. So actually that's open as a perspective that impairment of red blood cells, eNOS may contribute to the pathogenesis of hypertension. So this is the most important thing I think here in clinician point of view.

Dr. Pishoy Gouda:

Yeah, absolutely. Lots of different ways that this research might be heading. And like you were saying earlier, Tatiana research is really a longitudinal process. You started this almost a decade ago and I'm sure that there's more projects and plans that you have with this for the future. What are you working on now?

Dr. Tatsiana Suvorava:

Well, I'm still in academia and I'm still doing academic career, actually. We continued our study and we also studied pathophysiological significance of red blood cells eNOS for cardio protection. For example, in regulation of coronary blood flow, myocardial performance in myocardial infarction, acute myocardial infarction in vivo. We recently published this and here we could also see involvement of red blood cells eNOS, which limit infarct size in acute myocardial infarction. In a pipeline is also a manuscript about red blood cells and endothelial cells eNOS in exercise induced cardio protection and of course the other focus would be the role of red blood cells eNOS in other disease conditions and a chronicle kidney disease for example. It will be also investigated. So we are full of plans, however, I changed department, but I'm still having eNOS in focus and hypertension as well.

Dr. Pishoy Gouda:

Well that's really exciting stuff and yes, I just wanted to congratulate you both again Dr. Leo and Suvorava and thank you for taking the time to share with us your very clear passion for this topic and I wish you guys both the best of luck. Congratulations again.

Dr. Francesca Leo:

Thank you so much.

Dr. Tatsiana Suvorava:

Thank you so much.

Dr. Pishoy Gouda:

Well congratulations again to our award recipients and Peter, why don't you tell us a little bit about what article we're going to be talking about next?

Dr. Peder Myhre:

Yes, thank you so much Pishoy. And first, I must say it was so much fun to listen to you guys discuss the paper. You can really feel the passion for the science coming through the microphone. And that was for me as a clinician as well. I learned a lot. And now we're going to actually take a step and move over back to clinical science and we are going to talk to the winners of the James T. Willerson Award. So welcome doctors, Jeanne du Fey and Dr. Alexandra Prepoudis.

Dr. Jeanna du Fay de Lavallaz:

Thank you very much for having us on the podcast. It's a pleasure to be here and we're also very happy to be able to discuss this paper with you. And of course we were extremely glad to receive this award, so we're excited about the discussion.

Dr. Peder Myhre:

And so for the listeners who are not familiar with the Willerson Award, this award recognizes the best clinical paper published in circulation in the preceding 12 months. And this award honors Dr. Willerson, who was a major leader within American Heart Association. And among his roles, he served for over a decade as the editor-in-chief of circulation. And during his tenure, the journal transitioned away from a once monthly format, vastly expanded its international footprints and rose substantially in stature and impact. And speaking of international footprint, today we have authors from all over the world and I know both of you, Jeanne and Alexandra are from the amazing biomarker group in Basel led by Christian Mueller. So Alexandra, if we can start with you, I just want to learn a little bit more about you. Where do you work, where are you in your career and your areas of interest?

Dr. Alexandra Prepoudis:

Good evening and thank you for the introduction. My name is Alexandra Prepoudis and I'm currently a cardiology fellow at the University Hospital of Basel in Switzerland. I have always been very interested in clinical research, so I decided to join the group of Professor Christian Mueller in Basel for a year prior my residency in internal medicine. And that's how I met Jeanne and the whole study team.

Dr. Peder Myhre:

Very nice. And Jeanne, what about you?

Dr. Jeanna du Fay de Lavallaz:

So my name is Jeanne du Fey and I'm currently also a cardiology fellow at the hospital in Zurich. I moved a little bit, but my main research is still based in Basel. You don't leave Professor Mueller's group once you're in it. So I sticked around. So I am undertook physician scientist track after med school and for my MD PhD I was very lucky to integrate Dr. Mueller's group into the paper we are going to discuss tonight is actually the very first study that I designed during my PhD of course with a lot of help from the whole group of Professor Mueller, professor Mueller himself and of course Alexandra who joined a little bit later and really helped us tackle quite a big piece of the biomarker research that I'm very excited to talk about.

Dr. Peder Myhre:

So that is amazing. So this is the first paper you designed and what a wonderful debut because today we're going to discuss this award-winning paper and it is entitled Skeletal Muscle Disorder and Non-Cardiac Source of Cardiac Troponin T. And of course we are within the field of troponin and I must admit Jeanne and Alexandra that I myself is a troponin nerd myself. I love research and learning more about troponin and for me this paper was really something I was eager to learn more about because we've all been questioning what is the impact of skeletal muscle disease on troponin. So perhaps Jeanne, if you could start to explain the background for this study, and what was the research question?

Dr. Jeanna du Fay de Lavallaz:

So in the past years, I think there were quite a few reports. These were mostly case series of what you have just mentioned. So it's this observation that skeletal muscle disease might actually have an impact on some troponin measurements and we were not exactly sure which. So there are these two main isophones of troponin, the troponin T and the troponin I. Depending on the hospital, depending on the country, one of both might be measured either the troponin I or the troponin T. And then for troponin T we have only one essay and then for troponin I there are several of them. So there is kind of a big mix up there of what is possibly obtainable to assess cardiovascular health and basically also more coronary health, well cardiovascular health in patients that we see every day in the clinic.

And well, as you just mentioned, we had noticed in the past that sometimes it's troponin T was behaving in weird way in patients that were also suffering of some muscle skeletal muscle disease. So Prof. Mueller is leading a very large group biomarkers on troponin research and this is something that we decide to tackle in a very structured way in order to be able to rehab an answer and bring something to the field that might be maybe a little bit more consistent than this, however very interesting case series, but that were maybe a little bit done on very specific disease and a little bit all over the place.

Dr. Peder Myhre:

Exactly, and this is exactly what really made this paper so amazing is that first of all, you structured the clinical part of it with a prospective cohort. You did multiple essays on the patients and you even included some translational work on top of that, which is truly amazing. So I was wondering, Alexandra, if you perhaps could start with explaining the clinical part of the study, the patient cohort, the mythology use, et cetera. So please, Alexandra.

Dr. Alexandra Prepoudis:

We enrolled patients with muscle complaints. So for example, muscle pain, weakness, stiffness or fasciculations. And we enrolled them at four sites in two countries, most of them during ambulatory visits. And from each patient we collected a blood sample and we measured four different high sensitivity cardiac troponin assays. So one for troponin T and three for troponin I. Then patients underwent the cardiac workup including E C T, echo cardiography and cardiac M R I depending on the clinical indication. As a control group, we used patients from a prior study where patients who presented to the emergency department with the leading symptom of chest pain were enrolled. So of these we analyzed patients without skeletal muscle disease in whom a cardiac cause of chest pain could be excluded.

Dr. Peder Myhre:

Great. So really a big and well pheno typed group of patients. And before we go to the results, we're going to also learn a little bit about the experimental part of the study that you conducted. So Jeanne, if you would just explain what was, this was something with the gene expression in the muscles, right.

Dr. Jeanna du Fay de Lavallaz:

So we decided to be a little bit original and to bring it back to the bench instead of bringing it to the bedside as we usually do. And-

Dr. Peder Myhre:

I love it.

Dr. Jeanna du Fay de Lavallaz:

We will soon. We were also very lucky to have amazing collaborators because that allowed us to collaborate with a rheumatologist with neurologists. And these doctors might have in the past collected some muscle tissue for completely different muscle analysis. So in order to phenotype the diseases that the patients were actually suffering of and we're also lucky enough so that there was sometimes some of this muscle tissue is still available and we basically extracted mRNA from these skeletal muscle samples. And what we looked at was the mRNA of the different troponin genes that we could find in there. So as you probably know, there is some genes coding for skeletal troponin and there are some genes coding for cardiac troponin. And what we could see that was, we might come to that in the results, but basically our goal was to look at the expression of the different skeletal or cardiac troponin in these skeletal muscle samples.

Dr. Peder Myhre:

Exactly. And the next question is going to be difficult because I want you to summarize the findings and there are so many findings to supplement. This is really, it's like pressure. But please Alexandra, can you try to summarize the primary results of this paper?

Dr. Alexandra Prepoudis:

Yes, of course. I will try my best. So maybe first about half of the cohort showed the cardiac disease IE the coronary heart disease, atrial fibrillation, or chronic heart failure. So cardiomyocyte injury resulting from cardiac disease was a major contributor to elevated troponin T and I concentrations even in these patients with skeletal muscle disorders. But troponin T concentrations were above the upper limit of normal in about 55% and the concentrations were significantly higher compared with control subs checked. While troponin I concentrations were elevated to a significantly lower percentage, which were also comparable to the concentrations in the control group. Also, we found that the elevated troponin T concentrations were restricted largely to patients with non-inflammatory myosis and myositis. And maybe one thing to the gene expression regarding the gene expression analysis, we found the eightfold up regulation for the gene and coding for cardiac troponin T in skeletal muscle compared with controls without skeletal muscle disease.

Dr. Peder Myhre:

Wow, that is so great. So please let me try to summarize these important findings to the listeners. So you actually found in patients with skeletal muscle disease, a much higher level of troponin T compared to healthy controls or at least controls without myocardial infarction. And for troponin, these differences were not that pronounced. So that means gene, that troponin T in patients with certain types of skeletal muscle disease may be falsely positive. Is that correct? And how would you put these findings in relation to previous studies in the field and also perhaps some clinical implications of the findings?

Dr. Jeanna du Fay de Lavallaz:

So yeah, I think we can say that in the patient where that was the case, this is actually falsely positive because when we talk about cardiac troponin T, cardiac troponin, we expect it coming from the heart, certainly not from the muscle of the patients or at least it's what cardiologists have been trying to not diagnose in the past years by refining also the assays that we were using so that it doesn't cross-react with anything coming from a skeletal muscle. And I think regarding previous studies in the field, so we tackled, I believe several aspect with this paper that hadn't really been well investigated before. And our study design helped with that a lot. So first we included patients based on their complaints that was not a specific cohort with a certain type of disease. We really enrolled them if they presented with some muscle complaints, so not a specific already diagnosed disease.

So this was the first point. And then second also, we investigated several troponin I assays, which also allowed us to have a broader observation of how this assay are actually interacting also with each other or how they relate to this troponin T assay, which is the only one existing. And then finally, I think this translational part with the MRN analysis really helped us to go back to the primary hypothesis, how does that work? Why is this the case at all? And finding this re-expression of the cardiac troponin T in the skeletal muscle really tells us that this might actually not be a problem with the assay itself but might really be that we have some cardiac troponin T circling in the blood and being measured by a perfectly well working assay, which is a totally different mechanism than for instance, cross reaction that we might sometimes observe for instance, with troponin I assays.

Dr. Peder Myhre:

Exactly. And the findings were so consistent across the 3 troponin I assays and supported by the biopsy findings, I think they were so robust. And you know, we're talking about how this might impact adjudication of a suspected myocardial infarction, but also troponin is a very strong prognostic marker within chronic conditions and in ambulatory patients. And even there it may really impact the utility of troponin as a risk marker. Alexandra, don't you think so?

Dr. Alexandra Prepoudis:

So, to come back to the first part of your question, what about patients with myocardial infarction? Our study did not directly investigate the impact of these unexpected troponin T concentrations on the diagnosis of myocardial infarction. But we believe that it's reasonable to say that if patients with a known chronic skeletal muscle disease present with chest pain to for example the emergency department and the first troponin T comes back elevated, the clinician should be aware that the skeletal muscle can be a possible source of this biomarker. So if possible, a troponin I should be obtained in these patients.

Dr. Peder Myhre:

Excellent. And that brings us to the last question of today, I think Jeanne, and that is the future direction of this field. We now know, I think for certain that some skeletal muscle disease have an elevated cardiac troponin T, or perhaps not cardiac, but at least troponin T. So what do we need to learn more about this? And is there any way we can improve the assays? Please, Jeanne, let me know your thoughts about the future.

Dr. Jeanna du Fay de Lavallaz:

So that's a complex question. I think already we are kind of running into troubles when we already just see the current situation with these assays. Depending on the countries, depending on the hospitals, depending on the laboratory background that all the laboratory measurement system that we might have. Some hospitals have a total different approach on which troponin to measure and what's troponin to make available for their physicians. But I think these biomarkers haven't finished to surprise us and also most likely to bring us some very good prognostic tools. And I believe once we can really refine the exact origin of which elevation in which patient and what this does imply for their prognosis, we might also be able to just predict much better where with our patients are going, what kind of diagnostic or treatments that we need to use in order to improve their life on the short and long term. So I have quite a lot of hope for these different assays to be better understood in the coming years.

Dr. Peder Myhre:

What a wonderful way to finalize this podcast. Jeanne and Alexandra, thank you so much for participating and for sharing your knowledge in the field and to learn about your current situation with work and your choices of career. And also a big thank you to Francesca and Tanya for the winners of the LOSCALZO Award for sharing their research. So on behalf of Pishoy and myself, I want to thank everyone for listening and thank you to the amazing authors and winners of the awards. This is Peter Myra, and on behalf of myself and Pishoy Gouda, we thank you for listening.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation December 20, 2022 Issue

19 december 2022 | 19 min

This week, please join author Mads Liisberg and Guest Host Mercedes Carnethon as they discuss the article "Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study from 1996 to 2016."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke, National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is about aortic dissections and it's the first nationwide population based study investigating the clinical characteristic, incidents, and mortality based on validated diagnosis of aortic dissection in a national patient registry. You want to hear more? Well, you have to just keep listening. Let's go on though first to discuss the other really important papers in today's issue, shall we?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

You know what, Greg? I'm going to start while you grab a coffee. I want to talk about high sensitivity cardiac troponins and how they have allowed the use of strategies in the emergency department, for example, to rapidly rule out acute MI within one to three hours and potentially facilitate early discharge of low-risk patients. Now, the ability to rapidly rule out MI of course depends on the turnaround time of these high sensitivity cardiac troponin results from the central laboratory, which is often delayed due to specimen transport and handling and all these things.

So, point-of-care assays can reduce this turnaround time by even 40 minutes, and early studies have actually used frozen plasma bio banks to assess these point-of-care assays... But no study has evaluated these point-of-care assays with fresh whole blood to safely rule out MI in the emergency department. That is until today's paper. So in today's study led by corresponding other Doctor Fred Apple from Hennepin Medical Center in Minneapolis, Minnesota and his team, they aimed to derive and validate an optimal high sensitivity cardiac troponin threshold concentration using whole blood point-of-care troponin eye assay on a single sample at presentation in the emergency department to identify patients at low risk of index MI for potential early discharge.

Dr. Greg Hundley:

Fascinating study Carolyn. So point-of-care testing, high sensitivity troponin from whole blood in the ED. So what did they find?

Dr. Carolyn Lam:

Among consecutive emergency department patients from two prospective observational studies with suspected acute coronary syndrome, a point-of-care, whole blood, high sensitivity cardiac troponin eye assay, the Atellica VTli provided a sensitivity of 98.9% and a negative predictive value of 99.5% for ruling out MI. A single measurement using a cutoff of less than four nanograms per liter for whole blood was successful in rapidly identifying patients at low risk of MI cardiac and all cause death and unplanned revascularization at 30 days.

Dr. Greg Hundley:

Very nice Carolyn, and could be quite practical. So Carolyn, my next paper comes to us from the world of preclinical science and it pertains to cardiac regeneration. So cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes. However, certain animals readily regenerate lost myocardium via process involving dedifferentiation, which unlocks their proliferative capacities. So inspired by this concept, these investigators led by Professor Patrick Hsieh from Academic Sinica, generated mice with inducible cardiomyocyte specific expression of the Yamanaka factors enabling adult cardiomyocyte reprogramming and dedifferentiation in vivo.

Dr. Carolyn Lam:

Wow. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So two days following induction, adult cardiomyocytes presented with a dedifferentiated phenotype, an increase proliferation in vivo. Microarray analysis revealed that the up-regulation of ketogenesis was central to this process. Now adenovirus driven HMGCS2 over-expression induced ketogenesis in adult cardiomyocytes and recapitulated cardiomyocyte dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue. And HMGCS2 knockout mice showed impaired cardiac function and response to injury, and so in summary, Carolyn, these data demonstrated the importance of HMGCS2 induced ketogenesis as a means to regulate metabolic response to cardiomyocyte injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

Dr. Carolyn Lam:

Wow, that's so cool. From cell regeneration to autoimmunity in this next paper. Now autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. However, the functional features of cardiac autoimmunity in humans remain undefined due to the challenge of studying immune responses in situ. Now, these authors previously described a subset of c-Met expressing memory T lymphocytes, which preferentially migrate to cardiac tissue in mice and humans. In today's study, these authors led by co-corresponding authors, Dr. Federica Marielli-Berg and Saidi Mohidden from William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, and Queen Mary University of London, and their colleagues performed in-depth phenotyping of peripheral blood T cells in groups of patients with inflammatory and non-inflammatory cardiomyopathies, patients with non-cardiac autoimmunity and healthy controls... And they found that c-Met positive T cells were selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies.

The phenotype and function of c-Met positive T-cells were distinct from c-Met negative T cells, including preferential proliferation to cardiac myosin and co-production of multiple cytokines. Further, circulating c-Met positive T cell subpopulations in different heart muscle diseases identified distinct and overlapping mechanisms of heart inflammation. Furthermore, validation studies in experimental autoimmune myocarditis showed that elevations of auto-antigens specific c-Met positive T cells in peripheral blood, marked the loss of immune tolerance to the heart. Importantly, disease development could be halted by pharmacologic c-Met inhibition indicating a positive role for these c-Met positive T cells.

Dr. Greg Hundley:

All right, Carolyn, as you always ask me. So what's the take home message here?

Dr. Carolyn Lam:

This study demonstrates that the detection of circulating c-Met positive T cells may have utility in the diagnosis and monitoring of adaptive cardiac inflammation and additionally defined new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury... And this is discussed in an editorial by doctors at Abplanalp, Merten, and Dimmeler.

Dr. Greg Hundley:

Very nice, Carolyn. Wow. More fantastic preclinical science. Well, in the mail of the bag today, there is a Research Letter by Professor Burr entitled “Cannabis Inhalation Acutely Reduces Muscle Sympathetic Nerve Activity in Humans.”

Dr. Carolyn Lam:

There's an ECG Challenge by Dr. Reddy entitled “Shortness of Breath and Near Syncope During Exertion In a Child, When Patient Worry Syndrome.” There's also a Perspective by Dr. Weitz on what is the future of Factor 11 inhibitors.

Dr. Greg Hundley:

Well Carolyn, I'm looking forward to learning more about aortic dissections and that large Danish population-based study. Wow.

Dr. Carolyn Lam:

That's great. Let's go Greg.

Dr. Mercedes Carnethon:

Well, welcome to this episode of Circulation on the Run. My name is Mercedes Carnethon, an Associate Editor of Circulation, and Professor and Vice Chair of Preventive Medicine at Northwestern University. I'm really excited today to be here with the senior author of a really exciting paper that we're featuring on clinical characteristics, incidences and mortality rates for aortic dissections type A and B, a nationwide Danish population-based cohort study, and we have with us today Mads Liisberg. So welcome today.

Dr. Mads Liisberg:

Thank you.

Dr. Mercedes Carnethon:

So thank you so much for joining us and really thank you for sharing your important research with Circulation. This topic is so critically important, particularly given the high mortality rates associated with aortic dissections. Can you tell us a little bit about the work that you and your co-authors did in this important space?

Dr. Mads Liisberg:

Yes. Well actually the work originated when I started my PhD thesis and we got a registry data dump from the Danish medical registries and we found that almost none of our patients in the registry were registered with a specific aortic dissection code.

So we did a validation study on the same time period from 1999 to 2006 where we went through all these medical records to ensure that we had the right aortic dissection TC 10 codes on population. Then we went a bit further and looked at the clinical characteristics of this patient, 'cause that's one of the really major things about Danish medical registries in our country, is that we have access to not only every patient's specific in hospital contacts, but also their medicine abuse, their drug use based on a TC code. So we can go really deep into each and everyone's drug history. When we did this study, we wanted to find out if the incidence rates during this timeframe had changed, which we find that it did, but also looking at mortality rates because, as you said, it's really high risk disease to be diagnosed with. So that's more the rationale for this study.

Dr. Mercedes Carnethon:

Thank you so much for sharing that. Certainly we know that the mortality rates from this are very high. I note that you report some changes over time between 1996 and 2016 in the incidents of these types of aortic dissections. So what did you find about the patterns of change in type A aortic dissections?

Dr. Mads Liisberg:

We found that it almost doubled from the beginning of our time period to the last, and the question is why is this? 'Cause that's one of the thing that the data doesn't reveal. We are only able to see that the incidence actually rises, but is it because that they are underdiagnosed in the beginning? Or is it because that we are better diagnosing in the end of the study that really are progressed?

Dr. Mercedes Carnethon:

That's a good question. I noted that when you studied the correlates of aortic dissection, you identified a number of characteristics and what stood out to me was the finding about the strong association of hypertension. I'm less aware of patterns of hypertension in the Danish population. Do you think that the changes in the prevalence of hypertension in the population contributed at all to these findings?

Dr. Mads Liisberg:

Well, most certainly, 'cause when you look at the prevalence of hypertension throughout any person's lifespan, the older they get the more likely they are to suffer from hypertension, and the Danish population has aged quite a lot in recent years. So I think that's one of the main reasons we find this, and also that most of our arctic dissection patients are actually quite old, which would correlate with hypertension as well.

Dr. Mercedes Carnethon:

One thing I really like, and you pointed this out, is really the richness of the data that you have in your health system, and I wonder, just going even a little deeper on the hypertension question, given that it is the most common medical diagnosis worldwide, were you able to study characteristics of hypertension that would be more strongly associated with aortic dissection? So for example, duration of hypertension, severity, prevalence of hypertension control?

Dr. Mads Liisberg:

That's actually a funny question 'cause the last study of my thesis, which hasn't been published yet or even submitted for that fact, examines the correlation between use and the risk of arctic dissection. On a very specific level, the way that hypertension is treated mostly in Denmark is with your general practitioner. So the way that we examine in studies like these, is that we look at prescription drug use. So if we find that an individual has a TC codes corresponding with anti-hypertensive drugs, then we are able to code them as hypertensive patients.

Dr. Mercedes Carnethon:

Okay, thank you for that. I always... I'm an epidemiologist myself, so I really love to see great population science studies and this registry is large, you have long-term follow up and you've got a great deal of data, but those people who feel as though it's obviously not appropriate to make causal conclusions around epidemiology and that perhaps epidemiologic findings shouldn't be driving clinical decision-making. In response to that, I think I would pose the question to you, which is how do you see clinicians and providers using this information from your observational study?

Dr. Mads Liisberg:

I think that's rather difficult. One of the findings that we present is to pose it over mortality for type B dissections when we exclude the 30-day mortality, but then we show that type A dissections have almost a corresponding mortality rate compared to a hypertensive cohort... And this finding is difficult to draw any clinical conclusions from, but there's actually a Danish randomized controlled trial just starting up in the next year. I think it's called the Sunday trial, where they will include all uncomplicated type B dissections and randomize them for treatment or no treatment, and the issue here is that you'll probably be over-treating some patients and under-treating others, but this discussion with the uncomplicated type B dissection has been ongoing for so many years. So it's difficult for me to just give one golden answer.

Dr. Mercedes Carnethon:

Certainly, and I appreciate the caution as we certainly don't want to overstep our findings. You did make a recommendation in the conclusion that it might be beneficial to treat type B aortic dissections more aggressively. Is this what you're alluding to, based on the other study that you're referencing?

Dr. Mads Liisberg:

Yes, yes, definitely. We see some clinicians being more cautious treating type B dissections with a TIVA or a surgery. So it's a difficult thing when they're uncomplicated, why treat them? But they can't be or become complicated quite easily and fast and then it's a difficult thing, because should you have treated them earlier? Or do you need to treat them now in their acute phase? Or wait for a chronic phase? It's a really good question.

Dr. Mercedes Carnethon:

No, I appreciate that and what I really love are the types of research studies that leave you with many more questions and next steps, and so I would like to really sort of bring us to a close with the big picture question, which is what do you see as the next steps in this line of research, given really what we all agree on is a very significant clinical problem.

Dr. Mads Liisberg:

We would really like to expand our database with even more clinical data as of now and include any image diagnostics for our cohort. So we're might be able to see any trends in our modulation before the dissection occurs. If any of our patients have any diagnostics done prior to being diagnosed.

Dr. Mercedes Carnethon:

I really want to thank you today for spending time talking with us. I know that our readers rarely have an opportunity to hear from everybody behind the scenes views on what the rationale was for carrying out a paper and really how the authors themselves hope that the paper will be used. So I really thank you for sharing that with us today, Matts, on behalf of your co-authors, this has been really a wonderful conversation, and thank you again for sharing your research with the journal, Circulation.

Dr. Mads Liisberg:

Oh, thank you for having me in for accepting our paper.

Dr. Mercedes Carnethon:

So thank you so much to our listeners for listening to us on this episode of Circulation on the Run. Please tune in next week as we will have more exciting insights.

Dr. Greg Hundley:

Circulation December 13, 2022 Issue

12 december 2022 | 25 min

This week, please join author Trisha Singh as she discusses her article "Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass for the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, very interesting feature discussion this week. Many times we hear in magnetic resonance imaging the use of gadolinium contrast. And remember, gadolinium is an extracellular agent. And when we apply it in the heart, we look for infarcts, or areas of the heart that are perhaps dead, or scarred over. This week's feature discusses manganese as a contrast agent and it is an intracellular contrast agent. And very interestingly, it identifies calcium handling, so it's a marker of viability. And these authors are going to apply manganese as well as gadolinium in trying to understand mechanisms behind Takotsubo cardiomyopathy.

But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue?

Dr. Carolyn Lam:

Oh, I'd love to tell you about the other articles. But just have to first say, I loved your description of the feature paper. It's right up your alley and I can't wait to learn more.

But my first paper today I want to talk about pulse field ablation. Now, what is that? Pulse field ablation, or PFA, is a unique and novel technique to treat atrial fibrillation. It has a unique safety profile largely related to its preferentially for myocardial tissue ablation. And thus, sparing the esophagus and thus, deemed to have a unique safety profile. Now, a pentaspline catheter was the first such PFA system studied for AF ablation. And in the initial trials the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation.

However, following its regulatory approval in Europe, in clinical practice, physicians have ablated both these locations and expanded lesions that could be in closer proximity to the coronary arteries. Now, this is an unstudied important issue since preclinical and maybe some clinical data have raised the potential for coronary arterial spasm. Hence, the investigators led by Dr. Vivek Reddy from Icahn School of Medicine at Mount Sinai and colleagues studied the vasal spastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries.

Dr. Greg Hundley:

Wow, Carolyn, this is a really interesting question. So what did they find?

Dr. Carolyn Lam:

In this retrospective analysis of a series of 25 patients undergoing PFA for atrial fibrillation in whom coronary angiography was performed pre, during and post ablation, they found that during pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur. However, cavotricuspid isthmus ablation provoked severe subtotal vasospasm in five out of five consecutive patients. And this was relieved by in coronary nitroglycerin. ST elevation was not observed. No patient had severe spasm if first pretreated with parenteral nitroglycerin, either intracoronary or intravenous.

And so in summary, coronary vasospasm was not provoked during PFA at locations remote from the coronary arteries. But when the energy is delivered adjacent to a coronary artery, like in cavotricuspid isthmus ablation, PFA did provoke subclinical vasospasm. And the phenomenon was attenuated by nitroglycerine administered either post hoc to treat spasm or as prophylaxis. And this is discussed in accompanying editorial, I like it, “Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and Sundeep and Saba.

Dr. Greg Hundley:

Very nice Carolyn. Very important research in this area using that particular methodology.

Well Carolyn, my next study comes to us again from preclinical science. And Carolyn, this study evaluated mechanisms responsible for pulmonary hypertension.

So as background, pulmonary hypertension is associated with increased expression of VEGFA and it's receptor VEGFR-2. But whether and how activation of VEGFA signal participates in the pathogenesis of pulmonary hypertension, that's unclear. And so these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2 signal activation and VEGFR-2 Y949 dependent vascular leak in lung samples from patients with pulmonary hypertension as well as in mice exposed to hypoxia.

Dr. Carolyn Lam:

Another one of those excellent translational pieces, isn't it Greg? So what did they find?

Dr. Greg Hundley:

Right Carolyn. So these authors found that pulmonary hypertension led to excessive pulmonary vascular leak in both patients and hypoxic mice. And this was owing to over activated VEGFA and VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling via a specific point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure. This, in turn, led to alleviation of pulmonary hypertension manifestations including muscularization of distal pulmonary arterials, elevation of right ventricular systolic pressure and right ventricular hypertrophy.

And so Carolyn, in summary, these results suggest that VEGFA, VEGFR-2 Y949 dependent vascular permeability is an important determinant in the pathogenesis of pulmonary hypertension and might serve as an attractive therapeutic target pathway for this disease.

Dr. Carolyn Lam:

Aw, thanks Greg for explaining that so well.

The next paper talks about transcatheter aortic valve replacement of TAVR, recognizing that it is a well established treatment now for high and intermediate risk patients with severe symptomatic aortic stenosis. However, the question asked here is what makes some, but not all patients improve their left ventricular ejection fraction following TAVR associated after load reduction?

Now, hypothesizing that circulating microRNAs may play a role here, the authors led by corresponding authors, Dr. Hosen and Jansen from University of Bonn and their colleagues profiled the differential expression of microRNAs in circulating extracellular vesicles in patients after TAVR. And in particular, the novel role of circulating microRNA 1225p in cardiomyocytes.

Dr. Greg Hundley:

Oh wow. So Carolyn, important study. So what did they find?

Dr. Carolyn Lam:

Well, first aortic stenosis increases circulating microRNA 1225p, which correlated with a lack of improvement of the EF in patients after TAVR. Extracellular vesicles harbored microRNA 1225p and facilitated its startling into the cardiomyocytes. Vesicular shuttling of this particular microRNA was regulated by a direct interaction with a multifunctional RNA binding protein called heterogeneous nuclear ribonucleoprotein U in a sequence specific manner. Extracellular vesicles containing the specific microRNA post transcriptionally repressed BCL2 an anti-apoptotic gene, which is central to cell viability and apoptosis.

So in summary, Greg, an increase in extracellular vesicle microRNA 1225p in patients with aortic stenosis represents a novel mechanism for the deterioration of cardiac function in patients following TAVR. And pharmacological manipulation of this axis may improve ejection fraction and cardiac function in patients with aortic stenosis by improving the viability of cardiomyocytes, which opens the door to a potential therapeutic approach in patients with limited EF improvement following TAVR.

Dr. Greg Hundley:

Oh Carolyn, beautiful, beautiful description of that wonderful preclinical science.

Well, let's reach into the mail bag and see what else is in the issue. And first, there's a research letter by Professor van Raalte entitled “Kidney Hemodynamic Effects of Angiotensin Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition Alone and in Their Combination: A Crossover Randomized Trial in People with Type 2 Diabetes.”

And Carolyn, there's also an In Depth piece from Dr. Marx entitled “GLP1 Receptor Agonist for the Reduction of Atherosclerotic Cardiovascular Risk in Patients with Type 2 Diabetes.”

Dr. Carolyn Lam:

Very, very nice papers, those two. There's also an exchange of letters between Drs. Hou and Sedej regarding the article, “Fine Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.” As well as a Perspective by Dr. Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More Precision in Aortic Care.”

Now, let's go onto the feature discussion of all things MRI, shall we?

Dr. Greg Hundley:

You bet. More on manganese.

Welcome listeners to this very interesting feature discussion on December 13th. And we have with us Dr. Trisha Singh from the University of Edinburgh in Edinburgh, Scotland.

Welcome, Trisha. This is a fascinating study incorporating manganese cardiovascular magnetic resonance to study some of the mechanistic underpinnings of hypokinesis left ventricular hypokinesis in patients with Takotsubo syndrome. So maybe just describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Trisha Singh:

Yes, of course. So we know with patients with Takotsubo syndrome, it predominantly affects middle aged women, patients present with a degree of left ventricular dysfunction, which is transient. And, unfortunately, it can be quite difficult to diagnose because it can phenotypically present very similar to an acute coronary syndrome. We know from previous studies that these patients do have ongoing symptoms despite normalization of their LV function. And actually their outcomes are not as benign as previously thought.

In terms of manganese enhanced MRI imaging, we at Edinburgh University have imaged patients with other cardiac conditions such as hypertrophic cardiomyopathy, and dilated cardiomyopathy. And have established that it can be used as a surrogate marker of myocardial calcium uptake and handling. So we were very interested to see whether or not patients with acute Takotsubo syndrome have got a myocardial calcium dysfunction and more importantly whether or not this translates into long-term dysfunction and perhaps could explain their symptoms and worse prognosis in long-term.

Dr. Greg Hundley:

Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is manganese different? You mentioned it's a nice marker for calcium handling. Is this widely used clinically? What kind of contrast does it provide?

Dr. Trisha Singh:

So manganese was actually one of the first contrast agents to be used with magnetic resonance imaging. It kind of came about in the 1970s and 1980s. And previous animal models have looked at how it is essentially an intracellular contrast agent. And what I mean by that is manganese is a calcium analog and therefore, in cells where they are viable and there's intact cell function, they will be taken up through a voltage gated calcium channels. So, for example, in the heart. So the theory is that manganese, when you've got normal viability, manganese is taken up into the myocardium via voltage gate calcium channels. And several studies have shown that if you then have disease myocardium, these tissues do not take up the manganese as normal tissue would.

And the main difference between manganese and gadolinium is they are both paramagnetic, which is why they're helpful and useful in MRI. But gadolinium, as a compound, is too big and it cannot cross an intact cell membrane and therefore, gadolinium is more extracellular. And as, we know, accumulates in tissues where there is increased edema, or water content. So gadolinium, for all intents and purposes, is incredibly useful contrast agent, certainly what we use predominantly at the moment in clinical practice, but it is extracellular. So the theory behind manganese is that it is an intracellular contrast agent as opposed to gadolinium. And where gadolinium accumulates in disease tissue, manganese accumulates in viable tissue. So they behave almost kind of in contrast to each other.

And currently, manganese is not used in clinical practice. I think the only clinical compound contrast agent utilizing manganese was mangafodipir, otherwise known as Teslascan, which I believe came off the market in 2012 and that was predominantly used for imaging liver metastasis.

Dr. Greg Hundley:

Well Trisha, thank you for clarifying for us the difference between manganese, the intracellular contrast agent, and gadolinium, the extracellular contrast agent, that's so widely used clinically.

Well, with that description, can you describe for us now, your study population and your study design?

Dr. Trisha Singh:

Perfect. So the study population was we aimed to recruit 20 patients with acute Takotsubo syndrome. The diagnosis of Takotsubo syndrome was based on a clinical diagnosis, so all our patients underwent a baseline echocardiography and invasive coronary angiography.

Now, for us, the coronary angiography was quite important because we wanted to ensure we ruled out anyone with an acute myocardial infarction, which can often be tricky in this cohort of patients.

So after recruiting 20 patients during the acute phase of Takotsubo, they all underwent a baseline gadolinium enhanced MRI scan followed by a manganese enhanced MRI scan. And these were done at least 48 hours a part. And then about three months roughly after the acute index, they were all invited to participate in a second manganese enhanced MRI scan.

Dr. Greg Hundley:

Very good. So two exams separated longitudinally over time. What were your study results?

Dr. Trisha Singh:

Our results demonstrated that during the acute phase as one would expect, patients had a degree of left ventricular dysfunction. The majority of our patients had afibrillar Takotsubo, so had afibrillar ballooning with preservation of the basal segments. With this, we also noted that in the areas that were affected by Takotsubo, so kind of the mid ventricular wall and the apex that all patients had significantly elevated native T1 and associated T2 as well. And as we expected there was reduced uptake of manganese and therefore kind of reduced calcium uptake in the myocardium in the area affected by Takotsubo syndrome.

Interesting, what we also noticed was that all these patients had significantly elevated LV mass, which has been described in previous Takotsubo papers, certainly by Professor Dawson. And when you measured the left ventricular wall thickness, the LV wall thickness is elevated in the affected and actually not even in the non-affected areas, which I suspect explains why in the acute phase people almost doubles up which kind I guess fit with kind of acute myocardial edema and intense water content.

And then, three months later when these patients returned for their follow-up scan, a lot of the acute changes had resolved. So native T2 values had improved and gone back to baseline. Native T1 and post contrast T1 values had remained elevated compared to the control population. And what we found was that manganese uptake, though it had improved, it still remained abnormal and reduced compared to the control population, which is a finding that we weren't expecting to find.

Dr. Greg Hundley:

Very interesting. So acutely we've got extracellular water there, elevation of myocardial T2, and also impaired manganese uptake. So intracellular abnormalities with calcium handling. Then later, so three months later, we have restoration of myocardial T2 so the extra water content is absent, but we have impaired manganese uptake indicating an abnormality with calcium handling. So how do we put this all together mechanistically? What does this tell us about the pathophysiology of Takotsubo syndrome?

Dr. Trisha Singh:

For one thing, I think we can say that there is, as described before, there is obviously intense myocardial edema present in patients with acute Takotsubo. And I think the significant elevation in T2 and LV mass kind of all fits together. Actually interestingly, as native T2 improves in their follow-up scans, the LV mass actually all return back to normal baseline. So I think the acute edema does resolve.

And as you said, interestingly, despite all of these patients, their LV function completely recover. And despite that their myocardial calcium uptake, or handling remain normal. And I think that's not been demonstrated before. And I think it just points to that there is obviously, still something going on in the myocardium and it's not behaving completely normally despite completely normal kind of gross LV function. And potentially, this might point in the direction of why these patients have ongoing symptoms. So, certainly, from our observational cohort group, about 70% of patients had ongoing symptoms and this was predominantly breathlessness and palpitations. And potentially, might be related to why patients have worse outcomes compared to the general population.

Dr. Greg Hundley:

Very nice. And Trisha, can you describe, was there a therapeutic intervention between the acute and then the three month later measurements? Were these patients administered any type of medical therapy and were there differences in what those therapies may have been between different patients in your study?

Dr. Trisha Singh:

So predominantly, most of the patient population that were started on some combination of heart treatment due to the baseline LV dysfunction. And this kind of was a combination of most of them were on Ramipril, a few of them were also on spironolactone or eplerenone. And then, every single one was on furosemide. And interestingly, I mean I appreciate, I think the population group was quite small, so it's very difficult to compare those that were on kind of full heart failure treatment versus those who were just on beta blocker and ramipril therapy. But even in that cohort there was a split of about, I think predominantly, I think 17, 16 patients were on kind just beta blockers and ramipril as opposed to beta blocker, ramipril, spironolactone. And there was no difference kind of in the recovery in manganese uptake in that cohort. But, again, the numbers are quite small, so I think it's difficult to extrapolate any kind of true meaning in that.

Of course, we know there's a lack of randomized control trial data looking at how to best treat patients with acute Takotsubo syndrome and certainly, what treatment may prevent these patients from having a recurrence of Takotsubo. And I know some of the TACA registry data has looked at actually despite the fact patients of being on beta blocker, or ramipril therapy, they still go having recurrence of Takotsubo and certainly of our cohort, one of our patients went on having a recurrent episode of Takotsubo within a year of her index event and she was on aspirin, beta blocker, spironolactone as well.

Dr. Greg Hundley:

Very nice.

And then lastly, when you made these measurements looking at the manganese uptake or lack thereof, were these in the regions of myocardium where you mentioned many had apical LV wall motion abnormalities, were they in those regions or did you also measure regions remote to where the wall motion abnormality occurred?

Dr. Trisha Singh:

Of course. So we took measurements in the affected regions of the heart that kind of demonstrated spironolactone syndrome. And we also took measurements in kind of, so to speak, the remote segments of the heart.

Now, for the remote segments of the heart, we could only measure native T1 and post contrast T1 at 30 minutes and to measure manganese uptake well, unfortunately, what we have to do is take a measurement over time, so we'd do every two and a half minutes for 30 minutes after the manganese contrast. So we weren't able to calculate manganese uptake in the remote regions. But what we could do was measure the native T1 in the remote region, and then the post contrast T1 and see how it differed with the region of interest in the affected portion of the heart, so to speak.

Dr. Greg Hundley:

Very good.

Well, Trisha, with this really exciting research and very nice methodology, what do you see as the next study to be performed in patients with Takotsubo?

Dr. Trisha Singh:

So I think, in terms of manganese enhanced imaging, I think it'd be really interesting to re-scan these patients at one year or at two years. And the question there is whether or not their manganese uptake ever recovers really. I know we previously talked about this and thought about whether or not these patients who go onto developing Takotsubo syndrome might actually have a kind of an underlying cardiomyopathy that puts them at risk of developing Takotsubo with stress. So it'd be interesting to see whether or not actually their calcium uptake ever recovers in the long-term, or whether actually they have more of a chronic heart failure type like picture.

And I think another area of interest would be to see potentially using manganese imaging as a noninvasive measure of kind of myocardial calcium activity and to see whether or there's any changes with therapy over the course of months to years or so.

Dr. Greg Hundley:

Very nice.

Well listeners, we want to thank Dr. Trisha Singh from University of Edinburgh in Edinburgh, Scotland for bringing us this really interesting article in patients with Takotsubo syndrome demonstrating that there is a marked perturbation of myocardial manganese uptake, which is most evident in the acute phase of Takotsubo presentation, but also persists for at least three months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema. All of this suggesting that abnormal myocardial calcium handling may be implicated in the pathophysiology of Takotsubo syndrome.

Well, on behalf of Carolyn and myself, we want to wish you a great week. And we will catch you next week on the run.

Circulation December 6, 2022 Issue

5 december 2022 | 22 min

This week, please join author Sean Pokorney and Associate Editor Shinya Goto as they discuss the article "Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial."

Dr Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and Backstage Pass of the journal and its editors. We're your cohost. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting topic. In patients that have end stage renal disease that require dialysis, questions emerged should we anticoagulate them to prevent stroke, but of course, there's a risk of excess bleeding. Well, this feature discussion today is a study comparing apixaban and warfarin for anticoagulation in exactly this patient population. But before we get to those results, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first?

Dr Carolyn Lam:

Absolutely, Greg. So my first paper is a pre-specified analysis of the Paradise MI trial and knowing you'll likely ask me what that was about, Greg, at least to summarize for everyone, the Paradise MI trial compared sacubitril/valsartan with ramipril and its effect on reducing heart failure events after an MI in more than 5,600 patients with an acute myocardial infarction complicated by LV systolic dysfunction, pulmonary congestion, or both. Now in today's paper, what Dr. Mehran and colleagues found was that among patients with a recent AMI and LV systolic dysfunction, heart failure are both, sacubitril/valsartan decreased the risk of coronary related events by 14% as compared with ramipril over a median follow-up of 22 months. The reduction in coronary events occurred with a favorable safety profile.

Dr Greg Hundley:

Wow, Carolyn, very interesting. Another indication perhaps for sacubitril/valsartan, especially relative to ACE inhibitors. So what does this mean for us clinically?

Dr Carolyn Lam:

Well, the results really cause us to consider if in addition to antiplatelets and lipid lowering therapies, sacubitril/valsartan may be explored as a potential agent to mitigate the residual risk in survivors of AMI. Of course, dedicated studies are necessary to confirm this finding and elucidate its mechanism.

Dr Greg Hundley:

Oh, very nice, Carolyn. Well, my first paper comes to us from the World of Preclinical Science and Carolyn, this study evaluated the scavenger receptors stabilin-1 and stabilin-2, proteins that are preferentially expressed by liver sinusoidal endothelial cells. Now, they mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. And studies suggest that stabilin-1 and stabilin-2 may impact atherosclerosis. So in this study, the investigative team led by Professor Cyrill Géraud from the University Medical Center and Medical Faculty in Mannheim, Heidelberg comprehensively studied how targeting stabilin-1 and stabilin-2 affects atherosclerosis.

Dr Carolyn Lam:

Huh. All right, nicely explained. And so what did they find, Greg?

Dr Greg Hundley:

Right, Carolyn. So inhibition of evolutionary conserved class H scavenger receptors, stabilin-1 and stabilin-2, reduced aortic plaque burden in preclinical models and athero protection was mediated likely through down regulation on transcriptional factor ERG1 in monocytes by multifaceted plasma protein changes. And then finally, Carolyn transforming growth factor beta induced periostin, reelin, and they are novel ligands of stabilin-1 and stabilin-2 and are implicated in the development of atherosclerosis.

Dr Carolyn Lam:

Okay. Wow. Could you give us a take home message, please Greg?

Dr Greg Hundley:

Right. Carolyn, I knew you had asked me this. So here we go. Monoclonal, anti-stabilin-1 and anti-stabilin-2 antibodies provide a novel approach for the future treatment of atherosclerosis. And in the future, perhaps the plasma proteome composition may serve as a predictive factor, biomarker or surrogate parameter for cardiovascular disease in patients.

Dr Carolyn Lam:

Wow. Thanks Greg. My next paper is a true story of discovery. Now I could ask you what you know about the condition hypertension with brachydactyly type E... Greg, I love that expression. I wouldn't be able to answer that too. So let me tell you the story. So hypertension with brachydactyly type E is an autosomal dominant Mendelian disease resembling essential hypertension. Untreated patients die of stroke by the age of 50 years. Now, these authors had previously demonstrated a gain of function phosphodiesterase 3A gene mutations that caused the condition by increasing peripheral vascular resistance.

They studied a large family with the condition earlier and were puzzled that cardiac hypertrophy and heart failure did not occur despite the decades of hypertension. And so they hypothesized that in the heart, this phosphodiesterase 3A or PDE3A mutations could be protective. Isn't that neat? And so corresponding authors, Doctors Bader, Klussmann, Bähring and Hübner, all from the Max Delbruck Center for Molecular Medicine in Berlin, Germany. So they studied new patients as well as CRISPR-Cas9 engineered rat models of this condition of hypertension with brachydactyly type E. And they comprehensively phenotyped all of them with the human induced pluripotent stem cells carrying these PDE3A mutations as well. So analyzing all of this from cells to new patients to CRISPR-Cas9 models.

Dr Greg Hundley:

Wow, Carolyn, what an interesting story. So what did they find?

Dr Carolyn Lam:

So while in vascular smooth muscle, the PDE3A mutations caused hypertension, in the hearts, they conferred protection against hypertension-induced cardiac damage, hypertrophy and heart failure. The mechanism involved long-term adaptations of mRNA and protein expression as well as calcium cycling. Non-selective PDE3A inhibition was a final short term option in heart failure treatment to increase cardiac cyclic AMP and improve contractility. So the data argued that mimicking the effect of PDE3A mutations in the heart rather than non-selective PDE3 inhibition was cardioprotective in the long term. And these findings could indeed facilitate the search for new treatments to prevent hypertension-induced cardiac damage. This is discussed in a really lovely editorial by Dr. Chiong, Houslay, and Lavandero.

Dr Greg Hundley:

Very nice, Carolyn. Wow. What another... we have such great articles from the World of Preclinical Science. Beautiful description as well. Well, we have some other articles in the issue, particularly from the Mailbag. And we have a Research Letter from Professor Thiagarajan entitled “Yield of Cardiac MRI in a pre-participation cohort of Young Asian males with T-Wave inversion.”

Dr Carolyn Lam:

Interesting. There's an exchange of letters between Dr. Xu and Huang regarding the article associations of dietary cholesterol, serum cholesterol and egg consumption with overall and cause-specific mortality with a systematic review and updated meta-analysis. There is a Perspective piece by Dr. Marcus on Smart watch detected atrial fibrillation, the value in positive predictive value. Isn't that interesting? And now onto that very, very important question of anticoagulation in patients with kidney disease. Can't wait. Let's go, shall we?

Dr Greg Hundley:

You bet. Carolyn. Welcome listeners to our December 6th feature discussion. And we have with us today Dr. Sean Pokorney from Duke University in Durham, North Carolina, and our associate editor, Dr. Shinya Goto from Tokai University in Isehara, Japan. Welcome gentlemen. Well, Sean, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Sean Pokorney:

Yeah, absolutely. Thanks for having me to discuss the renal AF trial. And so I would say that the background information to the study was that we know that atrial fibrillation is an incredibly common condition in patients with chronic kidney disease. And the decision of anticoagulation in patients with end-stage kidney disease, on hemodialysis is really quite complex because these patients are at high risk for stroke and they're at high risk for bleeding. There are concerns with warfarin around calcific uremic arteriolopathy or calciphylaxis and there have been some data including from the original Aristotle trial that apixaban was even more favorable in terms of bleeding reduction relative to warfarin in patients with more advanced chronic kidney disease.

Although patients with creatinine clearance less than 25 were excluded from Aristotle and really all patients with endstage kidney disease on hemodialysis have been excluded from all trials of atrial fibrillation in the past. And so we really wanted to evaluate the safety of apixaban versus warfarin in patients with end-stage kidney disease, on hemodialysis. And the hypothesis was that apixaban was going to be non-inferior to warfarin with respect to safety in terms of major or clinically relevant, non-major bleeding in these patients with atrial fibrillation and end stage kidney disease on hemodialysis.

Dr Greg Hundley:

Thanks so much, Sean. And you've mentioned the renal AF trial. So could you describe for us, for your, I guess, substudy, what was the study population? Who did you include and describe for us also your study design?

Dr. Sean Pokorney:

Yeah, absolutely. So the trial included patients who had end-stage kidney disease, and/or on hemodialysis, as well as having concomitant atrial fibrillation. And the patients had to have a CHA-VASc score greater than equal to two. All of the patients had to be on hemodialysis for at least three months. So these were chronic hemodialysis patients. And the study design was an open label randomized trial that was 1:1 randomization between apixaban and warfarin with blinded outcome evaluation. And again, the primary endpoint of the study was major or clinically relevant non-major bleeding based on ISTH definitions. And there were secondary endpoints looking at stroke, systemic embolism, death, medication adherence, and I think a really important sub-study looking at PK data. And the goal was to have 50 patients where we included PK data that was going to more represent what chronic apixaban dosing data would look like in these patients with end-stage kidney disease on hemodialysis.

And originally the goal of the trial was to include over 700 patients. Originally we were trying to include 762 patients based on our initial power calculations to achieve true non-inferiority. Unfortunately, the trial enrollment was low and so the trial was ultimately stopped prematurely at 154 patients, although we were able to include the original targeted 50 patients in the PK substudy. The dosing that we used in the renal AF trial was 5 mg of apixaban twice daily unless patients had a second dose-reduction criteria in addition to chronic kidney disease. So the fact that they had end-stage kidney disease and were on hemodialysis counted as one dose reduction criteria and patients that were under 60 kilograms or less were 80 years of age or older, who had then a second dose-reduction criteria were treated with the 2.5 mg twice daily dosage. And this was important to note because this is different than the dosage that was used in the AXADIA-AFNET trial.

Dr Greg Hundley:

Very nice. And so Sean, what did you find?

Dr. Sean Pokorney:

Yeah. So again, a lot of this data is really exploratory because of the limited sample size, we weren't really able to definitively conclude anything about the major or clinically relevant non-major bleeding rates. I would say that some of the key findings that we saw was that there were high rates of major or clinically relevant non-major bleeding in both arms of the trial and one year bleeding event rates were 25% in the warfarin arm and 31% in the apixaban arm. And again, there was no statistically significant difference, although again, this is really exploratory. I would say that some of the other interesting findings that we saw was that there were very low rates of ischemic and hemorrhagic stroke in this patient population. Again, there were 82 patients randomized to apixaban, 72 patients randomized to warfarin. And there was a difference in the randomization because of the stratification by site that was performed with the randomization.

And so within the 82 patients that were randomized to apixaban, the patients, there was one ischemic stroke and one hemorrhagic stroke. There were no hemorrhagic strokes in the warfarin population and two ischemic strokes. Another key finding was the high rates of mortality in this patient population. So 26% of the apixaban patients experienced a mortality event, 18% in the warfarin arm. So again, the mortality rates in these patient populations were extremely high. I would also emphasize some of the data from the PK analysis. So we looked at the PK analysis in two different ways. For the patients that were treated with the 5 mg dose of apixaban, the PK data showed that there was consistent overlap in the steady state concentration at one month compared to patients in the Aristotle trial that had really mild to moderate, moderate to severe and severe chronic kidney disease.

And so there was a consistent overlap in those steady state concentrations between the end-stage kidney disease population on hemodialysis and the chronic kidney disease population who benefited from a apixaban in the Aristotle trial. Similarly, in the 2.5 mg apixaban dose, the patient who had a second dose reduction criteria in addition to chronic kidney disease, those patients had consistent steady state concentrations of apixaban relative to patients with mild to severe chronic kidney disease.

Dr Greg Hundley:

Very nice. Well thank you so much, Sean. And listeners, now we're going to turn to our associate editor, Dr. Shinya Goto. Shinya, can you, sort of, highlight for us some of the interesting findings that you see from these study results that Sean just presented?

Dr. Shinya Goto:

Thank you, Greg. Thank you, Sean for your wonderful summary of your study. We had a great discussion with an editor for this paper. As Sean pointed out, this is a kind of underpowered trial or just terminated early, hypothesis was not tested in the trial. But this population of patient clearly needs a real-world clinical trial, patient with atrial fibrillation, end-stage kidney disease, on hemodialysis; things a clinician could do. In some country, nephology society defined warfarin contraindicated in this population. As Sean pointed out, whether the development of this trial include this high-risk population patient. So we had a discussion whether the underpowered trial provided something or nothing may be better than something just provided here. Our consensus finally reached was, this limited trial still provide something like, you have to make a decision to use the anticoagulation. I mean, that the apixaban might be still used due to the PK data. That is the kind of interesting point of this trial.

Dr Greg Hundley:

Very nice Shinya. Well, Sean, turning back to you and Shinya with that nice lead in really, Sean, what do you think is the next study that needs to be performed in this sphere of research?

Dr. Sean Pokorney:

Yeah, absolutely. I think this is a challenging patient population to study. And again, our trial, the renal AF trial stopped early. Unfortunately, the AXADIA-AFNET 8 study also stopped early, which was also looking at apixaban versus warfarin outside the US and Europe. And so again, it is a challenging patient population to study. But again, I also think it's a really important population to study because one of the main unanswered questions in this population is whether or not they should receive anticoagulation. And so I think that ultimately more work and additional studies trying to determine whether or not these patients truly benefit from anticoagulation or stroke prevention, I think is really one of the critical directions that we need to take the field in.

Dr Greg Hundley:

And Shinya, do you have anything to add?

Dr. Shinya Goto:

Well, I fully agree with Sean. I mean, this is a very challenging area and still raising the question whether anticoagulation is necessary or not by your study. Maybe next generation oral anticoagulant such as Factor XI inhibitor that is more elevated to contact pathway may be beneficial. So we really need a good clinical study in this very important and known answered area.

Dr Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Dr. Sean Pokorney from Duke University in Durham, North Carolina and our own associate editor, Dr. Shinya Goto from Tokai University in Japan for bringing us the results of this randomized open-label trial of apixaban versus warfarin in patients with chronic kidney disease on hemodialysis, revealing high rates of bleeding in both groups, but due to low enrollment, was unable to identify its non-inferiority endpoint. It's important to note, however, as both our author and editorialists have identified further research is really needed in this area to really examine the efficacy of anticoagulation for stroke prevention in this high-risk patient population.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.

Dr. Greg Hundley:

Circulation November 29, 2022 Issue

28 november 2022 | 25 min

This week, please author Gemma Figtree and Associate Editor Nicholas Mills as they discuss the Frontiers article "Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development."

Dr. Greg Hundley:

Welcome listeners to this November 29th, 2022 issue of Circulation On the Run. I am one of your hosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder this week's feature discussion very interesting. It is a state of the art review and it involves noninvasive plaque imaging and really how we might assess plaques to evaluate whether coronary artery disease is accelerating. Very important information by a large group of clinician scientists that will develop programs that, maybe, can be used in therapeutic drug development.

Dr. Peder Myhre:

That's so interesting, Greg.

Dr. Greg Hundley:

Right. A great group of individuals all put together, but before we get to that interesting feature discussion how about we grab a cup of coffee and start with some of the other articles in the issue? How about this week I go first?

Dr. Peder Myhre:

Go ahead Greg.

Dr. Greg Hundley:

Peder, these authors led by Marianna Fontana from University College London Medical School sought to characterize changes in the clinical phenotype of 1,967 patients with a diagnosis of transthyretin cardiac amyloidosis over the last 20 years enrolled and participating in the National Amyloidosis Center from 2002 to 2021.

Dr. Peder Myhre:

Oh yes, Greg, please. This cardiac amyloidosis we have to learn more about it. Please, tell me what did they find.

Dr. Greg Hundley:

Right, Peder.

First, there's been a substantial increase in the number of patients diagnosed with transthyretin amyloid in recent years. This is associated with greater proportions of patients referred following cardiovascular magnetic resonance imaging and bone scintigraphy scans. Second, transthyretin amyloid patients are often now being diagnosed much earlier in their disease process, as evidenced by a shorter duration of symptoms prior to diagnosis, milder stages of disease, and more favorable structural and functional echocardiographic changes at the time of diagnosis. Then, finally, mortality in these transthyretin amyloids patients has improved substantially in recent times aside from any potential benefits from disease modifying treatment or participation in clinical trials.

Dr. Peder Myhre:

Wow. Greg, over the course of 20 years we have seen some differences in the diagnosis or cardiac ATTR amyloidosis, so what would you say are the take home messages from this paper, Greg?

Dr. Greg Hundley:

Right, Peder.

Transthyretin amyloid is now often diagnosed earlier in the disease process with improved prognosis. I think, more data needed to guide decisions on in whom and when to initiate treatment and then which treatments should be used at each stage of the disease. Peder, along with this article there's an excellent editorial by Doctors Patel and Maurer entitled “The Future for Patients with Transthyretin Cardiac Amyloid is, It's Looking Brighter.”

Dr. Peder Myhre:

Okay. Greg, I'm going to continue in the field of clinical research and this paper actually describes a new ablation technique for ventricular tachycardia. Isn't that exciting?

Dr. Greg Hundley:

Absolutely.

Dr. Peder Myhre:

The paper comes to us from corresponding author Miguel Valderrabano from Houston Methodist Hospital in Texas and is entitled “Substrate Ablation by Multi-vein, Multi-balloon Coronary Venous Ethanol for Refractory Ventricular Tachycardia and Structural Heart Disease.” Ablation of ventricular tachycardia, VT, in the setting of structural heart disease often requires extensive substrate elimination, which is not always achievable by endocardial radiofrequency ablation and epicardial ablation is not always feasible. The left ventricle venous circulation allows vascular access to reach intramural substrates of VT in the context of myocardial infarction or non-ischemic scar, where radiofrequency ablation has limited success. Greg, in this study the authors enroll patients with ablation refractory VT and used phonography and epicardial mapping to perform a double balloon venous ethanol ablation. That is, by blocking flow with one balloon and injecting ethnol via this second balloon.

Dr. Greg Hundley:

Peder, what a beautiful description and very interesting strategy to address this situation.

What did they find?

Dr. Peder Myhre:

Greg, after the venous ethanol ablation vein maps and epicardial maps showed elimination of abnormal electrograms of the VT substrate an intracardiac echocardiography demonstrated increased intramural echodensity at the target lesions of the 3D maps and at one year of follow up VT recurrence occurred in seven patients, which translates into a success rate of 84%. The authors conclude that multi-balloon multi-vein intramural ablation by venous ethanol ablation can provide effective substrate ablation in patients with ablation refractory VT in the setting of structural heart disease over a broad range of left ventricular locations.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful description. Excellent.

Well, this next paper Peder comes to us from the world of preclinical science and these authors led by Professor Christine Sideman from the Harvard Medical School evaluated alpha-kinase 3. Now, alpha-kinase three is a muscle specific protein in which loss of function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults. At presence the muscular functions of alpha-kinase 3 remain poorly understood, so to address this dilemma these investigators explored the punitive kinase activity of alpha-kinase 3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell derived cardiomyocytes. Mice and human patient tissues.

Dr. Peder Myhre:

Okay, Greg.

This sounds like impressive basic science work, so what did the authors find.

Dr. Greg Hundley:

Right, Peder.

Damaging variance in alpha-kinase 3 encoding an abundant muscle specific protein caused both neonatal and adult onset cardiomyopathies and led to both ventricular dilation and hypertrophy. Now, although alpha-kinase three contain an alpha kinase domain the team showed that it lacks catalytic activity and is really a pseudo kinase. Then finally, Peder, alpha-kinase 3 localizes to both the nuclear envelope of cardiomyocytes and the M-band of the sarcomere where it regulates the expression and localization of myomesins, myomesin 1 and myomesin 2, and additional M-band proteins important for sarcomere protein turnover.

Dr. Peder Myhre:

That is a beautiful summary, Greg. Since you did so well at summarizing this difficult topic, I'm not going to ask you what a clinical implications, but rather to take home messages here.

Dr. Greg Hundley:

Very nice. Glad you asked Peder.

First, alpha-kinase 3 cardiomyopathy may cause impaired contractility and ventricular dilation due to miss localization and dysregulation of myomesin proteins which are critical for force buffering in cardiomyocytes. Next, alpha-kinase 3 cardiomyopathy may cause hypertrophy due to dysregulation of key M-band proteins, which are important for sarcomere protein turnover. Then finally, therapeutic strategies to restore cardiomyocyte force buffering functions and sarcomere protein turnover may ameliorate disease phenotypes in patients with alpha-kinase three cardiomyopathy.

Dr. Peder Myhre:

Thank you Greg.

The next paper is also from the field of preclinical science and it is about the Hippo-YAP signaling pathway which maintains sinal atrial node homeostasis. It comes to us from the corresponding author Jun Wang from the University of Texas Health Science Center at Houston. Greg, this paper is not about hippos, but it is about the Hippo signaling pathway, which is known to control organ size and growth in animals and humans. These authors sought to investigate this pathway in relation to the sinal atrial node, i.e. The sinus node. As you know Greg, the sinal atrial node functions as the pacemaker of the heart initiating rhythmic heartbeats. Despite its importance the sinal atrial node is one of the most poorly understood cardiac entities, because of its small size and complex composition and function. To uncover the function of Hippo signaling in sinal atrial node the authors use knockout mice and a series of physiological and molecular experiments including telemetry, electrocardiogram recording, echochoreography, calcium imaging, immunostaining, ANA scope, quantitative real time PCR, and western blotting.

Dr. Greg Hundley:

Wow, Peder, that sounds like quite an extensive series of experiments. What did they find?

Dr. Peder Myhre:

Deletion of essential Hippo kinases caused increased fibroblast proliferation and fibrosis in the sinal atrial node. They also found evidence suggesting that Hippo signaling regulates calcium hemostasis in pacemaker cells and that may be partially mediated by the regulation of genes and coding key calcium handling proteins such as RYR2. Finally, the demonstrated that deletion of Hippo effectors in the sin atrial node can rescue the defect previously described.

Greg, the take home messages is that Hippo signaling was found to be an important regulator of the sinal atrial node homeostasis and that this provide insights applicable to the treatment of patients with sinus node dysfunction.

Dr. Greg Hundley:

Ah, beautifully done Peder. Beautifully done.

We've got some other articles in this issue. Let me tell you about a Research Letter. It's from Professor Nazer entitled “Targeted Screening for Transthyretin Amyloid Cardiomyopathy in Patients with Atrial Fibrillation.” Then Tracy Hampton has a whole series of cardiology news highlighting first that primary cilia are critical for exercise induced muscle hypertrophy. This is from the proceedings of the National Academy of Sciences. Next, there's a discussion of whole body reperfusion techniques to restore function in pig organs after death, that comes to us from nature. Then lastly, there's a final article scientists identify diverse pathogenic gene variants that lead to heart failure from the journal science.

Dr. Peder Myhre:

Thank you, Greg.

Finally, there is one Perspective piece by Dr. Rajiv Agarwal from Indiana University School of Medicine entitled “Hydrochlorothiazide versus Chlorthalidone: What is the difference?”

Now, let's move on to the feature discussion that I know you are very excited about, Greg, to learn more about the non-invasive plaque imaging in our frontiers of medicine.

Dr. Greg Hundley:

You bet.

Well listeners, welcome to this feature discussion today on November 29th and we have with us Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. Welcome to you both. Listeners, this is a really interesting feature discussion. It's one of our Frontiers articles that combines where we are in the past, but also where we want to move in the future and a very nice comprehensive review with many articles.

Gemma, can you describe for us the genesis really of this article and what you've been working on?

Dr. Gemma Figtree:

Thanks so much, Greg. Look, I think it's very exciting times at the moment and it's a really important time for all of our community to actually get together in this space. We are driven by trying to make a more efficient process for drug discovery and translation to occur and to basically move into humans in the space of coronary artery disease. We've actually known, obviously, for a long time that the underlying process driving heart attack, but we've not been able to image and treat the actual underlying disease. What this article focuses on is how we actually merge top current technology with policy and approval of drugs. We are very excited about the team of over 20 different institutes around the world trying to work on the best measures of corona artery disease as the disease itself.

Dr. Greg Hundley:

Very nice. Now, help us understand different techniques and why is this a frontier?

Dr. Gemma Figtree:

Look, I think it's a mixture of the fact that, obviously, we're getting great advances in noninvasive imaging techniques that allow us to actually measure plaque burden, but also plaque characteristics. In the case of drug translation this is an absolutely fundamental piece. You can transform a clinical trial where you can look at the underlying pathology and be able to enrich trials or be able to look at the effect of trials of a new drug in humans.

It's really important to acknowledge the fact that humans are really the only animal on the planet that get corona artery disease itself. To be able to translate some of the exciting new drugs that target the plaque itself and work synergistically with some of our agents on cholesterol, and blood pressure, et cetera, we really need to have these measures of coronary artery disease itself. It's a combination of the technology, but also how we apply it to a clinical trial and then how do we work with our regulatory authorities and policy advisors around getting this into humans. We really aiming to try to accelerate the development of drugs that can try to tackle our greatest burden of cardiovascular disease around the world.

Dr. Greg Hundley:

I'm hearing cardiovascular disease, I also heard in their imaging and lots of different modalities, and then I heard regulatory bodies. Are you thinking maybe we need standards?

Dr. Gemma Figtree:

That's exactly right. I think, importantly, whilst there's a lot of exciting technology and a lot of us are pursuing potentially different avenues of this we also need to be able to coordinate and develop a simple and harmonized approach that's able to be applied across the world in an equitable fashion. Whilst we, obviously, have developing exciting new toys we have to make sure that a measure that we want to work with regulatory authorities is able to be applied in all of our countries around the world to make sure that the drug development is applied in an equitable fashion.

Dr. Greg Hundley:

Very nice. Well listeners, next we're going to turn to our associate editor, Dr. Nick Mills. Nick, you evaluate many manuscripts. What attracted you to this particular paper? Also, help us put it in the context of why you think it's a new frontier that is emerging or needs to emerge in cardiovascular disease.

Dr. Nick Mills:

Yeah, thanks Greg.

Three things, the expertise of this group, the focus and novelty of the topic, and the fact that it's a really timely issue Gemma just outlined. Gemma a phenomenal job bringing together people from all over the world to tackle this area that includes imaging expertise, drug development expertise, industry that gives it a very balanced and diverse range of views and marks it out from other reviews that focus on particular imaging modality. Novelty's really important, but timeliness as well. We've seen in the last five years major breakthroughs in the treatment of diabetes and heart failure. But, drug development of coronary heart disease is stalling. I cannot remember the last time I went to a really exciting late breaking trial on a new development for coronary heart disease that has changed the outcomes for patients. We do need to rethink.

Gemma's absolutely right, that requires us to work with regulators to stimulate industry involvement in drug discovery, and delivery, and testing. This is occurring at a time where we've got more fabulous imaging modalities then we've ever had before. Critically, they're noninvasive. They're easy for patients, they're easy for serial testing, and that really opens up many opportunities. It's the fact that it's timely, novel, great expertise, and also really exciting area for cardio of medicine.

Dr. Greg Hundley:

Very nice. Well listeners, we're going to go back to Gemma. Gemma, what do you think are some of the next research studies that we need to perform to support what we're trying to indicate today in this Frontiers article?

Dr. Gemma Figtree:

Yeah. Thanks very much, Greg.

I think, ultimately, the features that need to be taken into consideration for a surrogate endpoint to be approved by our regulatory authorities need to be considered. There are many drug companies, but also individual investigators with ideas of drugs to take forward. What we need to do is make sure for all those studies that we're actually working together and ideally having a harmonized endpoint for use there. I think, working early with regulatory authorities is going to be key.

I think, if you actually, within the tables that are presented in the paper we demonstrate very clearly that these measures of plaque, particularly, the CT coronary angiography measures of low attenuation plaque are pretty ready for consideration by regulatory authorities. I think, agents that we already know work to reduce mortality, such as statins, we know that they actually have direct effects on plaque both from a pathophysiological perspective, but also from these imaging studies. We know that that change in the plaque characteristics and volume predict the outcomes.

In a sense, we've got a fabulous array of data already. In fact, new agents that have come through have also demonstrated effects on these measures. I think, by bringing all of this together in this article we're already in a position to work with regulatory authorities to see what is needed next. I think, listening to that's going to be very important. I do think that the next steps are really going to be working with effectively, I guess, our colleagues to make sure that we don't continue to rapidly advance the measures whilst losing the opportunity to work with regulatory authorities.

In answer your question about the research side of things, I think, as we gather more and more information about this we have to make sure that phase two studies are then linked and we can retrospectively see how they predict the outcomes in phase three studies, but I firmly believe that we're in a position that over the next couple of years we should be able to do harmonized approaches at phase two studies and then as a whole community be able to look at how that predicts outcome and work with our regulatory authorities to get more confidence in these endpoints as key. This is all driven by my clinical observations and interest in people who look up and say, "Why me" when they're having a heart attack? In our community where we're getting very good primary prevention we see up to 25% of our heart attack patients having plaque events and catastrophic heart attacks without those traditional risk factors that would've worn them.

Part of this is also opening up avenues for driving new diagnostic tools that can pick up the disease itself. Picking up... Treating coronary disease as the disease and using that for diagnostic and therapeutic purposes, I think, is a great opportunity to tackle this great burden that we're currently not winning with.

Dr. Greg Hundley:

With the group that you had assembled were there any primary suggestions on how to unite some of these efforts on a global scale? I really liked, very early in our conversation today, you mentioned that and I wondered what this collective you assembled may have suggested.

Dr. Gemma Figtree:

Yeah. Look, I think at the moment it is a collection of experts. I haven't quite figured out the name for such a thing, but we are also working with some of the leading organizations now to try to also make sure we get their auspicing of the concepts and how to best do that. I think, by not coming out of one particular organization and evolving from the members itself, and in particular, having industry and regulatory authorities involve and drug discovery experts right from the beginning has been fantastic. Also, making sure that we have that pragmatic approach and that consideration of equitable access. Particularly, making sure that any phase two trial can be done or enrichment for phase three trial can be applied right around the globe and make sure we get diversity of patients enrolled in these studies.

Dr. Greg Hundley:

Very nice. Coming back to you, Nick, any additional thoughts to build on Gemma's comments here?

Dr. Nick Mills:

Well, to say as someone who's worked in the field of cardiac biomarkers for many years and felt that we could tackle this with the regulators and drug delivery, but I've seen inflammatory biomarkers, lipoproteins come and go without changing. I think, it's just a really exciting opportunity that we now have the ability to phenotype an image, coronary artery disease noninvasively, but a highly specific surrogate endpoint that we've never had before. It's why I'm starting to do research into DT.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills for bringing us this really provocative Frontiers article highlighting a new strategy. Bringing together regulators, leading researchers, and industry to advance new methodologies and trying to tackle globally how we might address atherosclerosis.

Well, on behalf of Peder, Carolyn, and myself we want to wish you a great week and we will catch you next week on The Run.

Circulation November 22, 2022 Issue

21 november 2022 | 20 min

This week, please author Jung-Minh Ahn and Associate Editor Emmanouil Brilakis as they discuss the article "Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial."

Dr. Greg Hundley:

Welcome, listeners to this November 22 issue of Circulation on the Run. And I am Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway, and also a social media editor interpolation.

Dr. Greg Hundley:

Well Peder, our feature this week, we are reviewing a comparison between drug eluting stents and bypass surgery for multi vessel coronary artery disease. Really an extended follow up from the Vest trial.

Dr. Peder Myhre:

I can't wait, Greg.

Dr. Greg Hundley:

Right. But before we get onto that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?

Dr. Peder Myhre:

Sure, I'd love to. And the first paper today is a clinical one and it is entitled, “Efficacy of a Drug Eluting Stent Versus Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease: Primary Results of the Eminent Randomized Trial.” And it comes to us from the corresponding author Yann Gouëffic from Groupe Hospitalier Paris St. Joseph in France. So Greg, a clear patency benefit of a drug eluting stent over bare metal stents for treating peripheral artery disease of the femoropopliteal segment has not been definitely demonstrated. But today's paper publishes the primary results of the eminent randomized trials, which was designed to evaluate the patency of the Eluvia drug eluting stent. And this stent is a polymer based paclitaxel eluting stent and it was compared with bare metal stents for the treatment of femoropopliteal artery lesions. In fact, with 775 patients, Eminent is the largest randomized trial of drug eluting stent treatment for symptomatic femoropopliteal arterial disease to report patency to dates.

Dr. Greg Hundley:

Very nice, Peder. So describe for us, what were the results of this very large randomized clinical trial?

Dr. Peder Myhre:

Sure, Greg. So the primary effectivity outcome was primary patency at 12 months, defined as independent core laboratory assessed duplex ultrasound peak systolic velocity ratio less than or equal to 2.4 in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesions. And primary effectiveness analysis from the Eminent randomized study demonstrated superior one year primary patency for the Eluvia drug eluting stent versus bare metal stent. And that is 83.2% versus 74.3% with a P value less than 0.01. And this treatment was associated with a greater incident of Rutherford classification improvement without the need for re-intervention, and functional parameters demonstrated improvements in both groups, and there were no statistical difference observed in one year mortality between patients treated with the Eluvia drug eluting stents and bare metal stents. So in summary, this high level evidence supports the one year benefit of polymer based paclitaxel elusion over bare metal stents to treat superficial femoral artery and/or proximal popliteal artery lesions. What'd you think of that, Greg?

Dr. Greg Hundley:

Very nice. So sounds like for peripheral arterial interventions, a benefit from the polymer based paclitaxel eluting stents.

Dr. Peder Myhre:

Exactly. And there's also an editorial putting these results in context from Doctors Mosarla and Secemsky entitled, “From Imperialism to Eminence: The Noble Rise of the Second Generation Peripheral Drug Eluting Stents.”

Dr. Greg Hundley:

Excellent, Peder. Well, my article comes to us, Peder, from the world of preclinical science. And Peder, these investigators led by Professor Volker Spindler from University of Basel evaluated arrhythmogenic cardiomyopathy. And as you know, arrhythmogenic cardiomyopathy is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life threatening arrhythmias. So a substantial proportion of arrhythmogenic cardiomyopathy is caused by mutations in genes of the desmosomal cell to cell adhesion complex, but the underlying mechanisms are not well understood. So to address this, the team mutated the binding site of desmoglein two, a crucial desmosomal adhesion molecule in cardiomyocytes. This desmoglein two W2A mutation abrogates the tryptophan swab, a central interaction mechanism of desmogenin two based on structural data. Now, the impaired adhesive function of this DSG2W2A was confirmed by cell to cell dissociation assays and for spectroscopy measurements by atomic force microscopy.

Dr. Peder Myhre:

Wow. We continue to learn more about this disease, arrhythmogenic cardiomyopathy. And this sounds so interesting. Greg, please tell me what did they find?

Dr. Greg Hundley:

Right, Peder. So they found that the DSG2W2A mutation impaired binding on the molecular level and compromised intercellular adhesive function. Now, mice bearing this mutation, developed a severe cardiac phenotype recalling the characteristics of arrhythmogenic cardiomyopathy including cardiac fibrosis, impaired systolic function, and arrhythmia. Now, a comparison of the transcriptome of the mutant mice with arrhythmogenic cardiomyopathy patient data suggested deregulated integrin alpha V beta six and subsequent TGF beta signaling as a driver of cardiac fibrosis. Now accordingly, blocking integrin alpha V beta six led to reduced expression of pro-fibrotic markers and reduced fibrosis formation in the mutant animals in vivo.

Dr. Peder Myhre:

Oh, this is so important mechanistically. And Greg, can you please tell us something about the clinical importance of these findings?

Dr. Greg Hundley:

Right Peder, just like Carolyn always driving at that clinical significance. So these authors show now that disruption of desmosomal adhesion is sufficient to induce a phenotype which fulfills the clinical criteria to establish the diagnosis of arrhythmogenic cardiomyopathy confirming the dysfunctional adhesion hypothesis. Now mechanistically, deregulation of integrin alpha V beta six and TGF beta signaling was identified as a central step in the process toward developing fibrosis. And then finally, a pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. So perhaps, new information leading to future therapeutic strategies to halt myocardial fibrosis in patients with arrhythmogenic cardiomyopathy.

Dr. Peder Myhre:

Oh wow. What an amazing issue this is, Greg, and we actually have even more in the mail bag. We have a Perspective piece by Dr. Prystowsky entitled “Rate versus Rhythm Control for Atrial Fibrillation, Has the Debate Been Settled?” And we have some Cardiology News by Bridget Kuehn entitled, “Fitness Rather than BMI Appears to be Better Predictor of Survival for Women with Heart Disease.” I'm sure Carolyn would love to read that one. And in this paper, Bridget Kuehn discusses a new study published in European Journal of Preventive Cardiology.

Dr. Greg Hundley:

Very nice, Peder. Well, I've got a couple other articles in the issue. First, Dr. Tonelli has a Primer entitled, “Increasing Societal Benefit from Cardiovascular Drugs.” And then Professor Januzzi has a Research Letter entitled, “Association Between Sacubitril/Valsartan Initiation in Mitral Regurgitation Severity and Heart Failure with Reduced Ejection Fraction: The PROVE HF Study.” Well, now let's get on to that feature discussion in this issue to discuss PCI versus CABG for multi vessel coronary artery disease.

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Welcome listeners to this November 22nd feature discussion and we have with us today Dr. Jung-Min Ahn from Seoul, South Korea and our own associate editor, Dr. Manos Brilakis from Minneapolis, Minnesota. Welcome gentlemen. Jung-Min, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Jung-Min Ahn:

Thank you, Greg. So the everolimus-eluting stent Freedom trial, showed a higher mortality after PCI than after bypass surgery in multi vessel disease. However, these findings maybe delimited predictability in the contemporary practice because such trials use the first generation drug stent which may have higher rate of stent thrombosis. The Press trial is the first randomized trial using the second-generation drug eluting stent. The initial approach was published in New England Journal of Medicine five years ago. So they showed that the 4.6 years of follow the PCI with everolimus-eluting stents showed a significantly higher rate of prime endpoint deaths, MI, the target revascularization, but overall mortality, there was no significant difference. So the hypothesis that, in a long term follow, more than 10 years follow, so we want to see the mortality difference between the PCI with the second generation everolimus-eluting stent versus bypass surgery. So we designed this extended follow trial best studies.

Dr. Greg Hundley:

Very nice, Jung-Min. And can you describe for us the study design, and who was your study population, and how many subjects did you enroll?

Dr. Jung-Min Ahn:

Actually, this study is the extended follow original Press trial, enrolled 880 patients from mostly Korea, China, Malaysia, and Thailand. So the study population was Asian population with a symptomatic or symptomatic coronary artery disease with angiopathy confirming the multi vessel coronary artery disease population. One additional criteria is the patient with coronary artery disease should report PCI and bypass surgery decided by the attending physicians and surgeons.

Dr. Greg Hundley:

Thank you, Jung-Min. And so, can you describe for us your study results?

Dr. Jung-Min Ahn:

Yes. During the extended follow-up study we found that there is no significant difference between the PCI with everolimus-eluting stent and bypass surgery regarding prime endpoint deaths, MI, vascularization. In addition, more importantly, we reduced the compost endpoint of death, MI, stroke. There was no significant difference in addition regarding the mortality. Also, there is no significant difference during the long term follow.

Dr. Greg Hundley:

Really interesting results, Jung-Min. Did you notice any differences in men versus women or in younger versus older individuals?

Dr. Jung-Min Ahn:

In our sub-group analysis, there is no interaction according to the sub-groups except the diabetic sub-groups. In diabetics and long term outcomes, have interaction with the treatment assignment regarding the primary endpoint, prime endpoints, death, MI, target vascularization. Even though contrary to the Freedom trial, the overall mortality rate, there is no significant difference between the PCI versus the bypass surgery even in diabetic populations.

Dr. Greg Hundley:

Well thank you so much, Jung-Min. And now listeners, we're going to turn to our Associate Editor, our expert in the area of advanced percutaneous coronary artery interventions, Dr. Manos Brilakis from Minneapolis, Minnesota. Manos, you have many papers come across your desk. What attracted you to this particular paper and how do you put its results in the context of other studies that have been performed to compare multi vessel percutaneous coronary artery intervention versus coronary artery bypass grafting?

Dr. Manos Brilakis:

Yeah, thank you, Greg. And again, congratulations to Jung-Min for a great paper. And the reason we were very interested in this paper is because it is an area that is still debated clinically quite extensively. As Jung-Minh mentioned, there is the Syndex trial showing that there was higher mortality amongst the PCI group over long term, but that was done a long time ago with previous generation drug diluting stents, and the data, the contemporary data with recently the currently used DS, is much more limited. So I think the appeal for us, and I think frankly for the practicing interventionalist, is that this paper provides long term outcomes with contemporary drug eluting stents over a fairly large patient population, and it does so fairly well, but there are plus and minuses.

There was no difference in mortality, which continues to be debated. But this paper is fairly equivalent on this respect. And if we see the coupled myo curves, they also look very similar. And there was some differences in death in myocardial infarction to be taken into consideration. But all this information is important for deciding for each patient we treat right now, which is the best way to go in terms of coronary devascularization.

Dr. Greg Hundley:

Very nice. And so, let's circle back next to Jung-Min. What do you see as the next research study really to be performed in this sphere of investigation?

Dr. Jung-Min Ahn:

Thank you, Greg. So I'd like to talk about the future study, but I'd like to say something about the how to do PCI. So what is the difference between the Press trial and previous randomized trial? In the Pres trial, we used the intracoronary imaging in 72% of PCI population. This is a huge higher rate than what was used compared with the previous randomized trial. Only 10% or less than 10% PCI population used intracoronary imaging. So I think to get the comparable research to the bypass surgery, I think we have to optimize the PCR region. What is the best way shortcut to get optimizing PCR region? It could be intracoronary imaging guided PCI, could be one important way to get optimized PCR region. I think this is very important to take a message from the first trial.

Dr. Greg Hundley:

Well, Jung-Min, it sounds like from your description that the application of intracoronary imaging was very important in this study. Do you want to expand on that for our listeners? You know, what were maybe some subgroup analysis results of using intracoronary ultrasound? And then, how would you recommend to our listening audience that that particular technique be applied?

Dr. Jung-Min Ahn:

Thank you, Greg. So I mentioned that the Press trial used the intravascular ultrasound in 72% of PCI. So we analyzed the the PCI with I, without I. PCI with I showed a very comparable primary endpoint and overall mortality rate to the bypass surgery group. But PCI without I showed a significantly higher rate of primary endpoint and overall mortalities. So intravascular ultrasound guided PCI may improve the PCI outcomes and we can compare our clinical outcomes to the bypass surgery.

Dr. Greg Hundley:

Very nice. And Manos, do you have anything to add?

Dr. Manos Brilakis:

Yeah, I think the era of doing multiple huge mega trials may be tough to find these days. I think we may not have big trials comparing those two modalities, but I do agree with Junh Minh. I think the conclusion from this study as well as the previous studies is that you can choose which way to go. But if you're going to go with PCI for example, you do want to make sure that you do the best possible outcome so that you use intravascular imaging, you use physiology. We know from phase three, that use of intravascular imaging was very limited. So if you're going to go with PCI for a specific patient, the decision of course depends on the study's results and the previous studies and the patients' specific preferences. But if you're going to do PCI, you want to take your time to get the best possible result, make sure you can get as complete revascularization as possible because that will translate into better clinical outcomes as well.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank our main author today, Dr. Jung-Min Anh, and our own associate editor, Dr. Manos Brilakis, for bringing us this important study highlighting that in patients with multi vessel coronary artery disease, there were no significant differences between PCI and coronary artery bypass grafting in the incidence of major adverse cardiac events, the safety composite endpoint, and all cause mortality during an extended follow up period. Well, on behalf of Peder, Carolyn, and myself, we want to wish you a great week and we will catch you next week On the Run.

Dr. Greg Hundley:

Circulation November 15, 2022 Issue

14 november 2022 | 24 min

This week, please join authors Qiang Zhang and Matthew Burrage as well as Senior Associate Editor Victoria Delgado as they discuss the article "Artificial Intelligence for Contrast-free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from University of Akershus University Hospital in Norway.

Dr. Carolyn Lam:

Peder, today's feature discussion is on AI for contrast-free MRI. Isn't that so cool, using AI to perhaps understand what we could see only with contrast, but now in a contrast-free manner. Now I know that sound a bit confusing, but I hope very, very enticing, because everyone's going to have to wait for a little while before we get to that interesting feature discussion. And for now, let's talk about some of the papers we have in today's issue, shall we?

Dr. Peder Myhre:

Yes, Carolyn, I can't wait for the feature discussion, but we're going to start with some of the other papers in this week's issue, and we're going to start in the world of preclinical science with a paper looking at human cardiac reprogramming, because Carolyn, direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as one of the promising strategies to remuscularize the injured myocardium. Yet it is still insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails and underlying molecular mechanisms are not really well understood.

Transcriptional factors often act in concert and form tightly controlled networks featuring with common targets among different transcriptional factors. Therefore, missing one component during heart development could lead to heart function defects and congenital heart disease. And in this study by corresponding author Yang Zhou from the University of Alabama at Birmingham, the authors perform transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes to assess additional factors that govern transcriptional activation of gene programs associated with sarcomere contractility.

Dr. Carolyn Lam:

Wow. Really nicely explained. Thanks, Peder. So what did they find?

Dr. Peder Myhre:

So Carolyn, through these computational analysis of transcriptomic data, the authors identified TBX20 as the most under expressed transcription factor in human induced cardiomyocytes compared to endogenous cardiomyocytes. They also demonstrated that TBX20 enhances human cardiac reprogramming and improves contractility and mitochondrial function in the reprogrammed cardiomyocytes.

Dr. Carolyn Lam:

Nice. Could you summarize the clinical implications, please?

Dr. Peder Myhre:

Yes. So the clinical implications are that enhancing the efficiency and quality of direct cardiac reprogramming for human fibroblast is a critical step in the clinical translation of this technology, and better understanding of this synergistic regulation of key cardiac transcription factors during reprogramming will provide new insights into the genetic basis in normal and diseased hearts. Well, Carolyn, please tell me about your next paper.

Dr. Carolyn Lam:

Thanks, and we're moving now to kidney disease. Now end stage renal disease is associated with a high risk of cardiovascular events, but what about mild to moderate kidney dysfunction? Is it causally related to coronary heart disease and stroke? Well, today's authors give us a clue, and it's from corresponding author Dr. Di Angelantonio from University of Cambridge and colleagues who took a very unique combined approach to answer this question.

They first conducted observational analyses using individual level data from four huge population based data sources, namely the emerging risk factors collaboration, Epic CVD, Jillion Veteran Program and UK Biobank. Can you imagine this comprised almost 650,000 participants with no history of cardiovascular disease or diabetes at baseline, yielding almost 43,000 and 15,700 incident coronary heart disease and stroke events respectively during a 6.8 million person years of follow up.

So huge observational study, which they then followed with a Mendelian randomization analyses using a genetic risk score of 218 variants for GFR and involving participants in Epic CVD Million Veterans Program and the UK Biobank.

Dr. Peder Myhre:

Wow, Carolyn, this is a topic that I think many of us have really been wondering and thinking about. The mild to moderate kidney dysfunction, what does it really mean? And what a beautiful study to answer this. So what did they find?

Dr. Carolyn Lam:

First, there was a U-shaped association of creatinine-based GFR with coronary heart disease and stroke with higher risk in participants with GFR values below 60 or more than 105 mills per minute per 1.73 meters squared. Mendelian randomization analyses for coronary heart disease showed an association among participants with GFR below 60, but not for those with GFR above 105.

Results were not materially different after adjustment for traditional cardiovascular risk factors and the Mendelian randomization results for stroke were nonsignificant but broadly similar to those for coronary heart disease. So in summary, in people without manifest cardiovascular disease or diabetes, mild to moderate kidney dysfunction is causally related to the risk of coronary heart disease, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Dr. Peder Myhre:

Thank you, Carolyn, for such a great summary and an important result from that study. I'm going to now take us back to the world of preclinical science and talk about diabetic cardiomyopathy and exercise. And we both know that patients with diabetes are vulnerable to development of myocardial dysfunction, and that exercise, our favorite thing, for maintaining cardiovascular health, especially in patients with diabetes.

And despite a wealth of evidence supporting that cardiometabolic benefits of exercise, the precise exercise responsive signals that confer the beneficial effects of exercise in cardiomyocytes to remain poorly defined. And previous studies have identified fibroblast growth factor 21, FGF21, a peptide hormone with pleiotropic benefits on cardiometabolic hemostasis as an exercise responsive factor.

And in this study from Aimin Xu from the University of Hong Kong, the authors investigated a six-week exercise intervention program in FGF21 knockout mice and wild-type litter mates that all had diabetic cardiomyopathy induced by high fat diet and injection of streptozotocin.

Dr. Carolyn Lam:

Nice. So what did they find?

Dr. Peder Myhre:

Yeah, the authors found that exercise lowers circulating FGF21 levels, therefore remodeling the heart as an FGF21 sensitive target organ. And the protective effects of exercise against diabetic cardiomyopathy are therefore compromised in mice with deficiency of FGF21. They also identified Sirtuin-3 as an obligor downstream effector on FGF21, preserving mitochondrial integrity and cardiac function. Finally, the authors demonstrated that FGF21 induces Sirtuin-3 expression through AMPK-FOXO3 signaling access.

Dr. Carolyn Lam:

So could you put that together for us better? So what are the clinical implications?

Dr. Peder Myhre:

So the clinical implications from this paper is that circulating FGF21 is a potential biomarker for assessment of exercise efficacy in improving cardiac functions. And exercise is a potent FGF21 sensitizer in cardiomyocyte and has the potential to enhance the therapeutic benefits of FGF21 analogs in diabetic cardiomyopathy, and selective activation of FGF21 signal in cardiomyocytes may serve as exercise mimetics and represent a promising targeted intervention for precise management of diabetic cardiomyopathy.

Dr. Carolyn Lam:

Oh my goodness. That is fascinating. Thank you, Peder. Well let's wrap up with what else there is in today's issue. There's an On My Mind paper by Dr. Weir entitled, “The Emperor's New Clothes: Aren't We Just Treating Grades of Heart Failure with Reduced Ejection Fraction.”

Dr. Peder Myhre:

And there is a Research Letter by Dr. James Martin from Baylor College of Medicine entitled “Gene Therapy Knockdown of Hippo Signaling Resolves Arrhythmic Events in Pigs after Myocardial Infarction.”

Dr. Carolyn Lam:

Very nice. Thanks, Peder. So wow, let's go onto a featured discussion on AI for contrast-free MRI and a virtual native enhancement here coming right up.

Dr. Peder Myhre:

Awesome.

Dr. Carolyn Lam:

Now we all know that myocardial scar is currently assessed non-invasively using cardiac MRI with late gadolinium enhancement as what we would call the imaging gold standard. Wouldn't it be amazing to have a contrast-free approach, which could provide the same information with many advantages such as a faster or cheaper scan, and without contrast associated problems? Well guess what? We're about to discuss that today in a feature publication in today's issue, and I am so pleased to have the co first authors with us today. They are Dr. Qiang Zhang and Dr. Matthew Burridge, both from University of Oxford, and to discuss it as well, our senior associate editor, Dr. Victoria Delgado from Barcelona. So welcome, everyone.

Qiang Zhang, could I start with you and ask you, I understand you're a machine learning expert, which means you're probably smarter than all of us here. Could you maybe explain in simple terms what made you and Dr. Burridge do the study?

Dr. Qiang Zhang:

First? Thank you so much, Carolyn and Victoria, for the invitation. As you have mentioned, late gadolinium enhancement, or LGE, has been the imaging gold standard in clinical practice for myocardial catheterization including scar assessment for patients with myocardial infarction. However, LGE requires the injection for gadolinium contrast, and this is cautioned in some patient groups and increases the scan time and cost.

On the other hand, pre-contrast CMR such as Sydney T1-T2 mapping, a gadolinium-free alternative for myocardial catheterization. But their clinical use has been hindered by confounding factors and a lack of clear interpretation. So with our cross deceptor team at Oxford, we developed an artificial intelligence, virtual native enhancement technique VNE.

It can produce a sort of a virtual LGE image but without the need for gadolinium contrast. And we have previously tested it in patients with hypertrophic cardiomyopathy as published in this journal last year. And in this new study together with Matt here, we tested in patients with history of chronic or prior myocardial infarction.

Dr. Carolyn Lam:

Oh wow. Cool. So audience, you heard it. Instead of LGE, we now have VNE, virtual native enhancement. That's super cool. Thank you. Matt, could I bring you in here? So tell us a little bit more about the population you studied and what you both found.

Dr. Matthew Burrage:

Yeah, absolutely. And thank you so much for the invitation as well. So as Chang has said, this was a single sensor study that we performed at the University of Oxford and specifically targeting assessing myocardial scar in patients with a history of chronic or prior MI. So we had two sources for our population data. Well, first we used our real world clinical service data from our institution.

So we screened 11 years worth of patient data for presence of MI. So patients were included. There was a evidence of a previous MI based on an ischemic pattern of LGE, but we specifically excluded patients who had an acute presentation, or if there were features of acute MI on the CMR scan such as presence of myocardial edema or microvascular obstruction. The reason for this is we wanted to keep this as a clean population to avoid the potential confounding effects of myocardial edema or MVO on native T1 values. And so we also excluded other myocardial pathologies such as underlying cardiomyopathies and infiltrative diseases.

A second population dataset came from the OX Army study, which is a single center prospective study of patients presenting with acute MI. And for these patients we used their six month follow up scan to again avoid the confounding effects of edema and pathology. So overall we had a total of 912 patients who have contributed over 4,000 image data sets. The patient characteristics, 81% were male, they had a mean age of 64 years and there were cardiovascular risk factors such as diabetes melitis, hypertension, hypercholesterolemia in 20 to 40% of patients, while just over half had a history of previous revascularization.

We also separately applied the VNE technology to a pig model of myocardial infarction, which was thanks to our collaborator, Rohan Domakuma in the US. And so those were scans performed eight to nine weeks after an induced MI in the LAD territory in a series of pigs. And so this gave us the ability to provide a direct comparison between LGE, VNE, and histopathology in this model.

Dr. Carolyn Lam:

Wow. And results?

Dr. Matthew Burrage:

So what we found and the key results were firstly that VNE provided significantly better image quality than LGE, and this was on blinded analysis by five independent operators from our test data sets. Secondly, the VNE correlated strongly with LGE in terms of quantifying infarct size and the degree of transmurality, so the extent of the MIs in our test data set. We had pretty good overall accuracy of 84% for VNE in detecting scar compared to LGE with no false positive VNE cases.

And finally there was also excellent visuospatial agreement with the histopathology in the pig model of myocardial infarction. So really this, we think, is a technology that provides clinicians with images in a format that firstly they're familiar with, which looks like LGE, provides essentially the same information as LGE, but it can be achieved without the need for any gadolinium contrast agents and can be acquired in a fraction of the time.

So it takes less than one second to generate the VNE image. So as we've said before, we feel there's a lot of potential here for this technology to potentially eliminate the need for gadolinium contrast in a significant proportion of CMR scans, reduced scan times and costs, increased clinical throughput and hopefully improve the accessibility of CMR for patients in the near future.

Dr. Carolyn Lam:

Oh wow. That is tremendous. So first of all, congratulations to both of you. Before I ask Victoria for some thoughts, could I also just check with Qiang Zhang, because all AI algorithms need to be externally validated or surely there's some catch to it, or so-called limitations, or something else you may study. Could you maybe round up by saying is there anything that clinicians should not be applying it to or be aware of some limitations or?

Dr. Qiang Zhang:

Thank you, Carolyn. So a limitation of this study is that the dataset that is used for developing the models, the majority of them are patients around six month after the acute infarction. So where the myocardial infarction is still evolving, which may include residual edema and microvascular obstruction, and that is difficult to assess using the current VNE model.

And also we found it challenging to assess small sub endocardial infarction and actually to address those limitations, we are working on improving the VNE models, training it on even larger data sets and training it on LGE to detect small sub endocardial function. And we will further develop it to detect, for example, acute edema and a microvascular obstruction, and in the meantime develop quality control driven AI models to inform the clinical users of and unreliable results.

Dr. Carolyn Lam:

Wow, thank you. So Victoria, now I'm dying to hear your thoughts. How do you think this fits in the landscape of all AI imaging now?

Dr. Victoria Delgado:

I think that it's an excellent development and I congratulate the others for the article and the proof of concept that we can move away from the late enhancement and the use of gadolinium enhancement. I think that this is a major step forward because as Matt said, they are going to decrease very much the time of scanning and the post processing because is automatically done as far as I understand. So even if you can interpret yourself the amount of so-called virtual enhancement, the system gives you a value for that extension of the virtual in non-gadolinium enhancement. So that reduces very much the variability that can be in each observer if that is done automatically.

But my question to them is also if that can be influenced by the type of scanner that you use, for example on echocardiography, that's much more my field of interest, it depends very much sometimes how the images are processed of which are the vendors that we have used to acquire the images. Is this a limitation for your software? Can you foresee there some variability or is completely independent?

Dr. Qiang Zhang:

Thank you, Victoria. So we are aware of actually the difference of the data produced by different scan of vendors and the advantage of AI-driven methods is that it is data driven. So we plan to incorporate dataset from other vendors so that the trend that VNE models can work with like multiple scanner vendors. This actually will be done alongside the ongoing standardization program of T1 mapping in our group, which is the underpinned technology for VNE. And this is led by Professor Stephan Pitchnik and Vanessa Farrera. And we actually hope the VNE technology as AI driven methods could contribute to a solution to the CMO standardization between the scanner vendor.

Dr. Victoria Delgado:

And another question, if I may follow in this CMR, it has been proposed as a very valuable imaging technique to assess infarct size and to see the efficacy of some therapies to reduce the myocardial infarction size. How do you think that this new methods will impact in future trials and the way we have been interpreting the previous trials, like for example, the one that you use for the validation?

Dr. Matthew Burrage:

Yeah, thanks Victoria. It's a really, really excellent question. I think there's a lot of potential for the new VNE technology to also become a clinical endpoint in some of these trials in terms of reduction in infarct size, because the information that we get is more or less the same as we get from the LGE. So there's lots of potential that we can, again, use this as a biomarker in trials for looking at reduction in infarct size and reperfusion therapies. But it has the benefit that it can be done quicker and without gadolinium contrast.

Dr. Victoria Delgado:

This is amazing guideline and really I would have a lot of questions for them as well. And knowing the literature, for example, in the Scenic center in Madrid that they have been scanning the evolution of myocardial infarction from 0.02 weeks to see how this would translate with your technique. That will be amazing to understand how this can be done.

Dr. Carolyn Lam:

Oh wow, there you go. New research idea right there. Well how about if we end with a very quick question for each of the first authors. So maybe Matt, you could start, I mean is this ready for primetime and clinical use? And if it's not, what needs to be done to get there? In other words, where are you headed as the next step?

Dr. Matthew Burrage:

So again, thank you, Carolyn, that's a really excellent question and I think the next step before this becomes ready for primetime clinical use is validating this technology really across the spectrum of other myocardial pathologies. So the next work that we are developing this on is in patients with acute myocardial infarction, and then extending this to sort of acute inflammatory conditions like myocarditis, other non-ischemic cardiomyopathies, things like amyloidosis as well.

So this will be the next step into rollout and we are looking to track things like VNE burden and how that relates to clinical outcomes, similar to the previous LGE papers have done across different myocardial pathologies, but then ultimately aiming towards clinical rollout within the next few years.

Dr. Qiang Zhang:

Yeah, I think pretty much what Matt has said, we're going to develop the deep learning methods and test it further on pretty much the whole spectrum of commonly encountered diseases, and then more complex pathologies such as acute pathologies like edema, microvascular obstruction, and then we test on large population study like UK Biobank and other prospective clinical trials. And of course the most importantly is to roll out for real world clinical use. And as Matt said, we are aiming to do this within the next two to five years.

Dr. Carolyn Lam:

Wow, this is amazing. Both Victoria and I said thank you, congratulations on this landmark piece of work. Thank you for publishing it in circulation. Audience, thank you for joining us today from Greg, Peder, myself. You've been listening to Circulation on the Run, and don't forget to tune in again next week.

Dr. Greg Hundley:

Circulation November 8, 2022 Issue

7 november 2022 | 22 min

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. And...

Dr. Peder Myhre:

I'm Dr. Peder Myhre from Akershus University Hospital, and University of Oslo in Norway.

Dr. Carolyn Lam:

Peder, I'm so excited about our future discussion. It's about a very important topic of detecting atrial fibrillation in the population using wearable devices. It talks about the Fitbit Heart Study. So exciting, but we're going to keep the audience waiting a bit, because we're going to talk about some other things in the issue. And I would love to start with this now.

We know that fulminant myocarditis presentation is a rare and severe presentation of myocarditis. But, what is its natural history, and clinical features associated with poor outcomes? Peder, what do you think?

Dr. Peder Myhre:

Oh, that's a great question. We really don't know, because prior studies have been relatively small and selected. So Carolyn, let me know.

Dr. Carolyn Lam:

You're absolutely right. But today's paper from Professor Saito, from Nara Medical University in Japan and colleagues, is the largest nationwide cohort study of patients with histologically proven fulminant myocarditis presentation. They study 344 patients, hospitalized with histologically proven myocarditis, who underwent catecholamine and/or mechanical support from 235 cardiovascular training hospitals across Japan, between 2012 and 2017, and here's what they found.

Over a median follow up of 600 days, the accumulative risk of death or heart transplantation at 90 days was 29%. So, really high. These were the risk factors associated with a higher risk of death or heart transplantation, and they were non-sinus rhythm, older age, ventricular tachyarrhythmia, lower left ventricular ejection fraction. Severe histological damage was also associated with a worse 90 day outcome in lymphocytic myocarditis. Cool, huh?

Dr. Peder Myhre:

Oh wow. That was some really solid data. And now Carolyn, I'm going to take us over to the world of preclinical science. And the next paper entitled at “APIC Associated De Novo Purine Synthesis is Critically Involved in Proliferative Arterial Disease” by Yuqing Huo from Augusta University in Georgia.

Dr. Carolyn Lam:

Cool.

Dr. Peder Myhre:

And as you know, Carolyn, vascular smooth muscle cells are extremely important in vascular health. They're located in the medial layers of arteries, and normally exhibit a contractile phenotype that contributes to the regulation of blood vessel tone, blood flow distribution, and blood pressure in normal mature blood vessels. And in response to disease processes, the vascular smooth muscle cells are switched to an activated synthetic and proliferative phenotype, that contribute to the development of a variety of arterial diseases, including atherosclerosis, in-stent restenosis, and bypass graft occlusion. And nucleotides that we are familiar with, such as ATP and GTP, are essential for a large number of biological processes in cells, including proliferation.

And Carolyn, the previous studies have demonstrated that de novo synthesis of purine is a critical pathway for nucleotide synthesis. And in this study, the authors assessed the role of de novo synthesis of purine in vascular smooth muscle cells by using knockout mice.

Dr. Carolyn Lam:

Oh, that was beautifully explained. Thanks, Peder. So what did they find?

Dr. Peder Myhre:

So the authors found that the de novo purine synthesis was increased in proliferative vascular smooth muscle cells. Moreover, they identified an important enzyme in the process called A-P-I-C, APIC. Which was observed in the neointima of the injured vessels, and atherosclerotic lesions in both mice and humans.

Finally, they showed that in a mouse model with knocked out APIC, the atherosclerosis and arterial restenosis was attenuated.

Dr. Carolyn Lam:

Cool. So tell us what the clinical implications are.

Dr. Peder Myhre:

So these findings provide novel insights into the reprogramming of purine metabolism underlying vascular smooth muscle cells proliferation in the development of arterial disease. And that targeting APIC may be a promising therapeutic approach to combat arterial diseases.

So Carolyn, please tell me about your next paper.

Dr. Carolyn Lam:

Ah, thanks, Peder. Well, back to the clinical world, this time, talking about arrhythmogenic right ventricular cardiomyopathy. We know that is characterized by progressive cardiomyocyte loss and fibro fatty replacement. And we know that patients with this a ARVC are at risk for life-threatening ventricular arrhythmias and sudden cardiac death.

The placement of an ICD is a crucial component of ARVC management. But arrhythmic risk stratification and the selection of the optimal candidates for ICD, especially for primary prevention of sudden cardiac death, has, of course, been challenging.

As background, a ventricular arrhythmia risk calculator, in patients without previous sustained ventricular arrhythmias, has been proposed, and includes seven clinical variables derived from non-invasive tests that are routinely performed in these patients. However, the possibility of integrating additional parameters, such as ventricular tachycardia inducibility on programmed ventricular stimulation, with this risk calculator, has been suggested, but not conclusively investigated in a large cohort. And so, here comes corresponding author, Dr. Cadrin-Tourigny, from Montreal Heart Institute and colleagues, who studied 288 patients with a definite ARVC diagnosis, no history of ventricular arrhythmias at diagnosis, and programmed ventricular stimulation performed at baseline. And these patients were identified from six international ARVC registries.

Dr. Peder Myhre:

Oh wow. So we're talking risk stratification for patients with ARVC. Such an interesting topic, Carolyn. So please tell me, what did they find?

Dr. Carolyn Lam:

So, programmed ventricular stimulation significantly improved risk stratification, above and beyond the calculator predicted risk of ventricular arrhythmias, in a primary prevention cohort of patients with ARVC. And this was mainly for patients considered to be at low and intermediate risk by the clinical risk calculator. If negative, its high negative predictive value of 93% in low and intermediate risk patients, may support the decision to forego ICD use in some patients. So, programmed ventricular stimulation results may be applied to the non-invasive ARVC risk calculator, in a two step approach to facilitate personalized decision making for ICD in such patients.

Dr. Peder Myhre:

Thank you, Carolyn. That was a great summary and a great paper. So we're going to move in to see what else is in the mail bag, Carolyn.

Dr. Carolyn Lam:

You bet. There's a letter by Dr. Agirbasli regarding the article, “Coronary Artery and Cardiac Disease in Patients with Type Two Myocardial Infarction, A Prospective Cohort Study,” and this, followed by a response by Dr. Chapman.

There's an ECG Challenge by Dr. [Jingnan] Han, entitled, “Tachycardia Associated with Pacing.”

From our own Molly Robbins, we have highlights from the Circulation Family of Journals. And she covers the experience with stereotactic radio ablation and electrical storm, reported in Circulation: Arrhythmia and Electrophysiology.

The impact of accessibility to primary care on hypertension awareness and control is reported in Circulation: CV Quality and Outcomes.

There's an analysis of lifestyle factors and their impact on the risk of heart failure by background genetic risk, and that's in Circulation: Heart Failure.

There's a deep learning model of PET scans and coronary flow reserve reported in Circulation: CV Imaging.

And finally, OCT based measurement of stent expansion and associations with outcomes are presented in Circulation: CV Interventions.

A lot.

Dr. Peder Myhre:

Yeah, and there's more, Carolyn. In this issue, there is an extensive Frontiers review by the AF-SCREEN International Collaboration, entitled, “Consumer LED Screening for Atrial Fibrillation.”

There is also a Research Letter by corresponding author Qi Fu, from University of Texas Southwestern Medical Center entitled, “Neuro Cardiovascular Dysregulation During Orthostasis in Women with Posttraumatic Stress Disorder.”

And finally, a Research Letter by Pankaj Arora from University of Alabama entitled, “Mechanical Circulatory Support Devices Among Patients with Familial Dilated Cardiomyopathy, Insights from the INTERMACS.”

Dr. Carolyn Lam:

That's awesome, Peder. Thank you. Now let's go onto our feature discussion on atrial fibrillation detection and the Fitbit Heart Study, shall we?

Today's feature discussion is about the Fitbit Heart Study, and none other than the first and corresponding author Dr. Steven Lubitz, from Massachusetts General Hospital in Boston to join us today. Steve, welcome. Congratulations. Am I right to say, this is the largest study of its kind to look at the detection of atrial fibrillation using wearable devices?

Dr. Steven Lubitz:

Thanks for having me, Carolyn. And that's right, this is.

Dr. Carolyn Lam:

Oh my gosh. Okay. Tell us all about it, what you did, what you found.

Dr. Steven Lubitz:

Well, thanks, Carolyn. So as we know, undiagnosed atrial fibrillation is a potential hazard that can cause strokes. And if we can identify people who have undiagnosed atrial fibrillation early, we may be able to prevent strokes. In addition, undiagnosed atrial fibrillation may be associated with additional morbidity, which can be addressed through a number of different ways, if we can detect atrial fibrillation. Obviously, the challenge is to detect atrial fibrillation.

We also know that people are increasingly wearing devices that have sensors on them, specifically using photoplethysmography technology, which can detect the pulse rate. Software algorithms can now be developed, that can assess that pulse rate for regularity or irregularity. But they really need to be assessed and validated, to minimize the potential for false positives, which can have obviously, downstream adverse consequences of their own, if atrial fibrillation is incorrectly identified or diagnosed as a result.

As I was mentioning, we developed this novel software algorithm with frequent overlapping photoplethysmography, post tachogram sampling, which is unique. And then we tested the algorithm's positive predictive value for undiagnosed AFib in a large scale remote clinical trial, using a range of Fitbit wearable fitness trackers and smart watches.

It was a remote trial, so participants were invited. These were people who already had a Fitbit account, they were invited to participate. And in span of just a few months, in the middle of the pandemic, over 455,000 people signed up to participate in the study. And so, big thank you to all of the participants in the study.

Dr. Carolyn Lam:

Wow, that is big. And what did you find?

Dr. Steven Lubitz:

So of the 455, over 455,000 participants that enrolled, over 4,000, had an irregular heart rhythm detection and received a notification. And after inviting those participants to attend a telehealth visit, and at that telehealth visit, the telehealth provider confirmed eligibility criteria, confirmed that they didn't have preexisting atrial fibrillation, for example, and a variety of other inclusion/exclusion criteria.

They were mailed a one week ECG patch, that they applied themselves, and then returned that ECG patch. So in the end, after those exclusions, in participants that returned analyzable patches, 1057 participants were included in this ECG monitoring analytic cohort, of whom, 340 had atrial fibrillation during that ECG patch monitoring period.

The primary endpoint of the study was the positive predictive value of irregular heart rhythm detection that occurred during the ECG patch monitoring period. So a participant had to have an irregular heart rhythm detection to get notified that they were eligible to meet with a telehealth provider and receive an ECG patch monitor. And then, they had to have another irregular heart rhythm detection during ECG patch monitor wear. So the primary outcome was the positive predictive value of the first irregular heart rhythm detection for concurrent atrial fibrillation that occurred during ECG patch monitoring.

Dr. Carolyn Lam:

Okay. Cool. So many questions here, but maybe you should tell us the results first.

Dr. Steven Lubitz:

Sure. So the primary endpoint, the positive predictive value of the IHRD during ECG patch monitoring was 98.2% in the overall cohort. And it was similar between men and women, and those aged 65 or older, or those aged less than 65. And I should mention that, in this study, about 13% of participants enrolled in this study overall, were above the age of 65.

Dr. Carolyn Lam:

And you included more women than in prior similar studies. Right, Steve?

Dr. Steven Lubitz:

Yeah.

Dr. Carolyn Lam:

I was going to congratulate you for that.

Dr. Steven Lubitz:

Yeah, that's right. That's right. We're very excited to see that.

Dr. Carolyn Lam:

Okay, so that's cool. Wow. A positive predictive value of 92%. So couple of things here with-

Dr. Steven Lubitz:

98.

Dr. Carolyn Lam:

Sorry, 98%. That's right. Wow. Okay. Now with this AFib detection, it's always about duration. Right? And what do you call a positive alert? Could you maybe elaborate a bit about that here?

Dr. Steven Lubitz:

Sure. So I think this is an important point. A few points. One, the algorithm is designed. This particular algorithm requires at least 30 minutes of an irregular pulse to be detected, in order for a detection to occur. Which means that, this is unlikely to be detecting trivial amounts of atrial fibrillation. And indeed, that's what we observed. We observed that the median burden of atrial fibrillation was 7% among those who had AFib on the ECG patch monitor. We observed that the median longest episode of atrial fibrillation was seven hours. And just by way of comparison, in other studies in which ECG patch monitors have been distributed to people without this irregular pulse pre-screening, the burden is usually on the order of only a couple of percent, tops. So this, by nature, these types of algorithms, and this algorithm specifically, probably enriches for individuals who have a higher burden of atrial fibrillation. Meaning that, if these detections occur, then it's probably not detecting trivial amounts of atrial fibrillation.

Dr. Carolyn Lam:

Right. And a lot of it seems to send a very clear message that this study, and perhaps even the algorithm, is designed to be specific. Right? So that duration, as well as what you used as the outcome. How much price do you pay in terms of sensitivity? Do you know what I mean? Since we optimized for specificity, am I right to say that?

Dr. Steven Lubitz:

Sure, that's a great point. The algorithm is really optimized for specificity, as you mentioned. And although we didn't specifically calculate the sensitivity of the algorithm, in a secondary analysis, we examined the sensitivity of an IHRD during that ECG patch monitoring period, to detect any AFib that was documented on the ECG patch monitor, and it was about 67%.

So we know that we probably don't detect some atrial fibrillation. Largely, that's a function of this technology at the moment. It's very difficult to assess the pulse rate during periods of activity in motion. So a lot of these algorithms, and this algorithm in particular, doesn't operate during periods of motion. The accelerometers and the devices can tell the algorithm that motion is occurring, and then the algorithm won't operate on that information at that time. So a lot of this has to do with limitations of the technology at the moment.

Dr. Carolyn Lam:

Ah. So the detection probably occurs best at rest or at night.

Dr. Steven Lubitz:

That's exactly right. And we encourage participants to wear their devices at nighttime during the study.

Dr. Carolyn Lam:

Oh, cool. And then of course, I suppose a question you'd anticipate, I mean, we know about the Apple Heart Study, we know about the watch study, and how does this compare? How is this technology different, and the results?

Dr. Steven Lubitz:

Essentially, one of the most remarkable things about these studies is that, it appears that this pulse rhythm pre-screening really enriches substantially for people who have atrial fibrillation. So for example, in the Fitbit Heart Study, we observed that about 32% of people who had an irregular heart rhythm detection and then returned an ECG patch monitor, had AFib on it. And by comparison, in the Apple Heart Study, that number was about exactly the same, just over 30% or so.

So when we further compare this pre-screening type approach to confirming atrial fibrillation, using an ECG patch monitor, with other approaches in which say, elderly individuals were mailed ECG patch monitors to screen for atrial fibrillation, we usually only see detection in the order of four to 5% of people. So this irregular pulse based pre-screening markedly enriches for atrial fibrillation. And we also know, this is only a one week ECG patch monitor, and if we monitor people longer than one week, we're likely to detect more atrial fibrillation, since this is often paroxysmal atrial fibrillation that we're detecting.

So there are a lot of similarities, and I think the point is that, these types of consumer electronic devices are going to be great tools for identifying undiagnosed atrial fibrillation in the community. I think we have a lot of challenges ahead of us, in terms of figuring out how to integrate that information into our routine healthcare workflow, and counseling consumers and users of these types of technology on exactly what they should be doing when they do get an alert. And then also, counseling providers on how to act on these findings, what they mean and how accurate the technology is.

Dr. Carolyn Lam:

Yeah. And I appreciated a sentence in your manuscript that talks of, what are our society guidelines going to say? If you could look into a crystal ball now, Steve, based on what you found, what would you advise both patients and clinicians, if you don't mind?

Dr. Steven Lubitz:

Well, I think that, in short, if a clinician is alerted by a patient, that they received in a regular heart rhythm detection on their device, in short, I would say, don't blow it off. Take it seriously. Because the odds are, that it does represent an abnormality, and the odds are that that abnormality is atrial fibrillation. And given the potential adverse consequences of undiagnosed atrial fibrillation, there's a real opportunity to intervene, and prevent morbidity in the patient. And then, if you're a consumer who happens to have one of these devices, and you've turned on this feature, and hopefully you have, if you do have an alert, don't blow it off. Contact a provider. Because it may very well mean that you have an irregular heart rhythm that merits attention, and could be addressed to prevent downstream consequences and morbidity for you.

Dr. Carolyn Lam:

Nice. And keep your Fitbit on at night.

Dr. Steven Lubitz:

Yes. And if you do want to maximize the utility of these algorithms that use photoplethysmography, probably wearing them at nighttime will maximize the sensitivity, or utility of the devices and algorithms.

Dr. Carolyn Lam:

Aw, that's just great. What nice take home messages. Thank you so much, Steve, for publishing this really unique and important study in Circulation.

So audience, you heard it right here on Circulation on the Run. From me, Greg, and Peder, please do tune in again next week.

Speaker 4:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

Circulation November 1, 2022 Issue

31 oktober 2022 | 24 min

This week, please join authors Kevin Roedl and Sebastian Wolfrum, as well as Associate Editor Mark Link as they discuss the article "Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the Journal and its editors. We are your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, very interesting, a randomized clinical trial of temperature control after in-hospital cardiac arrest. But before we get to that exciting study, let's grab a cup of coffee, and jump in and discuss some of the other articles in the issue. Carolyn, would you like to go first?

Dr. Carolyn Lam:

Yes. Starting with a great quiz. So Greg, which is better? How about this? It's multiple choice. Is it A; transradial, or B; transfemoral access, in terms of post-procedural mortality?

Dr. Greg Hundley:

I'm going to go with transradial. It has been, hopefully, I'm okay on this. It just seems so many fewer complications.

Dr. Carolyn Lam:

But that's exactly that we need to meta-analyze the studies that have been done. Exactly what this paper did, led by Professor Valgimigli, from USI in Lugano, Switzerland. So what they did is, they performed an individual patient data meta-analysis of 21,600 patients, enrolled in seven multi-center randomized control trials, comparing the transradial with transfemoral access, among patients undergoing coronary angiography with or without PCI. And they found that transradial access was associated with a lower incidence of the primary outcome of all-cause mortality, and the co-primary outcome of major bleeding at 30 days, compared to transfemoral access.

There was also evidence for reductions in major adverse cardiac and cerebral vascular events, net adverse clinical events, vascular complications, excess site bleeding, and blood transfusion. MI, stroke, and stent thrombosis, did not differ. And crossover was higher in the transradial access group.

At predefined subgroup analysis, the authors confirmed that the benefit observed the transradial group was generally consistent across the majority of pre-specified subgroups, except for those with significant baseline anemia. Patients with baseline anemia appear to derive a substantial mortality benefit with transradial access rather than transoral access, compared to those with mild or no anemia.

So, the authors concluded, that the meta-analysis provides evidence that transradial access should be considered the preferable access site for PCI, in patients with acute coronary syndrome, supporting most recent recommendations on the preferential use of this radial approach. So you were right, Greg.

Dr. Greg Hundley:

Very nice, Carolyn. A really important piece of science to disclose to our listeners, in that hurried state, and moving quickly door to balloon times, et cetera. And here we find another positive outcome in study result for transradial approaches.

Well Carolyn, as we know, my next paper, it's really going to come to us from the world of preclinical science. And it pertains to hypertension, which is a common cardiovascular disease, and is related to both genetic and environmental factors. But the mechanisms linking the interplay between the domains of genetics and the environment have not been well studied.

Now, DNA methylation, a classical epigenetic modification, not only regulates gene expression, but is also quite susceptible to environmental factors. Thereby, linking environmental factors to genetic modifications. So therefore, Carolyn, these authors, including Professor Jingzhou Chen, from Fuwai Hospital, National Center for Cardiovascular Diseases, and the Chinese Academy of Medical Sciences, and the Peking Union Medical College, and their colleagues, felt that screening differential genomic DNA methylation, in subjects with hypertension, would be important for investigating this genetic environment interplay in hypertension.

So this study, Carolyn, like many from the world of preclinical science and circulation, incorporated both human and animal model subjects. Methodologically differential genomic DNA methylation in hypertensive, pre-hypertensive, and healthy control individuals, was screened using the Illumina 450K BeadChip, and then verified by pyrosequencing. Plasma oviduct glycoprotein 1, or OVGP1 levels, were determined using an enzyme-linked immunosorbent assay. And OVGP1 transgenic and knockout mice were generated to analyze the function of OVGP1.

Dr. Carolyn Lam:

Wow. Nice approach, Greg. And what did the authors find?

Dr. Greg Hundley:

Right, Carolyn. These authors found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension.

Now Carolyn, in OVGP1 transgenic mice, OVGP1 over expression caused an increase in blood pressure. Also, dysfunctional vasoconstriction, and vasodilation, remodeling of the arterial walls, and increased vascular superoxide stress and inflammation. And these phenomenon were exacerbated by angiotensin II infusion.

In contrast, OVGP1 deficiency, attenuated angiotensin II induced vascular oxidase, stress, inflammation, and collagen deposition.

Now pull down, and co-immunoprecipitation assays showed that myosin heavy chain 2A, or MYH9, interacted with OVGP1. Whereas, inhibition of MYH9 attenuated OVGP1 induced hypertension and vascular remodeling.

Dr. Carolyn Lam:

So Greg, let me try to summarize, is that okay? So hypomethylation, at that specific site in the promoter region of the OVGP1 gene, is associated with hypertension, and induces its upregulation. The interaction of this OVGP1 with myosin heavy chain 2A contributes to vascular remodeling and dysfunction. And so, OVGP1 is a pro hypertensive factor, that promotes vascular remodeling by binding to this myosin heavy chain. So, really cool stuff. Thanks for teaching us.

Dr. Greg Hundley:

Very good.

Dr. Carolyn Lam:

Well thanks so much, Greg. And we go back to the clinical world now, and ask the question, what is the efficacy and safety of prophylactic full dose anticoagulation and antiplatelet therapy, in critically ill COVID-19 patients? So I'm going to tell you the results of the COVID-PACT trial. And this was a multi-center, two-by-two factorial, open label, randomized controlled trial, with blinded endpoint adjudication in 390 ICU level patients. So, severely ill patients with COVID-19, from 34 US centers. Patients were randomized to a strategy of full dose anticoagulation, or standard dose prophylactic anticoagulation. And in the absence of an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find?

Dr. Carolyn Lam:

Full dose anticoagulation substantially reduced the proportion of patients experiencing a venous or arterial thrombotic event, and there was no benefit from treatment with clopidogrel. Severe bleeding events were rare, but numerically increased in patients on full dose versus standard dose prophylactic anticoagulation, without any fatal bleeding events, GUSTO moderate or severe bleeding was so significantly increased with full dose anticoagulation, but with no difference in all-cause mortality.

So in summary, in a population of critically ill patients with COVID-19, a strategy of prophylaxis with full dose, versus standard dose prophylactic anticoagulation, but not the addition of clopidogrel, reduced thrombotic complications, with an increased risk of bleeding, driven primarily by transfusions in hemodynamically stable patients, with no apparent excess in mortality.

Dr. Greg Hundley:

Very nice, Carolyn. What a important piece of information, as many of us around the world are taking care of critically ill patients with COVID-19.

Well, how about we see what is in the mail bag this week? So first, Carolyn, there's a Frontiers piece by Dr. Packer, entitled, “Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 inhibitors, and Reaffirmation of the Nutrient Deprivation Signaling Autophagy Hypothesis.”

Next, there's a Research Letter, from Professor Airaksinen entitled, “Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-stage Renal Disease.”

Carolyn, there's another Research Letter, from Professor Solomon, entitled, “Aptamer Proteomics for Biomarker Discovery in Heart Failure with Reduced Ejection Fraction.”

Also, Carolyn, [a] wonderful Cardiovascular News summary from Tracy Hampton, reviewing three articles. First, “Mechanisms Behind Cannabis Effects on Heart Health.” The second, “Exercise Inducible Metabolite Suppresses Hunger.” And then lastly, “Piezo1 Initiates the Cardiomyocyte Hypertrophic Response to Pressure Overload.”

Dr. Carolyn Lam:

Cool. There's also an exchange of letters between Doctors Jha and Borlaug on latent pulmonary vascular disease in therapeutic atrial shunt.

And finally, an On My Mind, by Dr. David Kass entitled, “What's EF Got To Do, Got To Do With It.” I love it. You must read it. It's so, so cool. All right. But now, let's go on to our feature discussion, shall we?

Dr. Greg Hundley:

You bet, Carolyn.

Welcome listeners, to our feature discussion today, and really delving into the world of in-hospital cardiac arrest, and how we manage those patients. And we have with us today, Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from University of Texas Southwestern in Dallas, Texas. Welcome gentlemen. Kevin, we're going to start with you. Can you describe for us, some of the background information that went into the construct of your study, and what was the hypothesis that you wanted to address?

Dr. Kevin Roedl:

Thank you, Greg. We thank you for the kind invitation to this podcast. We're very likened to do this podcast with you. And so, talking about the background of hypothermia in-hospital cardiac arrest, we have to go back like two decades almost, because there were two studies in New England Journal of Medicine published 2002, who introduced mild therapeutic hyperthermia to the treatment in post cardiac arrest. Primary, these two studies show the benefit of the therapy in this kind of patients. And then, 2003, it was introduced in also the international guidelines. However, these studies only addressed out-of-hospital cardiac arrest patients, and also, only shockable rhythms. And so, the question arised over the years, what about other patients like non shockable rhythms, or also in-hospital cardiac arrest?

And so, that's basically was the primary aim of our study to address this special population. Because when you see the states, the numbers, there are 290,000 in-hospital cardiac arrests a year. So it's actually, a very large population. And there's no randomized control trial to show any benefit, or maybe harm, in this group. There were some observational studies, 2016 in China published. From China, in this group, they looked at the Get With The Guidelines registry, and actually, they saw that there was probably a negative influence of hypothermia in the study. However, it was only observational. So actually, there were no randomized control trials. And that primary hypothesis was, that we wanted to know actually, does thus mild therapeutic hyperthermia work in this group of patients in the in-hospital cardiac arrest setting? And what is the outcome? Is it like in the out-of-hospital cardiac arrest setting, or not?

Dr. Greg Hundley:

Wonderful, Kevin. And so, can you describe for us then, your study population and your study design?

Dr. Kevin Roedl:

Yes, of course. We did a randomized control trial. There were over 1000 people screened, and overall, we included 242. So you see how hard it is to get people in there. And actually, in terms of hypothermic temperature control, we are 120 about, and long term at 118, and the final others of the endpoints. And when we look at the baseline characters of these patients, they were well balanced actually, about 72 years. When we look at the initial cardiac arrest rhythm, that's interesting because about 70% non-shockable rhythms, and 25% shockable rhythms. And probably also interesting, the location of the cardiac arrest. Medical boards about 50%, and ICU or ED was 22%. So that's probably summed up the baseline characteristics of our study.

Dr. Greg Hundley:

Perfect. And so Kevin, can you describe for us what was the hypothermic target for the group that was going to have their temperature recused?

Dr. Kevin Roedl:

Yes, hypodermic target was 32 degrees to 44. And so two degrees Celsius, basically the same target like in earlier trials.

Dr. Greg Hundley:

Very nice. Well listeners, now we're going to turn to our second co-author, Dr. Sebastian Wolfrum. And Sebastian, can you share with us the study results?

Dr. Sebastian Wolfrum:

Yes, Greg. Thank you very much for the opportunity to participate in this podcast. Only wanted to include unconscious patients, and therefore, we took a time and took 45 minutes after their cardiac arrest, to let the patients get away if they did so. We also excluded patients that had severe functional deficit before the cardiac arrest; since we could not really define the neurological outcome if we would've included those. And we didn't see any differences. Neither in mortality, not in the functional outcome, either when they're treated with 33 degrees Celsius, or whether normothermia was used.

The death rate after six month was in a range which is comparable to other in-hospital cardiac arrest studies, and higher than those performed in the out-of-hospital cardiac arrest studies. It was about slightly over 70% in both groups. And the number of patients with the good functional recovery after six months was 23% of the patients in the hypothermia group, and 24% of the patients in the normothermia group.

And if we look at only the survivors, we see that the ones which are worse functional outcome, were most of them dead after six months. We then also focused on the temperature curves in our patients, and to see whether we have achieved our goal. And we saw that we have reached the target temperature within four and a half hours after cardiac arrest in our hypothermia group. Which is not as fast that we had expected, but still in the range, which is comparable to other studies on this field. And we also saw that our control group was about 37 degrees, within the first 12 and 48 hours. So we truly avoided fever, which has not been done in every previous study on cardiac arrests.

Dr. Greg Hundley:

Very nice. And any differences between the hypothermia and normothermia groups, related to the age of the patient? Or, whether or not they had a shockable rhythm at the time of presentation?

Dr. Sebastian Wolfrum:

We saw as a result of our study, that age is a predictive factor for mortality. But age did not differ between our treatment groups, and therefore, did not interfere with our results. And we didn't see differences in the shockable or non-shockable rate in our patients in the different treatment groups.

Dr. Greg Hundley:

Thank you. Well listeners, now we're going to turn to our associate editor, Dr. Mark Link, one of our expert electrophysiologists at Circulation. And Mark, you have many papers come across your desk, and what attracted you to this particular paper?

Dr. Mark Link:

There were a number of things. One, it's hard to do RCTs in resuscitation, and I thought they did a very nice job with this RCT. Two, the subject of hypothermia, or therapeutic temperature management, is a very hot one in resuscitation. It's one of the few treatments in the past that have been shown to make a difference in outcome. And so, all of those trials were done in out-of-hospital arrest. So to have a trial done in in-hospital arrest was very intriguing also.

And I think we're all disappointed that it wasn't a positive trial, but we have to take the negative trials also. And I think, part of the reason it may have been a negative trial is because the normal thermic group avoided hyperthermia. And I think that's something that's coming out of a lot of these trials is avoid fever. It may not be so important to get hypothermic targets, actually, looks like it's probably not, but it looks like it's very important to avoid fever.

Dr. Greg Hundley:

Very nice. Well listeners, we're going to turn back to our expert panel here really, and start with you Kevin. Kevin, what do you think is the next study that needs to be performed in this sphere of research?

Dr. Kevin Roedl:

Thank you for this interesting question. Yeah, a bunch of studies could be performed, especially maybe in the out-of-hospital cardiac arrest study, because we don't know. This fever harmful, we have to find certain subgroups in which this treatment works. So maybe in this subgroups there is data on this and it could be a benefit. So these are, I think, the two main topics that should be done in the future.

Dr. Greg Hundley:

Thank you. Sebastian, what are your thoughts?

Dr. Sebastian Wolfrum:

As Mark said, the hypothermic treatment was, for decades, maybe the only treatment which we could give to cardiac arrest patients, which has been proven to reduce mortality. And all other studies following didn't see any be benefit of hypothermia, not even in a subgroup. Also, the TTM trials did not. So I'm questioning myself, where is the original HACA study group that benefits? Where did this hide in the other studies?

So I would think, to do another study in out-of-hospital cardiac arrest patients, whether in ventricular fibrillation that had shown in the HACA trial to reduce mortality. This should be done in a similar way to the original study, to see whether there is this subgroup. People who support the idea of hypothermia also focus very much on the fast onset of their hypothermic treatment. And they say we saw a difference in mortality in the HACA trial, and we could very fast. And I think the other studies have to show that they cool as fast as the HACA study. So the main focus should be on the time calls of hypothermia after cardiac arrest, cooling very fast to a target temperature of 33 degrees, maybe holding on for 24, maybe 48 hours.

Dr. Greg Hundley:

Very nice, Sebastian. So focusing on the speed and the timing of that cooling. And Mark, anything to add?

Dr. Mark Link:

Yeah, so if I sit here with my writing group hat on for the HA and say, "What are we going to do for the resuscitation guidelines in 2025?" I think you look at the totality of the data for targeted temperature management. And I think, the main thing you say, walking away from this, is avoid fever. Don't let your patients get hot. I'm not sure you can say much more than that right now, until we get more data.

Dr. Greg Hundley:

Very nice. Well listeners, a really interesting provocative discussion today. And we want to thank Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from Dallas, Texas, bringing us the results of this study highlighting that hypothermic temperature control is compared with normothermia did not improve survival, nor functional outcome, at 180 days in patients presenting with coma after in-hospital cardiac arrest.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On The Run.

Circulation October 25, 2022 Issue

24 oktober 2022 | 30 min

This week, please join Circulation's Associate Editor Marc Ruel and Executive Editor James de Lemos as they summarize all of the articles found in Circulation's annual Cardiovascular Surgery-Themed Issue for 2022.

Dr. James de Lemos:

Hi, welcome to Circulation on the Run. Greg and Carolyn are off today. My name is James de Lemos. I'm the executive editor for Circulation and I'm delighted to be joined today by Marc Ruel, who's the editor of our themed issue on cardiac surgery and leads the development and curation of all of the cardiac surgery content in Circulation. Marc, congratulations to you, to Mike Fischbein, to the whole Circ team on another spectacular effort to pull together this issue. Glad to have you here today.

Dr. Marc Ruel:

Well, thank you very much, James. It's really a team effort. I want to salute and thank the vision of Circulation to really give an important component to surgical science. As you often hear me say, your surgery provides the most durable and robust solution for advanced heart disease, right? So it's a very important part of the mission of Circulation as the premier cardiovascular journal. I want to thank you and also Joe Hill, our Editor-in-Chief and obviously the entire team of Circulation as well as all staff. Augie [Rivera], who is helping us on this call as well as Nick [Murphy] and many others who have made this issue possible.

Dr. James de Lemos:

Well, great. Well, let's get to this. And you recognize as well Mike Fischbein, who's the Cardiac Investor surgeon at Stanford who helps to edit the themed issue and really helps us to think about basic science into surgical specialties. Let me start, Marc, with cardiac bypass surgery. We have actually three papers in this issue that cover various aspects of CABG. The first one is one that you and I really resonated with, I know, because we talked about this. It's a paper by Ono from the SYNTAX Extended Survival study titled "Impact of Patient Reported and Pre-Procedural Physical and Mental Health on 10 year Mortality after PCI or CABG." And this is a really fascinating paper, looked at obviously patients with left main or multi vessels coronary disease, but used objective measures of physical and mental function from the SF-36 score and calculated summary physical and mental component scores.

And then used those scores to evaluate whether there were treatment interactions based on physical and mental performance metrics with regard to the benefit of CABG over PCI. And really fascinating, first that there was an interaction and that the magnitude of benefit of CABG over PCI for multi vessel disease was substantially greater among individuals that had higher physical performance as well as mental health performance. What did you think of this paper and data? I know you wrote a tremendous editorial to this. So this is something that you thought about as we were bringing the paper in, but also had to think about in terms of putting this paper in the context of this daily decision for patients with multi vessel disease.

Dr. Marc Ruel:

Thanks James. And I agree with you. I think this is a bit of a new paradigm, right, to really think of the individual patient decision. It's a form of precision medicine if you will, with regards in this case to physical functioning and mental functioning prior to something as invasive as undergoing CABG. So I want to thank you, the Circulation leadership for inviting Anne Williams who's a cardiologist and yours truly to write a tutorial on this piece because I do think you, that is really, it is something that's quite intriguing and it makes sense. I think it is intuitive. I think clinicians who send patients to CABG and see them come back and hopefully in a good state, the very vast majority of the time, do realize nevertheless that CABG is a very invasive procedure. So the patient has to be actively involved in her or his recovery.

And interestingly as you pointed out, there's quite a effect modification if you will, between the benefits of CABG over PCI in the SYNTAX trial, which many will remember as having randomized either left main or three vessel disease, coronary artery disease patients to PCI versus CABG. So there was an effect modification in those patients who had better functioning, not only physical, but interestingly, even more so mental component score of the SF-36 prior to operation. These patients would derive a greater benefit from having been randomized to CABG over PCI. So I think this is obviously logical, it makes sense and the converse will be true, but it's nice to see it formalized, to my knowledge, for the first time in the context of a rigorous randomized control trial such as SYNTAX with a long-term follow up.

Now obviously this, like any study, there are a few caveats. Not every single patient had their SF-36 at baseline, but roughly about 90 plus percent of patients did. And I think that is quite an important clinical lesson in terms of allocating PCI versus CBG... I've often said over the years as a division head and someone who performs this operation often to my more junior colleagues, "Don't perform bypass surgery if someone's not going to live five years." That might be a bit of a simplistic approach but the data and the conclusions from this paper would support that. It's probably not too farfetched to think as such.

Dr. James de Lemos:

I think that's a great point and your clinical experience is so valuable for us here. One question I have is, do you think that it would be advantageous to objectively measure these parameters or is this something that the heart team or the surgeon at the bedside can assess intuitively? Because I think that's the question, right? Is this something... It certainly fits with what we would expect intuitively, that the more complete and durable procedure works better in people that are more robust physically, mentally. But should we be measuring this preoperatively to help make that decision or should this be a intuitive decision by expert clinicians?

Dr. Marc Ruel:

It's a great question and I think it's one that's not yet answered. I mean, the data from the paper would suggest that it has to be a formalized physical component score and mental component score and then ready allocate according to turnstiles. But that being said, we all know that we can address those issues by an end of bed type of eyeball test, right? So I think you're absolutely right. It may be that a clinical expert may provide the same type of information. Unfortunately we don't have that from the paper but I think there will be several subsequent papers that will look at this.

I think we are in the era of precision medicine and one would even think, why has this not been done before considering how invasive bypass surgery is? You guys, you cardiologists and primary care physicians all know that it takes patients six to 12 months to be recover from sternal bypass surgery. Surgeons all be, I'll say that with a blink in my eye, don't always necessarily always see that, right? And think that's more like a one to three months but the data would suggest including that from randomized controlled trials such as Feedem, that it takes six to 12 months. So it's been one of my career long quest if you will, to make bypass surgery less invasive. And I think this type of paper really provides the impetus to do so.

Dr. James de Lemos:

Well, thanks. Let's shift gears from a study that makes perfect sense and fits our preconceived notions to maybe one that doesn't. And this is a research letter from a group led by Steve Goldman at University of Arizona looking at long term mortality from the VA study comparing radial arteries with saphenous vein conduits in CABG. And this looked at long term mortality from this study, which included over 700 individuals that had extended follow up beyond 10 years. At one year, the cath data had not shown differences in patency in this study, I think important to interpret, but they find absolutely no difference in mortality within similar median survival of 14 to 15 years after CABG in this study. This was controversial among the editors when we discussed it, but what are your thoughts about these data and how this informs the radial artery question in CABG?

Dr. Marc Ruel:

Absolutely. You are so right in seeing that this was controversial because there are in fact two ways to look at this paper, right? You can drain the information that's in there or you can be a naysayer. And there's credence to both approaches, in my opinion. One could say, "Well, there was no difference at one year in terms of graph patency, so why would there be one at 14-15 years?" Well, the answer to that would be the durability of the compared conduits would be potentially different, right? One to five years is what we call the "golden age of saphenous vein grafts." And beyond that time period, one could perhaps expect that the radial artery would do better and start translating into clinical benefits. But that was not seen in this long-term analysis of the VA RCT that compared the use of a saphenous vein versus a radial artery.

The other way to perhaps find why the data is discrepant versus the methodology that had been performed before showing an advantage for the radial artery, would be that this is more perhaps of a real world type of experience. It comes from VA centers. Perhaps the expertise or the level of penetrance if you will, of use of the radial artery was not the same as other centers that maybe more "academic" and more vested into using the radial. So it's possible that those could have played a difference in nullifying if you will, the results of radial artery. But I nevertheless think that it's very important data. It makes us think and it is the largest single series data available that compares the radial to saphenous vein in a randomized control setting. So one cannot ignore it, and I think it's a very important piece of information that strengthens the surgery themed dish.

Dr. James de Lemos:

Thank you, Marc. And then the last CABG related article that I'd like to talk about is the prospective piece by Mario Gaudino and Bruce Lytle discussing the right internal thoracic artery for bypass. Asking the question, did we get it wrong? And this is really a very interesting piece. I encourage our readers to look at. That attempts really to reconcile the strong promise of the RITA with the disappointing results from art and the higher than expected failure rates in other trials. And what the authors do here really resonates with, Marc some of your points about individualizing treatment.

They point out that some of the worse than expected RITA results may reflect the artery to which the RITA has been anecimosed, simply that results when an anecimosed to non-LED targets aren't as good and potentially the experience of the operators. Their final conclusion really isn't that, the reader's not a superior conduit but that perhaps more individualization, both at the patient level but also based on physician experience, maybe what's needed to achieve the optimal selection of conduits and bypass results. What did you think of this? How did their conclusions and interpretation resonate with you?

Dr. Marc Ruel:

I agree with your summary James and I think you are spot on. What's interesting in addition from this frame of reference is that it unites the opinions of two key opinion leaders, i.e Mario Gaudino, who's essentially behind much of the data favoring the radial artery over the use of the saphenous vein. And Bruce Lytle, who historically was behind really proposing the use of the right internal thoracic artery and this bilateral ITA grafting if you will, and they are really coming together and putting their thoughts in a really sensible manner with regards to the points that you raised already. I would add in my own opinion, it's twofold. One, there's nothing biologically wrong with the right internal thoracic artery. So if the LITA works, the RITA should work as well from a biologic point of view. In fact, surgeons know that it's often bigger than the left internal thoracic artery and even more suitable or suited as account with.

What might be wrong is the applicability of it and that question really goes in a couple of important manners. Let's remember surgery is a craft, right? And it's a bit different. It's something I like to repeat, and it's not always captured. It's not really a pure science, like for instance, giving atorvastatin 40 milligrams would be this much more variability. And if you allow me a ten second example, if you were to take one of the bronze tools from Rodin, a grape sculptures, and take it away from him, the sculptures would not be as good. But if you were to give that tool to all semi-professional sculptures around the globe, the United States or France for instance, you may not see any benefit from that tool. So again, the crafty example of surgery is something that we have to compose with all the time.

So the RITA is a great conduit, but it's often not onto the LED per se. And we know that LED in an average patient, which doesn't exist, it's probably about 50% of the left heart profusion. So really the LITA has an advantage from that point of view. And when we compare studies that have used the RITA on a non LED target, there are in some cases bound to fail or at least be neutral. So I think the jury's still out but really the perspective that's denoted here, as you said, is a fascinating one coming from two key opinion leaders, each in their camp of radial versus right internal thoracic artery use.

Dr. James de Lemos:

Well, fabulous discussion, Marc. I really appreciate your insights. I think as cardiologists, the decision making about conduits can often be opaque, and this is really insightful. Let's switch gears and talk about valve surgery. We have two papers on valve surgery. First, an original research article by Johan Wedin from Uppsala on bicuspid aortic stenosis demonstrating adverse ventricular remodeling and impaired cardiac function prior to surgery with a heightened risk of postoperative heart failure. This is a really interesting study that looked at 271 patients that were undergoing surgical aortic valve replacement.

About half with bicuspid valves and half with tricuspid aortic valves, and they did comprehensive preoperative echo-cardiography and then followed the patients for four to five years after followup. And despite the expected finding that the bicuspid patients for younger, they had a substantially worse LV echo parameters pre-op with greater LV wall fitness, greater LV mass, worse preoperative LV function. And that translated even after successful AVR into increased risks for postoperative heart failure hospitalizations when compared to individuals with tricuspid aortic valves. And so the authors conclude that at least in contemporary practice, perhaps individuals are undergoing surgery for bicuspid aortic valve stenosis relatively later in the natural history, and they might merit closer civilians and possibly earlier intervention. What did you think of these data and do they make you think about your timing of recommendation for surgery with bicuspid aortic stenosis?

Dr. Marc Ruel:

Absolutely, and thank you James. I think this is very much in line with the current precision medicine led trends of operating earlier on patients with aortic stenosis. I think this is another subgroup that really deserves our attention. I think there are two things at play here with regards to patients who would have a comparable degree of hemodynamic aortic stenosis, either coming from a bicuspid aortic valve phenotype versus a normal tricuspid aortic valve phenotype. And I think the two important differences are, first, often the bicuspid valves are more prone to have a mixed disease and being more calcified as well. We often see surgery, what I call these black valves, like the valve is so calcified and necrotic that it actually turns black or navy blue in color. And this is not an uncommon finding in younger patients typically than tricuspid aortic valve patients.

The second thing is that we have to remember that bicuspid aortic valve disease is a lifelong illness. So these patients often go undetected for a very long time. They may be 55 years old compared to someone who's 68 and have the same degree of hemodynamic aortic stenosis and even AI. But the disease has really, in the bicuspid aortic valve patient, has probably been there for decades, sometimes even the whole life. So I think the effects on the left ventricle are destined to be worse, and also in terms of recovery after resection and after aortic valve replacement. So I think these are humbling tidbits that come from this paper that really even allow us in this era of early TAVR and now two randomized trials that have looked... One from Europe and one from Korea that have looked at asymptomatic aortic valve replacement interventions with favorable results towards early intervention. That really tell us that we should pay even closer attention to those patients with bicuspid aortic valve phenotypes.

Dr. James de Lemos:

Thanks, Marc.

And the second valve related paper is a prospective piece by [Rebecca] Becky Hahn, Vincent Chan and David Adams, evaluating current indications for a transcatheter edged edge repair of the mitral valve for primary mitral regurgitation. I thought this was a really well done piece and one that I appreciated focus specifically on primary micro-regurgitation. The piece includes a terrific algorithm for clinicians that really helps to guide decision making through a multidisciplinary approach.

They talk about the importance of specialized valve imagers, given the complexity of evaluating even the etiology of micro-regurgitation. The importance of excellence in determining the quantitation of severe MR, valve morphology and dimensions. And then really take it a step further to drive decision makings based on risk assessment of the patient. Obviously for primary MR for adequate surgical risk patients surgery is recommended, but then it walks through the decision making for which of the patients that are not surgical candidates might be optimal candidates for transcatheter techniques. How do you think this field's moving and how did this perspective change your thinking?

Dr. Marc Ruel:

This is such an excellent piece as you denoted. I think it really comes from three experts in the field representing different school of thoughts, if you will. One, more hybrid, more catheter based and more surgery based. And I think the jury's still out on transcatheter edge to edge repair, especially for primary marginal regurgitation. It's paradoxical as we're hoping that edge to edge repair would be primarily used in secondary MR and have great results. We now know and somewhat humbling, that it works not as great as we were hoping for secondary MR and it seems to be working pretty well where we already had a fantastic surgical therapy for it, which is essentially primary MR and Fibroelastic Deficiency type of lesions. Now, as you know, these patients do extremely well with surgery. There are several series of 800, 900, a thousand patients operated either conventionally or minimal invasively with maybe one death. Still one too much I would argue, but extremely low risks.

These are the healthiest patients that a cardiac surgeon often can operate because I would argue this probably an inverse correlation with coronary artery and peripheral vascular disease in those patients. It's hard to know. There's some elements of the answer that we don't have yet. What about the very long term follow up? What about 10 years? What happens when an edge to edge repair fails and it was for primary MR in a younger patient?

And I think the authors really captured those very important caveats quite elegantly and provide a very balanced view. So like you, I'm very happy with this piece. Lastly, I'll conclude by saying there's even controversy as to sub-clinical parameters with edge to edge versus surgical mitral valve pair for primary MR. What does two plus mitral regurgitation that is post-procedure, What does that mean? Is this something that's going to impact the patient at 10 years, at 20 years and perhaps churn, what was it initially, a great therapeutic solution into one that's not so desirable? So again, as I said, the jury's still out on this and I think these really captures the main element of the answer as we know them in 2022.

Dr. James de Lemos:

Excellent points. I think really, I love your conclusion that hopefully there will be a better transcatheter solution than this for patients that aren't surgical candidates, obviously, because it doesn't, unlike TAVR, this doesn't come close to matching the surgical option. The last couple of papers in the issue focus on putting cardiac surgery in the greater context of the patient experience and the healthcare system experience and are in the health services research phase. The first one is from multi-centered team led by Amgad Mentias at Cleveland Clinic and Ambarish Pandey at UT Southwestern. And it focuses on a new performance metric that they're calling, 90 day risk standardized home time for cardiac surgery hospitals in the US.

And this group has done several studies with this new metric that basically is attempting to evaluate performance at the patient level with a very patient-centric metric of how much time they spend at home. They've published previously using data from heart failure patients and post MI patients and now are extending this to cardiac surgery and using risk adjustment of time outside the hospital in the 90 days after surgery to evaluate the variability among cardiac surgical programs. And they find that the metric correlates with mortality and readmission, that higher volume surgical centers are associated with more time spent out of the hospital.

And then when they compare it more directly with approaches that are used to currently rank performance, they see that this results in some reclassification of performance categories versus the other metrics. It's early in the life of this new metric but I'm interested to see intuitively is a cardiac surgeon, how does another tool to evaluate your performance, your team's performance and your hospital's performance resonate? And does this have any intrinsic advantages to you over the other risk standardized tools that are currently being used? Certainly in the US I don't know what's happening in Canada.

Dr. Marc Ruel:

Great points, James and I agree, this is an impressive data set. It's almost on 1 million patients from more than 1000 centers in the US. And as you said, it is a new patient based metric. It's a bit of a patient before the outcome if you will, those PROs that are so more commonly now the object of research with regards to outcomes. I would somewhat simplistically say that there are three possible outcomes to any heart surgery, patient survives and feels better. That's number one, that's what we want to achieve for everybody. Unfortunately, there are two other outcomes that can happen. Patient survives but patient is not improved by the surgery or has a complication as a result of it and quality of life does not improve. And third, obviously the one that is the obvious, highly detrimental is that patient does not make it from the surgery.

But I think really what this paper highlights is the importance of really focusing on the first one by the number of days spent at home during the first 90 days post intervention, post-surgery itself. So I think it is really a marker of how well the patient's doing. It closes the loop, if you will, with the first paper that we looked at, in an observational large data set type of way. But it again calls to, how was the patient functioning pre-op? And that data, as we know, is not available from this series. So it could be three things essentially. It could be performance and definitely it pleases the mind to think that the performance of the institution i.e, the quality of the care provided has a huge impact. But it could also be two other things.

It could be the level of functioning of the patient. The ability to get back and spend many of those first 90 days at home versus not, of the patient himself or herself, depending on the various populations that are served by those institutions. And third, it could also be a little bit of a recurrent theme of mine and I apologize for that, but it could be the degree of invasiveness that's provided if you out of surgeries offered to these patients. So I think these are interesting paradigms. They are very important. Again, they're completely in line with precision medicine and I think that this performance measure, as you alluded to, is an important point because a patient who survives but doesn't go back home really is not deriving a benefit from any operation.

Dr. James de Lemos:

Yeah, great points. And I think this discussion really leads us into our discussion, the last paper, which is another paper that attempts to put surgery in the greater context of the population and environment in which patients come. And this is led by Aditya Sengupta and her team from Boston Children's Hospital evaluating contemporary socioeconomic and childhood opportunity disparities in congenital heart surgery. This is a really next level analysis of associations between socioeconomic status and outcomes after congenital heart disease surgery in children focusing in one high volume quaternary center in Boston. And what they did is developed a novel predictor that was a US census tract based nationally normed composite metric of contemporary childhood, what they called neighborhood opportunity. And this comprised 29 indicators across three domains.

The three domains were education, health, and environment and socioeconomic domains. And they classified the patients into very low, low, moderate, high and very high neighborhood opportunity. And then they looked at evaluations across multiple outcomes. They did not see any association of neighborhood opportunity with early deaths, which I think is encouraging, but they did see that children with lower neighborhood opportunity had longer length of stay, higher healthcare costs and then significantly higher late deaths following surgery when the multiple components of long term care of these children probably have time to operationalize. I found this sobering and a complex message that excellent cardiac surgery can deliver superb outcomes across all levels of opportunity but if these issues aren't addressed, there are financial implications, but more importantly, the long term benefits of the cardiac surgical procedures aren't fully realized. Interested to hear your thoughts on this and how this might apply more broadly even to adult surgery.

Dr. Marc Ruel:

I agree, James and I too, really love this paper. As you say, it is sobering. It's a paper for physicians, but I would argue it's probably bedtime reading for Mr. Biden, any other country leaders as well. Whether it's Mr. Macron or Mr. Trudeau. Definitely something that is shows that what happens after the hospital stay, even in something as complex as congenital heart surgery, performed at Boston children, obviously a great institution. But what is shown here is that the institution with its top quality outcomes as we know them to be, is a fantastic societal and outcome equalizer, if you will. But once that passage through the tertiary or coronary institution has occurred, then reality sets in. And the childhood opportunity index that the authors had previously published in JAMA proves to be, again, a very important predictor of how these kids do later on. So this refers really to the societal contract that we're all part of as physicians. And we obviously, a big part of our mission is to improve the outcomes in hospital, but also beyond it. And I think this paper illustrates this very nicely as you so eloquently summarized.

Dr. James de Lemos:

Well, thanks. And I'll just, before I hand it over to you to conclude and wrap up, just compliment you and Mike and the entire team, as well as the authors who have submitted not just these but so many other superb papers covering the full spectrum of surgical sciences Circulation. I'm proud for us to have the opportunity to share these terrific papers with our readers and with researchers. And congratulations again to you for pulling this together.

Dr. Marc Ruel:

Well, you're very kind and thank you, James. To you and Joe, Darren and our and entire editorial leadership for the important place given to surgery within Circulation. It's something that I believe is important and resonates with surgeons but also non-surgeons who are part of the greater cardiovascular community. So it's tremendously important and we're very thankful for that opportunity.

Dr. James de Lemos:

Well, I'd like to thank all our listeners for joining us today and remind you to tune in next week when Greg and Carolyn will be back for their regularly scheduled podcast.

Dr. Greg Hundley:

Circulation October 18, 2022 Issue

17 oktober 2022 | 23 min

This week, please join author Sunil Rao and Guest Editor and Editorialist Gregory Lip as they discuss the article "A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction" and the editorial "Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is about the factor XI inhibitor asundexian. It's the trial that we've been waiting for the PACIFIC-AMI trial. You really have to listen to it because these factor XI inhibitors are super interesting. What? We're going to tell you about the other papers in today's issue first. Aren't we, Greg? Do you want to go first?

Dr. Greg Hundley:

You bet, Carolyn. Thank you so much. Carolyn, did you ever consider the genetic underpinnings of venous thromboembolism? Well, as you know, venous thromboembolism is a complex disease with environmental and genetic determinants. And in this study, this large investigative team represented by Dr. Nicholas Smith from the University of Washington in Seattle, and their colleagues present new cross-ancestry meta-analyzed genome-wide association study results from 30 studies with replication of novel loci and their characterization through in silicone genomic interrogations.

Dr. Carolyn Lam:

Wow. Sounds like a really large effort, Greg. What did they find?

Dr. Greg Hundley:

Right, Carolyn. In the author's initial genetic discovery effort that included 55,330 participants with venous thromboembolism: 47,000 were European, 6,000 African, and a little over 1000 Hispanic ancestry. They identified 48 novel associations of which 34 are replicated after correction for multiple testing. In their combined discovery replication analysis, so that's 81,669 venous thromboembolism participants and ancestry stratified meta-analyses from the European, African and Hispanic ethnic groups. They identified another 44 novel associations, which are new candidate venous thromboembolism associated loci requiring replication. And many of the replicated loci were outside of known or currently hypothesized pathways to thrombosis. Carolyn, in summary, these findings from this very large GWAS analysis highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of anti-thrombosis treatments with reducing the risk of bleed.

Dr. Carolyn Lam:

Wow. Super interesting and very related to that feature paper that we just discuss. But nonetheless, this next paper I love as well, if I may say so myself. It deals with frailty and as we know, frailty is increasing in prevalence. And because frail patients are often perceived to have a less favorable benefit risk profile, they may be less likely to receive new pharmacological treatments. And so, we and led by Professor John McMurray from the University of Glasgow, decided to investigate the efficacy and tolerability of dapagliflozin according to frailty status in the DELIVER trial.

Dr. Greg Hundley:

The DELIVER trial. Carolyn, tell us about the DELIVER trial?

Dr. Carolyn Lam:

Sure. In deliver dapagliflozin compared to placebo, reduced the risk of worsening heart failure events or cardiovascular death and improved symptoms in more than 6,000 patients with heart failure and mildly reduced and preserved ejection fraction, so ejection fraction above 40%. Now in this pre-specified analysis, we examine the efficacy and safety of dapagliflozin according to frailty status. That was determined using the Rockwood cumulative deficit approach.

And so, what we found was that greater frailty was associated with more impairment of health status and worse clinical outcomes in patients with heart failure and ejection fraction of 40%. The beneficial effects of dapagliflozin compared to placebo on clinical outcomes were consistent regardless of frailty class. But interestingly, the improvement in symptoms, physical function and quality of life were larger in the frailest patients. Adverse events were not more common in individuals randomized to receive dapagliflozin compared to placebo irrespective of frailty class. And so, the take home message is the benefit risk balance related to frailty in patients with heart failure with mildly reduced and preserved ejection fraction is favorable for dapagliflozin. And so, these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail.

Dr. Greg Hundley:

Wow. Carolyn, really interesting. You could see with the diuretic effect in someone that's frail, the potential hesitancy, but very interesting study results in this world of frailty and the use of dapagliflozin. Well, Carolyn, this next study is very interesting and it comes to us from the world of preclinical science that takes a very interesting approach to a scientific question. Now, as you may know, RNA-binding proteins or RBPs are master orchestrators of genetic expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs, thus characterizing RBPs targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, thereby limiting our understanding of their function.

Carolyn, these investigators led by Dr. Grégoire Ruffenach from UCLA were interested in assessing pulmonary arterial hypertension and they turned to the world of cancer research. Carolyn, in cancer, the RNA-binding protein hnRNPA2B1, and we're going to abbreviate that as A2B1, promotes a pro proliferative anti-apoptotic phenotype. The same phenotype is present in pulmonary arterial smooth muscle cells and is responsible for the development of pulmonary arterial hypertension. However, the A2B1 function that's never really been investigated in pulmonary arterial hypertension.

Dr. Carolyn Lam:

Oh, Greg, that's not only fascinating, but so beautifully described. Thank you. What did they find?

Dr. Greg Hundley:

Right, Carolyn. These authors found that A2B1 expression and it's nuclear localization are increased in human pulmonary arterial hypertension, pulmonary arterial smooth muscle cells. Using bioinformatics, they identified three known motifs of A2B1 and all mRNAs carrying them and demonstrated the complimentary non-redundant function of A2B1 motifs as all motifs are implicated in different aspects of the cell cycle. In addition, they showed that pulmonary arterial smooth muscle cells and A2B1 promote the expression of its targets. Additionally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. And so, Carolyn, through the integration of computational and experimental biology, this team study revealed the role of A2B1 as a master orchestrator of pulmonary arterial smooth muscle cells in pulmonary hypertension and that phenotype and its relevance as a therapeutic target in pulmonary arterial hypertension.

Dr. Carolyn Lam:

Wow, that's super, Greg. Thanks. Shall we go through what else is in today's issue?

Dr. Greg Hundley:

You bet, Carolyn. There's a Research Letter from Professor Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium Current versus Calcium Calmodulin‐dependent Kinase II.”

Dr. Carolyn Lam:

There's also an exchange of letters between Doctors Omarjee and Diederichsen regarding vitamin K2 and D in patients with aortic valve calcification: [an] absence of evidence might not be evidence of absence? And finally, there's an On My Mind paper by me and Scott Solomon and it's entitled, “Delivering Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure.” But let's go on now to talk about the Factor XI inhibitor, shall we, Greg?

Dr. Greg Hundley:

You bet. Well, listeners, welcome to this feature discussion on October 18th at a very special article today. And we have with us the lead author, Dr. Sunil Rao from NYU in New York City and also our associate guest editor as well as editorialist, Dr. Gregory Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Sunil Rao:

Yeah, great. Thanks so much, Greg. It's a real pleasure to be here with you. The background of the PACIFIC-AMI study is really rooted in the fact that patients who have acute myocardial infarction are really at risk for recurrent thrombotic events, even after their event. And this risk continues despite the fact that we have evidence based therapies that are really around targeting the platelet as well as aspects of the coagulation cascade. There have been studies that have looked at the use of dual antiplatelet therapy plus an anticoagulant or single antiplatelet therapy plus an anticoagulant. And those studies have shown a benefit. However, their clinical use is limited because of the bleeding risk.

Factor XI is an interesting target, because factor XI is likely involved in the amplification of thrombin generation after plaque rupture. But it really doesn't play much of a role in hemostasis. And so, as a target in reducing events after acute coronary syndrome, activated factor XI is a very attractive one. And so, the hypothesis of this study was that a highly bioavailable oral, direct, selective activated factor XI inhibitor called asundexian would be safe and effective in the treatment of patients who experience acute coronary syndrome at reducing adverse events. Now, this is a phase two study, so it really wasn't powered for clinical events. It was really a dose-finding study, so it was really looking at adverse events and sort of bleeding complications.

Dr. Greg Hundley:

Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can you describe for us your study design and then maybe a little bit more about the study population, how many subjects?

Dr. Sunil Rao:

Sure. Again, this is a phase two study. It was a randomized, double-blind, parallel-group design where patients, who were admitted with acute coronary syndrome were randomized to three different doses of asundexian and or placebo in a one-to-one to one-to-one fashion. Patients who met criteria for enrollment were: patients who were admitted with a diagnosis of acute MI; if they were older than or equal to 45 years of age; they were hospitalized in acute coronary syndrome that did not occur in the context of revascularization, so it was not a type 4 event; and they were planned to be treated with dual antiplatelet therapy after hospital discharge.

Dr. Greg Hundley:

Sunil, thank you for describing this very interesting study design. Now, how many subjects did you include and could you just describe for us the study population?

Dr. Sunil Rao:

We had a total of 1,601 patients that were randomized at 157 centers in 14 countries between June 2020 and July 2021. And in order to be eligible for enrollment into the study: patients had to be admitted with a diagnosis of acute MI, they had to be greater than or equal to 45 years of age, and be hospitalized with that acute MI that did not occur in the context of revascularization, so type 4 MIs were excluded. The other inclusion criteria was that they had to be planned to be treated with dual antiplatelet therapy after hospital discharge. Now, we allowed randomization up to five days after hospital admission and randomization occurred after patients were clinically stabilized and any planned PCI was performed. We included both patients with STEMI as well as non-ST segmental elevation ACS, but we capped the number of patients with STEMI that were included to no more than 50%. Now, the main exclusion criteria were things that you would expect for a phase two trial. Obviously, hemodynamic instability at the time of randomization, active bleeding or bleeding dialysis, severe renal dysfunction, planned use of full-dose anticoagulation.

Dr. Greg Hundley:

Very nice. And so, we have several doses of this new factor XI inhibitor. Describe for us your study results?

Dr. Sunil Rao:

Again, this was a phase two trial that was really looking at safety and adverse events as you would expect. The study groups were pretty balanced across all of the dosing arms. When we looked at the pharmacokinetic and pharmacodynamic data, we found something really interesting, which was that there was a dose relationship between the dose of asundexian and the factor XIa activity. Factor XIa is activated factor XI. The higher the dose, the more suppression of factor XI activity. In fact, the highest dose nearly eliminated factor XI activity. The drug clearly works in the way that it was intended. Now again, the clinical data, it wasn't powered for clinical data. But when we look at the bleeding results, we found that there was in fact an increase in bleeding as the dose of asundexian increased. The overall rate of bleeding in the highest dose of asundexian was in 50 milligrams was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about 9.02%. Again, the efficacy outcomes, very, very low rates of overall events. Again, not powered to show a difference. Essentially, very similar across all the arms.

Dr. Greg Hundley:

And did you find the same results for the men and the women? And what about older individuals and younger individuals?

Dr. Sunil Rao:

Yeah. We did look at some subgroups. And you had to be a little bit cautious because again, the trial itself is relatively small. I mean, we didn't notice any significant patterns across these subgroups. And the overall interaction p-values were really non-significant. But I think what this does show is like a phase two trial that the drug works as in the way that it's intended. Overall, safety was as expected. And I think it really sets up data for a larger study.

Dr. Greg Hundley:

Well, listeners, what a fantastic presentation. And now, we're going to turn to our guest editor and editorialist, Dr. Gregory Lip from Liverpool. Greg, I know working for circulation, you have many papers come across your desk. What attracted you to this particular paper? And then maybe secondly, can you help us put the results of this study in the context of other studies that have been evaluating these factor XI therapies?

Dr. Gregory Lip:

Thanks, Greg. Well, I think this is an important paper, because it is a phase two trial with a novel, orally bioavailable inhibitor factor XI. And this is intriguing because factor XI efficiency in humans and experimentally in animals is associated with a reduced risk of thrombotic events like stroke or venous thromboembolism. But spontaneous bleeding is rare and also bleeding in response to trauma or surgery is much milder. Really it's the holy grail of trying to get an anticoagulant that reduces thrombosis but doesn't cause an excess of bleeding. Now, this was the quest with different anticoagulants.

And I think it was very exciting to see this particular paper in the patients who've had an acute coronary syndrome, because there was a lot of interest in the use of anticoagulants, particularly in combination with antiplatelet therapy from trials such as ATLAS and COMPASS, where there was certainly a reduction in adverse cardiovascular events. But a downside with those drugs and when using combination, was an excess of bleeding by the combination of the available anticoagulants now plus antiplatelets. The factor XIs agents offered the possibilities we might have combination therapy to reduce cardiovascular events but not causing an excess of bleeding.

Dr. Greg Hundley:

Well, listeners, what a wonderful discussion that we've had here. Let's circle back with both individuals. Sunil, we'll start with you. What do you see as the next study to really be performed in this sphere of research?

Dr. Sunil Rao:

I think that factor XI is a very attractive target in patients with acute coronary syndrome. Again, the rationale for why we did this phase two trial was to show that inhibition of activated factor XI should result in a low rate of ischemic events without a significant increase in bleeding. This phase two trial was really to try and decide which doses result in potent inhibition of factor XIa and potentially which doses should be carried forward into a larger study. What we found in the PACIFIC-AMI trial was that the doses of asundexian and the factor XIa inhibitor were very, very well tolerated with a low rate of adverse events. It resulted in a dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. I think, again, it's a very attractive target in patients with ACS and this really provides support for a larger adequately powered clinical trial in patients with acute coronary syndrome that is really looking at clinical events such as MACE as well as bleeding.

Dr. Greg Hundley:

And Greg as an editorialist, what did you see with this paper? Maybe some unanswered questions that we'd like to pursue further?

Dr. Gregory Lip:

Well, I think this does raise a lot of questions in the sense that it'll be interesting because as a phase two trial, it's a relatively moderate sized trial. It's not like a phase three large outcome trial and phase two trials also testing different doses of the novel agent. We need to see the definitive phase three trial and to look at the magnitude of benefit versus potential for bleeding if in the large phase three trial and obviously, the net clinical benefit and importantly are some of the subgroups: ST elevation, myocardial infarction, undergoing primary PCI, for example, those with renal impairment. And I think particularly intriguing would be looking at the patients in this scenario who get the new antiplatelet drugs such as ticagrelor and prasugrel. And the reason I say that is what we have with warfarin or Coumadin and from the current DOACs or NOACs, depending on the risk side upon. We refer to them, that's the direct oral anticoagulants or non-vitamin K antagonist or anticoagulants.

Well, if you give a more potent antiplatelet like prasugrel or ticagrelor, the risk of bleeding not surprisingly is higher. Hence, the guidelines recommend that if you use an anticoagulant or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as opposed to the more potent ones. If this new class of drugs, the factor XI inhibitors can work well in combination with one of the more potent antiplatelets without causing an excessive bleeding, again, this is going to be a substantial advance.

Well, with these new class of anticoagulants, will be really interesting to see the phase three trials when applied to other chronic conditions. For example, stroke prevention and atrial fibrillation. And the other category of patients would be those who've had an embolic stroke of uncertain source or ESUS or in old terminology cryptogenic stroke. With the ESUS group of patients, they're currently treated with aspirin because the trials which tried a NOAC or DOAC, they were not showing a positive result. They'll be interesting again with the factor XI inhibitors, whether we are going to see this benefit with the reduction in recurrence stroke with no excessive bleeding.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Sunil Rao from NYU in New York City and Dr. Gregory Lip from the University of Liverpool for bringing us this study highlighting that in patients with recent acute myocardial infarction, three doses of asundexian when added to aspirin plus a P2Y 12 inhibitor resulted in dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. And certainly, the data from this study support the investigation of asundexian at a dose of 50 milligrams daily in an adequately powered clinical trial of patients following acute myocardial infection.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation October 11, 2022 Issue

10 oktober 2022 | 20 min

This week, please join author Michelle O'Donoghue and Associate Editor Parag Joshi as they discuss the article "Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, very interesting feature this week. Evolocumab, another application for that in patients with established atherosclerotic cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other very interesting articles in this issue?

Dr. Carolyn Lam:

Oh, I'd love that. And I'd like to go first, because Craig, have you heard of hybrid debranching repair? I know, I know. I had that same look, and can I tell you about it? Because I found it so interesting.

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

Now, the management of complex aortic aneurysmal disease involving the visceral vessels is challenging due to its very high morbidity and mortality. After four decades of experience in open repair, only a few centers worldwide report laudable results. And numerous factors limit total endovascular repair, including the access to devices, experience in deploying them, and several anatomical restrictions. So, hybrid debranching procedures were introduced for those patients who are unfit for the open or endovascular excluded patients. And while these have been developed, small series have only been done and revealed a wide range of short term results. So, today's paper is very important, and it's from Dr. Oderich from UT Memorial Herman Texas Medical Center and colleagues.

It's a large multi-institutional study, which contains the five year outcomes in 200 patients offering greater clarity in the usefulness and limitations of these hybrid debranching repair procedures. What they found was that hybrid aortic debranching had a low early mortality when done in lower risk patients, but mortality remained very elevated in high risk patients. And so, this suggests that deep branching could be a good alternative in patients adequate for traditional open repair, although pulmonary complications are quite common. The bypass grafts to the visceral vessels had very good patency with a five year primary patency of 90%. Permanent spinal cord injury occurred in 6%, suggesting that deep branching in experienced centers may offer outcomes comparable to centers of excellence for open thoracoabdominal aortic aneurysm repair.

Dr. Greg Hundley:

Wow, Carolyn, very nice and so beautifully explained.

Dr. Carolyn Lam:

You know what, Greg? I'm on a roll and I'd like to tell you about one more, this time a preclinical study. First, a little bit about the background. You see, transplantation with pleuripotent stem cell derived cardiomyocytes, as we know, represents a very promising therapeutic strategy for cardiac regeneration. We even have first clinical studies in humans, but yet little is known about the mechanism of action underlying graft induced benefits. So in this paper from Dr. Weinberger from University Medical Center Hamburg in Germany and colleagues, they explored whether transplanted cardiomyocytes actually actively contribute to heart function by injecting these cardiomyocytes with an optogenetic off on switch in a Guinea pig cardiac injury model.

Dr. Greg Hundley:

Wow, Carolyn, this is so interesting. So what did they find?

Dr. Carolyn Lam:

So, light induced inhibition of endo-grafted cardiomyocyte contractility resulted in a rapid decrease in left ventricular function in about 50% of the animals that was fully reversible with the offset of photo stimulation. So in conclusion, this optogenetic approach demonstrated that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force generating myocardium can serve as a regenerative therapeutic strategy.

Dr. Greg Hundley:

Oh wow, Carolyn. That was just fascinating. Such incredible preclinical science in our journal. Well, Carolyn, this next paper comes to us from the world of myocarditis. And Carolyn, it involves a population based cohort of 336 consecutively recruited patients with acute myocarditis enrolled in both London and Maastricht. And the authors, led by Dr. Sanjay Prasad from Royal Brompton Hospital, investigated the frequency and clinical consequences of dilated cardiomyopathy and arrhythmogenic cardiomyopathy genetic variants in this population based cohorts of patients with acute myocarditis. Now, Carolyn, all participants underwent targeted DNA sequencing for well characterized cardiomyopathy associated genes and their comparison to healthy controls, of which they had 1,053 that were sequenced on the same platform. Case ascertainment of their outcomes in England was assessed against their national hospital admission data, and the primary outcome was all cause mortality.

Dr. Carolyn Lam:

So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So these authors identified for dilated cardiomyopathy or arrhythmogenic cardiomyopathy associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of desmoplakin truncating variants in those with normal LVF, and then titin truncating variants in those with a reduced LVF. So Carolyn, importantly, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing would be considered in patients with acute myocarditis to help reassure the majority of individuals that don't have one of these genes, while improving the management of those that do have one of the underlying genetic variants. Very interesting findings from the world of myocarditis.

Dr. Carolyn Lam:

Great. And a great clinical take home message. Thank you, Greg. Well, this next paper sought to investigate the influence of age on the diagnostic performance of cardiac troponins in patients presenting with suspected myocardial infarction. Dr. Atul Anand from the BHF Center for Cardiovascular Science and University of Edinburgh and colleagues did this by performing a secondary analysis of the high stakes stepped wedge cluster randomized control trial that evaluated the implementation of a high sensitivity cardiac troponin ISA in consecutive patients presenting with suspected acute coronary syndrome.

Dr. Greg Hundley:

Oh wow. Carolyn. Super interesting, and very applicable clinically. So what did they find here?

Dr. Carolyn Lam:

In older patients presenting with suspected MI, the majority of cardiac troponin elevations are explained by acute or chronic myocardial injury or type two MI. The specificity and positive predictive value of high sensitivity cardiac troponin to identify myocardial infarction decreases with age and is observed, whether applying sex specific or age adjusted 99th percentile diagnostic thresholds or a rolling threshold for the triage of patients at high probability of myocardial infarction. Serial troponin testing incorporating an absolute change in troponin concentration increased the discrimination for myocardial infarction in older adults.

Dr. Greg Hundley:

Oh wow, Carolyn. Such clinically applicable findings in this particular study, particularly when managing our aging population. Well, Carolyn, how about we discuss some of the other articles in this issue. And there's a very nice In-depth piece by our own Sami Viskin entitled “Arrhythmogenic Effects of Cardiac Memory.” And then, there's an exchange of letters by Drs. Giannitsis and Mueller regarding the article, “Unexpected Sensitivity Issue of Three High Sensitivity Cardiac Troponin I-Assays in Patients with Severe Cardiac Disease and Chronic Skeletal Muscle Diseases.”

Dr. Carolyn Lam:

Nice. There's also a Research Letter by Dr. Szendroedi on “Impaired Mitochondrial Respiration in Humans with Prediabetes: A Footprint of Prediabetic Cardiomyopathy.” And there's a CV case series by Dr. Kalra on very high cholesterol mimicking homozygous familial hypercholesterolemia. Interesting case. Well, I suppose that wraps it up. Let's go on to the feature discussion, shall we, Greg?

Dr. Greg Hundley:

You bet.

Evolocumab. Welcome listers to this feature discussion on October 11th, and we're very fortunate today. We have with us Dr. Michelle O'Donoghue from Brigham Women's Hospital and Dr. Parag Joshi from UT Southwestern, the Associate Editor for this paper. Well, Michelle, can you describe for us some of the background information that went into the preparation of your study, and then what was the hypothesis that you wanted to address?

Dr. Michelle O'Donoghue:

Sure. Happy to do so, and thank you for having me. So by way of background, the Fourier study, which was previously published in the New England Journal, compared Evolocumab to placebo in 27,000 plus patients with established atherosclerotic cardiovascular disease, and Evolocumab significantly reduced the risk of major adverse cardiovascular events. But, the follow up duration was relatively short. Median follow up was 2.2 years. So this was now an open label extension study to Fourier known as the Fourier OLE study that allowed an additional median follow up time of five years, during which time all patients were now treated with open label Evolocumab. T.

He primary hypothesis that we were testing in this extension study was primarily to look at long term safety. We had limited data to really assure us of the safety of PCSK9 inhibitors over the course of several years. And so, safety was the primary hypothesis that we were testing, but also of course of key interest, during the parent Fourier study, we know that the benefit for cardiovascular risk reduction appeared to grow over time. So this was also an opportunity to see that pattern and to see whether or not there was in fact legacy effect for patients who were treated earlier with Evolocumab versus placebo.

Dr. Greg Hundley:

Very nice, Michelle. And so, sounds like we have a substudy of the Fourier trial. Can you describe for us a little bit more, for this substudy, your study population and your study design?

Dr. Michelle O'Donoghue:

Sure. So the patients enrolled in the open label extension were a subset of those who participated in the parent study. So as I previously mentioned, more than 27,000 participated in Fourier. It was a global study. For the open label extension, it was more than 6,500 patients who participated, and those were patients who were at sites in Europe and United States. And so, those patients were then followed on average for a meeting of five years. So that means that all together, patients who had been randomized to Evolocumab in the parent study had potentially more than eight years of drug exposure for us to examine safety.

Dr. Greg Hundley:

Very nice. And so, what did you find?

Dr. Michelle O'Donoghue:

Well, first, looking at the first hypothesis of safety, we saw no evidence that there was any increased risk of any adverse events of interest when it comes to PCSK9 inhibitors as a drug class, or achieving very low levels of LDL cholesterol. So there was no uptick in terms of neurocognitive events, the risk of diabetes. We do know that there was an increased risk of injection site reactions with the PCSK9 inhibitors, but not one that appeared to persist over time. So first was the safety, but importantly, I think that the more interesting results perhaps were those for MACE, for cardiovascular risk reduction. So we saw, even though all patients were being treated with open label Evolocumab during the extension phase, the benefit that was seen during the parent study persisted.

So there was a 15% reduction in the primary outcome, a broad composite of cardiovascular events. There was also a 20% reduction in the triple composite of cardiovascular death, MI, or stroke. And then perhaps of the most interest to your listeners is that there was a 23% reduction in cardiovascular mortality, and that was not something that was seen in the parent study. It really took time for that mortality benefit to emerge.

Dr. Greg Hundley:

Very nice. Michelle. Just a couple quick clarification points. Did you see these effects in both men and women? And then was there any impact of age on those results?

Dr. Michelle O'Donoghue:

Great questions. Some of those subgroup analyses are still ongoing, but no, we did not see any evidence of effect modification at first pass. But again, we'll be continuing to dig into all potential subgroups.

Dr. Greg Hundley:

Very nice. Parag, I know you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Parag Joshi:

Yeah, thanks. And congratulations again, Michelle. It's a really phenomenal study, and the findings, as you highlighted, are just really impactful for the field. I think for our journal at circulation, this is a really high impact finding in terms of extending out, giving us a rigorous way to look at long term follow up for people on PCSK9 inhibitors and really reassure that there is safety there. And as you highlighted, a sustained reduction in LDL cholesterol, other compounds in the space, Bococizumab in particular, that there were induced antibodies against the monoclonal antibody, and that sustained response was not there. So I thought that was also really reassuring, that over the course of eight years, we see sustained LDL reduction. And with that, really reaffirming the idea that the longer you can reduce LDL, there's an associated reduction in events.

And as you highlighted, the initial Fourier, there was some question about why there wasn't a CV death mortality signal while there was in the Odyssey outcome study and slightly different patient populations of course, but just really needed more time to start to tease that out. So all of this, I think this is the first that we're seeing this kind of long-term data on this impactful class of medications that really made this a fantastic manuscript for us at Circulation.

Dr. Greg Hundley:

Wow. Boy, Parag, I don't know that you could have stated that any better. So Michelle, looking forward, what is your group thinking? And then maybe just as your comment on the field in general, what do you think is the next study or series of studies that needs to be performed in this sphere of research?

Dr. Michelle O'Donoghue:

Well, I think he started to touch upon the areas of interest to us, is that I think that there are still many opportunities to answer more questions even within this existing data set. In particular, there was a dedicated neurocognitive substudy that was built into the parent study. And we also have that now through the extension period. So, that was a sort of more rigorous assessment of neurocognitive outcomes. And so, that's another analysis that we're going to be pursuing in the near future and I think is of potential key interest. And then beyond that, I think that the PCSK9 inhibitor class in general is just so interesting. There are additional compounds that are under study, such as small interfering RNA, so different mechanisms of getting to the PCSK9 protein. And I think it'll be reassuring to see whether or not they are consistent results, regardless of how you lower PCSK9, whether it translates into similar types of clinical benefit. So I think it's an exciting field. And then stay tuned. I think there'll be more to come.

Dr. Greg Hundley:

Parag, do you have anything to add? What do you see really as the next series of studies that might be performed here in this area of research?

Dr. Parag Joshi:

Yeah, I think Michelle hit the nail on the head that seeing confirmatory evidence here would be great. And then really, what's so exciting about this space is there's so much interest in ways to address this protein, including gene editing, vaccination against it. And now you're getting the necessary evidence that, hey, you can really suppress these levels in patients for years without concerning safety signals, at least from what we've seen so far. So that's more excitement as to long term ways to address cardiovascular risk.

Dr. Greg Hundley:

Wow. Well, listeners, we've been very fortunate today to have with us Dr. Michelle O'Donaghue from Brigham and Women's Hospital, and Dr. Parag Joshi from UT Southwestern as the Associate Editor of Circulation to really bring us these exciting results, highlighting that long term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events over eight years that did not exceed those observed in the original placebo arm during the parent Fourier study, and led to further reductions in cardiovascular events compared with delayed treatment initiation.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation October 4, 2022 Issue

3 oktober 2022 | 26 min

This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study."

Dr. Carolyn Lam:

Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA?

Dr. Greg Hundley:

Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure.

Dr. Carolyn Lam:

Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology.

However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes.

Dr. Greg Hundley:

Oh wow, Carolyn, this sounds really informative. So what did they find?

Dr. Carolyn Lam:

Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts.

Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis.

Dr. Greg Hundley:

Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction.

So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily.

Dr. Carolyn Lam:

All right. So the Paradise MI echo substudy, what did they find?

Dr. Greg Hundley:

Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure.

Dr. Carolyn Lam:

Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial.

Dr. Greg Hundley:

Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us?

Dr. Carolyn Lam:

Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction.

Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new.

Dr. Carolyn Lam:

Wow, that's interesting. So what did this paper find?

Dr. Greg Hundley:

Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension.

So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting.

Dr. Carolyn Lam:

Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing.

Dr. Greg Hundley:

Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke?

Dr. Carolyn Lam:

Yep. In patients with EF, here we go.

Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation.

Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place?

Dr. Signild Åsberg:

Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question.

Dr. Jonas Oldgren:

My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies.

So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?"

And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment?

Dr. Carolyn Lam:

Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used?

Dr. Jonas Oldgren:

Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence.

And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study.

Dr. Carolyn Lam:

Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results?

Dr. Signild Åsberg:

Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients.

Dr. Carolyn Lam:

That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome?

Dr. Jonas Oldgren:

Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well.

So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started.

So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention.

Dr. Carolyn Lam:

Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit?

Dr. Signild Åsberg:

We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase.

Dr. Carolyn Lam:

I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds?

Dr. Signild Åsberg:

We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale.

Dr. Carolyn Lam:

Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results.

Dr. Signild Åsberg:

Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that.

We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation.

Dr. Jonas Oldgren:

And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials.

So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences.

And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients.

Dr. Carolyn Lam:

Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view?

Dr. Signild Åsberg:

Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention.

Dr. Jonas Oldgren:

I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study.

Dr. Carolyn Lam:

And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week.

Dr. Greg Hundley:

This program is Copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

Circulation September 27, 2022 Issue

26 september 2022 | 27 min

This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway.

Dr. Carolyn Lam:

Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we?

Dr. Greg Hundley:

Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom.

New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination.

Dr. Peder Myhre:

Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find?

Dr. Greg Hundley:

Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population.

Dr. Peder Myhre:

Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners.

Dr. Greg Hundley:

Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings.

Dr. Peder Myhre:

Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs.

Dr. Greg Hundley:

So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but-

Dr. Carolyn Lam:

Way to go, Peder. Way to go.

Dr. Greg Hundley:

Yeah. Well, the good news is, I can just say yes. I did know that.

Dr. Peder Myhre:

That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline.

Dr. Greg Hundley:

Oh, wow, Peder. So what did they find?

Dr. Peder Myhre:

So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59.

And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline.

Dr. Greg Hundley:

Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension.

Dr. Peder Myhre:

Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg?

Dr. Greg Hundley:

Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung.

They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag?

Dr. Peder Myhre:

So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag?

Dr. Greg Hundley:

Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.”

Dr. Peder Myhre:

And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn.

Dr. Carolyn Lam:

Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis.

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found?

Dr. Hanna-Kaisa Nordenswan:

Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis.

The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up.

Dr. Carolyn Lam:

Great. What did you find?

Dr. Hanna-Kaisa Nordenswan:

So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis.

Dr. Carolyn Lam:

Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings.

Dr. Jukka Lehtonen:

Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis.

So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients.

So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases.

Dr. Carolyn Lam:

Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk.

Dr. Mark Link:

Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid.

Dr. Carolyn Lam:

Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah?

Dr. Jukka Lehtonen:

I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well.

Dr. Carolyn Lam:

Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD?

Dr. Hanna-Kaisa Nordenswan:

Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up.

Dr. Carolyn Lam:

That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark?

Dr. Mark Link:

Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data.

Dr. Carolyn Lam:

Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first?

Dr. Jukka Lehtonen:

Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference.

I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group.

Dr. Carolyn Lam:

Thank you, Hannah?

Dr. Hanna-Kaisa Nordenswan:

Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography.

Dr. Mark Link:

Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue.

Dr. Carolyn Lam:

Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation September 20, 2022 Issue

19 september 2022 | 29 min

This week, please join author Jonathan Sterne and Associate Editor Shinya Goto as they discuss the article "Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg, we've got a special treat for everyone today. We have a third co-host and he is none other than Peder Myhre from Norway! Really adding to the diversity of our podcast: me from Asia, you from the US, and Peder from Europe. Welcome, Peder.

Dr. Peder Myhre:

Thank you so much, Carolyn. It's truly an honor to be here and I'm looking forward to being part of this podcast today.

Dr. Carolyn Lam:

Awesome. Well, here we go. Looks like we have a feature paper, Greg?

Dr. Greg Hundley:

Absolutely, Carolyn. Peder, welcome. So, listeners, our feature today will involve COVID-19 and its association with arterial and venous thrombotic diseases. But before we get to that, we're going to all grab a cup of coffee from all over the world and get into some of the other articles in the issue. Peder, Carolyn, how about I go first?

My first study involves a prospective cohort of 94,000 individuals from the UK Biobank, who had device-measured physical activity from 2013 to 2015 and were free from myocardial infarction and heart failure. Now, Peder and Carolyn, the study was performed because although objectively measured physical activity has been found associated with acute cardiovascular outcomes, it has not been found associated with heart failure and, of course, a syndrome that's been expanding worldwide. As such this study led by Carlos Celis-Morales from the University of Glasgow aimed to investigate the dose response relationship between device-measured physical activity and heart failure by intensity of the physical activity. Now physical activity was measured with a wrist-worn accelerometer and time spent on light, moderate, and vigorous intensity physical activity was extracted. Incidental heart failure was ascertained from linked hospital and death records.

Dr. Peder Myhre:

Wow, Greg. That sounds amazing. Tell us, what did they find?

Dr. Greg Hundley:

You bet, Peder! These investigators found that, compared with participants who undertook no moderate to vigorous intensity physical activity, those who performed 150 to 300 minutes per week of moderate intensity physical activity or 75 to 150 minutes per week of vigorous intensity physical activity were at lower risk of heart failure. Now, interestingly, the association between vigorous intensity physical activity and heart failure was a reverse J-shaped curve with a potentially lower risk reduction above 150 minutes per week.

And so, the take-home message for this first paper is that device-measured physical activity, especially moderate intensity physical activity, was associated with a lower risk of heart failure. Probably current vigorous intensity physical activity recommendations should be encouraged, but not necessarily increased. In contrast, increasing moderate intensity physical activity may be beneficial, even among those meeting current recommendations.

Dr. Peder Myhre:

Wow, Greg. That was a great summary. And the second original research article today is about high density lipoproteins. As you know, raising HDL cholesterol levels to prevent cardiovascular disease remains a hot topic. HDL plays a key role in reverse cholesterol transport and may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin cholesterol acyl transferase, LCAT, is the rate limiting enzyme in the reverse cholesterol transport and a recombinant human LCAT called MEDI6012 has previously been shown to increase HDL cholesterol. So in this study from the corresponding author, Marc Bonaca from University of Colorado School of Medicine, the investigators in the real team is 63B multicenter placebo control trial investigated whether randomized patients to, MEDI6012 or placebo would reduce the infarct size as measured by cardiac MRI, 10 to 12 weeks after the STEMI.

Dr. Greg Hundley:

Very interesting, Peder. So, MRI assessments of LV mass after PCI. So, what did they find?

Dr. Peder Myhre:

So, Greg, the authors successfully enrolled 593 patients with a median age of 62 years and 78% males. And the median time from symptom onset to randomization was 146 minutes and only 13 minutes from hospitalization to randomization. And the index MI was anterior in 70% and 65% had TIMI Flow grade 0-1. And then to the main results at 12 weeks, the infarct size did not defer between the treatment group. So that was a 9.7% infarct size for MEDI6012 versus 10.5% for placebo with a P value of 0.79. And there was also no difference in noncalcified black volume. So the authors conclude that enhanced reverse cholesterol transport with recombinant human LCAT did not reduce infarct size or late regression of noncalcified coronary REPL at 12 weeks. Okay, Greg. So tell me about the 3rd paper you have today?

Dr. Greg Hundley:

Peder, what a great description on that previous paper, beautiful job there. So Peder, this next article pertains to cardio toxicity related to the administration of anthracycline-based chemotherapy. And an example would be Doxorubicin. And this occurs in patients often with certain types of cancer. As you know, Doxorubicin is still utilized for the treatment of leukemia, lymphoma, soft tissue sarcoma and in the setting of adjuvant breast cancer treatment. And so to this end, the authors, led by Lorrie Kirshenbaum from St. Boniface Hospital abstract research, wanted to assess cytokine mediated inflammation in myocellular injury, as a result of some of the inflammation that's induced by the administration of Doxorubicin. So as a little bit of background, cytokines, such as TNF alpha, have been implicated in cardiac dysfunction and toxicity associated with Doxorubicin. Now, while TNF alpha can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart really somewhat remain cryptic.

The E3 ubiquitin ligase, TRAF2, provides a critical signaling platform for K63 length poly ubiquitin nation of rip K1, crucial for NF-kB activation by TNF alpha and survival. Whether alterations in TNF alpha, TRAF2, NF-kB activation signaling underlie the cardiotoxic effects of Doxorubicin, remains poorly understood. So herein, these authors investigated TRAF2 signaling in the pathogenesis of Doxorubicin cardio toxicity.

Dr. Peder Myhre:

Oh wow, Greg. So we're talking mitochondrial dysfunction in Doxorubicin cardiomyopathy. So please tell me, what did they find and what were the clinical implications?

Dr. Greg Hundley:

Very nice. Peder, you remind me of Carolyn, asking me the clinical implications. Okay, so first, in mouse models and in vitro measures in rats, mouse and human pluripotent stem cell derived cardiomyocytes, these investigators monitored TNF alpha levels, LDH, cardiac ultra structure and function, mitochondrial biogenics, as you just suggested, and cardiac cell viability. They found that a novel signaling axis exists that functionally connects the cardiotoxic effects of Doxorubicin to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by Doxorubicin, sensitizes cardiomyocytes to TNF alpha and BNIP3 mediated necrotic cell death. Perhaps, interventions that stabilize TRAF2, so here's the clinical implication, may prove beneficial in mitigating the cardiotoxic effects in cancer patients undergoing anthracycline-based chemotherapy.

Dr. Carolyn Lam:

So Greg, he may sound like me, but this is me going what an amazing summary and especially in something that is your specialty cardio-oncology, that's amazing. Thank you. Peder, I assume you've got one more paper?

Dr. Peder Myhre:

So Greg, now I'm going to sound like you and say that we are going to stay within the world of preclinical science. So genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease. However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. And there is evidence to suggest that the genetic influence of coronary artery disease sociability may partly act through vascular smooth muscle cells. So corresponding author, Shu Ye from University of Leicester, performed genotyping, RNA sequencing and cell behavior assays on the large bank of vascular smooth muscle cells with an N of almost 1500. And through these extensive analysis, they saw to identify genes whose expression was influenced by coronary artery disease associated variants.

Dr. Greg Hundley:

Very nice, Peder. So, more about cardiac gene expression. So, what did they find?

Dr. Peder Myhre:

Approximately 60% of the known coronary artery disease associated variants show statistically significant effects in vascular smooth muscle cells and the study identified 84 candidate causal genes whose expression quantitative trait, loci signals in vascular smooth muscle cells, significantly co-localized with reported coronary artery disease association signals, of which 38 of them are potentially druggable, so, that was the clinical implications. The authors conclude that a large percentage of coronary artery disease loci can modulate genes, gene expression in vascular smooth muscle cells and influence these cell behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. And Greg, accompanying this paper is a beautiful editorial by doctors O'Donnell and Bradner entitled "Bridging the Gap to Translating Genome-Wide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease."

Dr. Greg Hundley:

Very nicely done Peder, very nicely done. Well, as usual, we have some other items, we call it in the mail bag because we receive these wonderful research letters and also research correspondence. So I'll go first. First, Dr. Al-Khatib has a research letter entitled, "Duration of Anticoagulation Interruption before Invasive Procedures and Outcomes in Patients with Atrial Fibrillation Insights from the Aristotle Trial." And also there's a nice ECG analysis by Dr. Tsai entitled, "A Peculiar Wide-Complex Tachycardia During Flecainide Treatment."

Dr. Peder Myhre:

Nice, Greg, and there's also an exchange on letters to the editors and the response from Professors Zhao and Ding, and again, a response from Professor Zhang regarding the prior letter by Jin et al. pertaining to the previously published article "Micro RNA, 210 Controls, Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction."

Dr. Greg Hundley:

Beautifully done, Peder. Oh, wow. Welcome to this team. We're so excited to have you. And now Carolyn, I think we're going to jump over to that feature discussion and learn a little bit more about COVID-19 and arterial and venous thrombotic disease.

Dr. Carolyn Lam:

You bet! Let's go, Greg and Peder.

Now we all know that infection with COVID 19 induces a pro-thrombotic state, but the long term effects of COVID-19 on the incidence of vascular disease, both arterial and venous, remain unclear. That is until today's feature paper. We're so grateful to have corresponding author Dr. Jonathan Stern, from the University of Bristol, as well as our associate editor, Dr. Shinya Goto from Tokai University School of Medicine to join us and discuss this very important paper today. Jonathan, could you start us off on telling us why it's so important to look at this? Haven't we always known that infections, COVID or not, are associated with pro-thrombotic state? So what's so different about what you did and what you found this time?

Dr. Jonathan Stern:

So, yes, I think we already knew that serious infections, in particular infections leading to hospitalization, can result in thrombotic events, either arterial or venous. And it was also clear from January, February, March 2020, that COVID led to very serious infection and therefore was likely to lead to vascular events. The questions that we set out to address, beyond simply establishing that COVID does indeed do this, was to quantify by how much COVID multiplies the rate at which these thrombotic events occurred, to do that separately for different events, such as myocardial infarction, stroke, venous thromboembolism, pulmonary embolism. And then to importantly, because we analyzed a very large dataset, which we might want to talk about, to try to separate out the amount by which the rating events was multiplied over time and in important subgroups, for example, in hospital people who were hospitalized for their COVID, compared with people who weren't hospitalized for their COVID, by age and sex, and by other demographic characteristics.

Dr. Carolyn Lam:

I love that, you see, that really set out the novel information this added with, may I add, very important clinical implications, which we'll get to them. You've already teed me up to talk about this 48 million adults that you managed to look at. Oh my goodness! Tell us, how in the world did you do that?

Dr. Jonathan Stern:

Well, I think the first thing to say is that it's my absolute privilege to talk about this paper on behalf of a really incredible team that put the work together. And a lot of that work, or that work started with really unlocking the power of NHS data because of the COVID pandemic. So in the UK, we have a national health service, free at the point of delivery to everybody. The NHS assembled electronic health records, and there's been a long and proud history of research based on electronic health records in the UK. But for the first time, because of the pandemic, a combined data resource for the whole of England, so that's a population of about 58 million people, was established and that linked primary care data - data from family doctors, data on secondary care hospital admissions, data on COVID testing and subsequently, although it's not the subject of this paper, data on vaccination.

So those data were all linked and put into one place within what's called a trusted research environment with very strict controls on what can be output from the environment in order to protect patient privacy. And that was really done during 2020. And then the analyses for this paper took place during 2021, and it was an enormous amount of work by a large and absolutely fantastic team of people across multiple UK universities and national health service institutions.

Dr. Carolyn Lam:

Wow. Bravo! We talk about big data, we talk about using it. I trained in the NHS system. Who knew that this could come out to reveal such important results? So thank you for that as a background, but now, tell us what you found please?

Dr. Jonathan Stern:

So we found that rates of these conditions, they were primarily acute lymph infarction and ischemic stroke, which we grouped together with other conditions as arterial thrombotic events, and then deep vein thrombosis and pulmonary embolism, which we grouped together with other conditions as venous events. And we found that rates were substantially multiplied immediately after a diagnosis of COVID by up to 748 times, that the amount by which rates were multiplied diminished with time since COVID, but importantly that even six months to a year after that first diagnosis of COVID, rates of venous events were still about double in people who'd had COVID, compared to people who had COVID. And we found, it seemed quite clear that the persistence of the elevated risk was longer for venous events than for arterial events.

Dr. Carolyn Lam:

Just really fascinating results and Shinya, could I ask, what are your thoughts on this? And as you were managing this paper, the implications?

Dr. Shinya Goto:

First of all, thank you very much, Jonathan, for choosing saturation for your great paper. I'm handling quite a lot of papers, but your paper was very attractive. As Carolyn mentioned, it's huge data! 48 million, it's surprising, and also you also pick up booster rate of arterial embolism event for years, and you have also shown adjusted rate is initially increased quite a lot and then decreased gradually. And even after two months, three months still, there is a persisted higher risk. And as you mentioned, for the venous thrombo embolism, it's persisted for more than year to year. It's surprising. COVID-19's a different disease. Perhaps COVID-19 infection cuts to the vascular endarterial cell, perhaps, your research raised a lot of research questions, like endarterial damage induced by COVID-19 in the past 6 months; I would say more than half a year to one year. So that mechanistical insight is very important. And you raise a lot of any clinical questions.

Dr. Jonathan Stern:

Well, thank you very much for your kind words and you are right, I think we are left with questions about maybe in three areas. Firstly, for how long is there an elevation in risk? I should probably say, for those who haven't read the paper, that these results relate to events that occurred in England and Wales during 2020. And so that is in an era before vaccination and when we were dealing with the original variant, and to some extent, the alpha variant. So we are still waiting to see what the implications were over longer periods, and we will be doing that, we will be extending follow up. In fact, we are at the moment extending those results. I think, secondly, we are left with questions about the mechanisms, which you articulated, and thirdly, there's the question about, well, what are the implications for clinical management of patients with COVID-19? And in particular, for patients who've had severe COVID-19, for example, severe enough to be hospitalized for it?

Dr. Shinya Goto:

Yeah, you have also showed a very important point that even known hospitalization for COVID-19, the risk of thrombosis becomes high. So it's very surprising. And even non-hospitalized patients have a higher risk of thrombosis. That is probably the huge difference between other virus infections and COVID-19.

Dr. Jonathan Stern:

Yes. The good news, if you weren't hospitalized for your COVID, is that the elevation in risk declines more rapidly for people with less severe COVID who weren't hospitalized than for people with more severe COVID who were hospitalized. But nonetheless, as you say, particularly in the first week, two weeks, three weeks after COVID, there is a clear elevation in the risk of both arterial and venous events, even if you were not hospitalized for your COVID. We should probably also bear in mind that these results for 2020, when there were severe constraints for some of the time on health service resources. So you probably had to be pretty sick to get hospitalized at that time.

Dr. Carolyn Lam:

That was a very important caveat that you just highlighted. So thank you for contextualizing those findings for us, Jonathan, but then I kind of wish all podcast guests were like you, and you already asked a question, I was going to ask you. Which is, okay, so what's the clinical implication? Should we all be taking some low dose NOAC or aspirin? Whether you're hospitalized or not? Or if you were in 2020? Because, jokes aside, I know that you found some very important risk factors? Or these events which had clinical implications? Could you expand on it?

Dr. Jonathan Stern:

So maybe I'd start by saying that we didn't find that these patterns varied dramatically either by sex or by age. And in fact, when we were planning the analyses, I was convinced that we would see dramatic differences in these hazard ratios by age. And, broadly speaking, the facts on a multiplicative scale, the amount by which your rate is multiplied, looked similar across age groups and by sex. On the other hand, we did see the amount by rates of arterial and venous events were multiplied, appeared greater in people of Asian ethnicity or Black ethnicity than in people of White ethnicity. A counterintuitive finding was that the amount by which your rate was multiplied is lower, if you've had a prior event than if you hadn't. Those are the sorts of extents to which we can say something about how your own characteristics predict the consequences once you've had COVID.

In terms of management, obviously the pandemic has been tumultuous for medicine and for medical research and things have moved on greatly since the pre-vaccination era, 2020 and early 2021, to which these analyses relate. So the first thing to say is, don't get hospitalized with COVID, and the best way to not be hospitalized with COVID, is to be fully vaccinated for COVID. And that's a message that I think the whole of the medical profession has communicated loudly and clearly for a long time now.

So the second thing is, well, okay, what about if, nonetheless, you got COVID, particularly severe COVID, and we discussed this in the team extensively, and I particularly want to mention the senior clinical author, Dr. Will Whiteley from the University of Edinburgh in this regard, and I think the main message here is that risk factor management, cardiovascular risk factor management is always important, but it's probably particularly important in people who've had severe COVID to review risk factor management and make sure that existing guidelines in terms of cholesterol lowering, blood pressure lowering and so on, are being adhered to. We don't... So the most important thing is adherence to existing cardiovascular risk management guidelines. I think we don't have evidence that specific additional interventions are indicated in people who've had COVID, and COVID now in the era of Omicron and widespread vaccination is not the same as COVID during 2020.

Dr. Shinya Goto:

Jonathan, you have raised a very important issue. I strongly recommend all audiences to read this paper. We have to know persistent or higher risk of myocardial infarction, ischemic stroke, may be controlled more regularly controlled. Don't fear the COVID-19 infection to visiting the healthcare professional. In my country, some of the population stopped coming to the healthcare professional because they fear so much about infection from the hospital or clinic. But it's very important to keep that regular control like static and blood pressure control. Maybe we don't have that data about aspiring or not, but strong message your paper gave is that risk factor control after COVID-19 is very important.

Dr. Jonathan Stern:

I completely agree.

Dr. Carolyn Lam:

And I would add to that, remember the days when people were stopping their ACE inhibitors and so on for those fear? So what a great message and thank you for giving us a little bit of a peek into the future of what you're planning next with more follow up, in a population that is vaccinated from a different strain perhaps. And I think this still encourages hopefully more trials and research into this whole area of how we should be managing these patients. Well, thank you so much both of you for discussing this very, very current relevant, important paper. Thank you for publishing it in circulation with us. And to the audience, thank you for joining us today. From Greg and I, you've been listening to Circulation on the Run, and don't forget to tune in again next week.

Speaker 6:

Circulation September 13, 2022 Issue

12 september 2022 | 25 min

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism."

Dr. Carolyn Lam:

Welcome to Circulation On Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health Richmond, Virginia.

Dr. Carolyn Lam:

In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg?

Dr. Greg Hundley:

You bet, Carolyn. Well, how about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4.

Dr. Carolyn Lam:

Nice. Okay. Important question, what did they find?

Dr. Greg Hundley:

Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women.

Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome.

Dr. Carolyn Lam:

Oh, you are right. A lot of interesting data here. What's a take home message?

Dr. Greg Hundley:

Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step.

Dr. Carolyn Lam:

Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis.

Dr. Greg Hundley:

Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find?

Dr. Carolyn Lam:

Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC.

Dr. Greg Hundley:

Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight?

Dr. Carolyn Lam:

Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth?

Dr. Greg Hundley:

Yeah. Remember seven dwarfs, Sleepy.

Dr. Carolyn Lam:

Sleep.

Dr. Greg Hundley:

Very good. Great job, Carolyn.

Dr. Carolyn Lam:

Thank you.

Dr. Greg Hundley:

Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018.

Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression.

Dr. Carolyn Lam:

Okay, Greg. What did they find?

Dr. Greg Hundley:

Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years.

Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group.

Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large.

Dr. Carolyn Lam:

Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility.

Dr. Greg Hundley:

Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion?

Dr. Carolyn Lam:

Yes, let's go Greg.

Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found.

Dr. Senthil Selvaraj:

Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites.

To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment.

The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity.

Dr. Carolyn Lam:

Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati?

Dr. Svati Shah:

Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself.

To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn.

Dr. Carolyn Lam:

Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically?

Dr. Manuel Mayr:

Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress.

Dr. Carolyn Lam:

Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that?

Dr. Senthil Selvaraj:

I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space.

The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet.

Dr. Svati Shah:

Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do.

Dr. Carolyn Lam:

And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps?

Dr. Manuel Mayr:

Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis.

Dr. Senthil Selvaraj:

That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process.

Dr. Carolyn Lam:

Anything to add, Svati?

Dr. Svati Shah:

No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also.

Dr. Carolyn Lam:

Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view?

Dr. Manuel Mayr:

Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure.

Dr. Carolyn Lam:

Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you.

Dr. Greg Hundley:

Circulation September 6, 2022 Issue

5 september 2022 | 25 min

This week, please join author Keith Channon as he discusses the article "Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg, today's feature paper, something that's really been discussed a lot in the press and in lay public as well, the risk of myocarditis following sequential doses of the COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Everyone's going to want to tune into that one. But before we get there, shall we go through some of the key papers in today's issue?

Dr. Greg Hundley:

You bet, Carolyn. How about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

So Carolyn, this first manuscript involves the world of machine learning and ECG interpretation. And as you know, novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy detection; however, it's low prevalence, 0.5%, and resemblance to common diseases really present challenges. So Carolyn, these authors, led by Dr. Rahul Deo from Brigham and Women's Hospital, sought to develop machine learning models to detect hypertrophic cardiomyopathy and differentiate it from other cardiac conditions using EKGs and echocardiograms with a robust generalizability across multiple cohorts.

So Carolyn, what did they do? They used single-institution hypertrophic cardiomyopathy EKG models that were then trained and validated on data from three academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of hypertrophic cardiomyopathy from aortic stenosis, long-standing hypertension, and cardiac amyloidosis. And then finally, automated detection was compared to manual interpretation by three cardiologists on a data set with a realistic hypertrophic cardiomyopathy prevalence.

Dr. Carolyn Lam:

Wow, incredible. So what were the results?

Dr. Greg Hundley:

Right, Carolyn. So the authors identified 74,476 EKGs for 56,129 patients and 8,392 echocardiograms for 6,825 patients across the four academic medical centers. Now, while ECG models trained on data from each institution displayed excellent discrimination of hypertrophic cardiomyopathy on internal test data, the generalizability was limited, most notably for a model trained in Japan and then subsequently tested in the United States. Now, however, when trained in a federated manner, discrimination of hypertrophic cardiomyopathy was excellent across all institutions, including for phenotypic subgroups. The models further discriminated hypertrophic cardiomyopathy from hypertension, aortic stenosis, and cardiac amyloid. Analysis of ECG and echocardiography paired data from 11,823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists.

So Carolyn, in conclusion, federated learning improved the generalizability of models that use EKGs and echocardiograms to detect and differentiate hypertrophic cardiomyopathy from other causes of left ventricular hypertrophy compared to training within a single institution. It will be really interesting to see the future applicability of these methods.

Dr. Carolyn Lam:

Oh, I'm such a fan of this work. Awesome. Thank you, Greg. My paper, it's a preclinical paper that uncovers a novel mechanism through which GATA4 mutations can lead to heart disease.

Dr. Greg Hundley:

All right, Carolyn, no quiz this time, I'm just coming right out. I'm reversing the question on the teacher. Tell me, what is GATA4?

Dr. Carolyn Lam:

I'm glad you asked, Greg. GATA4 is a zinc finger-containing DNA binding transcription factor essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Now, in today's paper, authors led by Dr. Srivastava from Gladstone Institutes in San Francisco, California, showed that GATA4 regulated cell-type-specific splicing through direct interaction with RNA and the spliceosome in human-induced pluripotent stem cell-derived cardiac progenitors.

An unbiased search for GATA4 interacting proteins in these human iPS cells revealed interaction with many members of the spliceosome complex. GATA4 also bound to pre-messenger RNAs in a sequence-specific manner that resulted in generation of alternatively spliced isoforms in human iPS cells. Many of these GATA4-dependent isoforms had distinct functional properties illustrating the importance of the splicing regulation to cardiac function.

Dr. Greg Hundley:

Wow, Carolyn, another really interesting study from the world of preclinical science. So what's the take home message here?

Dr. Carolyn Lam:

So these results essentially uncover a previously unrecognized function for GATA4 in regulating alternative splicing through direct RNA interaction. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, thus suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Dr. Greg Hundley:

Very nice, Carolyn, wow. Well, my next paper comes to us from back in the world of clinical science and it's from Professor Bertrand Cariou from L'institut du Thorax in Inserm UMR1087. So Carolyn, only a few genes causally related to plasma LDL-C levels have been identified so far, and only one, ANGPTL3, has been causally related to combined hypocholesterolemia. In this study, the authors aim to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in four generations of a French family and used next generation sequencing and identified a novel dominant rare variant in the LIPC gene encoding for hepatic lipase, which co-segregates with the phenotype. They characterize the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance based lipoprotein profiling and lipids.

Dr. Carolyn Lam:

Wow, what an interesting approach to study patients and families with hypocholesterolemia for once instead of hyper. Interesting. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the investigative team found that this unique LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase without affecting triglyceride lipase activity. And second, the hypocholesterolemic phenotype related to LIPC-E97G variant is due to an increased clearance of cholesterol within triglyceride-rich lipoprotein remnants predominantly by extrahepatic tissues.

Dr. Carolyn Lam:

Wow, so what are the implications?

Dr. Greg Hundley:

Right, Carolyn. So the novel gain of function variant in LIPC potentially represents the second cause of familial combined hypocholesterolemia after loss of function variants in ANGPTL3. And second, this study highlights an unexpected and critical role of the phospholipase activity of hepatic lipase encoded by LIPC in LDL-C metabolism and identifies it as a potential novel drug target. And then finally, Carolyn, additional data, I think, are warranted to clarify the impact of LIPC-E97G-related combined hypocholesterolemia on atherosclerosis and atherosclerotic cardiovascular disease due to the occurrence of documented coronary stenosis and evolutive carotid atherosclerosis in index cases.

Dr. Carolyn Lam:

Oh, very, very interesting. Thanks, Greg. Well, let's wrap up with the discussion of what else is in today's issue. There's an In Depth paper by Dr. Hadley on protecting cardiovascular health from wildfire smoke. There's also a Research Letter by Dr. Mevorach on myocarditis after BNT162b2 COVID-19 third booster vaccine in Israel.

Dr. Greg Hundley:

Right, Carolyn. And then I've got an exchange of letters from Professors Condello and Doenst regarding the article Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis from the REMOVE study: Results From a Multicenter Randomized Controlled Trial. Well, how about we get on to that feature discussion and learn a little bit more about COVID-19 vaccine and SARS-CoV-2 infection.

Dr. Carolyn Lam:

Let's go, Greg, thanks.

Dr. Greg Hundley:

Listeners, welcome to this September 6th feature discussion. And with us today, very interesting topic pertaining to vaccination for SARS-CoV-2 virus prevention. And we have with us Dr. Keith Channon from Oxford, England, to discuss this very interesting paper.

Well, Keith, welcome. I wanted to start by asking you, can you describe for us a little the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Keith Channon:

Thanks, Greg, for the opportunity to join you in this interesting conversation today. A group of cardiologists in the UK based at the University of Oxford, and principally at the University of Edinburgh, have been interested in the question as to whether COVID infection and/or COVID vaccination might lead to a higher incidence of myocarditis. And this is a topic that has been the subject of previous publications in the field.

And the provocation for us undertaking this study is that those previous studies have tended to be relatively small, and they've also not been able to necessarily test the details, time association, between myocarditis occurring in relation to sequential doses of vaccination. And that's important because, of course, we're now all receiving sequential doses of booster vaccines, and also those vaccines are often delivered, different vaccine types to different people in different countries. So we wanted to test whether there does appear to be a significant association between the occurrence of myocarditis and both COVID infection and the sequential different COVID vaccinations.

Dr. Greg Hundley:

Very nice. So Keith, can you describe for us, what study population did you enroll for this initiative? And then also, what was your study design?

Dr. Keith Channon:

Thank you. So, one of the really exciting things about this type of study and probably what makes it unique is that in countries with healthcare system, like that in the UK, which is the National Health Service, and universities, such as the University of Oxford and the University of Edinburgh, where there are very strong academic links between researchers and the National Health Service, we've been able to leverage an enormous data set, which is almost 43 million people in the UK who underwent vaccination against COVID-19. And rather than having to follow up 43 million people as part of a research study, we were able to take advantage of National Health Service centralized coded hospital records, number one. Number two, we took advantage of the UK's national database on COVID vaccination. And number three, we were able to look at hospital outcomes and also COVID testing.

So we were able to put together those three data sets for us to understand who developed COVID infection, who received COVID vaccination, and if so, which vaccine and when, and who then was admitted to hospital with a coded diagnosis of myocarditis. And in 43 million people, even though myocarditis is a very uncommon outcome, there were sufficient cases in that very large population to draw statistically meaningful conclusions.

I think that the UK is probably one of the few countries where this type of research can be done. And academic organizations, like our universities, the National Health Service, and also cardiovascular research funders, such as the British Heart Foundation, have put in a lot of resource and effort into giving us those capabilities to answer questions like this, and it's turned out to be a very powerful capability.

Dr. Greg Hundley:

Very nice. And so Keith, can you describe for us your study results?

Dr. Keith Channon:

So the study looked at a large 43 million people approximately over a period of time during the early to mid-phase of the COVID pandemic and looked at the likelihood that people would be diagnosed with myocarditis following either vaccination or COVID test positive. And we compared that likelihood with the likelihood of myocarditis occurring outside of those periods; because, of course, myocarditis occurs reasonably commonly in the general population. So this is another powerful aspect of the study design. It has a curated approach to look at the incidence of myocarditis in the 28 days after either vaccination or COVID infection, and it corrects, or it controls for that relative to the incidence of myocarditis outside of those sampling periods.

And what we found simply is that there is indeed, as previous studies have shown, a small but significant association between receiving a COVID-19 vaccine and being diagnosed with myocarditis in the following 28 days. However, in the population as a whole, the risk of myocarditis after vaccination is substantially lower than the risk of developing myocarditis after COVID infection, and I think that's an important finding. When we looked at subgroups, which is interesting, we found that the highest risk of developing myocarditis was in men less than age 40, so younger men, and that was one finding. And also, there did seem to be some differences in the risk of myocarditis occurring after different sequential vaccine doses.

Dr. Greg Hundley:

Keith, just a quick clarification point, what vaccines did you examine?

Dr. Keith Channon:

So in the UK, the three vaccines that have been largely used of the AstraZeneca Oxford viral vaccine, ChAdOx1, which was of course introduced very early in the UK, along with the Pfizer mRNA vaccine, and then laterally, Moderna vaccine, which of course in the UK was brought in rather later. And I think that's interesting because, as we can go on and discuss, there do appear to be some possible differences between those vaccines in terms of the likelihood of being diagnosed with myocarditis afterwards. But of course, even our experiment in 43 million people is not a perfect design because it's an observational study, and the periods in the pandemic when people were receiving principally the first two vaccines, which were by far the most numerous, was a different period in the natural history of the pandemic than when we started administering Moderna.

So it is important to recognize that it was not a prospectively controlled randomized trial of different vaccines; it was an observational study of pretty much a whole country and how it responded to the implementation of those different vaccines, which were all given to different people at different times of the pandemic. And of course, different times of the pandemic means that many different people will have already had a COVID infection and then gone on to have a booster or third vaccination. So, if you like, the immunological landscape in which these different vaccines were given in this very large population will have been different.

Dr. Greg Hundley:

Right. So I understand there are differences in timing, great point, but did you see any differences in the occurrence of myocarditis relative to either of the mRNA vaccines versus the adenovirus vaccine?

Dr. Keith Channon:

Yeah, we did. What we found is that, interestingly, there did appear to be a higher likelihood of being diagnosed with myocarditis in the 28 days after the mRNA-1273 vaccine, Moderna vaccine, and that was particularly, as I've already said, in men younger than the age of 40 years. I should say again, of course, that vaccine was given to the smallest number of people in the UK and it also tended to be rolled out later, so it was the second or third dose of the vaccine where that signal was most seen. But again, the second and third dose was by definition typically the booster vaccine later on in the pandemic. But that's what we found.

We did find these interesting differences. The incidence of myocarditis was increased after all of the vaccine doses compared with the period when people had not received a vaccine, but this was a very modest increase for most of the vaccines; but for the mRNA vaccines, particularly Moderna, it seemed to be more strikingly increased in the 28 days after the second or third dose of the vaccine. So I guess the message from that result is that there do seem to be these intriguing differences, both in the response to different COVID vaccines, either viral or mRNA or indeed even different types of mRNA vaccine, and possibly after the different dose of vaccines. In other words, after second or third sequential doses.

Dr. Greg Hundley:

And Keith, you mentioned a few minutes ago that you also had an opportunity to examine situations where maybe a patient had a vaccine and then subsequently contracted COVID, or vice versa, maybe they had had COVID and then later on had a vaccine, did you find any differences in the incidence of myocarditis in those situations as opposed to, perhaps, patients that really never had a documented episode of a COVID infection and then always had received the two vaccines and the booster dose?

Dr. Keith Channon:

Yeah, that's a harder question and is less powerfully addressed by our study, even though we were able to temporally control for that. Previous COVID infection did not preclude the risk of myocarditis after subsequent vaccine doses, but it wasn't a big enough signal to be able to give much detail over the relative risk between... Because if you think of the permutations of COVID infection plus or minus three vaccines, there's a lot of different sequential steps there, but having had COVID first doesn't prevent this small but significant signal; having a vaccine before you then get COVID infection does reduce your risk of myocarditis along with pretty much all other COVID complications.

So I think that's a really important public health message here and indeed the overarching finding of our study, which you could argue is the least exciting one but perhaps the most important, which is that you have a higher likelihood of suffering with myocarditis after COVID infection compared with after a COVID vaccination. And if you have COVID vaccination, in general, your risk of myocarditis is lower, obviously your risk of COVID infection is lower, and your risk of getting myocarditis after that COVID infection, should you still get one is also lower. So I think these are very intriguing, interesting findings that might make us think about mechanism and vaccine policy, but ultimately there are very strong endorsement of getting vaccinated to prevent the consequences of COVID-19.

Dr. Greg Hundley:

Excellent point. And then, Keith, just quickly, next study that maybe your group is considering in this space with this large database?

Dr. Keith Channon:

Yes. Well, I think there are two aspects to the study. Our group, which, as I've said, focuses mainly on large epidemiological data sets, having established this infrastructure in the UK led by universities like Oxford and Edinburgh and funded by the British Heart Foundation and others, means that we now have this infrastructure. So the surveillance and the data collection and the analysis is ongoing and we'll be able to add more cases and more power and more data, and there will be other studies that we can look at.

Second, I think there are some really quite interesting mechanistic studies that could be done based on these provocative findings to try to understand which different types of vaccines and, indeed, the immune responses which those vaccines generate. How are they linked to myocarditis and, indeed, to other cardiac and even other organ complications from COVID-19? And there are ongoing studies in the UK and elsewhere in the world that are very much focused on looking at the organ-specific consequences of COVID infection in patients who've been vaccinated or not. For example, using detailed cardiac MRI to look at the heart and look for subclinical myocarditis and to correlate any evidence of subclinical myocarditis with the immune signature, both the antibody and the cellular immune response, in the blood from those patients.

So I think what we're going to see here are enormous epidemiological studies with n=43 million, and we're also going to see more mechanistic experimental medicine immunology studies to try and tease out mechanism, and I think to understand two things. One is how to protect ourselves best against COVID-19, and what are the best vaccines and how best to use them. And second, if we can learn something about the mechanisms of myocarditis along the way, that's a really useful bonus that's come out of this pandemic.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Keith Channon for bringing us this very interesting article from Great Britain highlighting that, overall, the risk of myocarditis is greater following SARS-CoV-2 infection as opposed to a COVID-19 vaccination, and even really remains modest following sequential doses, including the booster dose of some of the mRNA vaccines.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is a copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

Circulation August 30, 2022 Issue

29 augusti 2022 | 19 min

This week, please join author Rod Stables and Associate Editor Nick Mills as they discuss the article "Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass through the journal and its editors. We're your co-hosts! I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature... Very interesting. There is a lot of information about using fractional flow reserve during contrast coronary angiography. But how does that compare to just reviewing the angiograms when managing patients with coronary artery disease?

Well, we are going to hear some results from the RIPCORD 2 trial, and they may surprise you a little bit. But, before we get to that interesting feature discussion with authors and editors, how about we grab a cup of coffee and dive into some of the other articles in the issue?

Dr. Carolyn Lam:

Yeah, let's do that, Greg. Do you have a paper to share first?

Dr. Greg Hundley:

Oh, thanks Carolyn. Sure.

So Carolyn, as we know, Apolipoprotein B or apoB, provides an integrated measure of atherogenic risk. But whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndromes, beyond that provided by low density, lipoprotein cholesterol, or LDLC, that's uncertain. So Carolyn this study emanates from the Odyssey Outcomes trial, which compared the Proprotein Convertase Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite optimized statin therapy. Now the primary outcome was major adverse cardiovascular events. So MACE was coronary heart disease, death, nonfatal myocardial infarction, fatal non-fatal ischemic stroke, and hospitalization for unstable angina. And associations between baseline ApoB or ApoB at four months and MACE were assessed in adjusted Cox proportional hazards and propensity score matched models over median of 2.8 years.

Dr. Carolyn Lam:

Oh, right. So what were the results, Greg?

Dr. Greg Hundley:

Right, Carolyn so impatience with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline ApoB strata, and now evolocumab reduced MACE across all strata of baseline ApoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved ApoB was associated with lower risk of MACE, even after accounting for achieved LDLC or Non-HDLC indicating that ApoB provides incremental information. And therefore, Carolyn, if it is modified achievement of an ApoB level less than or equal to 35 milligrams per deciliter may reduce lipoprotein attributable residual risk after ACS. Isn't that interesting?

Dr. Carolyn Lam:

Yes. Very nice, Greg. Thank you. This next paper is a pre-specified analysis of the EMPEROR-Preserved trial, looking at patients with and without diabetes.

Dr. Greg Hundley:

So remind us, Carolyn, what was the EMPEROR-Preserved trial and what did it show?

Dr. Carolyn Lam:

Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor reduced risk of the composite of cardiovascular death or heart failure hospitalization, as well as first and recurrent heart failure hospitalizations and slowed renal function decline in patients with heart failure and an ejection fraction greater than 40%. So the current paper sought to determine if effects were consistent in patients with, and without diabetes, of the almost 6,000 patients enrolled, 49% had diabetes. The risk of adverse outcomes, first of all, was higher in patients with diabetes. Now the treatment effect of Empagliflozin was however, similar in that Empagliflozin reduced the rate of the primary outcome and total heart failure hospitalization, irrespective of diabetes status. The effect of Empagliflozen falls into attenuate GFR decline, however, was also present in patients with, and without diabetes, although more pronounced in patients with diabetes. Now across all these three endpoints, the effect of Empagliflozen did not differ in patients with prediabetes or normal glycemia. And importantly, there was no increased risk of hypoglycemic events in either subgroup compared with placebo. So a very nice paper there. And that was from Dr. Gerasimos Filippatos from Athens University Hospital Attikon and colleagues.

Dr. Greg Hundley:

Wow, Carolyn, just really interesting information coming out of the world of SGLT2 innovation. Well, Carolyn, my next paper comes to us from the world of preclinical science and it's from Dr. Kunhua Song from the University of Colorado Anschutz Medical campus. So Carolyn, abnormalities of calcium homeostasis are closely associated with cardiac arrhythmias and heart failure and conditions that cause death of millions of people every year. Now, Carolyn Triadin physically interacts with the Ryanodine receptor 2 and plays an important role in releasing calcium from the sarcoplasmic reticulum to increase the free intracellular calcium concentration in cardiomyocytes.

Now alternative splicing of a single Triadin gene produces multiple Triadin isoforms, the predominant cardiac Triadin isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons from one to eight. In humans, mutations in the Triadin gene that lead to a reduction in Trisk 32 levels in the heart cause cardiac dysfunction, cardiac arrhythmias and sudden death. Decreased levels of Trisk 32, in the heart, are also common in patients with heart failure. However, mechanisms that regulate alternative splicing of the Triadin gene to maintain levels of cardiac Triadin protein in the heart, remains somewhat elusive.

Dr. Carolyn Lam:

Wow. I am always learning from these cool papers. Thanks Greg. So what were the results?

Dr. Greg Hundley:

So Carolyn, the investigators found several things. First, the cardio MyoSite specific long non-encoding RNA or link RNA Triadin AS is essential for maintenance of cardiac function, exercise capacity and normal lifespan and Triadin AS knockout mice were found predisposed to cardiac arrhythmias in response to catecholamine challenge. And finally Carolyn, Triadin AS controls, levels, of cardiac Triadin isoforms, by regulating the splicing of the Triadin gene.

Dr. Carolyn Lam:

Oh, wow. All right. So could you bring it home for us, Greg? What are the clinical take home messages?

Dr. Greg Hundley:

Right, Carolyn. So cardiac explants from human heart failure patients as well as patients with cardiac arrhythmias, demonstrate reduced expression of Triadin AS and Triadin. And then next the mechanism of the Triadin AS and Triandin AS mediated alternative splicing of the Triadin gene to specifically control levels of cardiac isoforms of Triadin in the heart, provides a potential strategy for the treatment of cardiac arrhythmias and heart failure.

Dr. Carolyn Lam:

Wow. Thank you, Greg. Well, let's talk about what else is in today's issue. There's a Research Letter by Dr. Agarwal on Chlorthalidone for resistant hypertension and advanced chronic kidney disease.

Dr. Greg Hundley:

And Carolyn, I've got a perspective piece by Professor Cowie pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs. Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn, how about we get onto that feature discussion and review the utility of fractional flow reserve measurements, in patients undergoing contrast coronary angiography.

Dr. Carolyn Lam:

Great, let's go.

Dr. Greg Hundley:

Welcome listeners to this August 30th feature discussion. And we have with us this afternoon, Dr. Rod Staples from Liverpool and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. And gentlemen, welcome, Rod we'll start with you. Can you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Rod Staples:

Okay, well thanks very much for hosting today. I'm very grateful to be working circulation on this. I'm working with my co-lead investigator Professor Nick Harrison from Southampton, who's been doing an enormous amount of work on coronary physiology. He actually did the original RIPCORD study, what I suppose we'd now call RIPCORD 1, but it was called RIPCORD in the early days, an observational study that showed that systematic use of fractional flow reserve at the time of diagnostic angiography. Assessing the functional significance measured in each of the major coronary vessels, appeared in an observational study to have a dramatic effect on the subsequent management plans allocated to patients. And we decided to test this in a prospective randomized trial.

Dr. Greg Hundley:

Very nice. And so the exact hypothesis that you were going to test was what?

Dr. Rod Staples:

At the time of coronary angiography, a strategy of systematic measurement of fractional flow reserve in each and every coronary vessel, large enough to be considered for revascularization, would improve outcomes compared to a strategy based on angiographic assessments alone.

Dr. Greg Hundley:

Very nice. And so you mentioned a randomized trial. Can you describe further your study design and then which study population did you include?

Dr. Rod Staples:

Well, this is a classic multicenter randomized trial performed in the UK. We actually recruited in 17 different UK centers. We asked them to assess patients who were scheduled for invasive, currently angiography for participation against some very minimal inclusion and exclusion criteria, trying to keep the trial generalizable with good external validity. I think one important point to note is that we did allow the inclusion of both patients being assessed with elective angiography for stable symptoms, but in the end half of the population were recruited in the context of a stabilized acute coronary syndrome, a Non-ST-elevation event a day or so down the line.

Dr. Greg Hundley:

And just a quick breakdown, how many men, how many women?

Dr. Rod Staples:

Well, it's in that respect, the population is very, very typical for this type of cardiovascular trial. A 70, 30 split an age in the midsixties, a diabetic population in the high teens. So a very typical population we've seen in all this kind of trial environment.

Dr. Greg Hundley:

Very nice. And so about 1100 patients. And then what were your study results?

Dr. Rod Staples:

Well, I think there was a very good adherence to the study protocol, very, very few crossovers. And also we were pleased to see that our investigators stayed true to the protocol in that the median number of epicardial vessels assessed by FFR in that randomized arm was four. So there was a good assessment by FFR. The trial was interesting in another respect, in that we assessed an economic outcome based on all NHS hospital costs over the following year and a patient reported outcome based on quality of life using the WHOQOL, and interestingly we found no significant differences either in total subsequent hospital costs from randomization for a year, or indeed in patient reported quality of life by WHOQOL or Angina symptoms by the Canadian Cardiovascular Society classification.

Dr. Greg Hundley:

Very nice. And then, what about clinical events? Did you examine those as well?

Dr. Rod Staples:

We did. And again, just a little caveat here, the trial is again interesting in that, what is often in the UK these days called a lean efficient methodology. Whereby, rather than individually contacting individual trial participants or scouring medical records, we interrogated the central national NHS digital repository of all hospital admissions. And we examined electronically a download of every hospitalization event for every patient using algorithms based on diagnostic and procedural codes to define events. And again, we found a very credible representative rate exactly at incidents and events we would've predicted, but again, no difference between the randomized groups.

Dr. Greg Hundley:

Very nice, well listeners, now we're going to turn to our own Associate Editor, Dr. Nick Mills. And Nick, again, you see many papers come across your desk. What attracted you to this particular manuscript? And it's very interesting study results.

Dr. Nick Mills:

Thanks, Greg. Firstly, it addresses an important clinical question. Going beyond that, what appealed to me was it was investigator initiated. It was managed by independent trials unit. It recruited a target, it reported the registered outcomes and it was thoughtfully interpreted. And the fact that it didn't prove the hypothesis was irrelevant because it addresses a really important clinical question. And I think it requires some context, and that is that from the previous randomized trials The FAME series, we have been chastised as interventional cardiologists for not using FFR for relatively low use of FFR clinical practice. It's always around one in 20 patients in most series, given the evidence that FFR guided intervention improves outcomes. But actually what FFR is good at is discouraging you from stenting patients with stable Coronary Disease.

And so, I think a pragmatic trial that addresses that, the fundamental question, should we be doing more FFR more broadly in both acute and stable disease to guide revascularization with a definitive message that we shouldn't, it doesn't improve quality of life. It doesn't alter costs. Clinical outcomes are similar, but there are more complications associated with routine pressure wire use, gives us a very clear steer for the future. So this is a really important trial addressing a fairly fundamental clinical question.

Dr. Greg Hundley:

Very interesting. Well, Rod, we're going to turn back to you with Nick's comments and how we're really seeing an evolution in thought processes regarding both diagnostic angiography, and then also the use of functional testing. What do you see is the next study, really in this sphere of research that would be performed?

Dr. Rod Staples:

Well, I agree with Nick in a way that this raises important philosophical points about the use of intelligence, selective employment of tests or interventions, and that perhaps we need to reflect this in the way we conduct our future studies. I think we're all aware that fractional flow reserve and other measures of functional significance are tremendously valuable in certain clinical settings. And that value's been proven in randomized trials, but in PRECORD 2, for example, if a patient randomized to angiography only was an acute coronary syndrome patient, who had inverted their T waves in their anterior leads, had an associated troponin rise, an echocardiogram had shown some Hypokinesia in the anterior territory. Then I think the potential value of PCI in the LAD does not necessarily require FFR confirmation, and hence that patient will have an equivalent outcome in the angiography group. Similarly, high quality pre-angiography preparation in the elective population with functional testing, stress testing, other forms of imaging mean that we can reserve the use of invasive fractional flow reserve, tight indices to more selective use.

Dr. Greg Hundley:

And Nick, turning to you, what do you think is the next research study that could be informative in this space?

Dr. Nick Mills:

I think our whole philosophy by how to manage stable coronary disease is changing. In part because of some other landmark trials that the Ischemia trial and some of the key secondary analyses of the Ischemia trial that tells the Pathoma burden, low attenuation plaque, other aspects of chronic disease are vitally important in predicting major events in the future. And that leaves us with the role for FFR or CT FFR, primarily to manage symptoms. And I think we're getting increasingly good evaluating patients before they get to the Cathflow, optimizing their medical treatment. And so for me, the trial that we really need to help us, is a CT FFR trial to understand the role of Ischemia testing plus anatomical testing and how they dovetail in guiding treatment decisions before they get to the cath lab. I think we need to move this before the lab, always going to be a role for intelligent FFR testing in selected patients once we get to it. But I think that the question probably needs to be addressed before they get to the cath lab.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank, Dr. Rod Staples from Liverpool and Dr. Nick Mills from Edinburgh, Scotland for bringing us this very interesting study, highlighting that a strategy of systematic FFR assessment, when compared to angiography alone, did not result in a significant reduction in cost or improvement in quality of life.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run.

Circulation August 23, 2022 Issue

22 augusti 2022 | 21 min

This week, please join author Kory Lavine and Associate Editor Thomas Eschenhagen as they discuss the article "Donor Macrophages Modulate Rejection After Heart Transplantation."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature, we are going to the world of preclinical science and we are going to learn about a very important new finding pertaining to heart transplant rejection, and macrophages may modulate this, but before we get to that feature, how about we grab a cup of coffee and go through some of the other articles in the issue?

Dr. Carolyn Lam:

I got mine. Would you like to go first, Greg?

Dr. Greg Hundley:

You bet, Carolyn. Well, my first study comes to us from Dr. Michael Pencino from Duke University. Carolyn, this study was performed to understand the predictive utility of a previously derived polygenic risk score for long-term risk of coronary heart disease and its additive value beyond traditional risk factors and how that might be able to inform prevention strategies. To accomplish this, data from adults aged 20 to 59 free of cardiovascular health disease from the Framingham Offspring Study and the Atherosclerosis Risk in Communities, or ARIC Study, were analyzed. Now, since the polygenic risk score was derived from people of predominantly European ancestry, individuals who self-reported white race were those that were included.

Dr. Carolyn Lam:

Oh, interesting, so what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. Somewhat surprisingly, they found that, among 9,757 participants, both the traditional risk factor score and the polygenic risk score where significantly associated with incident cardiovascular heart disease in young, early midlife, and late midlife. Now, the delta C index, when the polygenic risk score was added to the traditional risk factor, score was 0.03, 0.02, and 0.002 in the young, the early midlife, and the late-midlife participants, respectively.

Carolyn, despite a statistically significant association between the polygenic risk score and the 30-year risk of cardiovascular heart disease, the C index improved only marginally with the addition of the polygenic risk score to the traditional risk factor model among young adults and did not improve among midlife adults and, thus, Carolyn, the polygenic risk score, an immutable factor, has limited clinical utility for long-term cardiovascular heart disease prediction when added to a traditional risk factor model.

Dr. Carolyn Lam:

I really like that, Greg, because I think it also tells us that the traditional risk factors, which we can do something about, are still very important. Isn't that great? Well, the next paper is about POTS. Remember what that is? Should I give you a quiz? All right. It's okay. POTS, or Postural Orthostatic Tachycardia Syndrome, is a disorder of orthostatic intolerance that primarily affects females of childbearing age. While the underlying pathophysiology of POTS is not fully understood, it has been suggested that autoimmunity may play a role. Now, the aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between 116 POTS patients and 81 healthy controls, and they were from Calgary, Canada, and Malmo, Sweden.

Dr. Greg Hundley:

Carolyn, really interesting, so what did they find here?

Dr. Carolyn Lam:

The investigators, led by Dr. Raj from University of Calgary in Canada, found that commercially available autoantibody concentrations to G protein-coupled receptors were not increased or altered in POTS patients relative to healthy controls as assessed using ELISA. Now, while this study suggests that these G protein-coupled receptor autoantibody concentrations alone cannot explain the pathophysiology of POTS, autoantibody activity and signals not picked up by ELISA should still be explored as these results may provide more insights into the pathophysiology of POTS.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next study comes to us from the world of pulmonary arterial hypertension. Carolyn, clinical worsening is commonly used as an endpoint in pulmonary arterial hypertension trials. These authors, led by Dr. Steeve Provencher from the Institut Universitaire de Cardiologie Pneumologie de Quebec, aimed to assess the trial-level surrogacy of clinical worsening for mortality in pulmonary artery hypertension trials and whether the various clinical worsening components were similar in terms of frequency of occurrence, treatment-related relative risk reduction and importance to patients.

Dr. Carolyn Lam:

Okay, so what did they find?

Dr. Greg Hundley:

Right, Carolyn, so they searched MEDLINE, Embase and the Cochrane Library for trials evaluating the effects of pulmonary arterial hypertension on clinical worsening and, among 35 independent cohorts, so 9,450 patients, the effects of pulmonary arterial hypertension-specific therapies on clinical worsening modestly correlated with mortality. Additionally, study-level clinical worsening was not found to be a surrogate for mortality in pulmonary arterial-hypertension trials. Moreover, components of clinical worsening largely vary in frequency, response to therapy and importance to patients and, thus, are not necessarily interchangeable.

Dr. Carolyn Lam:

Thank you, Greg. Can I tell you about some other papers in today's issue? There's a Research Letter from Dr. Cosentino on cardiorenal outcomes with ertugliflozin by baseline metformin use, and this is a post hoc analysis of the VERTIS CV trial.

Dr. Greg Hundley:

Oh, very good, Carolyn. Well, I've got an exchange of letters from Professors Boriani and Steinberg regarding the article “Driving Restrictions and Early Arrhythmias in Patients Receiving a Secondary Prevention Implantable Cardioverter-Defibrillator, the DREAM-ICD-II Study.” There's also an ECG Challenge from Professor Gao entitled “Syncope in a 3-Year-Old Child During the Perioperative Period. What is the diagnosis? What Signs Point Toward Impending Life-threatening Event?”

Then, finally, there's a nice, On My Mind piece from Professor Greenland entitled “Insurance Payers Should Cover Selective Coronary Artery Calcium Testing in Intermediate Risk Primary Prevention Patients.” Well, Carolyn, how about we get on to that feature discussion and dive into the world of rejection after heart transplantation?

Dr. Carolyn Lam:

Yay. Here we go.

Dr. Greg Hundley:

Welcome, listeners, to this feature discussion on August 23rd. We have a very interesting article today to discuss with our author and associate editor pertaining to preclinical science and cardiac transplant rejection. Our author today is Dr. Kory Lavine from Washington University in St. Louis and our associate editor today is Dr. Thomas Eschenhagen from Hamburg, Germany. Welcome gentlemen.

Kory, we'll start with you. Can you describe for us some of the background information pertaining to the construct of your study and what was the hypothesis that you wanted to address?

Dr. Kory Lavine:

Well, thank you for having me. Our study focused on heart transplant rejection, which remains a major clinical challenge that limits both the survival of heart transplant recipients as well as availability of donor hearts. Current clinical practice really focuses on suppressing the immune system in a global way, and that is somewhat effective, but carries important risks that include infection and life-threatening malignancies.

Many studies have appropriately focused on immune cells that infiltrate the transplanted heart that come from the recipient to search for new ways to suppress the immune system safely. What we've understood and learned over the past several years is that the donor heart has its own immune system and its own immune cells, and the majority of those immune cells that come with the donor heart are macrophages that can be broadly divided into two distinct lineages with different functions, tissue-resident macrophages, which lack the cell surface receptors CCR2, and monocyte-derived macrophages with expressed cell surface receptors CCR2. We tested the hypothesis in this study that these macrophages that come with the donor heart remain active for a period of time after transplantation and play important roles in either suppressing or accelerating heart transplant rejection.

Dr. Greg Hundley:

What was the hypothesis that you wanted to address with your study?

Dr. Kory Lavine:

Yeah, so our prior work and others' work within this field had suggested that tissue-resident macrophages, CCR2-negative macrophages, are inflammatory, and CCR2-positive macrophages have the opposite functions being inflammatory and play roles in potentiating and initiating inflammation in the heart. In this study, we hypothesized that CCR2-negative macrophages would protect from rejection, while CCR2-positive macrophages may promote heart transplant rejection and could serve as a new therapeutic target to prevent rejection in transplant recipients.

Dr. Greg Hundley:

Excellent. Kory, can you describe for us the study design that you used to test your hypothesis?

Dr. Kory Lavine:

Yeah. The study design and approach we used involved a mouse model of heart transplantation where we transplant a donor heart into a recipient mouse that's fully mismatched at all the MHC loci, and this serves as a nice model for both cellular and antibody-mediated rejection. To facilitate tracking these donor macrophages, we used various genetic lineage tracing systems and, to study their phenotypes, we used single-cell RNA sequencing and, to understand their function, we used mouse models that allow us to specifically deplete each of the donor macrophage populations as well as genetic models to manipulate their activation and signaling.

Dr. Greg Hundley:

The outcome measures were going to be what?

Dr. Kory Lavine:

Yeah. The outcome measures for transplant rejection in this mouse model are allograph survival, so the survival of the transplanted heart. We're able to directly look at how much rejection is present by histopathology, and then we're able to observe various mechanistic features using detailed phenotyping such as single-cell RNA sequencing and T-cell activation assays.

Dr. Greg Hundley:

Very nice, Kory. Well, all, our listeners, we're very excited to hear what were your study results?

Dr. Kory Lavine:

We learned that donor macrophages are dynamic and they survive for a period of time after transplantation or eventually lost due to transplant rejection. When we phenotyped the macrophages that came from the donor heart, we learned that they remained transcriptionally distinct from immune cells that enter the heart that were derived from the recipients, and they had important and distinct functions. If we depleted the tissue-resident macrophages that were CCR2-negative, we observed reduced allograph survival and increased rejection. If we depleted CCR2-positive macrophages that came from the donor heart, we observed improved allograph survival and reduced rejection.

Mechanistically, we learned that CCR2-positive macrophages are activated through a MyD88-dependent pathway and, if we inhibited MyD88 cytokines which controls the expression of pro-inflammatory cytokines and chemokines, we could prolong the survival of the donor heart for a very significant period of time, reduce rejection and prevent the development of T-cells that would attack the donor heart. From a mechanistic aspect, what we uncovered is that this signaling pathway in CCR2-positive macrophages regulated the recruitment of an activation of antigen-presenting cells which played important roles in generating T-cells that would target the transplanted heart.

Dr. Greg Hundley:

It sounds like a really informative and leap forward in the whole sphere of transplant rejection. Well, listeners, now we're going to turn to our associate editor, Dr. Thomas Eschenhagen.

Thomas, you have many papers come across your desk. What attracted you to this particular paper and then, secondly, how do you put the results of this study really in the context of other research examining heart transplant rejection?

Dr. Thomas Eschenhagen:

Yeah, thanks for having me. I mean, first, we got attracted by this paper because it's somewhat an out-of-the-box approach. It's not the standard approach to improve the systemic immunosuppression as many studies did and with actually a lot of success over the last 30 years, survivor got much better. There had been a lot of progress in the field of transplantation medicine as we all know, but as Kory said already, we still have 30% rejection, and these immunosuppressions come at a price. Having this study which turns around somehow the argumentation and looks at the donor organ was something which really attracted us. It uses advanced methods and it applies somewhat in a practical way a concept which emerged over the last, I don't know, maybe decade this concept that macrophages are really very different kind of cells. They're all called macrophages, but they're quite different and even maybe in certain respects having opposing effect.

I think many people know about this M1/M2 concept. It's CCR2 receptor positive and negative. It's criticized by some people, but here we see that it really seems to be really important and, of course, then the third argument why we really like the story is that it has a specific, clear translation impact. I mean, looking at the heart, the donor heart, and potentially even treating the donor heart before transplanting it is something which comes immediately out of the story, and that's something which we found super attractive.

Dr. Greg Hundley:

Really interesting, so really understanding the mechanism and focusing on donor hearts. Well, listeners, let's circle back with Kory.

Kory, given that, what do you think is the next study that really needs to be performed in this sphere of research?

Dr. Kory Lavine:

I think Thomas said it exactly as we're thinking about it, so the next area that we're really excited to attack and we're hopeful that the field will focus on is ways to build methods and technologies to treat the donor heart between the time of procurement and the time of transplant, when it's being transported and potentially even being perfused for a period of time. We're really interested in finding approaches to identify small molecules and other potential biologic therapies that could be used to prevent the activation of donor CCR2-positive macrophages.

It's a really attractive approach because treating the donor heart ex vivo decreases the risk of adversely affecting other organs that may be transplanted if you're treating the donor, for instance, and it may decrease the risk of immunosuppression and infection by not having to treat the recipient and we're catching the heart in this window where the risks are much lower.

The other area that we're really excited to focus on is trying to identify the exact mediators that are generated from donor CCR2-positive macrophages that mediate the recruitment and activation of antigen-presenting cells because that would represent another potential therapeutic target.

Dr. Greg Hundley:

Very nice. Thomas, what are your thoughts about what might be the next study to be performed really in this sphere of research?

Dr. Thomas Eschenhagen:

It's obviously something rather a question to Kory than to me, but I agree to what he said. I think it is pretty obvious what are the next steps mechanistically on the one hand, but practically on the other hand. I mean, at this point, we are at the mouse level, so the question is to which extent can this concept be translated into larger animals and then finally in humans? I was wondering, given these newer methods to keep donor hearts alive for long, extended periods, I was wondering which extent you are already collaborating with the respective groups who develop this approach because that obviously would increase the window of opportunity here for drugs. I think it's really an exciting and pretty visible next steps which we see here, and I can just hope that you're going this path and that it will be successful.

Dr. Greg Hundley:

Kory, any thoughts on those collaborations that Thomas just spoke of?

Dr. Kory Lavine:

We're definitely establishing collaborations to focus on ex vivo profusion of donor hearts because that's, as Thomas mentioned, is a perfect window to manipulate the immune populations that are within the donor heart. Those studies have to be team science, they have to be collaborative and they have to have a focus on large animals and then moving into clinic. We're definitely forming those collaborations and excited to work as a group.

Dr. Greg Hundley:

Very nice. Well, listeners, what an exciting paper to discuss here as part of this feature discussion from the world of preclinical science. We want to thank Dr. Kory Lavine from Washington University in St. Louis, Missouri, and also our own associate editor, Dr. Thomas Eschenhagen from Hamburg Germany, for really bringing us this research study highlighting that distinct populations of donor and recipient macrophages coexist within the transplanted heart, and donor CCR2-positive macrophages are key mediators of allograph rejection and deletion of MyD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograph survival.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart association, 2022. The opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation August 16, 2022 Issue

15 augusti 2022 | 30 min

This week, please join author Philipp Lurz and Editorialist Daniel Burkhoff as they discuss the article "Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction" and the editorial "HF?EF: The Mysterious Relationship Between Heart Failure and Ejection Fraction Continues."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

I just cannot wait to tell you about today's feature discussion, Greg. It's about heart failure with preserved ejection fraction and characteristics in the range of that ejection fraction that's above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow. How much are we going to be talking about this ejection fraction thing?" But I'm telling you, everybody has to listen to this. It's really a big stride forward in our understanding of these patients with heart failure and a higher ejection fraction. Plus it includes one of my mentors from Mayo Clinic days, and I just can't wait for everyone to hear this. But before we go there, we've got really, really cool original papers in today's issue too. Would you like to start first?

Dr. Greg Hundley:

You bet Carolyn, and I can't wait for that feature discussion, especially this is a real area of your expertise. So listeners, hold on for that feature discussion. Well, my first paper, Carolyn, really pertains to physical activity. And Carolyn, the study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan School of Public Health. And it evaluated a total of 116,000 adults from two large prospective US cohorts, the Nurse's Health Study and the Health Professional's Follow up Study that took place from 1988 to 2018. And they were examining self-reported leisure time physical activity and assessed the association between long term leisure time physical activity intensity and all cause and cause specific mortality.

Dr. Greg Hundley:

Now Carolyn, two types of physical activity were assessed. First, moderate physical activity and we're going to abbreviate that as MPA and that was 150 to 300 minutes per week, which is really recommended. Or second, vigorous physical activity for which it's really recommended that one performs 75 to 150 minutes per week. Now, Carolyn, as you know, some individuals accomplish both of these in their routine, some neither, some one or the other. And so it really remains unclear whether higher levels of long term vigorous or moderate are independently or perhaps jointly associated with lower mortality.

Dr. Carolyn Lam:

Oh, that's so interesting, Greg. Quick, quick, quick, tell us the results.

Dr. Greg Hundley:

Right Carolyn. So the nearly maximum association with lower mortality overall was achieved by performing approximately 150 to 300 minutes per week of long term leisure time vigorous physical activity or 300 to 600 minutes per week of long term leisure time moderate physical activity or an equivalent combination of both, so mixing those minutes. Also Carolyn, very interestingly, higher levels, suppose you go beyond those limits of either long term leisure time vigorous physical activity of more than 300 minutes per week or moderate physical activity of more than 600 minutes per week did not show clearly further lower all cause cardiovascular disease or non-cardiovascular disease mortality and nor did they show harm. So if you went above those thresholds, you really didn't experience greater harm.

Dr. Carolyn Lam:

Thanks, Greg. You know I'm going to be trying to apply that. That's so cool. All right. Well the next paper refers to the Cabana Trial, which I'll remind you is a trial in which catheter ablation did not significantly reduce the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest compared to drug therapy by intention to treat, but did improve quality of life and freedom from atrial fibrillation recurrence. In Cabana, the heart failure subgroup, ablation appeared to improve both survival and quality of life. The current paper led by Dr. Mark and colleagues from Duke Clinical Research Institute looked at the cost effectiveness of this ablation versus angio-rhythmic drug therapy in atrial fibrillation and which was a pre-specified Cabana secondary endpoint.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find?

Dr. Carolyn Lam:

Well in this trial based economic evaluation, catheter ablation was estimated to cost $57,893 per QALY or Quality Adjusted Life Year gained compared to drug therapy in the overall cohort. And this was primarily driven by improvement in quality of life. It also cost $54,135 per QALY gained in the heart failure subgroup, driven by both gains in quality of life and survival. In summary, catheter ablation of atrial fibrillation was found to be economically attractive compared to drug therapy in the Cabana trial overall at present benchmarks of healthcare value in the US and based on projected incremental qualities, but not live years alone.

Dr. Greg Hundley:

Very nice Carolyn. Well, my next paper comes to us from the world of Preclinical Science and it's corresponding author is Dr. Swapnil Sonkusare from University of Virginia School of Medicine. So Carolyn, calcium signals in smooth muscle cells contribute to vascular resistance and control blood pressure. Now increased vascular resistance in hypertension has been attributed to impaired smooth muscle cell calcium signaling mechanisms. And in this regard, transient receptor potential vanilloid four or TRPV4 smooth muscle cell ion channels are crucial calcium entry pathways for smooth muscle cells. However, their role in blood pressure regulation has not been identified.

Dr. Carolyn Lam:

Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So these authors provide the first evidence that TRPV4 smooth muscle cell channel activity elevates resting blood pressure in normal mice. A1AR stimulation activated TRPV4 smooth muscle cell channels through protein kinase calcium signaling, which contributed significantly to vasoconstriction and blood pressure elevation.

Dr. Greg Hundley:

Surprisingly, intraluminal pressure induced TRPV4 smooth muscle cell channel activity, opposed vasoconstriction through activation of calcium sensitive potassium channels indicating functionally opposite pools of TRPV4 smooth muscle cell channels. And so Carolyn, this team identified novel smooth muscle cell calcium signaling nano domains that regulate blood pressure and demonstrate impairment in hypertension.

Dr. Carolyn Lam:

Oh wow, Greg. Thank you so much for that. Well, let's cover the other articles in today's issue. There's a primer by Dr. Jaffe on High Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. There's also Research [Letter] in there by Dr. Fordyce on the eligibility for non-invasive testing based on the 2021 American Heart Association and ACC guideline for the evaluation and diagnosis of chest pain, implications from the Promise trial.

Dr. Greg Hundley:

Great Carolyn. Well, I've also got an exchange of letters to the editor from Professors Benali and Professor Della Bella regarding a previously published article, “Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients with an Implantable Cardioverter Defibrillator, Results from the Multicenter Randomized Partita Trial.” And also there's a very nice Perspective piece from Dr. Udelson entitled “Glucose Insulin Potassium Therapy for Acute Myocardial Infarction, 50 years on and Time for a Relook.” Well, Carolyn, I can't wait to hear more of the discourse between you, the authors and editors on heart failure and preserved ejection fraction.

Dr. Carolyn Lam:

Yay. Here we go. I'm so excited about today's feature discussion. It's on my favorite topic, heart failure with preserved ejection fraction. Although thanks to one of the authors, Dr. Daniel Burkhoff of the editorial that accompanies it, I don't even know how to pronounce, it's Heart Failure question mark Ejection Fraction. I love it. How would you pronounce that?

Dr. Daniel Burkhoff:

Yeah, no, we debated how to pronounce it. HFQRef…a question mark?

Dr. Carolyn Lam:

HFQRef. Oh my goodness. What are we going to come up with next?

Dr. Daniel Burkhoff:

And we actually thought the editors would have a problem with that. Whenever we put something cute in the title, we always get knocked down. So we haven't yet got knocked down, so we'll see.

Dr. Carolyn Lam:

No, I'm not knocking you down.

Dr. Daniel Burkhoff:

But it just really emphasizes that we're in a very confusing time now as it comes to heart failure and ejection fraction, that we have to move on beyond ejection fraction. And although we have these strict buckets and upper and lower limits for each range, that maybe this is in a little bit of a way, doing us a disservice and doing the patients at disservice in terms of treatment.

Dr. Carolyn Lam:

That's really great. And everybody that was Dr. Daniel Burkhoff from the Cardiovascular Research Foundation in New York. He's the editorialist of today's feature paper. And I'm so excited that we have the corresponding author of today's feature paper as well, Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first, I mean, or second, heartfelt congratulations on this beautiful paper, Philipp. If you could start with telling us all about what you did and what you looked at and what made Dr. Daniel Burkhoff call it now, Heart Failure, QREF?

Dr. Philipp Lurz:

Yeah. So thank you so much, first of all, obviously for having me for the kind introduction and your kind words about our work. The whole thing started with the observation that in recent drug trials, the response in HFpEF patients to drugs which were before proven to be quite successful in HFrEF actually showed a quite heterogeneous response in HFpEF patients. And that there were some patterns according to the range of ejection fractions. So it seemed that those HFpEF patients with the lower ejection fractions, they respond a little bit better to HFrEF medication than those with a higher ejection fraction.

Dr. Philipp Lurz:

And HFpEF studies, they included patients within and ejection fraction or 40 and above who normally would probably would consider HFpEF to start with 50 and above. But even in those truly HFpEF patients, so from 50 and anything above to 70, there was a suggestion that there might be differences. 50 to 60 might be something else and then 60 and above. And this is where we started to look into our cohort and to group them according to ejection fraction and see whether we can see some important and clinically meaningful differences in morphology, obviously in function, but then even also in terms of our biopsy results.

Dr. Philipp Lurz:

And that also implies that we did quite a deep phenotyping of our patients. So we use imaging, echo obviously. We use magnetic resonance imaging. We were able to acquire in a larger percentage of that cohort, by the way, it was 56 patients in total, we were able to get some left ventricular biopsies. And most importantly, when it comes to the functional properties of the left ventricle, we also acquired pressure volume loops. And that has the great advantage that we obviously we can look at low dependent parameters, but more important, also low independent in disease of both systolic and diastolic function. And that's pretty much what we did.

Dr. Carolyn Lam:

Oh my goodness. I mean, as an editor at Circulation, can I just first tell you that's what really, really stood out? It's the comprehensive, careful, in-depth characterization. It may be 56 patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it was a lot, a lot that you did. Could you boil it down to what you found and maybe just to first clarify to the audience, how did you bend the ejection fraction? And then what you found?

Dr. Philipp Lurz:

We divided the cohort in two groups. One with an ejection fraction 50 to 60, and the other groups higher than 60% left ventricular ejection fraction. We ended up in lower group, 21 patients, in the higher group with 35 patients. And they were quite different. They had distinct features in terms of morphology, means that the lower injection fraction group, they had larger ventricles. That's probably what you would expect when you group them according to eject fractions. So not that surprising.

Dr. Philipp Lurz:

And at that point, and they had the same stroke volume. The low ejection fraction group, you could say that they had a certain degree of eccentric modeling, whereas those were the high ejection fraction group, that concentric modeling. When we then looked at the biopsies, the group with the low ejection fraction group, so 50 to 60, they had higher percentage of myocardial fibrosis at 15%.

Dr. Philipp Lurz:

And then on left ventricular biopsy, we saw that patients with a high ejection fraction group, they had less myocardial fibrosis, so more fibrosis in those with the lower ejection fraction group. And this is really interesting because when we then look at the real size of the pressure volume loop analysis, despite the fact that the high ejection fraction group had less fibrosis, they had the most stiff ventricles on pressure volume loop analysis. So that's already a very important point because it illustrates once again that we should not mistake fibrosis with stiffness, and also not the other way around. There are other parameters which can cause stiffness such as cellular stiffness, and it's not just the extracellular matrix.

Dr. Philipp Lurz:

So that's an important point. Those patients with high ejection fraction, they had the most stiff ventricles. They had the most relevant limitations in left ventricular filling, so the most marked diastolic dysfunction. We also looked at systolic parameters and there we found that they had a very high contractility. So this is the end systolic pressure volume relationship or also called elastics and that's a marker for contractility. So these ventricles with high ejection fraction, they can contract very well. They have high contractivity. But this is also a marker of systolic stiffness. So they stiff, both in terms of diastolic properties, but also systolic properties. And there, their most important limitation is the limitation in filling.

Dr. Philipp Lurz:

The other group, injection fraction 50 to 60, they do have some stiffness. Obviously we are talking about HFpEF. This is a disease of a diastolic dysfunction. So they have increased stiffness, but to a lesser extent. They can feel a little bit better, but what we see there is a reduction in contractility, so systolic properties. So you could argue that in some extent, that group 50 to 60, they behave a little bit more like HFrEF. Whereas those with high ejection fraction, they're completely different. Very stiff, both doing diastolically and sistolly.

Dr. Carolyn Lam:

Thank you so much. Now I really have to get the gurus insight into this. And of course by guru, I mean, Dr. Daniel Burkhoff. First, I'm going to take this opportunity to share a little private personal story that it's very hard for me to call Dr. Burkhoff, "Dan", although if you will allow me it's because I was a fellow when I first met Dr. Burkhoff. And one of my first papers was actually communicating with Dr. Burkhoff trying to draw these PV loops based on the noninvasive measurements that I was obtaining at the Mayo Clinic in the Olmsted County Cohort. And so this is just really making me smile. So Dan, if I may, what do you make of all this? And if you could give us what you think may be the clinical take home message.

Dr. Daniel Burkhoff:

Thank you so much, Carolyn. And also again, Philipp, congratulations on really a really important paper. I think as Carolyn was saying, one of the many things that impressed me was the multifaceted aspects of the thorough evaluation using multi modality characterization, which is in my mind, unprecedented, especially for this particular group of patients. And you summarized the main results very well. But to me, the thing that really struck me and that we really tried to emphasize in our editorial was the differential response to exercise, to hand grip exercise in this point.

Dr. Daniel Burkhoff:

As you already said, and I don't think this could be understated, that in the lower range, the 50 to 60, these patients were able to fill, the ventricle was able to fill more, the end diastolic pressure still went up significantly into an abnormal range, which is of course is one of the requirements for the diagnosis of HFpEF. But those patients, the end diastolic volume was able to increase and that helped them to increase their cardiac output.

Dr. Daniel Burkhoff:

In the higher EF group, the greater than 60, the end diastolic pressure went up, but the volume did not increase. So the end diastolic pressure volume relationship became higher elevated. And this of course, was reminiscent of what was identified in the early nineties by Dalane Kitzman. And really, he didn't make this distinction between the lower half and the higher half. And we had also in a paper that we did with David K and others, seen a similar finding a couple years ago. And I think this is really, to me, was the along with the apparently disparate findings on myocardial biopsies with fibrosis going the wrong way, if you will, as you already commented on. So this is at least for the higher EF group, is identifying what I would refer to as really true diastolic dysfunction.

Dr. Daniel Burkhoff:

That means that the patients can't fill, there really is some problem why the EDP can go up, but the volume does not increase. And this is obviously for future research, we have to understand what is the difference between these two groups. There are several speculations about why it might. For example, one thing that has been proposed in the literature is the pericardial restraints. If the heart is constrained in a tight pericardium, the volume is recruited from the venous system, which is another what I think is a very important part of this HFpEF phenotype, but the heart is already constrained. That would elevate both the CVP and the wedge pressure without concomitant increases in RV or LV volumes, and therefore limit the ability to increase the cardiac output.

Dr. Daniel Burkhoff:

Another alternative is delayed relaxation. That means a true abnormality of active relaxation. The tau if you will, but I believe in your study, if I remember correctly, the tau was not that abnormal and did not really change very much in either group. So it was harder to really pin it on an abnormality of active relaxation. So that was one really, I think, really important finding.

Dr. Daniel Burkhoff:

The second is now in the group 50 to 60 where they could fill, one of the limitations of the study that you pointed out was that there's no control group. So why this population, this HFpEF population, the EDP increased, but the EDV the end diastolic volume also increased, so what's different between those patients and normals? That we don't really have an answer for yet. So that would be one thing is to compliment these findings with results in a true control group that does not have HFpEF.

Dr. Daniel Burkhoff:

So we still have this mystery of why does EDP go up in this group? My perspective is not an abnormality of diastolly. It's not a diastolic dysfunction, even though it's a HFpEF. I've been trying to promote this idea for more than 20 years, that all HFpEF is not an abnormality of diastolic ventricular properties. There may be extra cardiac factors even beyond the pericardium in this group. So I think these results are just further telling us how complicated and individualized our approach to the pathophysiology of these patients should be.

Dr. Daniel Burkhoff:

And also just one final comment, making a strict cutoff at 60% or 57% as we saw from Valsartan Cuba trial, Valsartan study, is clearly also not going to do us justice. Let's say that we're dealing with anyway, patients with two different pathophysiologies. There's going to be a distribution of these different mechanisms and there's going to be an overlap of these distributions. So we need to start thinking about how we individualize and characterize the pathophysiology in individual patients. So maybe patients with EF of 55, certain patients with EF 55 will not respond to Sacubitril- Valsartan and maybe some patients with an EF of 62 will. So we need to go more deep into the clinical characterization.

Dr. Daniel Burkhoff:

And methods that you use in particular, the pressure volume loop, seem to separate, very nicely, these two different, at least two different subtypes. So I think it's very exciting, and I think people should really take notice of what you found and build on this as a foundation and understand that we need to go deeper on the clinical side to phenotype these patients.

Dr. Carolyn Lam:

Philip, what are your thoughts?

Dr. Philipp Lurz:

No, I think that the concept about stress and unstressed volume is extremely important and fascinating, but that's where it gets really complex because you could make the conclusion from our results that especially the high ejection fraction group, they are have a very high preload sensibility, which means that when we reduce pre-load too much in them, they drop the stroke volume very suddenly. So that's probably also the clinical question for the future. There are many patients, HFpEF patients in whom we should reduce stress volume and they can benefit from that.

Dr. Philipp Lurz:

But I also believe that there is a cord of patients, and those are probably more those with high ejection fraction. They actually, they could experience some harm if you reduce preload too much because of the severe filling restrictions, because of the inability to increase end diastolic volumes, especially as an adaptation to exercise. And I think if we find out ways to differentiate who will benefit from preload reduction and from decongestion and who actually might experience even harm from these interventions, then we are certainly one step further.

Dr. Carolyn Lam:

If I may, I just, I could go on forever, but I know that there's going to be this question that the audience is immediately thinking. Here we are going into the weeds, hemodynamics, we all love it. In fact, I think we're all kind of a little bit geeky about it, but then you've got, Emperor preserved, the Deliver Trial sort of being positive in heart failure with ejection fraction above 40. So, do we really need to understand the different hemodynamic? What do you think is happening that this sort of blanket benefit can occur?

Dr. Philipp Lurz:

I don't think that everyone will benefit. And I think that a better understanding of the underlying pathophysiology will help to even increase the rate of responders and dissect of those who will not respond or we need a different therapy. Obviously here we group patients according to ejection fraction. We just discussed that this is a very rough way to characterize patients. So the next step certainly would be to understand or to see distinct patterns in left ventricular functional behavior irrespective of ejection fraction. Because you might can skip ejection fraction at one day, but the conclusion is not, at least not in my opinion, that all heart failure is the same.

Dr. Carolyn Lam:

Nice. And Dan, what do you think?

Dr. Daniel Burkhoff:

Well, I think with STLT2 inhibitors, first of all, we're looking forward to actually seeing the results from Deliver what the details of it in terms of mortality versus hospitalizations and quality of life. But with regard to HSGL2 inhibitors, I don't think we know the mechanism. I mean, I've read about six papers that definitively talk about different mechanisms of action. I think we don't know. And even despite, let's say positive studies, there's still a significant residual risk that these patients have. So these are not the end of the story by any means. I think this is the beginning of the story and there's still going to be a lot to learn.

Dr. Daniel Burkhoff:

I think with SGLT2 inhibitors, I think it's difficult to identify who is or how do you define a responder on an individual patient basis? When we look at groups and you look at mortality and hospitalizations, yes, you can identify them. But that group does not overlap exactly with those who have an improvement in quality of life. So I think that we're just at the beginning,

Dr. Daniel Burkhoff:

I do think that a deeper phenotyping is going to be the way to go ultimately and I think we're going to need more therapies. Thanks again, Carolyn for inviting me to do the editorial and to participate in this. And I would really be remiss if I did not mention the extraordinary contributions for Mickey Brener and also Barry Borlaug who were equal contributors to this editorial and the evaluation of this paper. So I'm really indebted to both of them for this interpretations. And thank you again, Philipp, for just a wonderful paper.

Dr. Carolyn Lam:

Couldn't have said it better and I just want to thank you once again for providing that deeper phenotyping for opening the door. Many of us said it again and again, this is the beginning and we need more studies, frankly, in yours. I mean, I think Dr. Burkhoff wants you to send normal, healthy people for MRI biopsies, exercise, echo. I'm kidding, on PV loops, but it's true. We need that data. We need the same and the HFrEF and really just to understand the whole thing. I'm so excited about what this paper opens up.

Dr. Carolyn Lam:

I am thrilled to see your editorial, Dan. I'm sure it's going to be well received. Everyone who's listening to this, Pick up the paper, pick up the editorial. Thank you so much for joining us today. You've been listening to Circulation on the Run and from Greg and I, don't forget to tune in again next week,

Dr. Greg Hundley:

Circulation August 9, 2022 Issue

9 augusti 2022 | 30 min

This week, please join authors John McMurray and David Cherney, editorialist Kausik Umanath, as well as Associate Editors Ian Neeland and Brendan Everett as they discuss the original research articles "Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF" and "Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and editorial ""Dip" in eGFR: Stay the Course With SGLT-2 Inhibition."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, it's the season of double features. Except this time, we're having a forum discussion of two related articles and an editorial that discusses both. What is it on? SGLT2 inhibitors. In the first paper, an analysis from the DAPA-HF trial, looking specifically at that initial dip in GFR that follows initiation of dapagliflozin in patients with HFrEF. Then we will discuss further, in a mechanistic way, the renal and vascular effects of combining SGLT2 inhibition on top of ACE inhibition. Lots and lots of good learning and insights, but let's go on first to the other papers in today's issue. Shall we?

Dr. Greg Hundley:

You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn, in this issue, wow, so many exciting original articles. In fact, there are two more articles that were going to pair together, both clinical and pertaining to TAVR procedures. In the first one, it was a group of authors led by Dr. Duk-Woo Park from the Asan Medical Center at the University of Ulsan College of Medicine. They conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy or DAPT, aspirin plus clopidogrel, in patients who had undergone successful TAVR and did not have an indication for anticoagulation. Now in this study, Carolyn, the primary endpoint was an incidence of leaflet thrombosis on four-dimensional computed tomography, CT, performed at six months after the TAVR procedure. Key secondary endpoints were the number and volume of new cerebral lesions on brain magnetic resonance imaging or MRI and the serial changes of neurological and neurocognitive function between six months and that time immediately post the TAVR procedure.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the two groups. Now because the study was underpowered, the results should be considered really as hypothesis generating, but do highlight the need for further research.

Dr. Greg Hundley:

Carolyn, there's a second paper pertaining to transcatheter aortic valve prosthesis. It's led by a group directed by Dr. Paul Sorajja from the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. Carolyn, these authors prospectively examined 565 patients with cardiac CT screening for HALT, or what we would define as hypoattenuating leaflet thickening, at 30 days following balloon-expandable and self-expanding TAVR. Now, deformation of the TAVR prosthesis, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the post-procedural CT. For descriptive purposes, an index of prosthesis deformation was calculated, with values greater than 1 representing relative midsegment underexpansion. A time-to-event model was also performed to evaluate the association of HALT with the clinical outcomes.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume was related to the occurrence of HALT in patients who underwent TAVR. What's the take home here, Carolyn? These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes in these patients. Now, Carolyn, both of these articles are accompanied by an editorial from Dr. Raj Makkar from the Smidt Heart Institute at Cedars-Sinai's Medical Center. It's a very lovely piece entitled Missing Pieces of the TAVR Subclinical Leaflet Thrombosis Puzzle.

Well, how about we check what else is in this issue? My goodness, this was a packed issue. First, Carolyn, there are three letters to the editor from Professors Ennezat, Dweck, and then a response from Dr. Banovic pertaining to a follow-up from a previously published study, the AVATAR study, in evaluating valve replacement in asymptomatic aortic stenosis. There's also a Perspective piece from Dr. Wells entitled “Treatment of Chronic Hypertension in Pregnancy: Is It Time For A Change?” There's a Global Rounds piece from Professor Berwanger entitled “Cardiovascular Care in Brazil: Current Status, Challenges, and Opportunities.” Then there's also a Research Letter from Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis.”

Dr. Carolyn Lam:

There's another Research letter by Dr. Borlaug on longitudinal evolution of cardiac dysfunction in heart failure with normal natriuretic peptide levels. There's also a beautiful Cardiology News piece by Bridget Kuehn on the post-COVID return to play guidelines and how they're evolving. Well, that was a great summary of today's issue. Let's hop on to our feature forum. Shall we?

Dr. Greg Hundley:

You bet, Carolyn. Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is actually a forum because we have two feature papers in today's issue. They all surround the cardiorenal interaction, should I say, of the SGLT2 inhibitors. For the first paper, discussing that initial decline or that dip in the GFR following initiation of dapagliflozin would be Dr. John McMurray, who's the corresponding author of this paper from DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now next, we have also the corresponding author of another paper, really going into the mechanistic insights of the renal and vascular effects of combined SGLT2 and ACE inhibition. Dr. David Cherney is from Toronto General Hospital, University of Toronto.

Dr. Carolyn Lam:

We have the editorial list of these two wonderful papers, Dr. Kausik Umanath from Henry Ford Health in Michigan. Finally, our beloved associate editors, Dr. Ian Neeland from Case Western Reserve and Dr. Brendan Everett from Brigham and Women's Hospital, Harvard Medical School. Thank you, gentlemen. Now with all of that, what an exciting forum we have in front of us. Could I start by asking, of course, the respective authors to talk a little bit about your papers? I think a good place to start would be with Dr. McMurray. John, please.

Dr. John McMurray:

Thanks, Carolyn. I think our paper had three key messages. The early dip in eGFR that we saw was, on average, very small in patients with heart failure, about 3 mLs/min or about 5%. Very few patients had a large reduction in the eGFR. It was around 3%. Dapagliflozin-treated patients had a 30% or greater decline compared to about 1% of placebo patients. Finally, very few of those patients had a decline in the eGFR below a critical threshold, which for cardiologists might be around 20 mLs/min. We saw that in only five patients; that's 0.2% of the dapagliflozin-treated patients. Second message was that that early decline partially reverses. The nadir in our study was about 14 days. But by 60 days, on average, eGFR had increased again. Hold your nerve if you see an early decline in eGFR.

Dr. John McMurray:

Maybe the most important message was that that decline in the eGFR is not associated with worse cardiovascular or renal outcomes. In fact, if anything, the opposite. If you look at the patients in the dapagliflozin group with a 10% or greater decline in eGFR, then compare it to patients who didn't have that decline, these individuals were about 27% less likely to experience the primary composite outcome of worsening heart failure and cardiovascular death. If you look at the placebo group, we saw exactly the opposite. Amongst those who had a greater than 10% decline in eGFR compared to those who didn't, those people with the early decline in eGFR were 45% more likely to experience the primary composite endpoint. The same is true for other cardiovascular outcomes for worsening kidney function. In the dapagliflozin group, decline in eGFR was not associated with more adverse events, not associated with more treatment discontinuation. That small decline in the eGFR is not a bad prognostic sign. If anything, it might be the opposite.

Dr. Carolyn Lam:

Thank you so much. That was really clear. David, are you going to tell us why this decline occurs?

Dr. David Cherney:

Yeah. Perhaps the paper that we published gives some insights into the mechanisms that are responsible for some of those changes in GFR that are thought to be acute hemodynamic effects. In the between trial, which is the trial that we published examining the effect of ACE inhibition followed by SGLT2 inhibition in patients with type 1 diabetes, we also saw that there was an expected effect of adding SGLT2 inhibition on top of an ACE inhibitor in people with uncomplicated type 1 diabetes. This acute dip in GFR was seen in this cohort of patients. We included only 30 patients in this small mechanistic study. At the same time, along with that dip in GFR, we also saw an increase in measures of proximal natriuresis. That proximal sodium loss is linked with changes in sodium handling in the kidney, which then causes changes in both probably afferent and efferent tone, which causes this dip in GFR primarily through natriuresis in this phenomenon called tubuloglomerular feedback. That was one major observation that gives insight into what we see in larger trials around the dip in GFR.

Dr. David Cherney:

In our mechanistic study, we also saw an additive effect on blood pressure. Blood pressure went down further with the addition of empagliflozin on top of an ACE inhibitor. In terms of the mechanisms that are responsible for the reduction in blood pressure, natriuresis certainly may be in part responsible, but we also saw a novel observation whereby there was a reduction in peripheral vascular resistance using noninvasive measures. There are likely several mechanisms that are responsible for the reduction in blood pressure. Then finally, we also saw reductions in markers of oxidative stress, which may also account for some of the effects that we see in blood pressure, as well as potentially some of the anti-inflammatory and anti-fibrotic effects that we see at least in experimental models that may have some clinical translatability to humans as well around the clinical benefits. I think the blood pressure, the renal hemodynamic effects, and some of the neurohormonal mechanisms are the major observations that we saw that may in part explain some of the really nice changes that were seen in Dr. McMurray's study.

Dr. Carolyn Lam:

Right. Thanks, David. But these were patients with type 1 diabetes and no heart failure. John, do you have any reflections or questions about how that may apply? By the way, what a beautiful study. Thank you, David.

Dr. David Cherney:

Pleasure. Thank you.

Dr. John McMurray:

Yes, David. I really enjoyed your study. In fact, I think, Carolyn, it does shed some insights perhaps to what's going on. As David pointed out, the reduction in peripheral arterial resistance, reduction in blood pressure, that may play some role in that early dip in eGFR as well as autoregulation in the kidney. Then the other interesting thing is that the distal nephron seems to adapt to that effect in the proximal tubule. Again, that may account for some of that recovery in eGFR, that reversal in the early dip that I spoke about, and which I think is very clinically important because, of course, physicians should make sure that they recheck eGFR if they see that early dip. Because they may find that few weeks later that that dip is much smaller and of much less concern.

Dr. Carolyn Lam:

Thank you, John. In fact, you're saying, stay the course, right-

Dr. John McMurray:

I have.

Dr. Carolyn Lam:

... with the SGLT2 inhibitors. I'm actually stealing the words of the title of the editorial, a beautiful editorial by Kausik. I love that. Stay the course. Kausik, please, could you frame both papers and then with an important clinical take home message for our audience?

Dr. Kausik Umanath:

Sure. I think the analysis by John and his group was really relevant with the large sample size. What's impressive? Similar to a lot of these other SGLT2 studies that have come out, both in heart failure and in kidney disease progression and so on, it's remarkable how the other analysis, like the analysis of EMPA-REG and CREDENCE and so on, of similar dips. All show more or less the same magnitude, the same relative proportions of this GFR trajectory. I think the mechanistic study only highlights that though it's working with a slightly different population of type 1 patients and much earlier in their course in terms of where their GFRs are.

Dr. Kausik Umanath:

The other piece is that ultimately we need to understand this dip and know to monitor for it and so on. But I think the general clinician should really understand that a dip of greater than 10% really occurs in less than half the population that takes these agents. That dip, if it occurs, certainly doesn't do any harm. That said, if they see a bigger dip in the 30% range, monitor more closely and consider making sure that there aren't any other renal issues out there for that patient because they are a much smaller proportion of patients in these large trials that generate that level of dip. They should be monitored.

Dr. Kausik Umanath:

The other thought that we had, and thinking through this in a practical sense, is because you expect this dip, many of our cardiologists or even the nephrologists when we titrate these drugs, they're on a suite of other drugs. It's probably best to not adjust their Lasix or their loop diuretic, or their RAAS inhibitor at the same time as you're adjusting the SGLT2 inhibitor or starting it because then you may just introduce more noise into the GFR changes that you see over the next several weeks. It may be a sequential piece or at least holding those other agents constant while this gets titrated and introduced is a prudent course of action, so you don't misattribute changes.

Dr. Carolyn Lam:

Thanks so much. What clinically relevant points. In fact, that point about the diuretic especially applies in our heart failure world. You see the dip. Well, first, make sure the patient's not overdiuresed. Remember, there's more that the patient's taking. Thank you. That was a really great point. Brendan and Ian, I have to get you guys to share your views and questions right now. But before that, can I take a pause with you and just say, aren't you just so proud to be AEs of Circulation when we see papers like these and we just realize how incredible the data are and the clinical implications are? I just really had to say that. All right. But with that, please, what are your thoughts, Brendan?

Dr. Brendan Everett:

Yeah, sure. Thank you, Carolyn. Hats off to all three of our authors today for doing some amazing science. Thank you for sending it to Circulation. I think, in particular, I handled David's paper. I'm not a nephrologist and I'm probably the furthest thing from a nephrologist. Had to do my best to try and understand these concepts that I'm not sure I ever even was exposed to in medical school many years ago. I think it shows the breadth of the interest in our readership. The fact that these changes in eGFR have become a primary focus for our cardiovascular patients and that the clinical implications are really important. I guess my question, David, is... In your paper, you talked a little bit about this hypothesis of hyperfiltration and the role that hyperfiltration plays in setting patients with diabetes up for kidney disease. Is that playing a role in John's observation or not? Again, as a non-nephrologist, I have trouble connecting the dots in terms of that hypothesis and John's observation of the clinical benefit for patients that have a reduction in eGFR as opposed to no change.

Dr. David Cherney:

Yeah. It's a great question. It's very difficult to know with certainty in a human cohort because we can't measure the critical parameter, which is intraglomerular pressure, which we think these changes in GFR are a surrogate for. But if we go along with that train of thought, along reductions in glomerular hypertension, it very much makes sense that the patients who dip are those who have the... They're taking their medication, number one. Number two, they respond physiologically in the way that you expect them to, which is that their GFR dips at least transiently and then goes back up again through some of the compensatory mechanisms that John mentioned earlier. As was mentioned not only in this paper, but also in previous analyses from CREDENCE and previous analyses from VERTIS CV and others have shown that indeed that dip in GFR is linked with longer term renal benefits, at least. That is reflected in a reduction in the loss of kidney function over time.

Dr. David Cherney:

The patients who are on an SGLT2 inhibitor and those who dip by around 10% or less, those patients tend to do the best over time in terms of preserving GFR, not losing kidney function compared to patients who are on an SGLT2 inhibitor but do not dip, or those patients who actually have an increase in GFR. That is consistent with this idea that there may be a reduction in glomerular pressure, which is protective over the long term. That ties back into your question around hyperfiltration that this may indeed be due to a reduction in glomerular pressure, which is linked with risk over the long term.

Dr. Carolyn Lam:

Ian?

Dr. Ian Neeland:

I wanted to echo Brendan's comments about the excellent science. When I read these papers, it really speaks to the existential struggle that cardiologists have between kidney function and these medications that we know have cardiovascular benefits. How do we manage that practically? It's so clinically relevant, both the observation that John's paper made about the dip in the DAPA-HF trial as well as, David, your mechanistic insights.

Dr. Ian Neeland:

I wanted to ask John potentially about the most fascinating aspect to me of this paper was that patients with a dip of 10% or more actually ended up doing better in terms of cardiovascular outcomes, specifically hospital heart failure and hospitalizations than people on placebo with a greater than 10% dip. It speaks to the fact that... Is the physiology going on here different between those individuals whose GFR went down on placebo versus those who are on SGLT2 inhibitors? All the mechanistic insight that David's paper had in terms of blood pressure and intraglomerular pressure, how does that feedback and speak to why heart failure is strongly linked to this mechanism? We see this not just with SGLT2 inhibitors, but there are other medications now coming out showing that there's a relationship between this dip in GFR and heart failure. Can you speak to why this heart failure-kidney connection is so important and becoming greater and greater in terms of our understanding?

Dr. John McMurray:

Well, thank you for asking me the hardest question and one that I truly don't think I have a good answer to. I think it's obvious to all of us that the kidney is central in heart failure and perhaps cardiologists have neglected that fact, focusing more on the other organ. But by definition, almost the fluid retention that characterizes heart failure in terms of signs, and probably is the primary cause of symptoms, that clearly is a renally-mediated phenomenon. The kidney must be central to all of this. I think David right. I think the decline in eGFR that you see with this drug is simply a marker that the drug is having its physiological effect or effects. Whatever those are, they're beneficial. Clearly, patients who have an eGFR decline on placebo are different and they reflect, again, the patients that we see all the time. As our patients with heart failure deteriorate, one of the things that we commonly see, in fact becomes one of the biggest problems that we have to deal with, is that their kidney function declines. As their symptoms get worse, as their cardiac function gets worse, their kidney function also declines.

Dr. John McMurray:

I think you're seeing two contrasting effects here. One is the background change in eGFR, which is the placebo patients, and we've always known that that's a bad thing. Then we're seeing that early within 14 days marker of the pharmacological or physiological action of the drug. I hope you don't ask me how SGLT2 inhibitors work in heart failure. That's the other most difficult question I can think of, but I think this is just a marker of the fact that they are working.

Dr. David Cherney:

Yeah. Just to add to that briefly, there is this difficulty in sorting out the mechanisms that are relevant around the acute effects in the kidney that the dip in GFR reflects natriuresis that could keep patients out of heart failure; that the reduction in glomerular pressure reduces albuminuria. Albuminuria reduction is linked with kidney protection. It's linked with heart failure and ASCVD protection. Then there's also this concept of if you dip and then you stay stable afterwards, your GFR stays stable afterwards, those patients with stable kidney function that's not declining, the dippers in other words, those patients are probably able to maintain salt and water homeostasis better than someone who's declining more rapidly. All these things probably tie together in order to reflect, of course, there's a renal protective effect, but that some of those mechanisms may also tie into the heart failure mechanisms that John was mentioning.

Dr. John McMurray:

But, David, it's hard to imagine if we don't protect the kidney, we won't protect patients with heart failure given how fundamental, as I said, the kidney is, and how fundamentally important worsening kidney function is. Not only because it is a marker of things going badly, but also because it often results in discontinuation or reduction in dose of other life-saving treatments. To Kausik's point, it was very important about the risk of changing background life-saving disease modifying therapy. Actually, we didn't see that in DAPA-HF, which was very intriguing. There was no reduction in use of renin-angiotensin system blockers or mineralocorticoid receptor antagonists.

Dr. Carolyn Lam:

Thank you so much, gentlemen. Unfortunately, we are running out of time, but I would really like to ask one last question to the guests, if possible. Where do you think the field is heading? What next? What's the next most important thing we need to know? David, do you want to start? Then John, then Kausik.

Dr. David Cherney:

I think one of the aspects that we need to know in the future is where else can we extend these therapies into novel indications and extend the boundaries of where we currently work with these therapies. People with type 1 diabetes, for example, with either heart failure or with significant kidney disease, patients with kidney transplantation, is there a renal or cardiovascular protective effect? Then another high risk cohorts who have not been included in trials, those on immunosuppressants, for example, who were excluded from the trials. I think those are some of the areas that we need to extend into now that we understand how these therapies work in even very sick patients and that we also know that they likely have at least some benefit through suppressing inflammation, and possibly reducing infectious risks. That would provide a rationale for extending into some of these new areas. I think that's certainly, hopefully on the horizon for us.

Dr. Carolyn Lam:

John?

Dr. John McMurray:

Carolyn, obviously I think looking at post myocardial infarction population, that's an obvious place to go. There are a couple of trials there. I suppose the trial that I would love to see, and which I think would address the core question that we've been discussing today, which is: Is this all about the effect in the kidney and how important is the diuretic and natriuretic action of these drugs in heart failure? I think the key study that would address this would be doing a study in patients on dialysis. Because in those patients we could, I think, separate the issue of natriuresis, diuresis, and maybe even the dip in EGR that we've been talking about. If these drugs prove to be effective in end-stage kidney disease, patients on dialysis, that would be really fascinating.

Dr. Carolyn Lam:

Kausik?

Dr. Kausik Umanath:

That is a very interesting point. I don't know that we know necessarily outcomes, but I think from working with the DAPA-CKD, we do have a little bit of the safety data because we did continue it. I was the US MLI for that study and we did continue the SGLT2 passed into renal failure. There is a little bit of safety data there. But I don't think once you've declared an outcome, you're not collecting outcomes data after that point. That's a very interesting area to look into.

Dr. Kausik Umanath:

I also think the other place where this field's heading is trying to better tier and layer the multitude of agents. I think we've been waiting for about 20 to 30 years, at least in the kidney field, for something new to affect the progression of kidney disease after the ACE/ARB trials and so on. This one we've got SGLT2 inhibitors. We've got the new MRA, finerenone, and so on, which also have very beneficial cardiovascular effects. The question becomes: How do we layer these therapies? Which sequence to go in? Some of the others that are in pipeline as well that are out there that have very beneficial cardiovascular effects that may indeed also help kidney function and diabetes control, which do you go with first and so on?

Dr. Carolyn Lam:

Wow! Thank you so much. We really could go on forever on this topic, but it has been tremendous. Thank you once again. On behalf of Brendan, Ian, Greg, thank you so much for joining us today in the audience. You've been listening to Circulation On the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

Circulation August 2, 2022 Issue

1 augusti 2022 | 37 min

This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical Trials."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials.

The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we?

Dr. Greg Hundley:

You bet, Carolyn. And how about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control.

Dr. Carolyn Lam:

Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease.

Dr. Carolyn Lam:

Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age.

Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart.

Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls.

Dr. Greg Hundley:

Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find?

Dr. Carolyn Lam:

Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients.

Dr. Greg Hundley:

Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.”

Dr. Carolyn Lam:

There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we?

Dr. Greg Hundley:

You bet.

Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all.

And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address?

Dr. Paul Ridker:

Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts.

The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there.

In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting.

Dr. Greg Hundley:

Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design?

Dr. Paul Ridker:

We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like.

What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in.

And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated.

It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it.

Dr. Greg Hundley:

Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women.

Dr. Paul Ridker:

No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results.

Dr. Greg Hundley:

Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article?

Dr. Allan Jaffe:

Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look.

So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on.

Dr. Greg Hundley:

Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts?

Dr. Robert Harrington:

So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials?

And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results.

And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial.

Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here.

It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know.

Dr. Greg Hundley:

Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform?

Dr. Paul Ridker:

Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture?

Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with.

On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with.

Dr. Greg Hundley:

Allan, turning to you. What do you think is a next study to perform in this space?

Dr. Allan Jaffe:

Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial.

Dr. Greg Hundley:

And Bob, your thoughts.

Dr. Robert Harrington:

Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial."

But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth.

Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?"

I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this.

On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently.

Dr. Greg Hundley:

Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events.

And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures.

Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen.

And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address?

Dr. Eric Van Belle:

Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population.

And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device.

In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease.

So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure.

Dr. Greg Hundley:

Very nice. And Eric, can you describe for us, your study design, and who was your study population?

Dr. Eric Van Belle:

Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population.

And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure.

Dr. Greg Hundley:

So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find?

Dr. Eric Van Belle:

So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population.

But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population.

Dr. Greg Hundley:

Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures?

Dr. Emmanouil Brilakis:

Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation.

I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds.

Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is.

Dr. Greg Hundley:

Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research?

Dr. Eric Van Belle:

Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this.

So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome.

Dr. Greg Hundley:

And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space?

Dr. Emmanouil Brilakis:

Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient.

So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.

Dr. Greg Hundley:

Circulation July 26, 2022 Issue

25 juli 2022 | 36 min

This week, please join authors Mikhail Kosiborod and Christian Schulze and Editorialist Stefan Anker as they discuss the original articles "Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial" and "Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From Antihyperglycemic Agents to All-Around Heart Failure Therapy."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

I'm so excited about the feature discussion this week. It is a paired feature along with their editorial and it's all focused on SGLT2 inhibitors. The first, results from the EMPULSE trial, Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure; and the second, the EMPAG-heart failure trial, The Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients with Acute Heart Failure. Incredibly important topics, incredibly important discussion. Wait up for it. We're just going to tell you a little bit more about two other original papers in today's issue, and I'm going to go first, Greg. Is that okay?

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

Now, really interesting topic here. We have strong evidence supporting the effective blood pressure and cardiovascular disease risk lowering properties of healthy diet such as the DASH diet, Mediterranean diet, and so on and so on. But what about the diet consumed by a fifth of the entire world's population? The Chinese cuisine. Interestingly, today's paper addresses just that. This is from authors, Dr. Wu, from Peking University Clinical Research Institute and colleagues who performed a multicenter patient and outcome assessor blind randomized feeding trial among 265 participants with baseline systolic blood pressure of 130 to 159 in four major Chinese cuisines.

And these are the Shandong, Huaiyang, Cantonese, and Szechuan cuisines, and here's how they did it. After a seven day run in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine based Chinese heart healthy diet for another 28 days. The primary outcome was systolic blood pressure. The study developed the first heart healthy Chinese diet that fits Chinese food culture and emphasizes its palatability by involving master shifts in developing the recipes.

Dr. Greg Hundley:

Oh wow. Carolyn, this is really interesting, especially one fifth of the world's population in studying a heart healthy diet. So did it work? I can't wait to hear the results.

Dr. Carolyn Lam:

Well, the change in systolic and diastolic blood pressure from baseline to the end of the study in the control group was five millimeters mercury and 2.8 millimeters mercury reduction, respectively. The net difference of change between the two groups in systolic and diastolic blood pressure were a reduction of 10 and almost four millimeters mercury, respectively. The effect size did not differ among cuisines, and so in summary, with a patient and assessor blind randomized feeding trial, this study really demonstrated that the blood pressure lowering effect of the Chinese heart health diet could indeed be substantial, and importantly, be compatible with medications while palatable and affordable in Chinese adults with high blood pressure, and so these results support the idea that food is medicine and will give many patients with high blood pressure the confidence to adopt heart healthy diets in their lifestyle treatment.

Dr. Greg Hundley:

Wow, Carolyn, that is really an interesting article. So many of these articles today could all be features in and of themselves. That was just outstanding. Well, my next paper comes to us from the world of preclinical science, and it's from Dr. Sean Wu from Stanford University School of Medicine. So Carolyn, immune checkpoint inhibitors are monoclonal antibodies that are used to activate the immune system against tumor cells. Now, despite their therapeutic benefits, immune checkpoint inhibitors have the potential to cause immune mediated adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Now histologically, patients with immune checkpoint inhibitor of myocarditis have lymphocytic infiltrates in the heart implicating T-cell mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in immune checkpoint inhibitor myocarditis are unknown.

Dr. Carolyn Lam:

Wow. So insights into the etiology of these immune checkpoint associated myocarditis cases must be very important. So what did they find?

Dr. Greg Hundley:

Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found to be significantly increased in the blood of patients with immune checkpoint inhibitor myocarditis corresponding with an analogous increase in effector cytotoxic CD8+ cells in the blood and hearts of PD-1 deficient mice with myocarditis. These expanded effector CD8+ cells had unique transcriptional changes, including upregulation of the chemokines CCL5, CCL4, and CCL4L2, and they may serve as attractive diagnostic therapeutic targets for reducing life threatening cardiac immune related adverse events in immune checkpoint inhibitor treated cancer patients, and Carolyn, just like so many of our articles, there's a very nice accompanying editorial by Professor Gianluigi Condorelli that also offers an update on current research pertaining to non-systemic steroid therapy to treat immune mediated myocarditis. Well, Carolyn, how about we jump to some of the other articles in the issue?

Dr. Carolyn Lam:

Oh, you bet, Greg. There's an exchange of letters between Drs. Madias and Knops regarding the article “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: The Analysis of All Appropriate Therapy in the PRAETORIAN Trial.”

Dr. Greg Hundley:

And also in the mail bag, Professor Mark has a Research Letter entitled “Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction, The SUGAR-DM-HF Study,” and our own Tracy Hampton has several synopses from articles published elsewhere in our piece on cardiovascular news. Well, how about we get onto that feature forum discussion, two papers, two editorialists. I can't wait.

Dr. Carolyn Lam:

Me too. Let's go, Greg.

Dr. Greg Hundley:

Welcome, listeners to this July 26th feature forum discussion. So remember, listeners, for forum discussions, we have several manuscripts that focus on a singular topic and we bring together the authors, our associate editors, and also an editorialist, and today, I want to introduce, we have with us Dr. Mikhail Kosiborod from Mid America Heart Institute in Kansas City, Missouri, Dr. Christian Shults from University Hospital Jena in Germany, Stefan Anker from Charité in Berlin, Germany, and our Associate Editors, Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, and Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentleman, and we'll start with you, Mikhail. Could you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Mikhail Kosiborod:

Well, thanks very much, Greg. The background for the study, which was the secondary analysis of the EMPULSE trial was patients that are hospitalized with acute decompensated heart failure represent a very high risk group. We know that they have high risk of death and hospitalizations, and we also know that they have very poor health status that's very high burden of symptoms, physical limitations, and poor quality of life, and so addressing those treatment goals, trying to reduce the risk of clinical events like death and hospitalizations and improve the symptoms and physical limitations in this patient population are very important treatment goals.

Now we previously demonstrated in the main results of the EMPULSE trials that using empagliflozin initiating empagliflozin SGLT2 inhibitor in this patient population as compared with placebo provided a significant total clinical benefit, which was a composite of total death, repeat hospitalizations for heart failure, or a change in a Kansas City cardiomyopathy questionnaire, which is a kind of a gold standard measure of patient's health status. What we tried to do in a much more granular fashion in this study is to understand the effects of empagliflozin as compared with placebo on this very important outcome, the Kansas City cardiomyopathy questionnaire, and we actually evaluate all of the key domains and composite symptoms, physical limitations, as well as quality of life.

Dr. Greg Hundley:

Very nice, and Mikhail, can you describe for us what study population specifically, and then what was your study design?

Dr. Mikhail Kosiborod:

Well, this was a population of patients that were hospitalized with heart failure and that EMPULSE was unique in its design because first of all, previous SGLT2 inhibitor trials mostly focused on patients with chronic heart failures that were in an outpatient setting, including prior trials of empagliflozin, and EMPULSE really focused on acutely hospitalized patient population, but it included patients regardless of ejection fraction. So as they were hospitalized with decompensated heart failure and reduced or preserved ejection fraction. They were enrolled regardless of if they had type 2 diabetes, they were enrolled essentially, regardless of kidney function, only patients with EGFR of less than 20 were excluded, and also importantly, was this study and a unique feature of the study in particular was that we enrolled patients whether they had acute de novo heart failure.

That means that was a new diagnosis of heart failure that was bad enough for them to be hospitalized or worsening chronic heart failure requiring hospitalization. So it was really an all-comer trial for patients acutely hospitalized for heart failure. So we had just over 500 patients and they were randomized in the hospital. After a brief period of stabilization, we use empagliflozin, 10 milligrams daily or placebo and treated for 90 days, and the primary outcome at 90 days was a total clinical benefit that I described that was a composite, hierarchical composite of total death hospitalizations, repeat hospitalizations for heart failure and changing KCCQ. In this study, again, we focused predominantly on KCCQ, trying to understand the effects on health status, again, symptoms, physical limitations, and quality of life.

Dr. Greg Hundley:

Excellent. And Mikhail, what were your study results?

Dr. Mikhail Kosiborod:

Well, what we observed, a couple of things. One is we first examined the effects of empagliflozin on the primary endpoint across the range of KCCQ and baseline, and what we found was that regardless of the degree of symptomatic impairment and baseline, empagliflozin was consistent in providing them total clinical benefits that I described previously, and then kind of shifting to what I think is the most interesting findings, the effects of empagliflozin versus placebo on KCCQ, what we found was that as you would imagine in this population of patients that were acutely hospitalized with heart failures, that had very poor health status, very low KCCQ at baseline, and within the first 90 days, which was observation period, both groups of patients had substantial improvements in KCCQs. As one would expect after acutely decompensated episode of heart failure and treatment in a hospital, everyone got better.

But patients treated with empagliflozin had significantly greater improvement in KCCQs than those that were treated with placebo, and that was first of all, a very substantial difference between the two groups. It was more than five points in favor of empagliflozin already at 15 days and was highly statistically significant, and it was maintained throughout the 90 day treatment period. So the fact that we saw both a clinical meaningful and statistically significant improvement in just 15 days, I think is a very important clinical message, and then finally, I guess what I will mention is these benefits of empagliflozin while main outcome we looked at was KCCQ total symptoms, we're focusing on the symptoms, but it was consistent when we looked at physical limitations as well as quality of life. So really, all key domains of KCCQ were impacted in a similar way.

Dr. Greg Hundley:

Very nice. So in acute heart failure, marked symptomatic improvement after the administration of the SGLT2 inhibitor empagliflozin at 10 milligrams per day. Well, now listeners, we're going to turn to our associate editor, Dr. Brendan Everett, and Brendan, again, you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Brendan Everett:

Well, thanks, Greg, and I think this manuscript caught my eye because of the importance of the clinical question, and Mikhail outlined why I think that was really relevant. So we understand that this class of medications or SGLT2 inhibitors have important effects on outcomes like re-hospitalization in patients with heart failure, and what was particularly striking about this paper is that it took patients rather than those with chronic heart failure, but as Mikhail mentioned, enrolled a patient population that was actually in the hospital, and I think this was an important frontier for this particular question about when to start the SGLT2 inhibitor and what kind of benefits there might be. Furthermore, I think the fact that they did not select the population based on ejection fraction was particularly striking, and of course, I think is remarkable, but now old news, they did not select on the presence or absence of diabetes as well.

And so those three components really attracted me to the paper. I also think the outcome is one that really is valuable and worth exploring, and specifically, I'm talking about how patients feel on the medication after a hospitalization for heart failure. Appropriately, we focused on re-hospitalization for heart failure and cardiovascular death in prior trials in this space, and I think we need to embellish those findings or further deepen those findings with a perspective on how patients actually feel when they get the medication, and of course, it goes without saying that what's particularly important here also is that it was a randomized placebo controlled trial, and so the results have some element of internal validity that I think is really important. So those were the things, Greg, that really attracted my attention as I read the paper for the first time.

Dr. Greg Hundley:

Thank you so much, Brendan. Well, listeners, we've got a second paper today and we're next going to hear from Dr. Christian Shults, and he also is focusing on really another aspect of the administration of empagliflozin in patients with acute heart failure and that pertains to the renal function of the patients. So Christian, could you describe for us the background pertaining to your study and what was the hypothesis that you were intending to address?

Dr. Christian Schulze:

Thanks, Greg. Well, it's great to introduce all study here in this running. So our study impacted those in acute decompensated heart failure. The impact HF trial was a study based on the hypothesis that we wanted to test, whether empagliflozin has effects in acute decompensated heart failure, and we focused on the patient population that was not addressed in EMPULSE, patients that came to the ER and needed to be treated right away, and we wanted to know and this was our main hypothesis, but are the diuretic and [inaudible 00:17:11] effects of the SGLT2 inhibitor on this case, empagliflozin, actually had an impact on diuretic regimens and kidney functions since this is one of the main end points that limits treatment, and also is one of the outcomes of patients with acute decompensated heart failure in the hospital.

Dr. Greg Hundley:

Very nice. And so Christian, what study design did you implement and who was included in your study population?

Dr. Christian Schulze:

So we also used the randomized two arm study design. We included patients with acute decompensated heart failure independent of left ventricular ejection fraction. Patients needed to have an NT-proBNP of more than 500. The average NT-proBNP in fact was 4,300 in our entire patient population, and we included patients within 12 hours of presentation. So many of these patients have been recruited in the ER, they presented two hour cardiology heart failure service, and then were immediately randomized to the trial in the two arms, and we tested not 10 milligrams of empagliflozin. We actually tested 25 milligrams of empagliflozin based on in-house data that 25 milligrams potentially had a stronger diuretic effect compared to 10 milligrams.

Dr. Greg Hundley:

And what did you find?

Dr. Christian Schulze:

So we followed patients for five days. It was a relatively short period of time. It was designed to address the in-house phase of patients with acute decompensated heart failure. The mean duration of stay was 6.3 days in the hospital so this was exactly the time that we wanted to test. We had a 30 day endpoint for safety issues, and what we could see is that patients on 25 milligrams on empagliflozin on top of standard diuretic regimens and medical care had 25% higher diuretic outputs compared to patients in the placebo group. We also found no differences in markers of renal injury dysfunction, and could in fact confirm that after 30 days, patients in the empagliflozin group had a better EGFR compared to patients in the placebo group. On top, we saw a more rapid decrease in body weight and also a more profound decrease in NT-proBNT values.

Dr. Greg Hundley:

And Christian, just for our listeners to put a little bit of this in perspective, what was the range of serum creatinine for the patients that were enrolled in your study?

Dr. Christian Schulze:

So the main EGFR in the entire population was around 60 and the creatinine values were around 107 on average in the entire cohort. So this is a very typical population. We had around 30% of the population with de Novo heart failure, around 20 to 30% of the population was pre-treated for preexisting heart failure. So very typical population of patients with heart failure presenting to the emergency room.

Dr. Greg Hundley:

And did you have any kind of lower level EGFR cutoff, I mean, for enrollment into this study?

Dr. Christian Schulze:

So when we designed the trial, we actually still had the sub classification of diabetes or impaired glucose or homeostasis as an inclusion criteria. We dropped it before we started the trial because the data came out that this is actually, in fact, not a critical issue for patients with heart failure. So diabetes was not a subgroup in our trial and the lower limit of EGFR was actually a thoroughly defined protocol.

Dr. Greg Hundley:

Very nice. Well, listeners, now we're going to turn to our second associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas, and Justin, similar to Brendan, and you see many papers come across your desk and so what attracted you to this particular paper by Christian and his colleagues?

Dr. Justin Grodin:

Well, Greg, I think first and foremost, and I think very similar to Brendan, but I think what's always striking is if I may just take a step back, decompensated heart failure in the United States is the number one cause for hospitalization among Medicare beneficiaries. So I think really, the brunt and really the truly public health message of the disease is very important in the applicability, and even though that decompensated heart failures is one of the most common things that we ever encounter when we practice, internists, cardiologists, et cetera, we have very, very little clinical trial guidance that tells us how to decongest individuals when they're hospitalized with swelling and heart failure and a lot of these individuals can be quite ill, and we have some clinical trial data, but largely, we have a lot of negative studies or inconclusive studies in this space.

So certainly, what drew me to this trial was definitely that context, and obviously, based on the mechanistic data with SGLT2 inhibitors, I think one of the natural questions, which Christian addresses, is that we know that up front, they do augment natriuresis. So I think it's very compelling to marry those two together because this is what many of us that use these medications regularly have been asking is whether or not they would have some efficacy in that regard, and then another thing that caught my eye and me as a cardiorenal investigator was, just as Christian highlighted, was we have a clinical trial that randomly assigned individuals, really that were ill and many of whom were not stabilized within 12 hours of presentation, and we're talking about patients that are coming into the hospital at all times during the day in and I think that's very remarkable that we have something with standard...

We have a study with standardized assessments where we're really trying to ask a very practical, pragmatic question, which is do these therapies lower the sodium balance in individuals with decompensated heart failure, and I think what's important is largely, we've got a lot of medications that supplement loop diuretics, which are the class of drugs that the majority of us use, and we have a lot of other therapies that we use that really have very little data or poor data that guide us such as thiazide diuretics, carbonic and hydrase inhibitors, mineralocorticoid receptor antagonists, and so here, we have a clinical trial that asks a question that's on many people's minds.

And then we do have very compelling, at least short term pragmatic and mechanistic data that does tell us that these individuals do have a greater natriuretic effect when empagliflozin is used as an adjunct to standardized loop diuretic therapy. So it's a very practical clinical question, and I think what's very important, and we could debate probably all day about the implications of GFR change and kidney function change while we're decongesting somebody with diuretics, but I think what's reassuring to all the clinicians is we really didn't see an effect on kidney function despite a greater natriuretic effect or enhanced diuretic effect, if you will, with the use of empagliflozin.

Dr. Greg Hundley:

Very nice. Well, thank you, Justin. Listeners, now we have an editorialist and as you know, editorialists really help us put the scientific presentation of an original manuscript into the perspective of really the global theme of a topic, and we have Stefan Anker from Berlin, and Stefan, can you describe for us how do we put these two manuscripts and results that we've heard about really in the context now of moving forward with the use of SGLT2 inhibitors in the management of patients with acute decompensated heart failure?

Dr. Stefan Anker:

Thank you so much. Really, I think these two papers, on the one hand, enhance our certainty about early use, and on the other hand, possibly show us that there might be even more to achieve by, on the one hand, moving even earlier with the application of SGLT2 inhibitors or possibly consider the higher dose. Now let's take one step back. These drugs were developed in type two diabetes and the first successful trial was the [inaudible 00:25:42] outcome trial. Many people have forgotten that this trial tested two doses and not only one, the 10 and the 25 milligram dose, and of course, with the success for improving kidney outcomes and heart failure hospitalization outcomes, we move forward into these two specialist areas, on the one hand, broadening it to the non-diabetic communities, but on the other end, narrowing it by focusing on the 10 milligram dose regardless of whether there is [inaudible 00:26:12].

And we basically now learn A, to use these drugs even earlier than we did in the big trials and we can now be sure to start their use in the hospital, and if you take the average change in quality of life results seen, you actually get a better result for the patient on quality of life when you start earlier than when you start late in the ambulatory studies where basically, in the chronic setting, maybe you have one and a half to two points difference. Here, you now have four and a half points in the study shown by Mikhail, and of course, it's also good to know that you can start this in any type of patient, regardless of their quality of life. The impact study from Christian, they basically moved it now even earlier, moving into the hospital space is possible based on EMPULSE. Moving it into the acute admission space is at least a consideration now based on what Christian here has shown.

And he is actually addressing the one question I hear very often in my presentations about SGLT2 inhibitors, what about this 25 milligram dose? Is there a place for this in cardiology as well, and a possible place is shown here, not only that this is a safe thing to do, but also you get urinary output. Of course, we may in the future, want to see this compared, directly compared to the 10 milligram dose, but of course, the world is not created in one day, but needs more than one and so really, I think these two studies, on the one hand, address an important issue, when to start using them. On the other hand, show us a little bit of a glimpse to the future.

Dr. Greg Hundley:

Very nice, Stefan, and listeners, we get to take advantage of having these authors, editors, and editorialists together and ask them what they see as the next study to be performed in this sort of sphere of research. So Mikhail, we'll start with you. In 30 seconds or less, what do you see as the next study to be performed in this arena of research?

Dr. Mikhail Kosiborod:

I think, Greg, what we've learned recently, including from the EMPULSE trial, we have this population of patients in a hospital with heart failure's a huge issue as Justin mentioned, and until recently, we had very little [inaudible 00:28:31] for them beyond the usual kind of decongestion with loop diuretics and trying to make them feel better, but you look at outcome data. It really was a dearth of effective therapies that have meaningful impact on important outcomes. Now that's changing, SGLT2 inhibitors is one example. There are some other recent examples in this patient population, like a firm HF and iron deficient patients with heart failure.

But the bottom line is it's no longer kind of a desert, if you will, of positive trials. We now have something we can do and I think what this proves is that we need to actually invest more, both in terms of resources and time to really do what we we're being able to do in other areas of heart failure and those patients with chronic, half and half where we can start developing pillars of therapy that can actually truly improve outcomes with this patient population and there is a lot going on that makes me optimistic that's going to be the case in the coming years.

Dr. Greg Hundley:

Very nice. And Brendan?

Dr. Brendan Everett:

Well, I think both trials mentioned today really pushed our understanding of this population forward. I think the biggest clinical question that I face when I'm caring for these patients is that we have four, at least, guideline directed therapies, right? We have beta blockers, we have ARBs, ACE inhibitors and ARNIs. We have mineral receptor antagonists and we have SGLT2 inhibitors. So which do we use in what order and how do we start them, and what kind of parameters do we use to guide us if we're limited either by renal function or by blood pressure or by some other factor.

And we often, if not always, have one of those constraints that we're dealing with and so I would say the next step for me is trying to sort out which of these therapies and what order ought to be our highest priority for patients with acute decompensated heart failure as we move quickly from the acute decongestion stage towards discharge and a chronic therapy that will then be followed as an outpatient over the ensuing days and months.

Dr. Greg Hundley:

Very nice. And Christian.

Dr. Christian Schulze:

Thank you again, and Brandon pointed out very nicely. I mean, we have good evidence now for chronic heart failure treatment. We have the four columns of heart failure medical therapy. Questions that remain open is what do we do with all these patients that are now guideline medicated, come to the hospital with an acute decompensation? Should we carry on with the medication? Should we terminate and in particular, should be carry on with full dose, 50% dose of SGLT2 inhibitors, and the next question is, what dose should we use, in fact, for SGLT2 inhibitors? Is it in group effects or is sotagliflozin comparable to empagliflozin, and then is there a role for a step by scheme that we initially have in high dose therapy that we then downgrade to 10 milligrams on the chronic heart failure treatments, and then of course, quality of life is very important. We should ask this question also in this patient population that is early on treated, do we see benefits that carry on in the outpatient setting and do we see an effect of early treatment on long term benefits?

Dr. Greg Hundley:

Justin?

Dr. Justin Grodin:

Well, I would have to agree with all of my colleagues here on this call. I think all have raised really good points, but I think one very simple, and I'll echo some of Brendan's statements, but one very simple question is we know that when we decongest people and initiate a negative salt balance in the hospital for decompensated heart failure, we cause neurohormonal activation and there are a lot of downstream untoward effects from chronic decongestive therapies, and I think one of the more compelling things is we still yet have defined what is the best way to decongest individuals with swelling or volume overload in the hospital. Here, we have compelling studies with SGLT2 inhibitors for quality of life and really, the way patients feel.

And this is really what's important to them, and then something very pragmatic to clinicians and let's make people pee more, but I think one of the compelling questions, and I don't know if it will be answered, is we have a lot of choices for supplemental therapies and different diuretic strategies when patients come in the hospital for decompensated heart failure, and I do think that these studies do move the needle with SGLT2 inhibitors. I think that's abundantly clear, but we still don't know what is the best way to dry out my patient or make my patient pee so that they feel better, but I do think that these studies do at least set the stage that there's some compelling advantages to SGLT2 inhibitors.

Dr. Greg Hundley:

And then lastly, Stefan.

Dr. Stefan Anker:

Thank you. Besides the detailed points mentioned by many, and Christian, totally support 25 versus 10 milligram, how long 25 milligram, if at all in the future. Besides this, I'm interested in the big picture question. So what about the post myocardial infarct congestion/heart failure situation, and there will be two trials in the next 18 to 24 months that report on this, and my pet kind of area is actually to treat heart failure where nobody thinks it is heart failure, and what I mean is for instance, advanced cancer patients, cardiac wasting cardiomyopathy. So the heart failure in sick cancer patients, and indeed, we are planning to do exactly that now in a study focusing on hospice care patients to really improve the quality of life, the very thing focus here on the EMPULSE trial.

Dr. Greg Hundley:

Well, listeners, we want to thank our authors, Dr. Mikhail Kosiborod from Mid America Heart Institute in University of Missouri, and Christian Shults from the University Hospital in Jena, Germany. Also, our associate editors, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, and Dr. Justin Grodin from University of Texas Southwestern in Dallas, Texas, and also, our editorialist, Dr. Stefan Anker from Charité in Berlin, Germany for bringing us these two manuscripts pertaining to two randomized clinical trials regarding the administration of the SGLT2 inhibitor, empagliflozin in acute heart failure, demonstrating first, marked improvement in heart failure symptoms and health related quality of life.

And second, in those with estimated GFRs greater than 30 mls per minute, an augmentation of natriuresis in the setting of the co-administration of diuretics without deterioration in renal function. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation July 19, 2022 Issue

18 juli 2022 | 39 min

This week, please join Associate Editors Mercedes Carnethon and Karol Watson, as well as Guest Editor Fatima Rodriguez as they present the 2nd annual Disparities Issue. Then join Rishi Wadhera and Ashley Kyalwazi as they discuss their article "Disparities in Cardiovascular Mortality Between Black and White Adults in the United States, 1999 to 2019."

Dr. Mercedes Carnethon:

Well, good day listeners. I'm Mercedes Carnethon, and I'm joined by my fellow editors, Karol Watson, and Fatima Rodriguez, Associate Editor and Guest Editor for Circulation. And we'd like to welcome you to Circulation on the Run, for our second annual disparities issue. We have a lot of articles to discuss today, many of which we'll summarize, but we encourage you to access the issue and read the articles. First off, Fatima, I believe you have a paper to discuss.

Dr. Fatima Rodriguez:

Sure thing, Merci. My first paper is a thought provoking article by Nilay Shah, and co-authors from Northwestern University, that examine factors associated with the racial gap in premature cardiovascular disease.

Dr. Fatima Rodriguez:

This study used data from a well-known cardiac cohort, that aims to identify factors that begin in young adulthood and predict the development of future coronary artery risk. The objective of this study was to examine the relative contributions of clinical versus social factors, in explaining the persistent black/white gap in premature cardiovascular disease. After following around 5,000 black and white study participants for a median of 34 years, black men and women had a higher risk of premature cardiovascular disease. After controlling for multi-level individual and neighborhood level factors measured in young adulthood, the racial differences in premature cardiovascular disease were attenuated.

Dr. Fatima Rodriguez:

The authors found that the greater contributors to this racial disparity were not only clinical factors, but also neighborhood and socioeconomic factors. The relative explanatory power of each of these factors varied by men and women. This is really noteworthy, since we spent so much of our time in clinical medicine, focusing on identifying and managing traditional risk factors. But in reality, these structural factors and inequities are critically important to address, and contribute to differences in clinical risk factors downstream.

Dr. Mercedes Carnethon:

Thank you so much, Fatima. That was a really excellent summary. And now, I'm turning to you, Karol. I'd love to hear what you're going to be talking about today.

Dr. Karol Watson:

I'd like to discuss the paper, Association of Neighborhood Level Material Deprivation with Atrial Fibrillation Care in a Single-Payer Healthcare System Population Based Cohort Study. This is by Dr. Abdel-Qadir and colleagues.

Dr. Karol Watson:

So in this study, the author sought to determine whether there was an association between neighborhood material deprivation, by that we mean, inability to attain the basic needs of life and clinical outcomes, in individuals with atrial fibrillation. The kicker here is, they did this in an area with universal healthcare. So they wanted to see, if you took away the differences between the ability to see a physician or get your drugs paid for, if you would see any disparities.

Dr. Karol Watson:

So they performed a population based cohort study, individuals over the age of 66 years of age with atrial fibrillation, in the Canadian province of Ontario. They have universal healthcare there, and full drug coverage for anyone over 65. The primary exposure was neighborhood material deprivation. That's a metric used to estimate the inability to attain basic material needs, like healthy foods, safe housing. Neighborhoods were categorized by quintile, from the least deprived, quintile one, to the most deprived, quintile five. They find that, among about 350,000 individuals with atrial fibrillation, their mean age was 79, and about half of them were women. Those in the most deprived neighborhoods, quintile five, had a higher prevalence of cardiovascular risk factors and non-cardiovascular work comorbidity, relative to those who were in the least deprived areas.

Dr. Karol Watson:

Even after adjusting for all the confounders, they found that those in the most deprived neighborhoods had higher hazards of death, stroke, heart failure, and bleeding, relative to those in the least deprived neighborhoods. They also found that, despite having universal healthcare and drug coverage, those in the most deprived neighborhoods were less likely to visit a cardiologist, less likely to receive rhythm control intervention, such as ablation, and have worse outcomes.

Dr. Karol Watson:

And then, the accompanying editorial by Utibe Essien, he reminds us that intervening only on traditional markers of access, like health insurance and drug costs, may not be sufficient to achieve health equity. We have to address all of the structural needs that make people unable to get good help. Further, he points out that, the association between atrial fibrillation and neighborhood deprivation is very likely true with other cardiovascular conditions, as well.

Dr. Karol Watson:

So, Merci and Fatima, this just reminds us again, that addressing all the social determinants of health are necessary to achieve the best health outcomes.

Dr. Mercedes Carnethon:

Thanks so much, Karol. I really appreciate that summary of that important piece, focusing on a different domain of disparity. My first paper is an excellent piece, led by one of my favorite other associate editors at Circulation, Dr. Wendy Post, from Johns Hopkins University. And I see a familiar name on here. That's yours, Karol. You two are joined by an all-star list of authors, to describe race and ethnic differences in all-cause in cardiovascular mortality, in the multi-ethnic study of atherosclerosis.

Dr. Mercedes Carnethon:

MESA is a longitudinal cohort study that launched in 2000, and recruited just over 6,800 adults who identified as black, white, Hispanic, and Chinese. While the study participants were initially free from cardiovascular disease, over an average of 16 years of follow up, 364 participants died from cardiovascular disease. There are a number of novel findings in this paper that led our editor-in-chief to select it as his pick of the issue.

Dr. Mercedes Carnethon:

The finding that really stands out to me is, how much of an influence the social determinants of health had on black versus white disparities in cardiovascular mortality. In fact, after adjusting for socioeconomic status, the disparities were nearly eliminated. Other critically important findings are that, the oft described Hispanic paradox of lower cardiovascular mortality in Hispanics, as compared with white adults, was demonstrated in this population. And finally, we have longitudinal data on Asians living in the United States. Asian participants in MESA had similar rates of cardiovascular disease mortality as their white counterparts. There's so much to learn in this well designed cohort study, and so many hypotheses about how social determinants and structural racism influence the disparities that we see.

Dr. Mercedes Carnethon:

So Fatima, I'd like to turn to you next. What else do you have to share?

Dr. Fatima Rodriguez:

Thank you, Merci. My second paper is a research letter for my home institution of Stanford University, led by my colleague, Dr. Shoa Clarke, discussing how race and ethnicity stratification for polygenic risk course, may mask disparities among Hispanic individuals.

Dr. Fatima Rodriguez:

This study used data from the Million Veteran Program, to determine how self-identified race and ethnicity impact the performance of polygenic risk scores in predicting coronary artery disease.

Dr. Fatima Rodriguez:

The investigators found, that the current polygenic risk scores predict coronary artery disease similarly well in Hispanic and non-Hispanic white individuals. However, what I found most interesting, is that there was so much more heterogeneity among Hispanic individuals as measured by K-Means clustering, than among non-Hispanic white individuals. And this study really confirms that there is much more heterogeneity within populations than between populations. And this is particularly true as we think of the extreme diversity of Hispanic populations. Lumping Hispanic populations into one category, may mask important differences in cardiovascular risk prediction outcomes, and even the notions of the Hispanic paradox that you just discussed, Merci.

Dr. Mercedes Carnethon:

I appreciate you bringing that up again, because there are so many different nuances to the observations that we see in these studies. But I'll keep moving, because we have an embarrassment of riches in this wonderful issue. So Karol I'll turn back to you.

Dr. Karol Watson:

Thanks, Merci. The next paper I'd like to discuss, is an On My Mind piece by Peter Liu and colleagues, and they entitle it, Achieving Health Equities in the Indigenous Peoples of Canada, Learnings Adaptable for Diverse Populations. Now the author's note that, lessons learned about addressing health disparities from indigenous peoples in Canada, can offer a lot of new lessons for other populations where there are similar disparities. They begin by offering historical perspective, and they say that, most of the health to disparities for the indigenous populations originate from early colonization, in dismantling of the sociocultural economic educational and health foundations, the indigenous communities had historically.

Dr. Karol Watson:

It's true that, that is true in a number of different countries. This is data from Canada, but we can see similar things in the United States. With the recognition of the historical and ongoing social health inequities, the Canadian government initiated what they call, the Truth and Reconciliation Commission, to recommend a path towards reconciliation, to create best practices for engaging indigenous populations.

Dr. Karol Watson:

For instance, in Canada, any health research or implementation program, requires the direct engagement of indigenous communities and their elders. They have to try to develop culturally safe environment, including what they say, quote unquote, anti-racism and cultural safety education for all, both indigenous and non-indigenous populations. They want to really respect community values, customs and traditions, including the access to traditional foods, and healing practices, and the support from elders. So they really are making it a very important point, that cultural sensitivity is absolutely critical to engaging these populations. You want to jointly collect data whenever available, to track progress and outcomes. And they offer many examples of successful programs developed using these principles, such as the Diabetes and My Nation program, in British Columbia, or the mobile diabetic telehealth clinic.

Dr. Karol Watson:

They offer discussion of future initiatives as well, that can help other communities in Canada. Such as, there's an initiative addressing hypertension in the Chinese population in Canada.

Dr. Karol Watson:

So this thoughtful paper, really looks at disparities in unique populations in Canada. More importantly, it offers potential roadmaps for other populations, solutions to address longstanding legacies of racism and colonialism.

Dr. Mercedes Carnethon:

Thank you so much, Karol, for that description from our neighbors from the north.

Dr. Mercedes Carnethon:

My second paper is really relevant during this hot month of July, in much of the United States and the upper hemisphere. And that's because Sameed Khatana and colleagues from the University of Pennsylvania, discuss how extreme heat is associated with higher cardiovascular mortality. For those of us who welcome the heat of summer and the opportunity to get out from behind our desks and exposed to some vitamin D, Khatana and colleagues reviewed county level daily data on temperature, and linked those data with mortality rates.

Dr. Mercedes Carnethon:

But before I summarize the findings, I invite you to California based cardiologists to join me in Chicago, where extreme heat is really only a problem for about 30 days a year. The authors found that between 2008 and 2017, when the heat index was above 90 degrees Fahrenheit, or 32.2 degrees Celsius, there was a significantly higher monthly cardiovascular mortality rate. In total, extreme heat was associated with nearly 6,000 additional deaths from cardiovascular disease. And sadly, black adults, older adults, and men, bore the greatest burden of mortality rates from extreme heat. So, we can all take lessons from that.

Dr. Mercedes Carnethon:

But turning to you now, Fatima.

Dr. Fatima Rodriguez:

Thanks so much, Merci. I'm from Florida, so I can definitely relate to the issues of extreme heat, but I'm very happy for the perfect year round weather here in Northern California.

Dr. Fatima Rodriguez:

My third paper is led by Dr. Zubair (and Chikwe) and colleagues from Cedar Sinai, and it describes changes in outcomes by race, in children listed for heart transplantation in the United States. I won't give all the details, but this research letter really nicely summarizes how the 2016 Pediatric Heart Allocation Policy revisions may have inadvertently widened health disparities between white and non-white children. This article touches on the difference between equality and equity, even in the most well-intentioned national policies. And I invite our listeners to read the full details in this special Circulation edition.

Dr. Mercedes Carnethon:

Thanks Fatima. Karol.

Dr. Karol Watson:

The next paper I'd like to discuss, is a community based cluster randomized pilot trial, of a cardiovascular mobile health intervention, preliminary findings of the FAITH! Trial, from LaPrincess Brewer and colleagues from the Mayo Clinic.

Dr. Karol Watson:

So it's well known that African Americans have suboptimal cardiovascular health metrics, such as less regular physical activity, suboptimal blood pressure levels, suboptimal diets. So the authors of this study hypothesize, that developing a mobile health intervention, in partnership with trusted institutions, such as, African American churches, might be an effective means to promote cardiovascular health in African American patients. So using a community based participatory research approach, they develop the FAITH! trial. FAITH stands for Fostering African American Improvement in Total Cardiovascular Health. The manuscript in this issue reports, feasibility and preliminary efficacy findings from this refined community informed mobile health intervention, using the FAITH! App, developed by the investigators.

Dr. Karol Watson:

They performed a cluster randomized control trial. Participants from 16 different churches in the Rochester, Minnesota and Minneapolis St. Paul, Minnesota areas. The clusters were randomized to receive the FAITH! App, that was the intervention group, or were assigned to a delayed intervention program. The 10 week intervention feature culturally relative and sensitive information modules, focused on American Heart Association's Life's Simple 7. Primary outcomes were changes in the mean Life Simple 7 score, from baseline to six months post intervention. They enrolled 85 participants, mean age was 52, and about 71% were female.

Dr. Karol Watson:

At baseline, the mean Life Simple 7 score was 6.8, and 44% of the individuals were characterized as being in poor cardiovascular health. The mean Life Simple 7 score of the intervention group, after the end of the intervention, increased by 1.9 points. In the control comparator group, it only increased by 0.7 point. Highly statistically significant, with P value of less than 0.0001 at six months.

Dr. Karol Watson:

Now this FAITH! Trial demonstrated preliminary findings, that suggest that a culturally sensitive and mobile health lifestyle intervention could be efficacious, promoting ideal cardiovascular health among African Americans. I think what's so important about this is that, they partnered with a very trusted group, the churches, and getting buy-in to a community that has had many reasons not to trust in the past, I think is critically important.

Dr. Mercedes Carnethon:

Well, thank you so much, Karol. My third paper is an original research investigation by Anoop Shah and colleagues from the University of Edinburgh, arguing that socioeconomic deprivation is an unrecognized risk factor for cardiovascular disease.

Dr. Mercedes Carnethon:

In their study, the authors evaluated how risk scores, with and without indicators of socioeconomic deprivation, performed in a population study in Scotland, the Generation Scotland: the Scottish Family Health Study, of over 15,000 adults. Again, I won't give away all the details, so that I keep our listeners excited to read the article, but all risk scores aren't created equally. And the observed versus expected number of events varied, based on whether the risk score included socioeconomic indicators or not. Further, the performance of the risk scores varied, based on the degree of deprivation that participants were currently experiencing. It's a thought provoking piece, that may challenge us to reconsider how we identify risks for cardiovascular disease in the population.

Dr. Mercedes Carnethon:

And I'm turning to you now, Fatima.

Dr. Fatima Rodriguez:

Sure thing, Merci. My last paper is led by Dr. Anna Krawisz, and is looking at how differences in comorbidities explain racial disparities in peripheral vascular interventions. This study used Medicare fee for service data from 2016 to 2018, to examine risks of death and major amputation, one year following peripheral endovascular intervention. They found that, black Medicare beneficiaries had higher population level need for peripheral endovascular interventions, and that black race was associated with adverse events following these interventions. However, after adjusting for the higher prevalence of comorbidity, such as diabetes, hypertension, and chronic kidney disease in black populations, this observation was eliminated. Again, like a common theme in many of the articles we've discussed today, this is to suggest, that moving upstream to reduce risk factors is really critical to eliminate disparities in cardiovascular disease outcomes. And this includes the understudy disease of peripheral arterial disease. Black adults were also less likely to be treated with guideline directed medical therapies in this study.

Dr. Mercedes Carnethon:

Well, thank you so much, Karol and Fatima, for your wonderful summaries of all of the excellent pieces in this issue.

Dr. Karol Watson:

And I'd like to thank all of the fantastic investigators who submitted their really fantastic work, so that we could produce this issue. And really, keep them coming. We thank you for this.

Dr. Mercedes Carnethon:

Well, thank you. So now we'll transition to our feature discussion with Drs. Wadhera and Kyalwazi, from Beth Israel Deaconess Medical Center, and the Harvard Medical School.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run podcast. I'm really pleased to host this feature discussion. My name is Mercedes Carnethon, from the Northwestern University Feinberg School of Medicine. And I'm pleased to have with us today, Drs. Ashley Kyalwazi and Rishi Wadhera from Beth Israel Deaconess, and the Harvard Medical School. And they shared with us a really important piece of work for our disparities issue, that is describing disparities in cardiovascular mortality, between black and white adults in the United States from 1999 to 2019. First of all, I really want to thank you both for submitting your important work to circulation.

Dr. Rishi Wadhera:

Thanks so much Mercedes, and thanks for the opportunity to submit and revise our manuscript.

Ms. Ashley Kyalwazi:

Thanks so much for having us.

Dr. Mercedes Carnethon:

Wonderful. I'd like to start out with you Rishi. Tell our listeners about the objectives of your study, and what your motivation was for carrying out this work.

Dr. Rishi Wadhera:

Well, I think it's been well established that, black adults are disproportionately impacted by cardiovascular disease, and experience worse cardiovascular outcomes, due to systemic inequities and structural racism. And so, the goal of our study was really, to perform a comprehensive national evaluation of how age adjusted cardiovascular mortality rates have changed for black adults, compared with white adults, over the past two decades in the United States, with a focus on some key subgroups, like younger adults and women.

Dr. Rishi Wadhera:

In addition, because we know that the neighborhood community or environment in which you live in the US, has an immense influence on cardiovascular health, we also examine changes in cardiovascular mortality for black and white adults by geographic region, rurality, and neighborhood racial segregation. And our primary objective was really, to understand whether disparities in cardiovascular outcomes between black and white adults improved, worsened, or didn't change, from 1999 to 2019.

Dr. Rishi Wadhera:

And there are some reasons to think we might have made progress in narrowing the mortality gap between these groups over this time period. There have been substantial improvements in preventative care and treatments for cardiovascular disease over the past two decades. And the expansion of insurance coverage under the Affordable Care Act, led to increases in access to care, cardiovascular risk factor screening and treatment, particularly, for black adults. At the same time, we know that, black adults were disproportionately affected by the economic recession of 2008, and experienced worsening poverty, job loss, and wealth loss, all of which are inextricably tied to cardiovascular health, and more broadly, health. And so that was our interest in really exploring how disparities in cardiovascular mortality have changed amongst black and white adults between 1999 and 2019.

Dr. Mercedes Carnethon:

Thank you so much for that summary. It's really nice to have these sort of pieces that really outline for us a lot of data, and across a number of different domains. Because it allows us really, a chance to think about those data, and how we can use those data in order to help improve health.

Dr. Mercedes Carnethon:

So tell me a little bit, Ashley, about what your study found.

Ms. Ashley Kyalwazi:

Absolutely. Yeah. So in the United States, overall, we found that age adjusted cardiovascular mortality rates declined for both populations, so both black and white adults, by around 40% from 1999 to 2019. So encouraging declines across the country. We found that these patterns were similar for both women and men, when we stratified by gender, over the 20 year period. While mortality rates declined in all regions, we still did find disparities when we stratified by age. So between the younger and older black women, versus younger and older black men, we found that, younger black men and black women were dying at higher rates, and were at increased risk of death from cardiovascular mortality, compared to younger white women and men, respectively. But we also found that black women and men living in rural areas consistently experienced highest mortality rates. And then finally, black adults living in higher areas of residential racial segregation, and compared to those living in low to moderate areas of residential racial segregation had higher mortality rates, as well.

Dr. Mercedes Carnethon:

Wow, this is a lot. And it's really describing a lot of disparities across multiple domains that we can easily measure. Which aspects of these results in your work did you find the most surprising, Ashley?

Ms. Ashley Kyalwazi:

Yeah, I was intrigued, I think overall, by just the gaps. I was very encouraged by, I think, the declines over time. On an absolute scale, the country has made a lot of progress, in terms of reducing cardiovascular mortality rates for both groups. But still, by the end of the study period, there were notable gaps between black adults and white adults. Particularly, between black, younger women and white, younger women, we see that by the end of the study period, black, younger women still remain over two times the risk of death from cardiovascular disease than younger white women. Which I think, leaves something to be desired from a public health and health policy standpoint, with regards to how we're going to kind of decrease these disparities.

Dr. Mercedes Carnethon:

I wanted to follow up on that point. Why do you think you see such disparities between black and white younger women? I love the opportunity of the podcast to allow authors a chance to speculate, beyond what they would do in the paper.

Ms. Ashley Kyalwazi:

Absolutely. I think that, there are a lot of great efforts on a national scale right now, to kind of address the disparities between black and white women. The Association of Black Cardiologists, for example, had a whole paper out about ways to really target and provide preventative measures for black women. So for example, working with communities, where there's a high proportion of black women, to figure out what community based research looks like. Engaging with churches, different types of methods, to really understand the barriers that black women face towards obtaining preventative care.

Ms. Ashley Kyalwazi:

I think the disparities that we are seeing, could potentially parallel well known and documented disparities in maternal health outcomes. So I think, from a perspective of preventative care, really thinking about, what are the barriers to healthy cardiovascular profiles for black women pre and postnatally, to ensure that their cardiovascular health is an actionable before and after the pregnancy?

Ms. Ashley Kyalwazi:

And then I think, broadly, the challenges that black women face, mirror the challenges of black adults, plus the additions of like social stressors, things that we looked at in this study neighborhood residential racial segregation, access to healthcare, and all of those things kind of contribute to the profile that black women face, in terms of being often, the heads of their households as well, and carrying on a lot of different societal challenges.

Dr. Mercedes Carnethon:

Thank you so much for that. I really appreciate that.

Dr. Mercedes Carnethon:

As I read the paper, one of the findings that I found the most surprising, and it was challenging for me to understand, is that while the absolute difference in rates was declining, or getting smaller over time, between black and white men and women, the rate ratios remained elevated across the course of time. I think, these concepts can be a little challenging to understand, not just to me, but to others as well. That when one measure of effect is showing progress, but another is still reporting a disparity.

Dr. Mercedes Carnethon:

Rishi, could you explain for our listeners, how we can see progress on one metric, but still find a mortality rate ratio that's 1.3 times higher in black, as compared with white men, for example?

Dr. Rishi Wadhera:

Thanks for that really important question, Mercedes. Just to summarize, we presented two outcomes that compared cardiovascular deaths among black and white adults in our paper, absolute rate differences, and then separately, rate ratios. And I think, both measures provide important complementary insights. I think that, understanding the absolute rate difference in cardiovascular deaths is critically important from a public health perspective, because it characterizes excess deaths experienced by black adults, compared with white adults. The fact that the absolute rate difference in cardiovascular death has narrowed over the past two decades between these groups is positive news. In contrast, the rate ratio provides us with important insights on the relative difference, or disparity or gap, between black and white adults.

Dr. Rishi Wadhera:

So again, both are important, both provide sort of synergistic and complimentary insights. And just to sort of cement that, as an example, you were talking to Ashley earlier, about some of the patterns we noticed amongst younger black women and white women. The absolute rate difference in cardiovascular deaths between younger black women, compared to younger white women, decrease from 91 per 100,000 in 1999, to about 56 per 100,000 in 2019. And that's good progress. However, our rate ratio analysis indicated that, still in 2019, young black women were 2.3 times more likely to die of cardiovascular causes than young white women. Highlighting that, we still have a lot of work to do, to address disparities between these groups. Some of which, Ashley already talked about.

Dr. Mercedes Carnethon:

Thank you so much for that excellent explanation. I know it's certainly, I find it alarming to hear, but then I remember I'm actually not young anymore. So maybe this doesn't apply to me quite as much. But no, I appreciate the explanation.

Dr. Mercedes Carnethon:

So your report was really unique, in that you studied these disparities, as we discussed, across a number of domains, age, geography, even racial residential segregation. Whereas, the pronounced disparities have been reported in a few of the other domains that you studied. I'm really interested in hearing more about racial residential segregation. I think, a lot of people don't fully understand what the concept is, and the ways in which racial residential segregation may contribute to higher rates of cardiovascular death among blacks.

Dr. Mercedes Carnethon:

Ashley, would you mind explaining to us first, what racial residential segregation is? And then really, how it would contribute to higher rates of cardiovascular death?

Ms. Ashley Kyalwazi:

Yeah, absolutely. So in its simplest terms, racial residential segregation is just the physical separation of two or more groups by race and/or ethnicity into different neighborhoods. What gets tricky is, like the long history within the United States of how we got to this point, where you see numerous degrees of segregation across the country. Residential racial segregation in the United States dates back to policies pre World War II, that resulted in kind of discriminatory banking practices and policies. For example, reverse red lining and gentrification, much of which the extent still exists today. And that's what we see kind of, I think, in our results when we looked at high versus low to moderate areas of residential racial segregation, and how those kind of track onto the trends that we see in cardiovascular mortality over time.

Ms. Ashley Kyalwazi:

The residential racial segregation impacts almost every aspect of life. You can imagine where you live, we know definitely impact, for example, your zip code can impact health outcomes. We've seen individual's cardiovascular health kind of trend with something as simple as your zip code. Where you live really does impact your, for example, access to affordable housing, health insurance, where your primary care physician is, whether or not you even have one. What that trip looks like to see your primary care physician, is it hours on end, and unrealistic to get to, or is it just around the corner?

Ms. Ashley Kyalwazi:

Educational opportunities, which leads to income, which we know is linked to cardiovascular disease employment in all of these aspects. Even access to green space. In some metropolitan areas that are more segregated, we see that, black adults, for example, have less access to green space, and numerous studies have shown that, that does impact overall health, but then also, from a cardiovascular disease perspective as well. So I think that, given that we know that lack of access to all of these key determinants can adversely affect cardiovascular mortality, and just general cardiovascular health, I think is very interesting that we found that, there was this link between high residential racial segregation and cardiovascular mortality. That we definitely can look into more, and understand kind of in more detail, that the mechanisms at play and ways to intervene.

Dr. Rishi Wadhera:

And just to layer onto and reinforce Ashley's really excellent answer to that question. We know that black adults are more likely to live in disadvantaged neighborhoods, because of the intentionally racist policies that were put in place many decades ago, that Ashley described so well. And black communities and segregated communities, as Ashley mentioned, are less likely to have access to primary care, high quality hospital care, and green spaces, but also, pharmacies and healthy foods. And we also know, there's a lot of empirical work that's shown that black communities, disproportionately experience psychosocial stressors, trauma.

Dr. Rishi Wadhera:

Also, these communities are disproportionately exposed to climate change, such as extreme heat. There was a recent paper that extreme heat has been linked to increases in cardiovascular mortality, and disproportionately affects black communities. These communities are also disproportionately exposed to pollution. All of these things we know are linked to cardiovascular health, and represent the effects of again, intentionally racist policies that were put into place many decades ago, the effects of which still persists today. Which will require equally intentional policies that aim to dismantle these longstanding effects, if we hope to make progress in advancing health equity, and specifically, cardiovascular health equity.

Dr. Mercedes Carnethon:

I appreciate the facility with which the two of you address the multiple complex contributors to cardiovascular health. It's even more impressive coming from two clinicians. So I really appreciate you taking the time to explain this. And this is where I really like the opportunity to open up and say, what more do you want your clinical peers to know about? For example, how does this affect the day to day encounters that you have in clinic with black patients, and other patients who've been traditionally underrepresented? How do you hope your clinical peers will use this information to promote cardiovascular health equity? And I'll open it up to either of you to respond.

Ms. Ashley Kyalwazi:

Yeah, I can get on that one. I think that, the disparities that our paper highlights, really requires a multisystem level approach to tackling, from public health to public policy. But I think at a provider level, to your question, Mercedes, physicians must be able to, I think at first, read the data and understand that these disparities exist.

Ms. Ashley Kyalwazi:

If there's no insight with regards to the risk profiles, that simply black women and black men have, because of systemic racism, because of these inequities, then I think, we're already kind of steps behind where we need to be. So recognizing disparities in cardiovascular disease burden for black men and women, prioritizing education on cardiovascular risk. A lot of the conditions are preventable with appropriate access to care and education around these topics. And so, providing education about the signs and symptoms of heart disease and treatment options for black men and women. Recognizing the history of medical mistreatment for black adults in this country. And really, tailoring the approach towards the individual who comes into the office, who might have very valid reasons for hesitating to take a medication, or a lot of questions that need time and consideration.

Ms. Ashley Kyalwazi:

At a research level, I think, more data and resources should be spent on studying risk prevention and treatment for cardiovascular disease in black adults, and really, developing more community based models, that really get at the specific interventions that work within black communities, that are culturally specific, that are targeted and relevant, for the populations that we're talking about.

Ms. Ashley Kyalwazi:

I think finally, and I'll let Rishi chime in, I think, this is shockingly low level of racial and ethnic representation in the field of cardiology as a whole. And we know that, diversity in healthcare can improve health outcomes. So from a cardiology perspective, I think, training the next generation of black young men and women to take up their seats at the table, and really advocate for some of these issues, alongside individuals who are already doing great work, would be essential towards reducing disparities that we see. And so all of the above, I think, I would encourage for my colleagues.

Dr. Mercedes Carnethon:

Thank you so much. Rishi, any final thoughts?

Dr. Rishi Wadhera:

No, I'll just add onto Ashley's again, really outstanding response that, this is a tension we face when we see patients in cardiology clinic all the time. I think, awareness about disparities, and the multiple factors that contribute to disparities in cardiovascular health, particularly, as it relates to race and ethnicity, are increasingly being recognized as they should be.

Dr. Rishi Wadhera:

And one of the challenges, how much can clinicians do within the bounds of hospital walls? We can make sure that we get patients the treatments they need. We can make sure we screen patients appropriately. But we know, as we've discussed, that so many factors beyond hospital walls, like widening income inequality, that's disproportionately affected black adults, and has been worsening over the last several decades. Widening educational inequality, that again, disproportionately affects black adults, and has been worsening over decades, also affect how. So I think, thinking about how clinicians, researchers, and policy makers, can work together to address some of these challenges, issues, and broader social determinants of health, that also exist outside our clinical practice, or hospital walls, will be really, really important, if we are serious about advancing health equity in this country.

Dr. Rishi Wadhera:

I don't think, we can operate in silos anymore. In the clinical world, in the research world, in the policy making world, we need more researchers and clinicians to have a seat at the table when it comes to policy making, individuals who understand how all of these complex factors are inextricably tied to one another, so that we can seek and implement solutions that advance cardiovascular health.

Dr. Mercedes Carnethon:

Thank you so much. The insights that we've gotten, from not only your written work, but even more importantly, this opportunity to speak with you today, and share with our readership, have just been invaluable. And I really appreciate the amount of time that you spent, in preparing the manuscript, and really contextualizing the findings with us today, as well as in writing. So thank you so much for contributing this really important work to our annual disparities issue.

Dr. Rishi Wadhera:

Thank you so much, Mercedes. We really appreciate all the time you and the Circulation team took to make the manuscript stronger.

Ms. Ashley Kyalwazi:

Thank you so much for having us. It was truly an honor to have this conversation and to submit our work.

Dr. Mercedes Carnethon:

Well, thank you.

Dr. Mercedes Carnethon:

That wraps up our feature discussion for this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, from Northwestern University, Associate Editor and guest editor of the disparities issues. So thank you so much.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit hajournals.org.

Circulation July 12, 2022 Issue

11 juli 2022 | 23 min

This week, please join author Ambarish Pandey and Editorialist Linda Peterson as they discuss the article "Frailty Status Modifies the Efficacy of Exercise Training Among Patients with Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the HF-ACTION Trial" and the editorial "Heart Failure With Reduced Ejection Fraction (HFrEF): ‘The Importance of Being Frail.’"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article, Heart Failure Reduced Ejection Fraction in Evaluating the Efficacy of Exercise Training. But guess what? It appears it may be more efficacious in those that have high Frailty Index scores, as opposed to those that may not. But before we get to our feature discussion, let's grab a cup of coffee and go through some of the other articles in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would love to, and this first paper is one that defines epigenetic biomarkers of lifelong cardiovascular health exposure and really contributes to our understanding of their roles in cardiovascular disease development. First though, a little quiz for Greg. So, Greg, what does DNA methylation mean to you?

Dr. Greg Hundley:

Well, Carolyn, DNA methylation. So, what I understand is these methyl groups get involved with our DNA and actually affect change over time that leads to phenotypic expression of, maybe, new traits. But I don't know. Maybe I'm not quite up to date.

Dr. Carolyn Lam:

Oh, you're perfect. Indeed, DNA methylation is a widely characterized epigenetic modification, which means exactly as you said. It's a regulatory modification to our DNA induced by environmental exposures and can affect gene expression. And this is the topic of today's paper by Doctors Zheng, Hou, and Lloyd-Jones from Northwestern University Feinberg School of Medicine and their colleagues. So, what they did is they studied blood DNA methylation at over 840,000 methylation markers measured twice over five years in participants of the CARDIA study. Epigenome-wide association analyses on a clinical cumulative cardiovascular health score were then performed in both CARDIA and compared in the Framingham Heart Study.

Dr. Carolyn Lam:

The authors identified 45 midlife DNA methylation markers associated with clinical cardiovascular health metrics, such as body mass index, blood pressure, blood glucose, and total cholesterol longitudinally measured since young adulthood. The methylation markers were located in genes involved in lipid metabolism, insulin secretion, and cytokine production, which could not be fully attributed to genetic factors. So, they proposed and validated in summary a methylation-based risk score to promote a personalized cardiovascular disease risk evaluation beyond traditional cardiovascular risk factors.

Dr. Greg Hundley:

Oh, wow, Carolyn. Interesting, a methylation-based risk score to promote personalized cardiovascular disease risk evaluation. Wow! That's really exciting.

Dr. Greg Hundley:

Well, I'm going to go to the world of preclinical science, and just like last week where we had a really nice article on myocardial regeneration, this week, we've got another. And so, Carolyn, early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a very short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than one week after birth.

Dr. Carolyn Lam:

Interesting. Now, I see that these investigators worked with possums. Could you tell me why they did that, and what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So, this work was led by Dr. Wataru Kimura from the RIKEN Center for Biosystems Dynamic Research and their colleagues. The reason they studied possums, so the marsupial possum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least two weeks after birth. Remember we stated before, all the other mammalian species, it's only one week after birth. So, this appears to be the longest postnatal duration of such a capacity among mammals examined to date, and AMP kinase signaling was implicated as an evolutionary conserved regulator of mammalian postnatal cardiomyocyte proliferation.

Dr. Greg Hundley:

And they additionally found that in a separate mouse experiment, the authors noted that the pharmacological inhibition of AMP kinase signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in neonatal mice, so really exciting work in the area of cardiomyocyte regeneration.

Dr. Carolyn Lam:

Wow, indeed! And I've learned now about possums. Thank you, Greg.

Dr. Carolyn Lam:

So, Greg, have you ever asked yourself, what is the frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated gene variants in the general population? Well, guess what? This next paper addresses just that in more than 18,600 UK Biobank participants who had undergone whole-genome sequencing, ECG, and cardiovascular magnetic resonance imaging.

Dr. Greg Hundley:

Wow, Carolyn, another really interesting study from the UK Biobank. So, what did they find?

Dr. Carolyn Lam:

So, this study is from Dr. Chahal from the Center for Inherited Cardiovascular Diseases Wellspan Health in Lancaster, Pennsylvania and colleagues, and they found that approximately one in six of adults with putative pathogenic variants in dilated cardiomyopathy genes exhibited early dilated cardiomyopathy features potentially associated with the genotype. And it's most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Dr. Carolyn Lam:

Among individuals with putative pathogenic dilated cardiomyopathy gene variants, ECG or CMR-detected early features were nearly four times more common than clinically manifest dilated cardiomyopathy or early features. Over 90% of subjects with these gene variants in dilated cardiomyopathy-associated genes did not have a prior history of dilated cardiomyopathy, and the overall clinical or subclinical penetrance of dilated cardiomyopathy-associated single pathogenic variants was highly variable between genes ranging from zero to 67%. And so, in conclusion, a genotype-first screening approach for dilated cardiomyopathy using a large genetic panel is currently not suitable in the general population due to incomplete understanding of the genetic architecture and reduced penetrance of the associated genes.

Dr. Greg Hundley:

Very nicely said, Carolyn. Wow! Well, let's take a look and see what's in the mailbag. And first, there's a Research Letter from Professor Huguenard entitled, “Frequency of Screening Detected Intracranial Aneurysms in Patients With Loeys-Dietz Syndrome.” And our own Bridget Kuehn has a really nice piece on Cardiology News.

Dr. Carolyn Lam:

Nice. There's also an On My Mind paper by Dr. Sattar, McGuire, and Gill entitled, “High-Circulating Triglycerides Are Most Commonly a Marker of Ectopic Fat Accumulation: Connecting the Clues to Advanced Lifestyle Interventions,” and an exchange of letters between Dr. Groothof and myself, Dr. Lam, regarding my article on “Efpeglenatide and Clinical Outcomes With and Without Concomitant SGLT-2 Inhibition in Type 2 Diabetes: An Exploratory Analysis of the AMPLITUDE-O Trial.”

Dr. Carolyn Lam:

Ah, that was awesome. Well, thanks, Greg. I am so excited to get to the future discussion that you queued us on so well, frailty in heart failure with reduced ejection fraction. Here we go.

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Welcome, listeners, to this July 12th, 2022 feature discussion. And we have with us today, Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and Dr. Linda Peterson, an editorialist for this article from Washington University in St. Louis. Welcome to you both. Well, Ambarish, We're going to start with you. Could you describe for us basically the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Ambarish Pandey:

Thanks, Greg, for having me on this, and thanks to Circulation for publishing our article. Yeah, I think the premise for this study stems from the longstanding known benefit of exercise training in patients with heart failure with reduced ejection fraction. Now, that was shown in the HF-ACTION trial, where individuals with chronic stable heart failure with reduced ejection fraction underwent exercise training, and there was demonstrated benefit in quality of life and adjusted analyses. There was a protocol-specified adjusted analysis that did demonstrate improvement in some of the key primary endpoint.

Dr. Ambarish Pandey:

Based on these results, CMS has approved exercise training and cardiac rehabilitation in patients with chronic stable heart failure with reduced ejection fraction. However, despite this mandate from CMS and generally well-accepted benefits of exercise training in heart failure with reduced ejection fraction, the uptake of exercise training has been pretty low, and there's a lot of heterogeneity in the improvement in outcomes that is associated with exercise training.

Dr. Ambarish Pandey:

So, we wanted to see whether frailty, which is a well-characterized syndrome of reduced physiologic reserve and impaired homeostatic tolerance to stressors and is common in patients with HFrEF, we wanted to see how frailty modifies the beneficial effects of exercise training in HFrEF. And based on the existing literature and some of the prior works we have done, we hypothesized that individuals who are frail and who have more functional impairments are going to have more targets for improvement in their functional status and thus would be more likely to benefit from exercise training. And we looked at this in the HF-ACTION trial itself and using the Rockwood Frailty Index and the difference in primary outcome and treatment effect of exercise among frail and non-frail individuals.

Dr. Greg Hundley:

Very interesting, so really sort of a look back in HF-ACTION data. Describe a little bit more for us that study design, and then specifically, what was the study population that you used to test your hypothesis?

Dr. Ambarish Pandey:

Right. So HF-ACTION was a randomized control trial multi-centered that was sponsored by NHLBI and was conducted in the early 2000s and basically focused on chronic stable patients with heart failure with reduced ejection fraction who have not had a hospitalization in the past six weeks and have ejection fraction less than 35% and class II to IV. And these participants were randomized in one-to-one fashion to getting aerobic exercise training followed by some home-based exercise versus the usual care.

Dr. Ambarish Pandey:

And in our study, what we looked at was we looked at the effect modification by baseline frailty status on the treatment effect of exercise training. So, we calculated the frailty index, which is a well-established measure of frailty using a Rockwood Index Model, and we stratified patients by frail versus non-frail status based on a Frailty Index cut-off of 0.21, such that higher index identifies more frail participants. And then, we looked at how the treatment benefit of exercise training on different outcomes was differential across the frail and non-frail strata. We looked at qualitative interaction, and we also looked at the Frailty Index, so the continuous variable to assess the benefits of exercise across the spectrum of frailty in the study population.

Dr. Greg Hundley:

And so, before we get to your study results, how many patients were in your study? Give us an idea of what was the range in age, and then also the composition of sex? How many men? How many women?

Dr. Ambarish Pandey:

Right, so this is really important because that's addressed to the generalizability of the study. So, the study included around a little over 2,100 participants. The mean age was 59 years. 28% were women, and 32% were self-reported black individuals with chronic stable heart failure. That was the demographic distribution. The age was slightly younger than what you've commonly see in observational studies with heart failure, and that is largely because the study recruited patients who were able to do exercise training and were able to do exercise tests with peak VO2 and peak VO2 peak excess capacity assessment at baseline and follow-up. So, that kind of selected for a slightly younger population.

Dr. Greg Hundley:

Very nice. And so, what were your study results?

Dr. Ambarish Pandey:

So our study results are, indeed, pretty interesting. We identified that around 60% of patients with chronic stable heart failure with reduced ejection fraction who were in the trial were actually frail based on the Rockwood Frailty Index Model. And we observed that among the study participants, the exercise training was associated with significant improvement in the primary composite endpoint of all-cause hospitalization or death in frail participants, but not in the non-frail or less fail participants. And there was a significant treatment interaction, such that baseline frailty modified the treatment effect of exercise training for the primary composite endpoint.

Dr. Ambarish Pandey:

Now, this was largely driven by a significant reduction in all-cause hospitalization among frail individuals who underwent exercise training, and not so much by an effect on mortality. And we did not see a significant difference in the mortality component of the primary composite endpoint across frail versus non-frail status participants. So, in a nutshell, baseline frailty did modify the treatment effect, largely driven by substantial reduction in the risk of all-cause hospitalization among frail participants more than non-frail participants.

Dr. Greg Hundley:

And before we get to Linda in her interpretation of your study, Ambarish, did you see the same effects in frail men, in frail women? And also, what about in individuals that might be a little older versus those that were perhaps younger?

Dr. Ambarish Pandey:

That's a really important question, and we were a little bit limited to do further subgroups because we are dealing with around, I think, 2,000 participants and we had frail, non-frail, and we did not do a further subgroup stratification by sex or by age. The age range was rather narrow. It's 58 years plus/minus 13 years, so we didn't really have a lot of older individuals above 75, something like what REHAB-HF Trial has shown in the news, a recent trial.

Dr. Ambarish Pandey:

We couldn't address the question of whether the effect modification was further modified by sex or age, so I think that's the two-level interaction. But I think that is something that would be interesting to test perhaps in a pool analysis of multiple exercise training studies, which is something we are considering.

Dr. Greg Hundley:

Thank you. Well, listeners, now we're going to turn to our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, and, Linda, very provocative results here, heart failure reduced ejection fraction. And certainly, we like to go to things like cardiac rehab, but we're hearing this it seemed to make a difference if you were frail versus not frail.

Dr. Linda Peterson:

Right, I think that's an important distinction here in this article as Ambarish has so eloquently put forth, and it's especially important because other articles have shown in looking at the PARADIGM-HF Study and ATMOSPHERE it appears that one out of two patients with HFrEF are actually frail. And so, the magnitude of these findings and the importance of these findings is highlighted by that study. And this frequency of frailty is roughly double that of community-dwelling adults who are over age 90, so we're thinking of frailty usually as much older adults, but in HF-ACTION, actually, the patients' average age was 60 in the patients with HFrEF.

Dr. Linda Peterson:

So, there's almost an accelerated aging phenotype we're seeing here in a large proportion of the patients who have HFrEF. I think this has an enormous impact on a lot of the patients that we're seeing with HFrEF, and we should be alerted to looking for frailty and potentially screening for frailty. And I think another highlight of this study is that it points out the importance of frailty because frail patients have a 50% higher risk of hospitalization and death, according to some other studies, particularly one by Faray and their group and also by Yang and their group.

Dr. Linda Peterson:

And so, it highlights the importance of getting patients who are frail with HFrEF into cardiac rehab or getting them some sort of aerobic exercise training. But paradoxically, frailty is also associated with a lower likelihood of those particular patients on getting into cardiac rehab and also getting on goal-directed medical therapy. And that was shown by Phil Ades and his group. So, I think the importance of these findings by Ambarish and his group are to be commended, and they're very important for a large proportion of our patients with HFrEF.

Dr. Greg Hundley:

Very nice. Well, let's turn back to Ambarish, and then follow up with Linda. Ambarish, what do you see as the next study that should be performed in follow-up to your study?

Dr. Ambarish Pandey:

I think that's a great question. And I think we are just beginning to realize the magnitude of impact that frailty has in the care of patients with heart failure. And this goes across the spectrum of ejection fraction, both HFpEF or heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Indeed, the burden of frailty is higher in patients with heart failure with preserved ejection fraction, and they are more of the accelerated aging phenotype.

Dr. Ambarish Pandey:

And I think the next study basically should look at a targeted approach to exercise training or category of intervention among patients who are most likely to benefit from it, which would be patients who have a high frailty burden or patients who have HFpEF. I think they go hand in hand when it comes to frailty and HFpEF. So, I think that's the next study to do is to see to what extent we can actually identify and target exercise training in the highest risk individuals who are most likely to benefit from it because that subset of highest modifiable risk is indeed identified by frailty and when you look at other subtypes by HFpEF which has a lot of high frailty burden.

Dr. Greg Hundley:

And, Linda, from your perspective, what do you see as the next study to be performed in this sphere of research?

Dr. Linda Peterson:

Yeah, I think this study really provides a springboard for future studies in HFrEF, in particular. One, what hospital interventions can be done in patients to get them moving more, and really assess is there a possibility of different types of exercises to get patients less frail even while they're in the hospital when they're enroute to going home? And then also, how do we have different mechanisms by which we can get more patients into cardiac rehab? Clearly, our national average of getting patients who qualify for cardiac rehab, which is a class I indication is 20% at best, and the aim from the AHA is 70%.

Dr. Linda Peterson:

There's a big gap there, so interventions looking at implementation and getting patients to cardiac rehab or looking at other types of aerobic exercise training, such as home-based cardiac rehab for patients who don't have a cardiac rehab center next to them, I think the field is wide open for different studies to springboard off of these findings.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, for bringing us this research study, highlighting that among patients with chronic stable heart failure and reduced ejection fraction, that baseline frailty modified the treatment effect of aerobic exercise training with a greater reduction in the risk of all-cause hospitalization.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Speaker 5:

Circulation July 5, 2022 Issue

4 juli 2022 | 26 min

This week, please join author Fabian Eichelmann and Associate Editor Svati Shah as they discuss the article "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we are going to get into the world of lipidomics and understand how some lipid metabolites may be more predictive of cardiovascular events above and beyond the conventional serum lipoproteins, like HDL and LDL. But before we get to that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

Sure thing. This first paper is about the basilar artery. Have you ever heard the analogy that the basilar artery is the neurologists' equivalent of our cardiologists' left main coronary artery? Well put, isn't it? Well, that's from the editorial that accompanies this paper, but basically, occlusion of either artery can be fatal without rapid re-perfusion. So that's why the basal artery is the neurologists' left main coronary artery. Re-perfusion therapies for acute basilar artery occlusion include thrombolysis or mechanical endovascular thrombectomy.

Dr. Carolyn Lam:

In today's issue, Professor Hu from University of Science and Technology of China, and Professor Nogueira from University of Pittsburgh School of Medicine in the US, these are the co-corresponding authors, and their colleagues, reported the outcome of the attention registry of more than 2000 patients with acute basilar artery occlusion who enrolled prospectively and consecutively at 48 sites in China from 2017 to 2021, and followed for the primary outcome of a favorable neurological functional outcome defined as a modified Rankin score of zero to three at 90 days.

Dr. Greg Hundley:

Wow, Carolyn, I love that analogy. So the basilar artery is kind of similar in the brain to the left main coronary artery in the heart. Whoa, what did they find here?

Dr. Carolyn Lam:

So, in this nationally representative observational study, the authors found a significant association between endovascular thrombectomy and better functional outcomes and survival at 90 days in patients with acute basilar artery occlusion, and this was compared to chemical thrombolysis. Now, notably, this relationship was modified by the baseline NIH stroke scale. Specifically, patients with baseline NIH stroke scale of 10 or more had an increased rate of favorable outcome when treated with endovascular thrombectomy, whereas no significant beneficial effect was seen in patients with baseline NIH stroke scores of less than 10. Now, all this is discussed in a beautiful editorial by Dr. Hankey, entitled, "Endovascular therapy for acute basilar artery occlusion."

Dr. Greg Hundley:

Oh, beautifully stated, Carolyn. What a great article. But guess what, Carolyn? I've got a quiz for you.

Dr. Carolyn Lam:

Uh-oh.

Dr. Greg Hundley:

This one's open answer, so it's not multiple choice. Can you name a unique feature of zebra fish pertinent to the study of cardiovascular disease?

Dr. Carolyn Lam:

Okay. Watch me hedge there because, first of all, I'm a daughter of a zoologist. So my dad would have a heart attack if I couldn't say something about the zebra fish. So, what I do know is the zebra fish is an excellent animal model for genetic studies of heart generation, basically development. So, there must be something really cool there about how we can observe that.

Dr. Greg Hundley:

Excellent, Carolyn. So very well done. As you know, and your dad knows, certain non-mammalian species like zebra fish, have an elevated capacity for innate heart regeneration. Now, understanding how heart regeneration occurs in these contexts can help illuminate cellular molecular events that can be targets for heart failure prevention or treatment, your area of expertise. The epicardium, the mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebra fish, and these authors, led by Dr. Jinhu Wang from Emory University performed single cell RNA sequencing and identified seven epicardial cell clusters in adult zebra fish, three of which displayed enhanced cell numbers during regeneration.

Dr. Carolyn Lam:

Oh, interesting, Greg. So did these cell clusters provide some clues that could be applied clinically?

Dr. Greg Hundley:

Yes. Carolyn. So these authors identified that these subsets of epicardial cells emerge in post embryonic, zebra fish and sponsor regions of active cardio myogenesis during cardiac growth and regeneration. And as the heart achieves its mature structure, these cells facilitate extracellular matrix hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. These cells associate with the function of the hyaluron and proteoglycan link protein 1 or HAPLN1 paralogue in production and organization of hyaluronic acid containing matrix in cardiac injury sites and thereby enable normal cardiomyocyte proliferation and muscle generation. And so Carolyn, potentially in the future targeting hyaluronic acid regulation by manipulation of HAPLN1 in human epicardial cells could potentially modulate cardiac repair after myocardial infarction.

Dr. Carolyn Lam:

Well, thanks, Greg. That was awesome. Well, the next paper I want to tell you about is one in which a novel ECG based machine learning approach was used to determine and predict multiple structural heart conditions. So the authors led by Dr. Chen from Department of Translational Data Science and Informatics at the Geisinger Health System in Danville, Pennsylvania. So these colleagues hypothesized that a composite model would yield higher prevalence and positive predictive value to facilitate meaningful recommendations for echocardiography.

Dr. Greg Hundley:

Oh wow, Carolyn. Machine learning, it's just emerging everywhere these days. So don't we need a large data set to do this?

Dr. Carolyn Lam:

Absolutely, and listen to how large this is. So using more than 2.2 million ECGs linked to electronic health records and echocardiography reports from almost 500,000 adults between 1984 and 2021, the authors trained machine learning models to predict the presence or absence of any of seven echo confirmed diseases within a year, and the composite model and the composite label that they used included moderate or severe valve disease and reduced ejection fraction. So their composite recommend model where reco is E-C-H-O we used age, sex ECG traces, and had an area under the receive operating curve of 0.91 and a positive predictive value of 42% at 90% sensitivity with a composite label prevalence of 17.9%. Whereas the individual disease models had area under curve ranging from 0.86 to 0.93 and lower positive predictive values from about 1% to 31%.

Dr. Carolyn Lam:

So in summary, they showed that an ECG based machine learning model using a composite endpoint can identify a high risk population for having undiagnosed clinically significant structural heart disease while outperforming the single disease models and improving practical utility with higher positive predictive values. So this approach may facilitate targeted screening with echo to improve under diagnosis of structural heart disease.

Dr. Greg Hundley:

Wow, Carolyn, really great article from the world of machine learning. Well, how about we jump to some of the other articles in the issue and I can go first. There are two Research Letters. The first Research Letter comes from Professor Adlam entitled "Pregnancy and Spontaneous Coronary Artery Dissection Lessons from Survivors and Nonsurvivors." And our own Dr. Joe Hill, our Editor-in-Chief also has a Research Letter entitled “Impaired AMP Kinase Signaling in HFpEF Associated Atrial Fibrillation.”

Dr. Carolyn Lam:

Wow, what an issue filled with great stuff. There's an AHA update by Dr. Churchwell on promoting nutrition security through policies and programs. And there are highlights from the circulation family of journals by our own Molly Klemarczyk, now known as Molly Robbins. I'd love to tell you a little bit about it. The association of new onset AF with cardiovascular outcomes in patients hospitalized with COVID-19 are described in Circ Arrhythmia, and EP. Rates of cardiovascular and cerebral vascular disease mortality among Asian subgroups are presented in Circ CV, Quality and Outcomes. Blood pressure and glycemic control are presented in patients with heart failure in Circ Heart failure. The associations of atrial update with technetium 99 pyrophosphate scans for transthyretin amyloid cardiomyopathy with incident atrial fibrillation and possibly earlier diagnosis of amyloid is presented in Circ Cardiovascular Imaging.

Dr. Carolyn Lam:

And finally the outcomes associated with larger burdens of residual thrombus after aspiration thrombectomy for STEMI are presented in Circ CV Interventions. Isn't that cool? And finally, we've got an On My Mind paper by Dr. Arany on “It’s Time to Offer Genetic Testing to Women with Peripartum Cardiopathy”. So that wraps it up, Greg. Let's go to our feature discussion, shall we?

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Welcome listeners to this feature discussion on July 5th, and we are very fortunate today. We have with us Dr. Fabian Eichelmann from the German Institute of Human Nutrition in Potsdam, Germany, and our own associate editor, Dr. Svati Shah from Duke University in Durham, North Carolina. Welcome to you both. Fabian, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Fabian Eichelmann :

Yeah, sure. So first of all, thanks for the invitation to speak here. So this project was basically comes from a collaboration between us and a group in Redding, UK and we are part of a consortium called FAME, which is short for fatty acid metabolism. And there, we are interested in the health effects of fatty acid metabolism in general. And in this paper that we did, this was particularly cardiometabolic diseases. And I think this is no surprise that we look at lipid metabolism in this context, because there's so many really now also causal factors, lipoproteins, total triglycerides for specific cardiometabolic outcomes. So this is the reason why we wanted to look at it. And through this collaboration, we were also able to harness the potential from two different study designs that I probably will go into later, but which really gave us an opportunity to really generate I think, quite interesting insights.

Dr. Greg Hundley:

Very nice. And so what was that hypothesis?

Dr. Fabian Eichelmann:

So the hypothesis was that since the lipid metabolism has formally only been mostly in the clinic, at least been measured by lipoproteins and total triglycerides, for example, but the lipidome of plasma, for example, is really rich. It's really heterogeneous and it contains many different lipid classes and different fatty acids. And through novel technologies and in this case, lipidomics, you can really dive in really deeply and look at this in a specific manner. And then the idea was to really look at this and potentially identify lipids that would be associated or could surface as biomarkers for cardiometabolic diseases and at the same time, if those lipids were also sensitive to a dietary intervention that really tried to modulate the dietary intake of a fat.

Dr. Greg Hundley:

Very nice. And so how did you set this up? What was your study design and what was your study population?

Dr. Fabian Eichelmann:

So we had two different study populations for this. So the first one was the EPIC-Potsdam, which is a cohort study, a large scale cohort study here in Potsdam, which started in the nineties. And there, we basically associated baseline concentrations of these lipid measurements with later on occurring incident cardio metabolic outcomes. And in this case, this was type two diabetes and primary CVD and CVD in our case meant myocardial infarction and stroke. And we did that we checked which lipids would be statistically significantly associated after multiple testing with at least one of these outcomes. And then we took those lipids further into intervention trial, which is called the DIVAS trial in Redding, as I said, UK. And there, they had basically a dietary intervention trial that really wanted to assess if the change in the fatty acid proportions in the diet affects the lipids. So there we had the lipidomics measurements at baseline and after four months, and then we compared three different trials to each other.

Dr. Greg Hundley:

Very nice. And so how many patients did you include and who were these patients? Men and women? And did they have, for example, prior cardiovascular disease?

Dr. Fabian Eichelmann:

So in EPIC-Potsdam, that's a population based cohort study. All of the participants were drawn from the registries and invited. So these were apparently healthy people. And in those we did these association analyses and those we used the design, which is a case cohort design, which is a sub sample of the whole cohort, which is a really effective way and efficient way of analyzing biomarker projects. And there we had in total 1,262 control participants, and then later on additionally, a 775 type two diabetics and 551 CVD cases. In the DIVAS trial, that was a trial where participants also men and women, which was also the case in EPIC-Potsdam were invited, and they were at a higher risk of at the higher cardiovascular disease risk, which was measured by score, but they didn't have any prior cardiovascular diseases. And those were 113 participants that were randomized to one of these diets.

Dr. Greg Hundley:

Right. So it sounds like two studies. One, a large case control study and looking at different plasma lipid concentrations in two separate groups. And then the second was a randomized trial, a smaller trial of 113 individuals looking at a dietary intervention. So with that established, tell us your study results.

Dr. Fabian Eichelmann:

Yeah. So in the first step, as I said, where we associated lip concentrations to later occurring disease, we found from the 282 lipids that we looked at, 69 were really associated to at least one of these outcomes. And interesting here we saw that only eight were associated to both outcomes and 49 were specific to cardiovascular disease and 12 for specific to type two diabetes. And from those 69, we found 19 were also sensitive to the dietary intervention, and what was really striking here was that of these 19, 17 were perfectly in agreement with a suggested beneficial effect, meaning that those lipids that were associated in the EPIC-Potsdam studies on the cohort study with a higher disease risk were reduced by these diets or in the opposite direction, we saw those lipids that were associated with lower risk were increased by these diets. So this was quite a striking observation there.

Dr. Greg Hundley:

So it sounds like from the lipidomics analysis, there was a construct of certain blood lipid markers that were associated with cardiovascular events, and then in your randomized trial, you were able to modify those by different dietary interventions?

Dr. Fabian Eichelmann:

Exactly.

Dr. Greg Hundley:

So listeners, now we're going to turn to our own associate editor, Dr. Svati Shah. And Svati, you see many papers come across your desk. What attracted you to this particular paper and how do we put this study's results in the context with other studies that have been published in really the sphere of lipidomics research?

Dr. Svati Shah:

Yeah. Thank you, Greg. I just want to point out that this is a really elegant translational study. I think these papers can be very complicated to understand, and I think the authors did a fantastic job of really laying out how you can combine cutting edge what we call omics, using these cutting edge technologies, but applying them to human cohorts with a very strong clinical lens. So it's not just what do we learn about biology, but also what do we learn about biomarkers that might be relevant to how we take care of patients? And that's really one of the biggest things I loved about this study is sort of, you get to have your cake and eat it too. You get to learn about biology, but with a very strong clinical lens towards identifying clinically relevant biomarkers. I think another really important strength of this study, which differentiates it is this sort of use of really cutting edge lipidomics.

Dr. Svati Shah:

So this is a subset of omics where we're really looking at these granular lipid classes. And some of the clinicians might say, well, we measure cholesterol, why is this different? And you know, Greg, really what lipidomics allows us is a much more granular snapshot of these complex lipid species that are only grossly captured by the cholesterol levels that we would measure normally if we were seeing a patient in clinic. So to be able to get this really granular snapshot of what is happening to lipid biology and how it might relate to cardiovascular events, diabetes, I think is really important. And finally, I think the coolest part about this study is, in other studies we always have a little bit of a hard time with what we call confounders. And what does that mean? That means there may be other things for why you're seeing these biomarkers associated with your disease and those might be uncaptured things, things that you didn't measure in this study. And we call that residual confounding.

Dr. Svati Shah:

And I think the authors in this study, not only statistically adjusted for those potential confounders, but also importantly, the DIVAS study, where they took the biomarkers that they found from EPIC-Potsdam and said, do they change with the dietary intervention? And in fact, they did find that many of these lipid, these granular lipid species improved, meaning they went in the proper direction in terms of your health with a diet that was higher in unsaturated fats. So really proving not only the potential biology of the benefit of diets enriched in unsaturated fats, but also that these particular biomarkers are modifiable, so they're able to be changed even in this case within 16 weeks with just a dietary intervention. So to me that really was just a beautifully laid out study that highlights really what translational omics and these biomarker studies can do as we think about the clinical care of patients.

Dr. Greg Hundley:

Very nice. And so it sounds like listeners, moving beyond the lipoproteins, LDL, maybe total cholesterol and these granular lipid species cholesterol esters, free fatty acids, fingo-lipids, glycerophospholipid, et cetera, that's what we were studying in this particular manuscript. So, well, let's turn back to Fabian. And Fabian, what do you see is the next study to really be performed in this sphere of research?

Dr. Fabian Eichelmann:

I think what would be really interesting and what would really kind of prove what we saw is if you could find a way that an intervention, be it like a drug intervention and not diet because we looked at dietary intervention, that kind of shows the same as we saw, but also that really specifically only alters these lipids and how obviously not really feasible, but if that would be going on for a long enough period, if you also saw these effects that we now saw after four months would also affect the health outcomes instead of just only these proxies.

Dr. Greg Hundley:

Very nice. And Svati, how about you? What do you see as the next study that might be informative in this sphere of research?

Dr. Svati Shah:

Yeah. Great question, Greg. I mean, to me, I really think about this gap that we have in actually translating these findings in how we take care of patients. So again, really provocative results here. We have really significant P values, strong effect sizes, biomarkers that are modifiable, but in the paper they show that it adds on top of a clinical model, so what we might use as clinicians in the clinic that these biomarkers may help on top of what we already know about patients. But we really need to implement these findings and study that implementation for how this might in a real world setting actually change outcomes in patients and how we can actually help explain to clinicians how these results might be beneficial for clinical care.

Dr. Svati Shah:

So on top of what Fabian already said, I think really implementation science is a huge gap in how we take these translational omics discoveries and use them in support of improving patient care. We have lots to learn about these lipid biomarkers and lots more discovery science that can be done. As Fabian said, can we find drugs that might beneficially modified these lipid subspecies? But again, I think this gap in implementation science is really important.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Fabian Eichelmann from the German Institute of Human Nutrition in Potsdam, Germany, and our own associate editor, Dr. Svati Shah from Duke University in Durham, North Carolina for bringing us these really provocative results, highlighting the identification of several lipids and their association with cardiometabolic disease risk. And then also nested within the same paper, a subset of individuals undergoing a randomized clinical trial demonstrating benefit by a dietary fat intervention, and there possibly supporting the substitution of dietary saturated fatty acids with unsaturated fatty acids perhaps as a potential tool for primary disease prevention.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation on the Run: Come Meet the CardioNerds™

28 juni 2022 | 24 min

This week's special podcast features the CardioNerds. Join Maryjane Farr, Vanessa Blumer, and M. Trejeeve (Tre) Martyn as they interview Amit Goyal and Daniel Ambinder, who started the Cardio Nerds podcast, website, and learning resources.

Dr. Maryjane Farr:

Welcome, everybody, to Circulation on the Run. My name is Maryjane Farr from UT Southwestern, and here we have an opportunity to take a week from Circulation on the Run and let our social media editors take over and do an interview of their choice. To welcome both two of our social media editors, first, Vanessa Blumer, who is going to be doing her postgraduate year seven in Cleveland Clinic, in advanced heart failure, and Trey Martin, who is a newly-minted faculty member in heart failure and amyloidosis and population health at the Cleveland Clinic. And they've chosen to interview Dan Ambinder and Amit Goyal of CardioNerds.

Dr. M. Trejeeve (Tre) Martyn:

So, thanks to Vanessa and to Dr. Farr for setting this up, and thanks for Amit and Dan for being here. Really excited to talk to you guys. The first thing I want to start off with is to get a little bit of an origin story about CardioNerds. And if you could tell us how you got started and how this all came to be, I think the listeners would be interested to hear that.

Dr. Daniel Ambinder:

Thank you so much, Trey, and it is really great to be here and nice to meet you. This is Dan. So, the origins of CardioNerds actually began early 2019. One of our mentors put us together, Dr. Reza Manesh, who's one of the co-founders of Clinical Problem Solvers, and thought that we should be thinking about potentially starting a podcast. And that definitely lit the spark and is it going to be something that's worthwhile pursuing?

Dr. Daniel Ambinder:

And so, we said to ourselves, at rounds we could teach five people at Noon conference, maybe we could reach out to 20 and to 40 people, but maybe with a podcast, we could reach 500 people at a time and that would be something that would be really worthwhile. So let's just sit down, create a script and start from there. And we created the first episode, aortic stenosis, and we did the recording and we just loved that process. And after that, we said, "This is worth it." So we made a couple more episodes-

Dr. Amit Goyal:

Hey, I'm just going to chime in here real quick. This is Amit. And I'll start off by saying, thank you so much for this invitation and what a joy it is to be doing this with two people who we respect so much, Vanessa and Trey. The process of creating this podcast and education, we learned so much. And it was so much fun that we decided why don't we just give it a shot and trial it by creating maybe three, maybe four episodes and seeing how it goes from there. So that was a backstory.

Dr. M. Trejeeve (Tre) Martyn:

I was curious how you guys thought about initially getting traction. Because that, I think, is the really challenging part and how you thought about getting listenership for your podcast and expanding. And was it focusing on the product, obviously? But I was curious how you, because now you have, you guys have this gravitational pull of prominent faculty and trainees that want to work with you, but how did you get there, and what was the strategy in doing that?

Dr. Amit Goyal:

I'll say that, initially, like Dan said, that we went out with the idea of just giving it a shot, seeing if it fit with our schedules, seeing if we enjoy the process and if there was enough of a need and a desire for this. And so, we said, why don't we create a short number of episodes? And if we could get 500 listeners, that would be the biggest audience that we have individually reached. And before you knew it, the 500 per episode turned into 5,000 per episode.

Dr. Amit Goyal:

And we realized that, even without actively and very deliberately trying to promote this, there was already a need and a desire for this. There was a niche that we were filling that we hadn't realized. The value of asynchronous medical education for people within or people who are interested in the care of patients with cardiovascular illness. So I think that's one. I think that's one takeaway, that there is value for open access, asynchronous education that is high quality.

Dr. Amit Goyal:

I think from there, our next big major pivot was well into COVID-19 when ACGME and the bodies decided that we should have virtual recruitment. This is when, enter Dr. Nosheen Reza, who was the chair of ACC FIT section at the time. And she messaged us on Twitter early afternoon, one day, saying, hey, is there maybe a way we could potentially use social media and the growth that cardio nurses has already had up until that point to maybe help connect residents with programs, ACGME accredited cardiology program, to have their fellows present a case, use one of their experts to provide an editorial expert commentary and then had the program director have a message for the applicants.

Dr. Amit Goyal:

And in discussing the case, the fellows would also talk about the program. And what that did was, I think, internally for us, it helps us realize that this just made it so much, the quality of the content and the breadth of the content, the depth of content just skyrocketed, right? I mean, we had fellows bring us cases of preeclampsia and bicuspid aortic valve, aortic stenosis with pregnancy. I mean, it was just, it was incredible that CardioNerds wasn't just about what we wanted, it was very rapidly turning into a communal entity that other people could take pride of. And so, that became really important to us.

Dr. Daniel Ambinder:

Yes. And I'll just add, again, as Amit's explained is, it happened sequentially. But it was actually a pivotal moment, right before the CardioNerds case report series was launched, where things were feeling stale. We definitely love to teach, there's no doubt about it, and that is a huge part of this. But there was a certain point where we were teaching and we just felt like there needs to be something more.

Dr. Vanessa Blumer:

Thank you so much, Dan and Amit. I mean, I think everything that you do, this is Vanessa. I think everything that you guys do, it's so inspiring for, I think, all generations, right? I think it's inspiring for future generations, but I think you guys inspire people at all levels. When you think about CardioNerds, what is your purpose? What drives you? What is your motivation? What do you think is your ultimate, why?

Dr. Daniel Ambinder:

While we had this passion to educate, that is not necessarily the why. And all of a sudden, as soon as we took off, there was multiple opportunities and multiple things dragging us in different directions. And we immediately sought out our mentor, Dr. Sanjay Desai, who is our program director at the Osler Medical Residency, and he said, "You got to find out your why right away." So, now our why includes to create and disseminate education, promote diversity, equity, inclusion, foster wellness, and humanity in the field of cardiology and in life, and provide mentorship and sponsorship and invigorating a love of cardiovascular medicine and science. Choices were easy. We can just say, "Does this fit the rubric of our mission? Is this an opportunity that we want to pursue? Is this something that's going to enhance this mission?"

Dr. Amit Goyal:

Putting words to a mission was extremely helpful for us. And actually, part of that conversation we're having at that time was around diversity and inclusion, because that's when Sanjay was saying you have to define what your organization stands for and what is a mission, and who are the people that are going to represent these cardiology fellowship training programs, in the eyes of residents who are thinking about a field in cardiology, and how deliberate we want to be about asking program directors to be cognizant about representing diversity in the fellows that they have representing the programs. And so, around these discussions, that's when Sanjay said, okay, there are a lot of things that you can do with CardioNerds, but before you do that, figure out what is your goal and how every action fits into that goal.

Dr. M. Trejeeve (Tre) Martyn:

Thanks, Amit. So, keeping that mission that you described in mind, what do you think is the ultimate goal of CardioNerds? Or, I guess I should say, where do you see CardioNerds being in five to 10 years? I know that's far out and some of the days you're just trying to get through the day you have in front of you. But if you could envision a future and, in the structure or the mission, keeping that in mind, where do you see CardioNerds in five years, let's say?

Dr. Amit Goyal:

Yeah, thanks, Trey. That is such an important question and a very difficult question to answer. I will say that things have evolved so quickly. And so, I think our one challenge that we talk about that we don't know how to resolve just yet is how to build CardioNerds in a way that's scalable, that outlives us. How do we make CardioNerds go beyond us? And that's Dan and I, but also everyone else within CardioNerds, a generation later. How do you maintain CardioNerds?

Dr. Amit Goyal:

And I think the logistic part of that is probably not that hard to figure out, right? You need admin support, you need resources, you need to delegate, you need leadership structure, but how do you grow it and have it outlive you in a way that still continues within the ethos of how you started it, within that mission, within the goals that you set it out to? And I think that's really something that we have to figure out, but that's going to be probably a deliberate way of how we grow it and how people grow into a leadership structure within it, how we design the programs. So I think that that part of the growth depends on the actions and the decisions we make today.

Dr. Daniel Ambinder:

Yeah. I definitely agree with all of that. And just to be brief, I just reiterate, CardioNerds is really for the people and what people want changes. And so, we're always listening and we're getting tons of feedback. And as the network grows, people are coming to us with projects and ideas, and we always try to find people that are just really passionate about what they want to do and give them a space to do it and try to give them as many resources and mentorship and sponsorship as we can, and then get out of the way. And so, that has already been a great recipe for a lot of different outpouchings and outgrowths of CardioNerds that really, again, goes back to the entire mission. And so, it's almost really hard to predict what will happen in five to 10 years, but we are ready and listening and looking to see what we can help the community with and vice versa.

Dr. Vanessa Blumer:

Thank you so much, Dan. And I mean, these answers have been fascinating, honestly. This interview, in general, has just been so enlightening. Dan, I think you touched on the point of democratizing cardiovascular education, which I think is, or should be, one of the highlights of this interview. Can you maybe touch a little bit more on this? And we talked about the why, can you talk about the how and see how you see this moving forward?

Dr. Daniel Ambinder:

Yeah. Thanks so much, Vanessa. We agree, democratization of cardiovascular education, what does that even mean? But what we mean by that is that why should somebody, somewhere off in a distant country, not have the ability to take care of their patients in the most topnotch way, because they may not have had the exposure to a particular part of cardiovascular education? Breaking down some of the formal barriers between levels of trainees, so, for example, CardioNerds' journal club really encompasses that.

Dr. Daniel Ambinder:

Once a month, our CardioNerds Academy, which you haven't talked about, puts on an amazing show. It's really a way where journal club hits Twitter in a traditional format, same process of discussing the article, but in the Twitter format. So it allows for this amazing group of, usually hundreds of people, honestly, to come together and discuss. And what's so amazing is that the scientific community has really gotten on board. So we often have authors of the papers that we're discussing join the actual Twitter club.

Dr. Daniel Ambinder:

And then we have medical students that are asking questions of the authors and this amazing engagement between multi-levels of education coming together. There are certainly ways that some, I wouldn't say the barriers, there are certain ways that these things can be helpful, like traditional learning and formats like that, but sometimes not. And so, we aim to be constructively destructive in terms of that way. And that's what we've done with democratization of cardiovascular education.

Dr. Amit Goyal:

If I might just add, then when we think about democratizing cardiovascular education, it's both for the learner, in terms of making high-quality education available and accessible, but also for the educators, right? I had a conversation with a mentee when he was a resident, and he called me and said, "Amit, I want to be an interventional cardiologist, but I also want to be a medical educator. How does that work?". And the fact that he was asking that is, for me, a problem, right?

Dr. Amit Goyal:

I've had this conversation with Dr. Katie Berlacher, who was also a medical educator, but is a cardiologist. Why does there seem to be strain between becoming a medical educator and becoming a cardiologist, right? That's not there for hospitalist medicine and other fields. So that's part of the reason we really enjoy having all sorts of trainees and faculty come on and teach on the show and be deliberate about how they want to teach on the show.

Dr. M. Trejeeve (Tre) Martyn:

Thanks a lot, Amit and Dan. In some ways, it sounds like you guys have been able to democratize another area other than education, which is clinical trials. And I wanted to get your perspective and hear a little bit more about the CardioNerds Clinical Trials Network. It really seems like an amazing program you guys have set up.

Dr. Amit Goyal:

It all goes back to the mission, but the origins of that is, Dr. Starling, he was a pretty early adopter for CardioNerds. He was a part of our very early heart failure series back in early 2020. And he was such a great supporter and source of encouragement and mentorship for so long. And Trey, I know you understand this, and Vanessa, you too, but he, for one reason or another, he brought up CardioNerds at a meeting about PARAGLIDE-HF. And I think present were Dr. Eugene Braunwald, who's part of the steering committee and Dr. Robert Mentz, who is the lead principal investigator, began recruiting around the time of COVID-19, affecting recruitment for a lot of trials. Lot of challenge there that I think we can all understand at this point.

Dr. Amit Goyal:

And we said, "Okay, well, not sure. We haven't thought about clinical trials, but why don't we think about it and get back to you?" So then, we said, okay, well, what's the core strength of CardioNerds? It's the people, right? After we did the CNCI recruitment series, hosting fellowship training programs, we realized that that worked out really well, because brilliant fellows from all these different programs came and elevated the education. So we established the Healy Honor Roll, after Dr. Bernadine Healy, of training programs who are part of the honor roll by nominating a FIT ambassador, a fellow and training ambassador, who's interested in education.

Dr. Amit Goyal:

We said, okay, well, why don't we just extrapolate that to a clinical trial? Instead of fellowship training programs, it would be trial sites that have training programs affiliated with them. Instead of a program director nominating a FIT ambassador for education, it would be the site PI nominating a FIT trialist for recruitment. But how would that fit as part of the mission? Well, with the Healy Honor Roll, with the academy, with everything else, hosting people on the podcast, it's always been, how do we pair content creation with personal and professional development?

Dr. Amit Goyal:

So, with a clinical trials network, the question was, how do we pair equitable trial enrollment with FIT personal and professional development? How do we meaningfully engage the fellows in the conduct of clinical trials, but also meaningfully help develop their interest in clinical trials and academic careers? How do we equip them with important skills and knowledge in the space? So we created a curriculum that's related to career development and equitable enrollment. And then, also, how do we make sure that they have, and deliberately, they have networking and mentorship as part of this?

Dr. Amit Goyal:

Since then, after we got all the fellows involved, the impact has been absolutely amazing. Because there are two goals here, right? There's equitable recruitment and there's fellow development. And just by having these meetings, by having the curriculum, the fellows are already engaged. So at the very minimum, half the mission is working out really well. But what about the other half, and that's equitable recruitment. So I will say from the time of the first FIT-recruited patient up until June 2nd, okay? So, that's February 8 to June 2nd, we account for 16% of all trial sites, but 49% of patients enrolled.

Dr. Amit Goyal:

Of the patients that we have enrolled, 54% are women compared to 47% for the non-CardioNerds sites. And 80% are BIPOC, or Black, Indigenous and people of color populations, compared to 19% for patients not enrolled by CardioNerds fellows. So, the impact there is, I think it's flooring, honestly. It is earth shattering and we are all amazed by it. And part of the question has been, can this be consistent, right? Is this a fluke? But since, when we had 30 patients enrolled, then we had 35 patients enrolled, we had 40 patients enrolled, these numbers had stayed relatively consistent.

Dr. Amit Goyal:

The question now is why? How is it that we've been so effective in disproportionately recruiting patients who had been historically underrepresented? And that's a very important question that we are really excited to dive deep into the data and try to understand. So our plans with Rob Mentz and the rest of the people who really made this possible is to really look at the numbers in terms of recruitment.

Dr. M. Trejeeve (Tre) Martyn:

That's really amazing, guys. And I have to applaud you on the vision to do that, and then to think about how to meet your mission, and then also to meet an unmet need that is... Because clinical trial enrollment, when you go through it, it's always slower than you hope. And this is such a great way to light that, to one, ignite a new generation into how to do clinical trials on the ground floor, but then also to increase the diversity of enrollment is amazing and you guys should be applauded for that.

Dr. Vanessa Blumer:

I also want to congratulate the both of you. Thank you. You guys are trailblazers and definitely are changing the world for all of us and making it a better place. So, we're so proud of you. We have to wrap up, so maybe just one last question before we go. So, maybe a two-part question, or you can choose to answer one or the other. But what do you guys feel most proud of? And what do you guys think has been the most important lesson that you have learned in the CardioNerds journey so far?

Dr. Daniel Ambinder:

Thanks, Vanessa. It definitely always helps to emphasize this. We really started this right before COVID. We had no idea COVID-19 would hit. And, really, the whole world was lurched into this virtual space. And there was always the hashtag, in real life? Is this even real life? And there was a sense that maybe it wasn't. And when we went to ACC and we met our people in person, and relationships were, not like they were just starting, but they had been ongoing for years. We really, really felt that this is something so real, and that is the lesson of CardioNerds. The lesson of CardioNerds is that the cardiovascular community is a real cohesive, beautiful community, and there's a lot of CardioNerds out there that embrace their nerdom when it comes to cardiology.

Dr. Amit Goyal:

I think in terms of what I'm taking away from this journey and what I'm going to keep relying on, the lessons I'm going to keep relying on, are one, is just find something you love and lean in. Right? I mean, when we first started telling people, "Oh, we're going to make a podcast and, hey, by the way, we're going to call the CardioNerds," the reactions we were getting from people, people we deeply respect and look to for advice and for role models, there were a lot of people who said, "Oh, that's great. It's so nice to have a hobby, but what are you going to do during your research block?" Right. That's great.

Dr. Amit Goyal:

But I think the reason why we've been able to stick with it is because we found something that we genuinely love to do. And so, I think that's really, whatever it is for you, that's really important. I think the second thing that's been extremely important for us is to surround yourself by people who inspire you, who push you, who will advise you, who make you want to be better. And that's people who are senior to you, people who are your peers, people who are junior to you, right? Because you can get as much inspiration from somebody who's 10 years your junior as you can from somebody who's 10 years your senior.

Dr. Amit Goyal:

I know I've taken a lot of inspiration from Vanessa and Trey and have relied on both of you for advice. I remember Vanessa, I think I had a very, a specific conversation about the clinical trials program when it was just a burgeoning idea way back when. And if number two is to take inspiration, take advice, take mentorship, number three is give. To flip that around and try to just give yourself and make yourself available to as many people around you, because that's how you build a community and that's how you give back and thank the people who give to you.

Dr. Maryjane Farr:

Okay, great. So, thank you. Thanks all of you. Four contemporaries who are leading the way into the future of cardiovascular medicine, science, and education. So, on behalf of Circulation on the Run, we have been so delighted and honored for you to spend some time with us, have a podcast about the podcasters. But you're not just podcasters, this is a real and amazing and innovative platform, and we are so excited to see where you go next. Any final, last words from Trey and Vanessa or Amit and Dan?

Dr. Vanessa Blumer:

Thank you so much to Circulation on the Run and Dr. Farr for this opportunity. Amit, Dan, like always, it's such a pleasure. I learn so much from you every single time that I get the opportunity to interact with the both of you and you are an inspiration to all of us. So thank you so much for this platform.

Dr. M. Trejeeve (Tre) Martyn:

Thanks to Dr. Farr for Circulation on the Run, for this platform, Amit and Dan for taking the time out of their evening to be here, Vanessa, for joining me in Cleveland. And I would say that you guys, the CardioNerds founders, you're an inspiration that you don't necessarily have to wait to make an impact.

Dr. Amit Goyal:

Yes. Thank you so much. I don't even know what to say. I'm speechless. I'll say that, for Dan and I, we're still just a couple of nerds. I do my recordings in my attic, Dan's in his home office. I think if you, we're still besides ourselves with disbelief that we are a topic of conversation for a platform like Circulation on the Run. It is absolutely a privilege and an honor for us. And so, I think all I can do is just say thank you so much, and then to Dr. Farr for the invitation to have this conversation for Circulation, and Dr. Hill for giving us this platform. I think this is just such a... Again, we are speechless. Thank you. Thank you so much.

Dr. Daniel Ambinder:

I'm equally as speechless and this podcast, Circ on the Run, really reminds me of my earlier roots, reaching out of my own institution, because it was a Circ social media team that first gave me a great glimpse at what happens outside of the institution that I had been training at for many, many years. And to see how the sausage is made, in terms of how research is vetted and undergoes a strict peer review, was really amazing. And I had the opportunity of meeting Dr. Hill and also being part of the team as COVID was revving up and Circulation had to... We're getting bombarded with all these COVID-related articles. And there was just a very important understanding that what gets published is going to be really, really important.

Dr. Daniel Ambinder:

So, watching that from the sidelines, under the mentorship of Dr. Amit Kara, just seeing how that happened, gave me such an important understanding that what you put out into the world, whether you're Circulation or writing a personal tweet or putting something out on CardioNerds is just really important and treat it as if it's something that's going to be there forever. And I learned so much about collaboration and I also learned so much about podcasting, because of Circ on the Run, it was actually the first podcast I was on and I don't like to listen to that very often. So thank you so much. This is such an honor to bring this full circle and come back and join you all.

Dr. Greg Hundley:

Circulation June 21/28, 2022 Issue

20 juni 2022 | 24 min

This week, please join author Roderick Tung, editorialist William Stevenson, and Associate Editor Sami Viskin as they discuss the article "First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial" and the editorial "Can Early Ablation of Ventricular Tachycardia Improve Survival?"

Dr. Greg Hundley:

Welcome listeners to this June 21st, 2022 issue of Circulation on the Run. And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Listeners, what a very interesting forum that we're going to have in this session today with Dr. Rod Tung, bringing us an article from first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy with concurrent defibrillator implantation. Some results from the Pause sudden cardiac death randomized clinical trial.

This article is really interesting because it is collecting data from multiple centers from multiple countries in Asia. But before we get to that article, why don't we grab a cup of coffee and go through some of the other articles in the issue? Well, the first is entitled cardiovascular magnetic resonance for rejection surveillance after cardiac transplantation. And it comes to us from Dr. Jim Pouliopoulos from the Victor Chang Cardiac Research Institute. In this study, CMR based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between cardiovascular magnetic resonance and endomyocardially based measures of cardiac rejection and determine the CMR cutoff values between various cardiac rejection grades.

Then after that, a prospective randomized noninferiority pilot study was undertaken in adult orthotopic heart transplant recipients who were randomized at four weeks post orthotopic heart transplant to either CMR or endomyocardially based rejection surveillance. And clinical endpoints were also assessed at 52 weeks. And so listeners, what did this investigative team find? Well, despite similarities in immunosuppression requirements, kidney function and mortality between the groups, the rates of hospitalization and the rates of infection were lower in the CMR group.

On 15 occasions, patients that were randomized to the CMR arm underwent endomyocardial biopsy for clarification or logistic reasons, representing a 94% reduction in the requirement for endomyocardially based surveillance. And so listeners, a noninvasive CMR based surveillance strategy for evidence of rejection in the first year after orthotopic heart transplantation is feasible. And interesting, listeners, these results really suggest the possibility for further studies to confirm whether CMR and perhaps in combination with other modalities could be used to survey orthotopic heart transplant patients for acute rejection without necessarily having to undergo endomycardial biopsy. There's an excellent editorial by Dr. Jim Fang from the University of Utah who also reviewed this paper.

Well, listeners, let's next turn to the world of preclinical science. And this paper comes to us from professor Simon Sedej from Medical University of Graz. It involves the insulin and insulin growth factor one or IGF-1 pathway. And that is known as a key regulator of cellular metabolism and aging. Now, although its inhibition promotes longevity across species, the effect of attenuated IGF-1 signaling on cardiac imaging really remains controversial. So what did the authors find? Well, they found that cardiomyocyte IGF-1R over expression in mice resulted in physiological hypertrophy and superior cardiac function in early life, but led to accelerated cardiac aging, heart failure and reduced lifespan in late life. Mechanistically, increased cardiomyocyte IGF-1R signaling accentuated cardiac dysfunction by reducing autophagy and mitochondrial oxidative capacity at old age, and therefore clinically pharmacologic inhibition of cardiac IGF-1R signaling in late life could suppress the age related deterioration of cardiac performance and perhaps increase lifespan. And therefore age should be considered as a major outcome determinant in future clinical trials, testing IGF-1R P13K inhibitors for cardiac benefits.

Well listeners, what is our next study? And this study is somewhat related to our feature discussion, which we'll get to in a few minutes. It's from Dr. Paolo Della Bella from San Rafael Hospital, and it is a two phase prospective multicenter randomized clinical trial that was performed to evaluate the benefit of ablation after first implantable cardiovert defibrillator, or ICD shock. And patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock. And that was phase A of the study. Then afterwards, they were re-consented and patients were randomly assigned in a one-to-one fashion in the second phase or phase B to immediate ablation. That's within two months from shock delivery or continuation of standard therapy.

And the primary endpoint of the study was a composite of death from any cause or hospitalization for worsening heart failure. And amiodarone intake was not allowed except for documented atrial tac-arrhythmias. So listeners, what were the results from this trial? Well, ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined endpoint of death or worsening heart failure for hospitalization, lower mortality and fewer ICD shocks. And these findings therefore provide support for considering ventricular tachycardia ablation after the first ICD shock.

Now this study and the feature which will be coming up in a few minutes is nicely reviewed in an editorial from Bill Stevenson at Vanderbilt University. Well listeners, what other articles are in this issue? Well, from the mail bag, we have a research letter from Professor Solomon entitled Health Status Trajectories Before and after hospitalization for Heart Failure. Also, there is a second research letter from Professor Eikelboom entitled Rivaroxaban 2.5 Milligrams Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients with Chronic Atherosclerosis. And then next there's an ECG challenge from Professor Rosenfeld entitled Around and Around, a Wide Complex Tachycardia.

Well listeners, what a great series of articles. And now we're going to get on and visit with Rod Tung, Sami Biskin and Bill Stevenson to evaluate first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy, concurrent with defibrillator implantation.

Well, listeners, welcome to this June 21st feature discussion. And we're very fortunate today to have with us Dr. Roderick Tung from the University of Arizona in Phoenix. We also have our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee. Welcome gentlemen. Well, Roderick, we're going to start with you. Rod, can you describe for us some of the background information that went into the construct of your study and what was the hypothesis that you wanted to address?

Dr. Roderick Tung:

Well, thank you, Greg, Pause is really the culmination of a lot of personal academic and cultural exchanges between many Asian centers and particularly in China. In terms of exchanges, where we would go across overseas, do a lot of different VT cases. And this all started in about 2013. And at that point in time, I was struck by a lot of differences that we were seeing, particularly whenever they wanted us to do a case, it tended to be a nonischemic etiology patient, and they always wanted to see some sort of epicardial procedure. And these are the ones that are enriched for epicardial substrates. As many listeners know, the ischemics tend to have more endocardially based scars. And that's why epicardial BT ablation is typically reserved for those that either have failed endocardial or those ARVC patients or non-ischemic cardiomyopathy.

So that was the first thing, is there's a paucity of ischemic cardiomyopathy in Asia, which is still inexplicable. The second thing that was really interesting in my observations going to Asia was that the defibrillator penetration and adoption is not widespread like it is in America. And in a very Amero-centric view, we always think that, oh, well, everything else is a departure from a standard of care. Well, when you look at 1.4 billion people, that's a really significant population at risk for sudden death that's not being treated the same way that we typically see it in a lot of Western cultures. So I felt like it was a perfect fertile grounds for clinical exploration. And that's really where Pause was born, is to be able to look at the impact of catheter ablation and ICD therapies on the risk of sudden death. And that's really how the trial began.

Dr. Greg Hundley:

And what was the hypothesis, Rod, that you wanted to address?

Dr. Roderick Tung:

Well, when we started designing Pause in 2014, 2015, there had only been two prior trials that were published and that was Smashed VT in New England Journal. And then there was VTAC by Karlheinz Cook in Lancet. So really the hypothesis was to be able to assess whether preemptive or first line catheter ablation at the time of defibrillator implantation, which is not what we do in the US, we usually wait till there's therapies, if that decreases the composite endpoint of recurrent VT cardiovascular hospitalization mortality.

Dr. Greg Hundley:

Very nice. And so describe for us, Rod, your study population, and then the design that you use to address the hypothesis.

Dr. Roderick Tung:

So this was a randomized controlled trial, multicenter across 11 centers in China, Korea, Japan, Taiwan. These were really well respected and regarded academic centers. I do want to give a shout out to many of them, Kyoko Sojima, who trained with Bill Stevenson, wrote so many seminal papers in VT. In Japan, Akid Nogogami who really was charged with and responsible for opacity some of the mechanisms of particular VT, then there's Yao Yin in Beijing who's done great work in atrial fibrillation, cardiac neuroablation. Ming Long Chen, Chan Yang Jeng. So some really great names, and it was done over 11 centers, one to one randomization between control, which was just ICD, and the active arm was ICD with catheter ablation within 90 days of the ICD implantation.

Dr. Greg Hundley:

And how many patients, and then what were your study results?

Dr. Roderick Tung:

So we ended up with 121 patients that were randomized, 61 versus 60, 180 were eligible and screened. And what was really also different about this trial compared to others is that we involved a non-randomized registry. Those were patients that refused to be randomized, and most typically didn't want to have a defibrillator. And that's where the cultural differences of ICD acceptance are different. For two reasons. Number one, physicians actually don't truly believe a lot of the defibrillator data is relevant to non ischemics in Asia and the Asian population. So there's actually a little bit of an academic barrier of generalizing historical ICD data to Asia, which I observed with a lot of the physicians.

And number two, patients sometimes don't want that technology in there, and they have different ideas of sudden death. So these patients were actually put into a registry and followed prospectively with catheter ablation alone without background ICD therapy. And that's very unique because the amount of data that has been prospectively followed for ablation sans ICD therapy is very few. So that was 47 in the registry. And there was 121 that was one to one randomized.

Dr. Greg Hundley:

And what did you find?

Dr. Roderick Tung:

Well, we found that those that underwent concomitant ablation with their ICD implantation that presented with monomorphic VT had a lower rate of the composite triple endpoint of VT recurrence, cardiovascular hospitalization, and death. This was largely driven by a nearly 20% absolute risk reduction in VT recurrence. There was a 4% absolute risk reduction in cardiovascular hospitalization, but this is not significant. And mortality rates were low. It was seven and 8% in those arms. So one of the things that we were hoping to get to was actually looking at mortality, but I think this is challenging with background ICD therapy there. And number two, it's challenging because mortality rates are lower in non-ischemic cardiomyopathy. And that's because they don't have the concomitant comorbidities of peripheral vascular disease, coronary artery disease, older age, cetera. So we actually had a pretty low rate of mortality, which we were hoping to get to, but that wasn't able to be assessed in this because of the low rates.

Dr. Greg Hundley:

Very nice. Well, now listeners, we're going to turn to our own associate editor, Dr. Sami Biskin. And Sami, many papers come across your desk. What attracted you to this particular study?

Dr. Sami Viskin:

Well, we need to better define what is the optimal timing for VT ablation in patients with the organic heart disease. As we have seen many patients that are referred too late for ablation, where they already have an arrhythmic storm and recurrent shocks. And on the other hand, we have seen studies like the Berlin Study from Cook that fail to show any benefit on endpoints like heart failure or mortality. So the study by Tung arrived shortly after the different study by Paolo Della Bella, the PARTITA study, that was also studying patients at an earlier stage. So in the Partita study, they were studying patients at the time of the first ICD shock. And then Rod came with this study where he studied patients at the time of ICD implantation.

Now, usually authors ask to get an executive review of their article. In this occasion, we as the editors, we saw the opportunity and asked Rod to submit his paper as fast as possible and made the correction as soon as possible so we could get the two papers dealing with early VT ablation in the same issue with an invited editorial by Dr. Stevenson so we could put everything in context.

Dr. Greg Hundley:

Very nice. Well, Bill, Sami has set you up very nicely here. And as the editorialist, help us put these results from Rod into the context of what we know already today in this sphere of investigation pertaining to VT shocks, defibrillator implantation.

Dr. William Stevenson:

Yeah. So first I want to congratulate Rod on a very important study. It has been so difficult to conduct randomized trials of VT ablation and intervention, and to be able to bring this to fruition and internationally in Asia is really quite an accomplishment. We definitely need more information that guides us as to when VT ablation should be performed in people who have defibrillators and are having spontaneous episodes of VT. And we know that in patients with ischemic heart disease, with coronary artery disease, post infarct VTs, that catheter ablation can reduce the episodes of recurrent VT and reduce shocks from VT. And this is a very important quality of life issue for patients with defibrillators. But we haven't really had good data, certainly not randomized multicenter data in other patient populations. And we still are grappling with, does a reduction in VT episodes improve other outcome measures?

Does it really improve quality of life? Does it reduce hospitalizations? Does it translate to a reduction in mortality? And so Rod's study, one of the strengths of it being in Asia is that there were a lot of patients who had non-ischemic causes of heart disease. And more than a third of patients had arrhythmogenic right ventricular cardiomyopathy, and his study makes it clear that those patients really benefit substantially with a reduction in VT episodes. And that overall, VT episodes are reduced in all three of the subgroups of different diseases, the ARVC and the ischemics and the non ischemics that were included in the trial. But I think it's worth digging in a little more to the non-ischemics, because they did not seem to receive the benefit that the arrhythmogenic right ventricular cardiomyopathy and the ischemic cardiomyopathy patients received. So that the efficacy was largely driven by the benefit in the ischemics and the ARVC patients.

So one of the important considerations I think is when you're in your office with a patient who has a defibrillator and has had episodes of VT, and you're considering does this patient need a VT ablation? I think that if they've got ischemic cardiomyopathy, this data strongly supports that approach. If they've got arrhythmogenic right ventricular cardiomyopathy, again, ablation is very likely to reduce their episodes of VT/ for the non-ischemic group, which is about a third of the patient population that Rod studied, the data are less convincing in that group. And we know that's a harder group to achieve success with, with ablation. So we'll definitely want more data in that group. And I'm looking forward to some of the more detailed and sub-study sorts of analyses that I'm sure Rod is planning.

Dr. Greg Hundley:

Very nice, Bill. Well, listeners, and Bill you've teed it up nicely to really sort of circle back through each of you and ask, what is the next study to be performed in this space? So we'll start with Rod and then Sami, and then finish up with you, Bill. So Rod, what is the next study that you see needs to be performed really in follow up to yours?

Dr. Roderick Tung:

Well, we're thinking Pause too might be a nice just ARVC study alone, because again, inexplicably, there's a very high incidence of ARVC in Asia, and I was always taught that this was a disease from the Veneto region of Italy. And that might not be the case, or there's a lot of sarcoid mimicking of it as ARVC and undiagnosed. But we're thinking about a Pause too being an ARVC study, maybe without background I,CD therapy with background ICD therapy, this might provide justification for that. Because again, those in the registry did quite well, but that's because they were younger and had ARVC and normal LV function. So that might be a nice area to explore worldwide. And then lastly, just to put things in perspective for the Circ listeners, you need 8,400 patients in paradigm to show benefit mortality and heart failure hospitalization for an ARNI. Right? For IRNESTO.

We're talking about 120 patient studies when we talk about VT ablation, with these very complex ablation trials. So I think we just need larger trials. And the hard thing for us as VT ablation centers is we often will get patients that have had recurrent VT after a failed procedure. So it's hard to come by these that are very early, but I think we need 500 patient studies, a thousand patient studies. And also for the listeners, it's very hard to show mortality reduction with a background ICD therapy. And that's the problem, is that ICD is so effective as an abortive treatment that it's very hard to show reduction and mortality. You'd have to show it in terms of heart failure.

Dr. Greg Hundley:

Very nice, Rod. And Sami, what would you like to add?

Dr. Sami Viskin:

Oh, obviously the last word on the optimal timing of VT ablation is not out there. And we need more studies to really define when is the appropriate time for the VT ablation. That's what we need.

Dr. Greg Hundley:

Very good. And Bill?

Dr. William Stevenson:

Yeah, I agree with Sami. And with rod, we need larger studies to assess the benefit, to really help guide our clinical decision making that can get at quality of life issues as well as the mortality and cardiovascular hospitalization issues in even more detail. But this is a wonderful first initial step into the ischemic, non-ischemic and ARVC populations.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Rod Tung from university of Arizona, Phoenix, Dr. Sami Viskin from the Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee, for bringing us this study that highlighting among patients, particularly with ARVC in an ischemic cardiomyopathy from Asia across multiple centers in different countries that early catheter ablation performed at the time of ICD implantation really reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. And these findings were really nicely driven by a reduction in the ICD therapies. Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week, on the run.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation June 14, 2022 Issue

13 juni 2022 | 28 min

This week, please join author Christan Mueller, editorialist Christopher deFilippi, and Associate Editor Torbjørn Omland as they discuss the research article "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T" and the editorial "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T."

Dr. Greg Hundley:

Welcome, listeners, to this June 14, 2022, version of Circulation on the Run. I am Dr. Greg Hundley, associate editor and director of Poly Heart Center at VCU Health in Richmond, Virginia. This week I don't have my good friend Carolyn with me, but we will grab a cup of coffee and work through several of the articles in the issue.

Dr. Greg Hundley:

Well, first, I want to tell you about the feature discussion today, and we're going to interview with Christian Mueller and talk about the utility of cardiac troponin T and its association with an elevation in those individuals with skeletal muscle disorders, but, before we get to that, let's go through some of the other articles in this issue.

Dr. Greg Hundley:

Listeners, the first study comes to us from Professor Haidong Kan from Fudan university. These investigators conducted a time stratified, case crossover study among 1,292,000 acute coronary syndrome patients from 2,239 hospitals across 318 Chinese cities between January 1 of 2015 and September 30 of 2020 to determine the associations between sub-daily or hourly levels of criteria air pollutants with the onset of an acute coronary syndrome.

Dr. Greg Hundley:

Now, hourly concentrations of fine particulate matter, coarse particular matter, nitrogen dioxide, sulfur dioxide, carbon monoxide and ozone were collected, and the hourly onset data of acute coronary syndrome and its subtypes including ST segment elevation myocardial infarction, non-ST segment elevation myocardial infarction and unstable angina were obtained.

Dr. Greg Hundley:

Listeners, what did the investigators find? Well, their results indicated that transient exposure to the air pollutants of fine particulate matter, nitrogen dioxide, sulfur dioxide, and carbon monoxide, but not coarse particular matter or ozone may trigger the onset of acute coronary syndrome even at concentrations below the World Health Organization Air Quality Guidelines. Now, greater magnitude of associations were observed among patients that were older than 65 years in age or those without a history of smoking or chronic cardiorespiratory diseases and those in the cold seasons.

Dr. Greg Hundley:

Listeners, next, we're going to move from the study of air pollution to the world of preclinical science. Listeners, this study comes to us from Dr. Ming-Hui Zou from Georgia State University. Indoleamine 2,3-dioxygenase 1 or IDO1 is the rate limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis, and vascular smooth muscle cells with an osteogenic phenotype promote calcification and features of plaque instability, but it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes vascular smooth muscle cell osteogenic reprogramming and arterial calcification.

Dr. Greg Hundley:

Listeners, what did this study find? Well, this investigative team and their results revealed the previously unrecognized protective role of IDO1 in arterial calcification in that vascular smooth muscle cells defective of IDO1 result in enhanced runt-related transcription factor 2 and ectopic calcium deposition in plaques. In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression.

Dr. Greg Hundley:

Also, listeners, the authors found that patients with coronary artery calcification have abnormal tryptophan metabolism, and serum IDO1 activity was inversely associated with calcification development in clinical settings, so, listeners, what are the clinical implications here? Well, this work reveals a protective role for IDO1 in mitigating arterial intimal calcification through kynurenine production and then, secondly, developing interventions toward the IDO1 kynurenine RUNX2 access may prevent the pathogenesis of arteriosclerotic complications.

Dr. Greg Hundley:

Well, listeners, a really interesting article, and now let's turn our attention to some of the other articles in the issue. Well, first, there's a Research Letter from Professor Modarai entitled “A Higher Incidence of Chromosomal Aberrations in Operators Performing a Large Volume of Endovascular Procedures,” and then, also, there is an AHA Update from our exiting AHA president who addresses “What Does the American Heart Association Do (and How Can You Help)?” Well, now, listeners, let's turn now to our feature related to a discussion of the utility of troponin T as well as troponin I in those with skeletal muscle disorders that may also present with acute coronary syndromes.

Dr. Greg Hundley:

Welcome, listeners, to this June 14 issue, and we're very excited today. We have with us Dr. Christian Mueller from the University Heart Center at Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and Dr. Chris deFilippi from Inova Heart and Vascular Institute in Falls Church, Virginia.

Dr. Greg Hundley:

Welcome, gentlemen, and, Christian, we'll start with you. Could you describe for us some of the background information that went into your study, and what was the hypothesis that you wanted to address?

Dr. Christian Mueller:

Thank you very much for giving me the opportunity in this podcast to discuss our study with you and together with Torbjorn and Chris, who both contributed so enormously to the field with their own research. It's about cardiac troponin, cardiac troponin, an essential pillar in our early diagnosis of myocardial infarction. In this specific study, we tried to address possible non-cardiac causes of cardiac troponin T. In our clinical practice, we use and guidelines recommend both cardiac troponin T and I more or less as equivalent in providing identical information and, when going back from the clinical practice to biology, we have learned that, the troponin complex, that it is composed of three isoforms, T, I, and C.

Dr. Christian Mueller:

While they are very similar in their function, they are distinct regarding amino acid sequence in configuration in cardiac and skeletal muscle. As the cardiac form, of course, is the one that we are interested in, cardiac-specific assays have been developed both for cardiac troponin T and cardiac troponin I. As with any other tests in medicine, they are very good, but they may have limitations, and the specific questions that we had set for this study is whether skeletal muscle disease might be non-cardiac source for cardiac troponin T as measured in blood, therefore, with the possible harm of having false positive increases that could lead to a misdiagnosis of acute myocardial infarction.

Dr. Greg Hundley:

Very nice. We're trying to understand the utility of cardiac troponin T measures in those individuals that may have concomitant skeletal muscle disorders. Christian, what was your study population, and describe for us your study design?

Dr. Christian Mueller:

Our study had two components, a clinical component and a translational component. The clinical component included 211 consecutive patients that presented with active and chronic muscle symptoms to a workup either with a rheumatologist or a neurologist or internal medicine specialist, so more or less elective workup for muscle, skeletal muscle symptoms, to have a population that is broad and reflects all possible skeletal muscle disorders, their possible impact on cardiac troponin T concentration.

Dr. Christian Mueller:

In this population, we quantified cardiac involvement as this is common in some of these musculoskeletal disorders to be either major, minor or are not. They're according to patient history, according to … ECG and cardiac imaging, and we did the measurement of high sensitivity cardiac troponin using the high sensitivity cardiac troponin T assays used all over the world and three high sensitivity cardiac troponin I assays to look for mismatches, the percentage of patients that might have elevated T concentration, but not I as a possible sign that the T might be from the muscle, not the heart, particularly in those patients that didn't have any imaging evidence of cardiac involvement, and then we correlated the amount of high sensitivity cardiac troponin T with the amount of muscle injury as quantified by CK.

Dr. Christian Mueller:

In the translational part, those patients who have received a skeletal muscle biopsy with quantified by differential gene expression, the MRNA of the cardiac isoform of cardiac troponin T as well as of I in those patients who had the biopsy and matched it and compared it to controls to see whether the cardiac isoform would be upregulated in those with the cases of skeletal muscle disease.

Dr. Greg Hundley:

Very nice, and so, Christian, was this one single measurement at one point in time or did you have a series of measures over time?

Dr. Christian Mueller:

In fact, this is a large, ongoing project where patients will receive followup appointments. The current study reports the first phase versus single measurement at a single time point was performed.

Dr. Greg Hundley:

Very good. Christian, what did you find?

Dr. Christian Mueller:

We first found that even in those patients with active skeletal muscle disease, cardiac troponin T still reflected the presence of cardiac disease. Those patients with severe cardiac disease did have significantly higher concentration than those patients with mild or with no cardiac disease. That was the good thing. However, the more challenging one for this biomarker in this setting is that high sensitivity cardiac troponin T was significantly higher in these patients as compared to controls. We had the chance to have a couple of thousand controls from another study that presented with non-cardiac chest and no skeletal muscle disease and, while high sensitivity troponin I concentrations were similar, cardiac troponin T was elevated, resulting in a much higher prevalence of elevated T concentration versus elevated I concentration and corresponding mismatches in these patients.

Dr. Christian Mueller:

In the second part, we were able to show that there was a significant correlation between high sensitively cardiac troponin T with CK quantifying somehow muscle damage while this was not seen in the correlation with high sensitivity I, and that signaled that some of the systemic cardiac troponin T concentration seems to be derived from the muscle. It was confirmed in the translational part of the study in which the differential gene expression showed an eightfold over-expression of cardiac troponin T in skeletal muscle biopsies of those patients with disease, so with active skeletal muscle disease. This … expression correlated with disease activity, a pathological score that quantifies the extent of damage in the skeletal muscle history and correlated with the high sensitivity cardiac troponin T plasma concentration measured with the immunoassay.

Dr. Greg Hundley:

Very nice. Listeners, it sounds as if, in patients with skeletal muscle disorders, Christian's team observed an elevation in cardiac troponin T, but not necessarily cardiac troponin I, and you've got mechanistic understanding from the biopsies where you see this cardiac troponin T expression in the damaged skeletal muscles. Well, Torbjorn, you have many papers come across your desk. What attracted you to this particular paper?

Torbjorn Omland:

Thank you, Greg. I think, in general, when I receive papers from circulation, there are three main criteria I consider. The first is whether this is an interesting research question and then, second, whether the study is well-designed and the third is whether they're in themselves are novel, robust and interesting with potential clinical implications.

Torbjorn Omland:

For this specific papers, I must say it seemed to me to fulfill all these criteria and that it would be able to bring this field forward. The study of re-expression of troponin T in skeletal muscle is not entirely novel because it has been done in small samples, but mainly with rare and neuromuscular diseases previously, but this study broadened that or generalized that to a much more clinically relevant population. The clinical implications also seemed to be much greater than what has been reported by previous papers.

Dr. Greg Hundley:

Very nice. Listeners, we have in addition to Dr. Omland, we have another expert with us today, Dr. Chris deFilippi, really in the area of biomarkers particularly as they pertain to cardiac injury.

Dr. Greg Hundley:

Chris, now turning to you, how do we put the context of the results today really with the broader scope of what we have learned about cardiac troponin I and cardiac troponin T and then their use in diagnosing acute ischemic syndromes or even forecasting future cardiovascular events down the road?

Dr. Christopher deFilippi:

Thank you, Greg, and thank you Circulation for inviting me to participate in this podcast and to write this editorial. First, Christian, this was a terrific paper and one that was probably great to review during the pandemic because, as I spent a good Sunday peeling back layers of the onion and reiterating what Torbjorn said, this paper makes a tremendous contribution where there already was some knowledge to maybe the expression of the cardiac specific troponin T and skeletal muscle, but there's something there for everyone just to get the takeaway message, but for those who really want to delve in, there are supplemental tables that contribute a huge amount of nuance and detail that I think will help guide researchers in the future in maybe how to optimally use cardiac troponin T and troponin I both in the evaluation for acute myocardial infarction and then in a variety of chronic conditions, so first putting this in context of how you would evaluate patients with acute myocardial infarction, and that's the predominant indication for measuring a high sensitivity troponin T or troponin I.

Dr. Christopher deFilippi:

As Christian in an earlier study has shown and others have shown, actually, the correlation between a high sensitive troponin I by a variety of commercial assays. Troponin T is really pretty good. I think in one study from Christian's group, it was measured at 0.89. Now, the issue that's relevant is more around the edges. People who come in with just a low elevation and, as Christian pointed out and colleagues pointed out in the paper, using the ESC algorithm, a number of those patients would have qualified for myocardial infarction with the skeletal myopathies particularly the myositis or the non-inflammatory myopathy. If there is an index of suspicion for these disorders I think particularly around the cutoff for troponin T, one has to be cautious. Whether one can actually look at serial changes and try to differentiate that way I think is an open question. It may be.

Dr. Christopher deFilippi:

I think the other thing that gets quite interesting for me in an area that we've delved in over the past decade is the use of high sensitive troponin T or troponin I as a measure of chronic injury that's been codified in the fourth universal definition of MI published four years ago to identify individuals at risk. These can be individuals who are living in the community without known cardiovascular disease or actually without, perhaps, a lot of other comorbidities other than advanced age, for example, who an elevated troponin I or troponin I can be indicative of an increased risk for incident heart failure over the next five to 10 years. It can be patients with other chronic comorbidities.

Dr. Christopher deFilippi:

Actually, what drew me to this paper and thinking along these lines was a paper that Torbjorn had published back in 2013 where, using the key study which are individuals who have chronic ischemic heart disease without heart failure, he measured both troponin I and troponin T and found there was quite a discordance. There, we're looking at … value of about 0.4 and found that troponin I was a great predictor for the risk of coronary heart disease event and an acute myocardial infarction in the future, but T was not, but both T and I were good predictors of incident heart failure in the future.

Dr. Christopher deFilippi:

Other investigators, the … investigators, investigators from Scotland have also found this discordance between I and T in chronic ambulatory populations with or without comorbidities, and so it opens an interesting question in individuals with maybe conditions of pre-frailty or frailty or some element of sarcopenia, subclinical skeletal muscle disease. Does this cause this discordance? Ultimately, we know particularly with heart failure, with preserved ejection fraction, it is a systemic disorder, and measures of skeletal muscle disease may be relevant in ultimately determining who's going to have symptomatic heart failure.

Dr. Christopher deFilippi:

I think it really opens things wide open potentially to further investigation. Is this modifiable? Is it through intervention simply like physical activity? Could you see changes in cardiac troponin T that may be reflecting cardiovascular changes and skeletal muscle changes, but maybe not so much with I, and does this have relevant prognostic implications? I think I was really excited about it based on the defined pragmatic findings with respect to evaluating patients for myocardial infarction who have these underlying skeletal muscle diseases, but also implications, what this might mean in chronic disease populations as well.

Dr. Greg Hundley:

Very nice. Well, Chris, you've led us really to our next series of questions, and maybe we'll circle back with each of you, first, Christian. What do you see, Christian, as the next study to be performed in this space?

Dr. Christian Mueller:

I think the next study should address two aspects. The first one is I think we already, with the current population have found that skeletal muscle disease includes various pathologies, and as indicated by Torbjorn, the cardiac troponin T re-expression seems to be at least of our current understanding limited to the two groups of myositis and the muscular dystrophies, whereas the other skeletal muscular disorders at least in those that we have currently investigated did not seem affected. However, we were limited by the number of patients in this subgroup, and so for sure need a larger population to cover all aspects or all classifications of skeletal muscle disease in more detail.

Dr. Christian Mueller:

The second point that I'd like to highlight is the followup and to look for cardiac events and to look for cardiac changes, functional or anatomical changes in cardiac imaging, because it still may be that some of the T that is more commonly seen in this patient, that the majority of this is derived from the heart, so it's not a black and white, it's only from the muscle or only from the heart. It's still possible that some of the higher concentration of T found in these patients, as in many of the skeletal muscle systemic disorders, they have cardiac involvement which may not be identifiable by current imaging techniques at the first visit. This may become apparent during followup, and so these studies will help us to get a better quantitative understanding, so ideally to understand is it just a tiny amount, I don't know, 10, 20% of the systemic T concentration that is derived from the muscle? Then it would have a very different clinical implication as compared to if, I don't know, more than 50% of the systemic concentration would be derived from the skeletal muscle rather than the heart.

Dr. Greg Hundley:

Very nice. Torbjorn, I would like to turn to you. What do you see as the next study to be performed in this space?

Torbjorn Omland:

Oh, I agree with Christian that the serial assessment of changes of disease activity versus troponin changes would be very interesting to study in more detail and also correlate that to changes, for instance, by cardiac MRI if you can see whether there are actually correlations there. Long-term prognostic implications of skeletal muscle derived cardio troponin is another subject, and then, finally, I think that we do need to know even more accurately what is the impact of these alterations on the diagnostic workup in the acute coronary syndrome setting. Is it really a clinically important confounder? I think studies that could address that will be important.

Dr. Greg Hundley:

Very nice, and then finally Chris, and, Chris, I want to add just another question. Just from my listening to this, if I'm trying to identify someone with an acute ischemic syndrome and then they may also have an underlying skeletal muscle disorder, both Christian was talking about inflammation, but you brought in frailty and things of that nature. Should we really then turn clinically to measuring cardiac troponin I in this setting when we're trying to rule out, for example, acute myocardial infarction?

Dr. Christopher deFilippi:

Yeah. I don't want to overstate that. I mean, Christian's work and others have shown actually a high sensitive troponin T and a variety of different high sensitive troponin Is in a very heterogeneous chest pain population have been equivalent, looking at receiver operator curves area under the curbs, and so they're probably our people at the margins where this will make a difference, but it should be. Listeners should be reassured at this point because troponin T is a very common assay that it's still quite efficacious and accurate for the diagnosis of acute myocardial infarction from what we know, and a lot of Christian's work has identified this.

Dr. Christopher deFilippi:

Again, moving into the more chronic disease population outside the evaluation of acute myocardial infarction, maybe where we can use it as a differentiator, it could be helpful in some instances to look at interventions. Earlier work has shown in just small numbers of patients have been published, but patients with hypothyroidism, patients with statin-induced skeletal myopathies, the treatment of these has actually led to a decrease in high sensitive troponin I corresponding with decreases in CK, so there may be opportunities for lifestyle interventions like physical activity, and you could see that response and whether that has prognostic implications. This could be of interest for future research.

Dr. Greg Hundley:

Very nice. Well, listeners, what an incredible discussion today. We want to thank Dr. Christian Mueller from University Heart Center in Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and also Dr. Chris deFilippi from the Inova Heart and Vascular Institute in Falls Church, Virginia, for really helping us understand that in patients... from this research, that in patients with active chronic skeletal muscle disorders, elevations in cardiac troponin T are common and may not be related to cardiac disease. These elevations were not observed in those with assessment of cardiac troponin I and, coming back to in the case of cardiac troponin T based on this wonderful biopsy work, the elevations of the troponin T appear related to re-expression of troponin T and skeletal muscle.

Dr. Greg Hundley:

Well, listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation June 7, 2022 Issue

6 juni 2022 | 24 min

This week, please join author Ratika Parkash and Editorialist Sean D. Pokorney as they discuss the article "Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial" and the editorial "The Evidence Builds for Catheter Ablation for Atrial Fibrillation and Heart Failure."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature discussion, oh, so exciting. We enter the month of June, and it pertains to heart failure and atrial fibrillation. And we are going to learn a little bit more from the RAFT-AF trial, involving randomizing patients to ablation and rhythm control, as opposed to just settling for rate control for patients with AFib. But before we do that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I absolutely would. And I will start by asking everyone a question. Could a single high-sensitivity cardiac troponin T level, below the limit of detection of six nanograms per liter, exclude an acute myocardial infarction? Well, you are going to find out because, remember that data for excluding AMI with a single high-sensitivity cardiac troponin level relies largely on the limit of detection, which is really a threshold of five nanograms per liter, which cannot be reported in the United States, per the FDA, because there, only the lowest reportable concentration is allowed, which is the limit of quantitation of six nanograms per liter.

Dr. Carolyn Lam:

So, today's authors Dr. Sandoval from Mayo Clinic and colleagues, very cleverly sought to determine whether a single high-sensitivity cardiac troponin T level below the limit of quantitation of six nanograms per liter could indeed identify patients at low risk for AMI.

Dr. Greg Hundley:

Very interesting, Carolyn. So we have the limit of quantitation and then the limit of detection. This is really intriguing. And of course, cardiac troponin T, as cardiologists, we receive a lot of requests for consults on this. So, what did this study find, Carolyn?

Dr. Carolyn Lam:

A total of over 85,000 patients were first evaluated in the CV data marked biomarker cohort, amongst which 29% had a baseline high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter. Among 11,962 patients with this baseline high-sensitivity cardiac troponin below six nanogram per liter and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% and a sensitivity of 99.6%.

Dr. Carolyn Lam:

In an adjudicated cohort, among those with a non-ischemic electrocardiogram, only 0.2% had myocardial infarction or death at 30 days. So in summary, Greg, this is the largest study evaluating a single high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter to identify patients at low risk for AMI.

Dr. Carolyn Lam:

And indeed, the present study demonstrates that a single high-sensitivity cardiac troponin level below six nanogram per litter is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.

Dr. Greg Hundley:

Oh wow, Carolyn, really informative study. Well, Carolyn, my next study comes from the world of preclinical science. And Carolyn, vascular smooth muscle cell phenotypic switching contributes to cardiovascular diseases. And epigenetic regulation is emerging as a key regulatory mechanism with the methylcytosine dioxygenase Tet2, acting as a master regulator of the smooth muscle cell phenotype.

Dr. Greg Hundley:

The histone acetyltransferases, HATs p300, and CBP are highly homologous and often considered to be interchangeable. And their roles in smooth muscle cell phenotypic regulation are not known. So Carolyn, these authors led by Dr. Kathleen Martin from Yale University School of Medicine assessed the roles of p300 and CBP in human vascular smooth muscle cells with knockdown in inducible, smooth muscle specific knockout mice, and in samples of human intimal hyperplasia.

Dr. Carolyn Lam:

Cool, Greg. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So, they found that p300 and CBP serve non-redundant and opposing function in vascular smooth muscle cell phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with Tet2 or HDACs. And Carolyn, targeting specific histone acetyltransferases therefore may hold therapeutic promise for future cardiovascular disease interventions.

Dr. Carolyn Lam:

Oh, that's great, Greg. Well, to round it all up, there are some other papers in today's issue. There's a Research Letter from Professor Zhang, entitled “Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time-Window of Cardiomyocyte Proliferation and Myocardial Regeneration.” There's also a Research Letter from Dr. Vaduganathan, entitled “Estimating the Benefits of Combination Medical Therapy in Heart Failure with Mildly Reduced and Preserved Ejection Fraction.” Ah, that's such a cool issue. Now, let's go on to our feature discussion. Shall we, Greg?

Dr. Greg Hundley:

You bet, and learn a little bit more about rhythm versus rate control in patients with heart failure and atrial fibrillation.

Dr. Carolyn Lam:

Our feature discussion today is about the long-awaited results of the RAFT-AF trial, and that is the randomized ablation-based rhythm control versus rate control trial in patients with heart failure and atrial fibrillation. Thank you so much, Dr. Ratika Parkash for joining us today as the first and corresponding author from Queen Elizabeth II Health Sciences Center in Canada, as well as Dr. Sean Pokorney, the editorialist from Duke University.

Dr. Carolyn Lam:

I am so, so excited to be discussing this paper. I really meant it. You know, as a heart failure cardiologist, we've been waiting for these results and trying to understand everything in context. So maybe, Ratika, could you please start off by telling us about the RAFT-AF trial and what you found?

Dr. Ratika Parkash:

Thank you, Carolyn. I'm happy to be able to talk about this study on behalf of the RAFT-AF investigators and my co-PI, Dr. Anthony Tang. So the trial... First of all, the rationale for the study, I think many of us, as heart failure or heart rhythm specialists, understand that in the past, we've done many trials looking at rate versus rhythm control, the AFFIRM trial being the largest, and then of course, specifically in heart failure patients, the AF-CHF trial, both of which were negative in reducing cardiovascular events and mortality in patients with or without heart failure, in terms of a rate to rhythm control.

Dr. Ratika Parkash:

One of the issues with those trials is that the form of rhythm control was antiarrhythmic drugs. So we have learned that catheter ablation is superior to antiarrhythmic drugs in maintaining sinus rhythm. And based on that premise, we decided to go forward with the RAFT-AF study.

Dr. Carolyn Lam:

That's great, Ratika, so thanks. And what were the results?

Dr. Ratika Parkash:

The main finding, so the primary outcome of the study was mortality and heart failure events. Heart failure events was defined as a heart failure hospitalization or any escalation of heart failure therapy that was done in the outpatient settings, including the use of intravenous Lasix in an emergency department setting.

Dr. Ratika Parkash:

So the main findings were that ablation-based rhythm control was not statistically significant in reducing mortality and heart failure events over rate control in patients with atrial fibrillation and heart failure. The study included patients both with preserved ejection fraction, as well as reduced eject fraction. And we did stratify based on ejection fraction at the entry point into the trial. The hazard ratio was 0.71 and the 95% confidence interval just crossed unity, ranging from 0.49 to 1.03 with a P value of 0.066.

Dr. Carolyn Lam:

Oh, ouch. So, thank you. And again, truly, congratulations on a very, very important trial. Sean, I said it before, I'll say it again, really, really loved your editorial. Could you put these findings in the context of... Maybe, start with even the most recent guidelines, the 2022 ACC/AHA/HFSA heart failure guidelines, which I believe gives catheter ablation a class 2A recommendation. Maybe, start from there, and how does this fall in place?

Dr. Sean Pokorney:

Yeah, no, absolutely. I think, first of all, it's a really important trial and it's great to have this additional data. I do think, as you said, that it's important to understand the context. We now have several recent guidelines that have commented on the role of catheter ablation in patients with heart failure.

Dr. Sean Pokorney:

You mentioned the most recent heart failure guidelines. We also have additional AFib guidelines and we have the 2019 AHA/ACC/HRS guidelines for atrial fibrillation that give catheter ablation a 2B recommendation in patients who have heart failure, to potentially lower mortality and reduce hospitalization. And it has a 2A indication in the 2020 ESC guidelines. And we're currently undergoing some revisions of the guidelines for atrial fibrillation, and there'll be new guidelines around atrial fibrillation coming out from AHA/ACC/HRS in the coming years. And so that will also be helpful, I think, to incorporate some of this additional data.

Sean Pokorney:

When you really look at the guidelines and see what's driving the guidelines, there are several trials now that are really driving the guidelines. And so I think, looking back on the data, we have the AATAC trial, which was a trial of 203 patients that looked at ablation versus amiodarone. And we have the CASTLE-AF trial, which had 363 patients in it and was looking at atrial fibrillation in patients with heart failure with reduced ejection fraction and defibrillators.

Dr. Sean Pokorney:

And when you put that data into context, the AATAC trial did find lower rates of death and hospitalization as a secondary outcome, and CASTLE-AF did identify a reduction in heart failure hospitalizations and death. At the three year follow-up, there was a statistically significant reduction, although the event number was lower than the previously sort of calculated target sample size.

Dr. Sean Pokorney:

And so in aggregate, these trials do show a modest evidence of benefit for clinical outcomes in this population. And that's where adding more data is really critical.

Dr. Carolyn Lam:

That's so true. And actually, Ratika, is there any plan for some meta-analysis or sort of adding the data? And if you could, also speak to, the trial was interrupted at some point, so how that may have impacted things as well.

Dr. Ratika Parkash:

Those are important questions. So, first of all, there is a planned longer term follow-up for the study, to look at whether or not following these patients out beyond our meeting follow-up of 37 months, it will actually produce a different result than what we observed in the current findings.

Dr. Ratika Parkash:

I think a meta-analysis is obviously going to show benefit for ablation-based rhythm control, based on the data that Sean had just described. One of the things that we'd need to keep in mind is that this trial, the RAFT-AF study really enrolled patients who were suitable for either ablation-based rhythm control or rate control. So it wasn't a study that looked at rhythm control only.

Dr. Ratika Parkash:

So, the CASTLE-AF trial had essentially two rhythm control arms. The medical therapy arm was, was amiodarone in that trial, versus catheter ablation. So patients could get rhythm control in both. And so, the types of patients that would've gotten into CASTLE-AF were different than the patients in our trial, even when you look at the reduced ejection fraction patients.

Dr. Ratika Parkash:

Having said that, our curves, when you look at the reduced ejection fraction group in our study does mirror what was observed in CASTLE-AF. So, even if a patient is not deteriorating initially with rate control, it appears that over time they begin to deteriorate. And that's what all of these trials have shown, is that patients do better with ablation-based rhythm control, the best form of sinus rhythm maintenance that we have.

Dr. Ratika Parkash:

And it takes time for them to deteriorate and it takes time to accrue those events. And this is evident in all trials of atrial fibrillation. You either need a very large sample size, like 15,000 patients, to look at heart failure in a short period of time, or you follow them longer, so that you can accrue those events.

Dr. Ratika Parkash:

In terms of the stopping of the trial, certainly, had we reached the sample size of 600, which was the intended sample size after recalculation during the study from 1000 down to 600, I believe we would have reached a positive outcome. But again, we hope that our longer term follow-up might shed some light on that. The interruption of the study was based on the DSMC decision and certainly could have affected the power of the study.

Dr. Ratika Parkash:

We have to remember that the other possibilities are that ablation-based rhythm control is not superior to rate control. And as someone who is pro-ablation, it's difficult to say that, but we see hints of benefit and we have to recognize that.

Dr. Ratika Parkash:

The other issue is that the secondary endpoints in our trial were all significant, as overall, it doesn't matter which group you looked at, NT-proBNP, six-minute walk test, quality of life, both for heart failure and atrial fibrillation, as well as ejection fraction, were all improved. And for many of the studies that have been done previously, those were the primary endpoints of those studies.

Dr. Ratika Parkash:

The idea of whether ablation-based rhythm control reduces heart failure per se, is from our study, purely from our study, we can't be a hundred percent certain. There's definitely a hint of clinical benefit there. From all the secondary endpoints, which are the current guidelines, is what they indicate ablation should be done for, is to improve quality of life. Our study was certainly supportive of that.

Dr. Carolyn Lam:

You know, Sean, I especially appreciated your discussion of these issues, the early stopping of the trial, the secondary endpoints. Could you know, share some of those thoughts?

Dr. Sean Pokorney:

I think it's really an important topic. I think that, again, as Ratika said, part of why this trial is so important is that many of the previous trials that have been published and many of the data sets have really looked at rhythm control versus rhythm control in this population, even including the analysis from CABANA, which included almost 780 patients from CABANA that had heart failure. And in that population, they did show a reduction in the composite primary endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. And again, CABANA was, as well, a study of rhythm control with ablation versus medical therapy, most patients getting rhythm control in that medical therapy arm.

Dr. Sean Pokorney:

And so this data really is additive. I think that one of the challenges is always, how do we make sure to get the most information out of a clinical trial once we commit patients to that scientific process? And I think here, at least in retrospect, it's obviously unfortunate that the trial was stopped early. I think that more data would certainly be helpful.

Dr. Sean Pokorney:

I appreciate the fact that longer term data may help solve that gap and close that gap a little bit. I think that, I guess, it'd be interesting to hear from Ratika a little bit more about the process that was involved with interaction with the DSMC and stopping the trial.

Dr. Ratika Parkash:

Yeah. Thanks, Sean. That also is a very good question. The DSMC really evaluated the data, evaluated the progress of the trial, back in 2017. It had been six years since we'd started the study. The data they had, in fact, did not show any benefit to ablation-based rhythm control over rate control at the time. So the follow-up period at the time was around two years.

Dr. Ratika Parkash:

And again, if you look at our Kaplan-Meier curves, you can understand why they would have made that decision at the time, based on 363 patients for the data that was available to them. They had a futility index that they looked at. it was calculated. The cutoff for stopping of the study was 0.8, and it was 0.81. So, there was a 19% chance that the study was going to show any benefit. And based on that, plus the progress of the trial, they made a decision to stop the study.

Dr. Sean Pokorney:

Yeah. I think it's really important when we look at these decisions, that there was example when we talk about this in the editorial as well with the ISIS-2 trial, where early on in the data, ISIS-2 was a trial looking at aspirin versus placebo. And basically in that trial, when you looked early on at the events that were accumulating, there was really roughly no difference between aspirin and placebo. And ultimately, that trial became positive and was a really critical trial. And if it had been stopped at that point for futility, we wouldn't have had some really critical data.

Dr. Sean Pokorney:

So, it's always a challenging decision. And obviously, the decisions are trying to be made in the best interest of the patients. Here, it just shows how important this additional follow-up data is for this trial, for RAFT in particular. And ultimately, it'll be interesting to see, as you mentioned, as we add additional long-term follow-up, how that will affect the results.

Dr. Ratika Parkash:

Absolutely. So, we hope that our additional follow-up is of benefit to clarifying our results. The unfortunate issue, I agree, was the stopping of the study, but we do trust our DSMCs. We have them for a reason and they perform an important function. So, we have to pay attention of course, to how they see things and evaluate the... at the time.

Dr. Ratika Parkash:

The other thing we should keep in context is that ablation for those, that time period, is not the same as it is today. Our safety has improved. You may have noticed that there were some adverse events in the study with ablation, and we would expect it to actually be lower, but in this day and age, but at the time, contact force wasn't available.

Dr. Ratika Parkash:

There were some tools and techniques that we now have at our disposal, improved mapping systems and so on, that allow us to do a safer and more efficacious job. But even in the context of that, our sinus rhythm maintenance was almost 80 to 90% for patients that you wouldn't normally expect to have that much sinus rhythm.

Dr. Sean Pokorney:

Yeah. I think that's a really critical point. You made a lot of really important points there, actually. Obviously, the vision of the field of electrophysiology is shifting, as you mentioned. And with data from EAST-AFNET 4, we're really shifting towards earlier rhythm control, as well as additional ablation trials attest, stop AFib or stop AF.

Dr. Sean Pokorney:

So again, there have been several studies that have shown the benefits of earlier rhythm control, EAST-AFNET 4, I think, being obviously one of the most relevant, looking at addressing atrial fibrillation of population of patients who've been diagnosed within the last year, and showing that there was a benefit to rhythm control, although the majority of rhythm control in that study was antiarrhythmic medications.

Dr. Sean Pokorney:

I think in the heart failure population, the challenge with rhythm control is that we're a lot more limited in terms of the medical therapies that are available for these patients. And I think that's where ablation really plays in a more important role, because not only have you shown that it seems to be efficacious in this patient population, with a really high rate of rhythm control, but in a lot of these patients, it's often a safer alternative than antiarrhythmic therapy.

Dr. Ratika Parkash:

Absolutely. And we've already shown that amiodarone is ineffective in this population, in AF-CHF. So, using that drug does not seem to be, in a population that could go for an ablation, the appropriate approach.

Dr. Sean Pokorney:

Yeah. And as well, I think that's important. And when you look back at data from SCD-HeFT as well, there were some concerns with safety signals of amiodarone in patients with heart failure as well, from that study, again, likely related to the side effects of the medication itself.

Dr. Sean Pokorney:

So again, it is a complex patient population in terms of decision-making and management. And I do think, again, we talked a lot about the trial being stopped earlier than we would've ideally liked. I still think that the data that you guys produced is really important and critical and additive. Again, we're consistently seeing these modest treatment effects across multiple studies. And the fact that all the studies are pointing in the same direction is very reassuring.

Dr. Ratika Parkash:

Yeah. I was just going to comment on some of the points that Sean had raised, with respect to early rhythm control and the concept of atrial substrate, and how advanced atrial substrate with a negative remodeling effect in patients with heart failure or prolonged atrial fibrillation may not necessarily be in our patient's benefits to then try to intervene, and trying to get these patients early would be useful.

Dr. Ratika Parkash:

So in RAFT-AF, patients did not have to fail an antiarrhythmic drug in order to get into the study. So that, again, critical, very much along the lines of EAST-AFNET and EARLY-AF, which was also published, demonstrating benefit for early intervention.

Dr. Carolyn Lam:

Wow. Just, thank you so much, both of you. That was such a rich discussion, really, really unpacking very, very important elements of the trial, not just the trial results, but also the implications of what happens with trial conduct and execution and so on.

Dr. Carolyn Lam:

Again, thank you so much Ratika, for publishing this very important paper in circulation, Sean, for your beautiful editorial that put it all in context, the audience for listening today. From Greg and I, you've been listening to circulation on the run. Thank you for joining us today, and don't forget to tune in again next week.

Dr. Greg Hundley:

Circulation May 31, 2022 Issue

31 maj 2022 | 31 min

This week, please join author Ronald Goldberg, Editorialist Hertzel Gerstein, and Guest Editor Rury Holman as we discuss the article "Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study" and the editorial "Shouldn't Preventing Type 2 Diabetes Also Prevent Its Long-Term Consequences?"

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Today. Oh, this feature discussion involves the glance of diabetes. Truly this interview, I felt like I was sitting among gurus and just learning so much about diabetes, the history and the whole topic is about long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its outcome study. Now, way more than that, we discussed. You have to have to listen. But okay, before that, let's summarize today's issue for our listeners. Shall we, Greg?

Dr. Greg Hundley:

You bet Carolyn. So the first paper that I've got to discuss today really comes to us from the world of interventional cardiology and it's led by Dr. William Fearon from Stanford University Medical Center. Well, Carolyn previous studies have shown quality of life improves after coronary artery revascularization, more so after coronary artery bypass grafting than after PCI. Now this study aimed to evaluate the impact of fractional flow reserve guidance, and current generation zotarolimus drug-eluting stents on quality of life after PCI compared with CABG.

Dr. Greg Hundley:

Now the study emanates from fractional flow reserve versus angiography for multi vessel evaluation or the fame three trial. And Carolyn, that's a multicenter international trial that included 1500 patients with three vessel coronary artery disease who were randomly assigned to either CABG or FFR guided PCI. Now, what did they assess? So quality of life was measured using the European Quality of life Five Dimensions. And we're going to abbreviate that EQ-5D questionnaire baseline, one, and then 12 months following the procedure. Also, Canadian cardiovascular class angina grade and working status were assessed at the same time points, and then also an additional time point in six months. And the primary objective was to compare the EQ-5D summary index at 12 months, and secondary endpoints included angina grade and work status.

Dr. Carolyn Lam:

Ooh, interesting Greg. So quality of life in the theme three trial. All right. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the EQ-5D, so that... European Quality of life Five Dimensions summary index at 12 months did not differ between the PCI and CABG groups, but the trajectory over the 12 months at the one month time interval between PCI and CABG did differ. Now, the proportion of patients with the Canadian cardiovascular class or CCS2 or greater angina 12 months was 6.2% versus 3.1% respectively in the PCI group compared with the CABG group. Additionally, a greater percentage of younger patients, so those less than 65 years old were working at 12 months in the PCI group compared with the CABG group. So in summary, Carolyn, in the fame three trial, quality of life after fractional flow reserve guided PCI with current generation DS compared with CABG was similar in one year. And the rate of significant angina was low in both groups and not significantly different. However, the trajectory of improvement in quality of life was significantly better with PCI as was working status in those less than 65 years old.

Dr. Carolyn Lam:

Wow. Thanks Greg. Hey, guess what? It's time for Greg quiz. The next paper is about the Chocolate Touch Study. So, Greg, is this about, A, the benefits of eating chocolate? B, the benefits of chocolate mud baths? Or C, the benefits of a second generation drug coated balloon?

Dr. Greg Hundley:

So, Carolyn, I just have one question. Where in the world do we get the benefits of chocolate mud bath? I don't think that's right. I do love eating chocolate, but I am going to go with the benefits of the second generation drug coated balloon.

Dr. Carolyn Lam:

Yeah, yeah, yeah. I made it easy for you. All right. So first generation drug coated balloons have significantly reduced the rate of restenosis compared to balloon angioplasty alone. However, high rates of bailout stenting and dissections persist. The chocolate touch drug coated balloon is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis, so you were right, Greg. In today's study led by Dr. Shishehbor, from University Hospital's Harrington Heart and Vascular Institute at Cleveland, Ohio. They studied 313 patients with claudication or ischemic rest pain, and superficial femoral or popliteal disease. And randomized them one to one to the chocolate touch or Lutonix Drug Coated Balloon at 34 sites in the United States, Europe and New Zealand. The primary efficacy endpoint was drug coated balloon success defined as primary patency at 12 months. The primary safety endpoint was freedom from major adverse events at 12 months. A composite of target limb related death, major amputations, or reintervention. Both primary endpoints was assessed for non-inferiority and have met sequential superiority testing for efficacy was pre-specified.

Dr. Greg Hundley:

Interesting, Carolyn. So this nitinol constrained balloon designed to reduce acute vessel trauma. So, what were the results of this study?

Dr. Carolyn Lam:

So in this trial, the second generation chocolate touch drug coated balloon met both non-inferiority endpoints for efficacy and safety. And was more effective than the Lutonix Drug Coated Balloon at 12 months for the treatment of femoral popliteal disease. Cool, huh?

Dr. Greg Hundley:

Very interesting. Great summary, Carolyn. So Carolyn, my next paper comes to us from the world of preclinical science. And the impact of three dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human dilated cardiomyopathy remains elusive. And so these authors led by Professor Lei Jiang from Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Science, generated a compendium of 3D epigenome and transcriptome maps from 101 biobank human dilated cardiomyopathy, and non-filing heart tissues and mouse models to further interrogate the key transcription factor implicated in 3D chromatin organization, and transcriptional regulation in dilated cardiomyopathy pathogenesis.

Dr. Carolyn Lam:

Oh, wow. Sounds like a lot of work. What did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So they found that enhancer promoter connectomes are extensively rewired in human dilated cardiomyopathy, which reside in pre accessible chromatin size and also hand one drives the rewiring of enhancer promoter connectome to induce dilated cardiomyopathy pathogenesis.

Dr. Carolyn Lam:

Okay, Greg. So what are the clinical implications?

Dr. Greg Hundley:

Right, Carolyn. So first, dilated cardiomyopathy enriched enhancer promoter loops identified in this study could be developed as novel 3D genomic biomarkers for dilated cardiomyopathy. And then second Carolyn, targeting hand one might be used as a novel approach for therapeutic intervention in patients with dilated cardiomyopathy.

Dr. Carolyn Lam:

Oh, nice. Greg. Well, also in today's issue, there's an On My Mind paper by Dr. Brook, entitled, “The Doctor is Out, New Tactics and Soldiers For our Losing Battle against Hypertension.” In another paper, we have Molly Klemarczyk bringing us highlights from the Circulation Family of Journals.

Dr. Greg Hundley:

Right, Carolyn. And also from the mailbag, there's a Research Letter from Professor Baggish, entitled, “Cardiovascular Outcomes in Collegiate Athletes, Following SARS-CoV-2 Infection: The 1-Year Follow Up From the Outcomes Registry for Cardiac Condition in Athletes.” Well, Carolyn, how about now we get onto that feature discussion and learn a little bit more about the long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program.

Dr. Carolyn Lam:

Hold on to your seats, everyone. Here we go. We know that lifestyle intervention and metformin have been shown to prevent diabetes. However, what is their efficacy in preventing the cardiovascular disease associated with diabetes development? Well, guess what? We're going to have data on that through today's feature paper and what a star crowd I'm talking to today. We have Dr. Ron Goldberg and he's a first end corresponding author from the University of Miami Diabetes Research Institute. We have the editorialist Dr. Hertzel Gerstein from McMaster University Population Health Research Institute. And a guest editor for this paper, Dr. Rury Holman from University of Oxford. I have to admit I'm starstruck. You gentlemen have totally defined the field. I cannot wait to learn more, but shall we start with you, Dr. Goldberg? Could you tell us a little bit more about your paper, what you did, what'd you found?

Dr. Ronald Goldberg:

So the background is that the Diabetes Prevention Program started in 1996 was a Diabetes Prevention Program to test the effects of intensive lifestyle intervention versus metformin, versus placebo on the prevention of diabetes in over 3000 individuals with impaired glucose tolerance, a form of prediabetes. And after demonstrating the efficacy of those interventions over about three years, we went on to do a follow up study in which the metformin group continued to receive it. Everybody got lifestyle because it worked so effectively. And we are now reporting after a further 18 years of follow up on the question of whether these interventions, now 21 years later, had any effect on cardiovascular outcomes. The background to that of course, is that people with prediabetes have a somewhat increased risk for heart disease and that rate increases as diabetes develops, particularly with severity of hyperglycemia and duration of diabetes. So, that was the study and we're now reporting on whether these interventions had a significant effect on the major cardiovascular.

Dr. Carolyn Lam:

Well, first Dr. Goldberg, congratulations on the foresight to get the informed consent and to plan ahead to be able to get these valuable data. But because I know this is going to be a critical point later. Could you tell us a little bit about the completeness of follow up and perhaps surveillance for outcomes before you share the results?

Dr. Ronald Goldberg:

Absolutely. So, 86% of the original randomized group of participants agreed to continue with a follow up study, so there was a loss at that point. And then of course, over 18 years of follow up, there's going to be a further loss. Some due to death and some due to loss to follow up. But despite that, I would say the group that entered the follow up study, we were able to maintain follow up in 85%.

Dr. Carolyn Lam:

Fantastic. And the results?

Dr. Ronald Goldberg:

The findings were that we found no significant effect of either of the two active interventions on our primary cardiovascular outcome, which was nonfatal myocardial infarction, stroke and fatal cardiovascular disease. We also had an extended outcome with more events in it, and similarly found no significant benefit or harm from either of those two intervention.

Dr. Carolyn Lam:

Oh, I love that paper. What a great, great, perhaps surprising conclusion that Dr. Gerstein loved the title of your editorial, you crystallize it. Shouldn't preventing type two diabetes also prevent long term consequences? So please tell us what was your thoughts when you saw this paper and how you frame it?

Dr. Hertzel Gerstein:

Thanks very much, Carolyn. And first of all, I was very impressed by the extensive amount of work and analysis done by Dr. Goldberg and his team. I thought that it's wonderful to see this sort of long term follow up. I've had the privilege in the past of speaking together with the DPP team on their trial and in their long term follow up. And I continue to be impressed by the extensive amounts of work and data collected and a rigor and academic value of the analysis. So, that was my very first impression and obviously it's a pleasure to write on this. I think the findings are clearly important and they both highlight the importance of long-term follow up as well as highlight the difficulties of long-term follow up in a study like this.

Dr. Hertzel Gerstein:

So this was a study done in a trial, originally done in a fairly young cohort of individuals who had very low risk for cardiovascular events. And over their 18 year follow up that Dr. Goldberg Ron described, the actual annual event rate for the primary outcome was 0.6% per year in that ballpark. Now, anybody... I've had the privilege as Ron Avery of doing many cardiovascular trials and we all know that we would never start a trial recruiting people with an event rate of 0.5% per year, 0.6% per year, because we would have to recruit 30,000 people and follow them for seven years in order to accrue enough events to be able to detect a clinically relevant benefit of the therapy. So because of this low event rate, the advantage was the long term follow up, the 26th year, I think it was in the end follow up. No, it was a 21 year median follow up period, because of the long follow up, you get a little bit away from the advantage of the low event rate.

Dr. Hertzel Gerstein:

But even then, over the course of the 21 years, there were only about 310 first cardiovascular events and most cardiovascular outcomes trials, for instance, we need close to at least a 1000, 500 to a 1000 is what we like to see. So that being said, it's perhaps not surprising that we didn't see a benefit of diabetes prevention because even if diabetes reduces the risk of a cardiovascular event by a quarter, by 25%, there would've only been a 50, 50 chance of detecting that with this particular cohort of people.

Dr. Hertzel Gerstein:

So I would say that the most conservative assumption is that diabetes prevention doesn't reduce the event rate by 25% or less or 30, but it's certainly... pardon me, by 25% or more, it could reduce it by 20%, 15% we would not have detected at all, or Ron would not have detected and his team would not have detected it with this thing. So I think that to me is the most important caveat in interpreting this does not mean that diabetes prevention has no effect on cardiovascular outcomes.

Dr. Hertzel Gerstein:

It means that diabetes prevention doesn't have a moderate or smaller effect. So, that's I think the most important message to take and as is even mentioned in the paper by Ron and the team is that there has been at least one diabetes prevention trial conducted in China many, many years ago that showed clearly that people who were randomly assigned to the diabetes prevention arm, 26 years later did have lower cardiovascular events and even death than people who were in the control arm. So, I think this adds to the story but it's clearly like everything, not the final word in this, but it certainly adds a lot of important data.

Dr. Carolyn Lam:

Oh, I would love to hear Dr. Goldberg's response to that. But before that, Dr. Holman, could I ask you to weigh in as well?

Dr. Rury Holman:

Yes. Sure. So, I agree with Hertzel that this is underpowered, but this is a question I've long wanted to see the answer to. And I congratulate Ron and his team for actually doing the work. All major studies should have long term follow up. People should be consented for life so that we can answer these questions. And Hertzel even though the power is perhaps minimal, we still need to do this analysis.

Dr. Rury Holman:

And if there had been a dramatic result, then we'd have all been very excited. I think one of the issues... one, if I could just bring it up, you mentioned the look ahead study in your discussion as being a negative dietary intervention. But I have a slightly different take on that. When you look at that paper in detail, what you see is that the people in the usual care group forgot quite a lot more risk factor reduction medications, and that's because their usual care physicians spotted the fact that their risk factor levels were higher than in the intensive care group, of course it was blinded at that point. But there's a whole point here is, in your paper you show an increase in the statin proportion, which is higher in the placebo group compared with the metformin and your intensive lifestyle, significantly so for the lifestyle one. So I'm just wondering whether even the low power was further blunted by the drop in effects of these other medications.

Dr. Ronald Goldberg:

Thanks very much for those comments guys, I think they're spot on. Let me first respond Hertzel with my thoughts on this, and then go over to your point, Rury. I think it's really interesting to look back over time and realize how much medical management has changed. And that goes right to your point, Rury, that doing a clinical trial like this where the primary care physicians are informed about what we're doing, what... communicated with on a regular basis, particularly when their patients develop diabetes, it just heightens the entire level of medical management. And I think you're absolutely right, but it's interesting to see what's happened to cardiovascular disease over the last 25 years, both in the general population and in the prediabetic population, the risk of cardiovascular disease has gone down. And then on top of that, we've got this very intensive cardio prevention intervention by primary care physicians, with high rates of statin usage, high rates of any hypertensive treatment, even the placebo group to your question, really lost weight.

Dr. Ronald Goldberg:

And they knew full well what was... and this was a very hands on type of study where our participants were really followed now for all these years, really became integrated with the research team. And so everybody knew what everybody else was doing. And so I'm sure the placebo effect was very strong, but I think nevertheless... Oh, and the last point I wanted to make was of course, the severity of the diabetes, even though 60% are developed diabetes, the severity of the diabetes was relatively mild. Even in those who developed diabetes, we know their average A1C was only about 6.7. And so I think that has a lot to do with blunting the acceleration effect of diabetes on cardiovascular disease. So, I think all of these factors contributed together to produce a negative result. But I think an important message, nevertheless.

Dr. Hertzel Gerstein:

I can highlight that point, that Ron was saying is that if diabetes prevention is going to prevent cardiovascular outcomes, it's going to do that because of a difference in glycemic exposure. The diabetes is by definition a disease of an elevated blood sugar. So if diabetes prevention prevents cardio, it means that the blood sugar's going to be lower than it would otherwise be. So if there's very little difference over the long term follow up in blood sugar because of co-intervention and therapy of all the treatment groups, then that would eliminate a lot of the benefits of diabetes prevention, because these are patients who are in this trial, who are being scrutinized even more than they would be if they were out there free range without being involved in any follow up. So, that's a spot on point. Rury, you wanted to comment.

Dr. Rury Holman:

Yeah. So, Hertzel just to expand on that. Obviously the glycemic impact on macrovascular disease is relatively modest compared to the impact on microvascular disease, which of course is what we all saw originally with type 2 diabetes. In fact, in KPDS35, when we looked or calculated what 1% reduction in A1C would do, it would only reduce stroke or MI by about 12 to 14%. So it's quite a shallow slope if you like. And your point is spot on is if that glucose levels are kept low by good treatment and good management role tell us about the great team they have. Then there was no room for a glycemic impact in this particular study. It's another question, whether you think metformin acts by different mechanisms to reduce cardiovascular disease, that's another question I had for Ron that he might like to address, is if there was a magic effect of metformin, why didn't we see that?

Dr. Ronald Goldberg:

And that's a really interesting question, Rury, because you may be aware that we published a paper a few years ago on our assessment of coronary calcification in a subgroup, in about 60% of the population who agreed to do this and who were eligible. And interestingly found that metformin did was accompanied by a reduction in the prevalence of coronary calcium in men, not women.

Dr. Ron Goldberg:

And the effect was actually when we did subgroup analysis, we found it was particularly strong in young men. And actually that gave us some sense of optimism that we might see something when we came to actual events. And of course, as you all know, metformin has beneficial effects on several cardiovascular risk factors. And so the question is whether there is some effect of metformin that might yet be identified, a coronary calcium after all is a surrogate of events and may take time, or it may be that... And we are really interested in the idea that both prediabetes and diabetes are heterogeneous. There's more and more interest in looking at subgroups of individuals who may be more predisposed. And it may be that metformin might have beneficial effects in some of those subgroups.

Dr. Hertzel Gerstein:

But also remember on the other hand, there was a lot of co-intervention with metformin in all groups after the trial was over. So all groups were offered metformin, et cetera. So even if metformin had an effect, it could have easily been washed out by the exposure of all the other groups to metformin during follow up. But Ron, you also touched on both the hope and the frustration too, because if we start thinking about subgroups, we can always think of subgroups. Yeah. But then the problem with subgroups is you have a study, let's say you have a cohort study with 7,000 or 10,000 people and it followed for five years and, oh, well the effect isn't in all 10,000, it's only in 20% of them. So now you have a study of 2000 people, that's not enough to detect an effect in a subgroup.

Dr. Hertzel Gerstein:

So, subgroups just eat away at power in an exponential, not a linear way, so that you just rapidly lose any ability to detect anything. And so, yes, this is going to work in people with these three snips on this gene, in this subpopulation. Good luck, that's the difficulty and the challenge of... We need to find sometimes better or more efficient ways of identifying outcome protective therapies, because we can't keep drilling into some groups because we just don't have the resources to find it really. I don't know what other people feel about that, but.

Dr. Carolyn Lam:

I'm personally so enjoying this conversation as I know the audience is and we covered a lot. I'm sure everyone wants to pick up the paper and the editorial. Now, we talked about being underpowered for the number of studies. We talked about profitable dilution of things like statins, antihypertensive agents, even the crossover of potential treatment in the placebo arm and so on. And then we started talking about, or is it the how you got there and the drug that was used. And here, please don't shoot me, but I just know I have the answers on behalf of everyone else's thinking it. What do you say of people who go, "Well, it's because it's metformin. What if it was an SGLT2 inhibitor? What if it was a GLP-1 receptor agonist?" And as you know, a lot of people say those would in spite of the effect on glucose.

Dr. Hertzel Gerstein:

I can quickly jump in. It's very clear. We've learned this in the last 10 years, is that there are glucose lowering drugs and there are glucose lowering drugs with benefits. And the GLP-1 receptor agonist and the SGLT2 inhibitors are glucose lowering drugs with benefits. They lower glucose, but they seem to have a separate cardioprotective effect. And with the SGLT2 inhibitors that cardioprotective effect does not seem to be related to the glucose lowering. There are a few meta regression analyses that suggest that with the GLP-1 receptor agonist, part of the cardioprotective effect is related to glucose lowering and part is not. And clearly mediation analysis with some of the trials have shown the same thing with the GLP-1 receptor agonist, not really with the SGLT2 inhibitors. So, maybe, that's my spin on this.

Dr. Carolyn Lam:

Dr. Holman.

Dr. Rury Holman:

Yeah. I was going to echo what Hertzel said in that regard, these other agents do have multiple effects. They change weight, they change blood pressure. And so other risk factors are brought into play other than glucose lowerings. We've already agreed, glucose lowering impact on cardiovascular disease is quite modest. I'd rather have it than not, but it wouldn't be my primary way to treat cardiovascular disease. And coming back to Ron's study, which is crucial today, the issue here is whether we could untangle an impact particularly of metformin, which has been foundation drug for type 2 diabetes for so long.

Dr. Rury Holman:

But clearly within the dataset we have here, underpowered it is. There are no clear messages in that respect, which is disappointing, but it doesn't mean that there isn't an effect. With longer follow up, with more data than you might see it. When the study... I'm coming for you Hertzel, was stopped for futility then the hazard ratio has changed, that often the way, not for the right way, but it's often what happens when you stop studies. I wondered if you wanted to comment on that aspect, because I know it's something that you've talked a lot about.

Dr. Carolyn Lam:

Dr. Gerstein. Did you want to?

Dr. Hertzel Gerstein:

I agree with what Rury said. I think the point you're making Rury goes back to power, and the ability to have enough people and enough events to detect and effect and that's clearly true, so...

Dr. Carolyn Lam:

Well, I hate to be the one to break the party up, but we have gone over time and intentionally so, there's just so much learning here. But Dr. Goldberg, could I give you the last say please? What do you think is the important clinical take home message of your paper?

Dr. Ron Goldberg:

Well, I think that the fact that we demonstrated that our study has been able to maintain really low levels of cardiovascular risk factors, low levels of A1C, even though that likely contributed to the negative finding still leaves the physician where the recognition that it is important to identify individuals with prediabetes to Institute Diabetes Prevention Programs, because I think it's entirely possible as I said earlier, and we've begun to identify them, subgroups of individuals who do progress more rapidly and who do warrant a more effective treatment, which would come from an early intervention program.

Dr. Carolyn Lam:

Wow. Thank you so, so much for that. Thank you so much. All three gentlemen for this amazing discussion. Well, audience, you heard it right here on Circulation on the Run from Greg and I thank you for joining us today and don't forget to tune in again next week.

Speaker 6:

Circulation May 24, 2022 Issue

23 maj 2022 | 28 min

This week, please join author Sanjiv Shah, Editorialist Evangelos Michelakis, and Associate Editor Justin Ezekowitz as they discuss the article "Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure" and Editorial "Atrial Shunt Devices in Patients with Heart Failure and Preserved or Mildly Reduced Ejection Fraction and the Pulmonary Circulation: Promises and Concerns."

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I love today's featured article. It's all about heart failure with mildly reduced and preserved ejection fraction, talking about device therapy and the response to therapeutic atrial shunt device. Now, this is a very interesting discussion of how specifically selecting patients based on latent pulmonary vascular disease may hold some answers, but we're going to keep everyone hanging here. You've got to, got to listen to the discussion. But first, we'd like to tell you about some of the papers in today's issue. And I think Greg, you've got one to start us with, right?

Dr. Greg Hundley:

Absolutely. Carolyn, thank you so much. Well, this first paper comes from Dr. Eliot Peyster from the University of Pennsylvania. And Carolyn, the aim of this study was to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies, to develop a precision medicine tool for predicting cardiac allograft vasculopathy, years before overt clinical presentation.

Dr. Carolyn Lam:

Ooh, interesting. Again, precision tools. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So there was a clinical predictive model that achieved modest performance on the independent test set, with area under the receiver operating curve of 0.7. But interestingly, a histopath- predictive model for predicting cardiac allograft rejection achieved good performance, with an area under the receiver operating curve of 0.8. Most importantly, however, a model, incorporating both clinical and histopathologic features, achieved excellent predictive performance, with an area under the receiver operating curve of 0.93.

Dr. Greg Hundley:

So in summary, Carolyn, these authors found that prediction of future cardiac allograft vasculopathy development is greatly improved by incorporation of computationally extracted histologic features. Their results suggest morphologic details, contained within regularly obtained biopsy tissue, have the potential to enhance precision and personalization of treatment plans for post heart transplant patients.

Dr. Carolyn Lam:

Aw, that's cool. Makes so much sense, but yet so novel. Thanks.

Dr. Carolyn Lam:

Well, for the paper I want to talk about, we are going to talk about dapagliflozin. Now we know the SGLT-2 inhibitor, dapagliflozin, improved heart failure and kidney outcomes in patients with Type two diabetes with or at high risk for cardiovascular disease, in the DECLARE–TIMI 58 trial. In the current paper, authors, led by Dr. Wiviott from the TIMI study group, aimed to analyze the efficacy and safety of dapagliflozin stratified, according to baseline systolic blood pressure.

Dr. Greg Hundley:

Ah, so an interesting question, since SGLT-2 inhibitors are known to reduce blood pressure. And given the concerns regarding the safety of SGLT-2 inhibitors, in patients with low to normal systolic blood pressure. So Carolyn, what did they find?

Dr. Carolyn Lam:

Nicely put Greg. So in patients with type two diabetes with, or at high risk of, atherosclerotic cardiovascular disease, dapagliflozin reduced the risk for heart failure hospitalizations and renal outcomes, regardless of baseline systolic blood pressure, with no difference in benefit for reduction in heart failure or renal outcomes, among patients with blood pressure from the normal range, all the way to severe hypertension. Moreover, there appeared to be no difference in adverse events of volume depletion, acute kidney injury, or amputations, across the levels of baseline blood pressure. So these results indicate that dapagliflozin provides important cardiorenal benefits in patients with Type two diabetes at high risk, the independent of baseline blood pressure.

Dr. Greg Hundley:

Oh, very nice, Carolyn. Well, my next paper comes to us from the world of preclinical science, and it's from professor Jeffrey Towbin and colleagues, at Le Bonheur Children's Hospital. So Carolyn, as we know, arrhythmogenic cardiomyopathy is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 has been reported to be the most common disease causing gene when mutation is positive. Now in the early concealed phase, the arrhythmogenic cardiomyopathy heart is at high risk of sudden cardiac death before cardiac remodeling occurs, due to mis-targeted ion channels and altered calcium handling. However, the results of pathogenic plakophilin-2 variants on myocyte contraction in arrhythmogenic cardiomyopathy pathogenesis, really remains unknown. So Carolyn, these authors studied the outcomes of a human truncating variant of plakophilin-2 on myocyte contraction, using a novel knock-in mouse model, as well as evaluation of human subjects.

Dr. Carolyn Lam:

Oh, interesting. So what were the results from this plakophilin-2 knock-in mouse model?

Dr. Greg Hundley:

Right, Carolyn. So serial echocardiography, a plakophilin-2 heterozygous mice revealed progressive failure of the right ventricle, but not the left ventricle, in animals older than three months of age. Now next, adrenergic stimulation enhanced the susceptibility of plakophilin-2 heterozygous hearts to tachyarrhythmia and sudden cardiac death. Contractility assessment of isolated myocytes demonstrated progressively reduced plakophilin-2 heterozygous RV cardiomyocyte function, consistent with right ventricular failure, measured by echocardiography.

Dr. Greg Hundley:

And the next, Western blotting of plakophilin-2 right ventricular homogenates revealed a 40% decrease in actin. In contrast, plakophilin-2 heterozygous left ventricular myocytes had normal contraction and actin expression.

Dr. Greg Hundley:

And finally, Carolyn, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in the right ventricles of end stage arrhythmogenic cardiomyopathy patients. So in conclusion, Carolyn, during the early concealed phase of arrhythmogenic cardiomyopathy, reduced actin expression drives loss of RV myocyte contraction, and that contributes to progressive RV dysfunction.

Dr. Carolyn Lam:

Wow. Thanks, Greg. Well, also in today's issue, there's an exchange of letters among Drs. Whitman, Ibrahim, and Løfgren, regarding physics at the heart of the matter, referring to the article, “Anterior–Lateral Versus Anterior–Posterior Electrode Position for Cardioverting Atrial Fibrillation.”

Dr. Greg Hundley:

Right Carolyn. And also in the mail bag, there's an On My Mind piece, from Professor Taegtmeyer, entitled, “The 2022 Beijing Winter Olympics, The Spotlight On Cardiac Metabolism.”

Dr. Greg Hundley:

Well, how about we get onto that feature article, and learn a little bit more about atrial shunts, and how they may be helpful in heart failure with preserved ejection fraction?

Dr. Carolyn Lam:

Ooh, can't wait.

Dr. Greg Hundley:

Well, listeners, we have a very interesting feature discussion today related to hemodynamics pertaining to interatrial shunt devices, in those with and without pulmonary hypertension. And we have, gosh, a repertoire of speakers today. We have Dr. Sanjiv Shah, from Northwestern University in Chicago, Dr. Evangelos Michelakis, from Edmonton Alberta, and our own associate editor, Dr. Justin Ezekowitz, also from Edmonton Alberta.

Dr. Greg Hundley:

Well, Sanjiv, we're going to start with you. Describe for us, some of the background pertaining to your study, and what was the hypothesis that you wanted to address?

Dr. Sanjiv Shah:

Great. Thanks, Greg. Thanks for having me today. Well, the background of our study is that, it was a subgroup analysis, or a secondary analysis, of the REDUCE LAP-HF II trial. Now this trial has been in the making for over 12 years, almost 13 years. It started out as an idea that was David Celermajer. David is a pediatric cardiologist in Australia, who had this idea that, in mitral stenosis patients, it's well known that, if there's a concomitant secundum ASD, a congenital secundum ASD, in these patients with mitral stenosis do better. They have a way to unload the left atrium, and distribute that blood to the systemic veins and the right atrium, the right side of the heart. And so could this be helpful in quote, diastolic, heart failure or HFpEF?

Dr. Sanjiv Shah:

And so, I started working with him about 12 years ago. This started out as a concept. It was studied in animal models, and then in humans, in open label studies, and then, in a first randomized controlled trial. Where we showed, that an intraatrial shunt device, an iatrogenic ASD, so to speak, put in humans with heart failure with risk preserved EF, results in a lowering of exercise pulmonary capillary wedge pressure. And so based on that data, we designed a pivotal trial, a Phase III trial, the largest trial of its kind, of heart failure with preserved and mildly reduced ejection fraction, to see if interatrial shunt device would improve outcomes. And we published that trial earlier this year in the Lancet. Unfortunately, it was a totally neutral trial. And when you have a neutral trial in any condition, but as we see often in HFpEF, the question is, was it neutral overall? Or was there a subgroup that benefited? And what we found in that trial was that, there were three predefined subgroups that came out that seemed like there was a difference.

Dr. Sanjiv Shah:

First, there was a sex difference. Women did better. Men did worse with the device. Then, there was right atrial volume. Those with bigger right atrial volumes did worse. If you had a smaller right atrial volume, you did better. But the most significant interaction and subgroup was exercise pulmonary artery systolic pressure.

Dr. Sanjiv Shah:

If the pulmonary artery systolic pressure was greater than 70 at 20 Watts of exercise, so just with a little bit of exercise, those patients did worse. And if PA pressure stayed low, the patients did better. And so we sought to further explore this to say, "Okay, what's exactly going on?" In a post hoc analysis, what's going on with the pulmonary vasculature during exercise, and how does that differentiate how patients potentially respond to the device? And that's what we hope to figure out.

Dr. Sanjiv Shah:

We hypothesize, that if exercise pulmonary vasculature resistance is lower, then the shunt can actually work, and blood can flow from the left to the right, into the lungs, and the right heart doesn't get too overloaded. And we know, that the normal response of the pulmonary vasculature is to vasodilate with exercise. And so, if patients had retained that response, the ability to do that, that they may benefit. And so, we sought to figure that out with this subgroup analysis.

Dr. Greg Hundley:

Sanjiv, it sounds like a really elegant, well thought out hypothesis. So what was your study design? And describe your study population.

Dr. Sanjiv Shah:

Yeah. This was a randomized controlled trial. And so this was 626 patients enrolled at 89 centers across the world. And it was really, heart failure with mildly reduced, so an EF of greater than 40, or preserved EF, and 93% of them had HFpEF. And what was unique about this trial is that we, this is the first trial really, that confirmed that these patients actually had heart failure, with mildly reduced or preserved ejection fraction. Most trials say, well, you have to have an elevated BNP, and you have to have some sign of structural heart disease, and maybe, a history of heart failure hospitalization. In this trial, every single patient had to undergo rigorous noninvasive echocardiography. And then, on top of that, they had to undergo exercise invasive hemodynamic testing. And people thought that it wasn't possible for 626 patients, but we did it. And every single patient had had an exercise pulmonary capillary wedge pressure greater than, or equal to, 25. And so this really was HFpEF. So it's a randomized trial.

Dr. Sanjiv Shah:

And then, beyond that, we did a subgroup analysis. So we looked on various subgroups, focusing on exercise PVR, and we really looked to see the effect on three outcomes. Number one, a hierarchical endpoint, a combination of cardiovascular death, ischemic nonfatal stroke, recurrent heart failure hospitalizations, and the KCCQ. And then the other two outcomes were just the individual recurrent heart failure hospitalizations, and the KCCQ. We looked at all of these, and tried to figure out if there are certain subgroups that benefit.

Dr. Greg Hundley:

Great detail. So Sanjiv, what did you find?

Dr. Sanjiv Shah:

Well, we found that, there's this group of patients, that during exercise, the pulmonary vascular resistance at peak exercise stays above 1.74 Wood units. Now that seems like an arbitrary number, but in fact, in older individuals that are healthy, when you exercise them, the PVR upper limit, the exercise PVR upper limit, is about 1.8. So we're right about the upper limit of where the PVR should be. And if it was above that, the patients actually did worse with the shunt device. They had a lot more heart failure hospitalizations. Their KCCQ got worse, didn't benefit. And if they were below that threshold, meaning they were, sort of compliant pulmonary vasculature, and it stayed compliant, or they vasodilated effectively with exercise, then they benefited from the device. And what we call this concept of exercise-induced pulmonary vasoconstriction, or inability to vasodilate, is latent pulmonary vascular disease.

Dr. Sanjiv Shah:

And so, if you have that latent pulmonary vascular disease, your win ratio is 0.6. That means you do worse. And if you don't have this pulmonary, this latent pulmonary vascular disease, your win ratio is 1.31. And that means, you do better with the device. And we saw very similar findings with the KCCQ. We saw similar findings with the recurrent heart failure hospitalizations.

Dr. Sanjiv Shah:

And the final thing is, we found that, we looked at various other subgroups, and it turned out that if there was no latent pulmonary vascular disease and no history of pacemaker, which we found was kind of associated with sex and right atrial volume, those patients, for about 50% of the group, actually did the best. And that was what we called, the responder subgroup.

Dr. Greg Hundley:

Thank you, Sanjiv. Well, listeners, we're going to turn now to our associate editor, Justin Ezekowitz. And Justin, you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Justin Ezekowitz:

So Greg, this paper kind of stood out for a number of different reasons, as I sent you. You're to be congratulated for a variety of reasons. But the number one is, pursuing the data from a neutral trial overall, to understand who might benefit and who might be harmed from a pretty novel device and way to treat patients in such a scale, that's not being done like this before. So it stands out by just the magnitude of number of right heart catheterizations, number of patients enrolled, number of procedures done. And all of those things really lead to us to be able to understand the area much better than I think we can in a human population.

Dr. Justin Ezekowitz:

Where this sits with other devices that are very similar, is hard to really know, if all devices are going to be the same or different, but your population is quite unique is if they're not all end stage, but they're sick enough to get into your trials. So there's this population we treat actively. And I wondered if you could touch on that continuous nature. And so for readers, there's this beautiful figure, which shows a continuous nature of exercise PVR. And I wonder if you could touch on that. Is this mid group, the group that we should target for our future therapies like this, or this needs further study?

Dr. Sanjiv Shah:

Well, I think it needs further study. I think the listeners should be aware that this is a post hoc analysis. We did pre-specify exercise PA pressure. This is one trial. But it makes a lot of sense, pathophysiologically. What we're doing here is we're shunting this excessive LA, overloaded LA, shunting the blood from the LA to the RA and into the pulmonary vasculature. Well, if that pulmonary vasculature can't accept that increased flow, the patient's not going to do well. And how can we simulate that? Well, we can simulate it with exercise. As the patient's pedaling on the bike, on the cath lab table, there's increasing blood flow to the pulmonary vasculature, and we're seeing what happens with the pulmonary vasculature. Does it vasodilate, does it not? And so, I think that's why we were excited about this finding.

Dr. Sanjiv Shah:

I do think that, there are at least seven other companies making shunt devices, interatrial shunt devices or therapies. And I do think, they need to pay attention to this and really look at this. Not all trials are doing exercise and basic hemodynamics, that needs to be done, I think. So it'll be really interesting to see.

Dr. Sanjiv Shah:

Now, one thing I will say is that, and I've written about this, this is a really interesting trial. Because the BNPs were lower, and so you would think, okay, these are patients that are less sick. And yet, their heart failure hospitalization rate was at least one and a half times higher than pharma Phase III trials. KCCQ was way lower, like 30 points lower. So there are these patients out there that are really sick, and they're the ones that I think, are where their life, their sort of quality of life, their outcomes, are being driven by the HFpEF. And that's what we found in this trial.

Dr. Greg Hundley:

Very nice. Well, listeners, let's turn now to our editorialist, Dr. Evangelos Michelakis. And Evangelos, two questions. How do we put the results of this substudy, really in the context of the main trial? And then secondly, do you have any, with your expertise in endothelial function, and understanding the mechanisms of pulmonary hypertension, can you describe what you think might be operative as a mechanism here, and why Sanjiv observed these positive results in some patients?

Dr. Evangelos Michelakis:

Thank you. So the first point is that, I have to also repeat, that it was a remarkable achievement to do all this right heart catheterization on a treadmill in the cath lab. It's a very complex procedure. And it is, they have to be congratulated, the authors, for actually doing this. There is no question that, like Sanjiv said, ongoing trials for future trials will need to include the hemodynamics in the trials, before and after the procedure.

Dr. Evangelos Michelakis:

So another important thing is that, the authors brought up this, they called it latent pulmonary hypertension, we could call it latent pulmonary hypertension, or probably, early pulmonary hypertension, as an entity. Now that entity, it's newer in the heart failure field. It's not that old in the PIH, the pulmonary interior hypertension field, since it used to be in the guidelines for this disease, that exercise pulmonary hypertension was a diagnostic criterion for that. Because the idea is that, exercise pulmonary hypertension reflects early pulmonary hypertension. So you needed to intervene with therapies early.

Dr. Evangelos Michelakis:

Now, I'm not sure that this is a fact. But it is very likely that these patients, in Sanjiv's trial, that had the early, that had the sort of enhanced response with exercise, did have at least, endothelial dysfunction in the pulmonary arteries. Not only because this population has a number of endothelial risk factors, diabetes, smoking, you name it. But also, there are newer problems like SNPs polymorphism mutations, that will recognize more into the pulmonary arterial hypertension field, to be more unique to the pulmonary circulation.

Dr. Evangelos Michelakis:

But the reason I say that is that, the reason that you dilate with exercise, is mostly because of your pulmonary arterial endothelial cells, secreting vasodilatory factors. And also, allowing previously closed capillaries to open up with increased flow. However, the problem is that, if you have pulmonary arterial endothelial cells in vitro, and you expose them to high flow, like in this case, you can actually change their identity. Turn them into cells that are not endothelial cells anymore, are proliferative pro-inflammatory, and they can actually cause structural pulmonary circulation damage.

Dr. Evangelos Michelakis:

Also, there are animal models and people working in PAH and ASD, where they've shown that, if you have, if you're given endothelial toxin in animals, and then, you do an aortocaval shunt, then you get really severe pulmonary hypertension with structural disease, that is not even reversible if you remove the shunt.

Dr. Evangelos Michelakis:

So from this trial, the conclusion that patients with pulmonary hypertension should not get the device, is very clear. And probably, the ones with exercise pulmonary hypertension. My theoretical concern is, for those that don't have exercise pulmonary hypertension, or those that do have it, could they get worse after a number of years, and have structural pulmonary vascular disease? And unfortunately, we didn't have a follow up right heart catheterization to prove that, whether this is right or wrong. Which is a thing, is the most important thing to do in the future. So mimic the protocol for this trial from now on, but also add a follow up right heart catheterization, perhaps not just in a year, but longer. In other words, enough time to allow the structural pulmonary remodeling get established, but also, affect the right ventricle, these things don't. So maybe in a few years. It's a very demanding thing for these protocols, but I think, that's what needs to be done before we say this device can actually be beneficial for those patients, or for some patients, or not hurt others.

Dr. Greg Hundley:

Very nice. And so, a great segue, Evangelos, into what we think the next studies may need to be performed in this particular sphere of research.

Dr. Greg Hundley:

So Sanjiv, in just 30 seconds, could you share your thoughts first, and then we'll circulate back to Justin, and then finish up with Evangelos. Sanjiv?

Dr. Sanjiv Shah:

Yeah. I think the key thing is, to do a confirmatory trial. And that's what we're aiming for, is to do a confirmatory randomized sham-controlled trial, but focus in on these patients with an exercise peak PVR of less than 1.75, around there. And I think, that'll help answer the question. The Qp/Qs we get with this device is 1.2 to 1.3. So I don't think it's a high flow. And we actually have open label studies, where we've gone out to three years, with repeat invasive hemodynamic testing, echocardiograms, and we've had patients who've been implanted for seven years. We're not seeing, at least at that point, any sort of worsening of pulmonary vascular disease, or RV function, or anything like that. And so, it remains to be seen.

Dr. Sanjiv Shah:

The last thing I'll say, which I think is provocative, in the field of HFpEF, all pulmonary vasodilator drugs have failed. And though, we only measure pulmonary vascular resistance at rest. And what we saw in this trial, is that some patients have a high PVR and it comes down. Some people have a PVR that stays low, and is low and stays low. Some people have a low PVR and it goes up. You know? So I think what we need to think about in the field of PH‐HFpEF, is more exercise genotyping, to determine what's the dynamic exercise PVR? And maybe, those with exercise elevation of pulmonary vascular resistance are the ones that respond to pulmonary vasodilators. So that's another thing that I think we can think about taking away from this trial.

Dr. Greg Hundley:

Thank you, Sanjiv. Justin.

Dr. Justin Ezekowitz:

Yeah. So my thoughts are mimicking Sanjiv's. But one of the things that we desperately need is, ways in which we can noninvasively assess the exercise PVR, so that we can think about the large scale interventions that might come down the road, if interventions such as this work well. Because the noninvasive scans will really help us look at broader populations. Those are, that don't make it into trials, and those that aren't traditionally in our studies of HFpEF. So I think, that's another area where we can really grow the field, and then, grow our knowledge.

Dr. Greg Hundley:

Very nice. And Evangelos.

Dr. Evangelos Michelakis:

So, yes. Of course, like everybody said, we need trials that will have a follow up right heart catheterization, at least address, if not both, like the investigators did. But because the big question is, are these patients having an earlier stage pulmonary hypertension or not? These patients that the authors called, latent pulmonary hypertension, we need to phenotype more their endothelial cells, or their disease. And in the absence of biopsies, the only way we could do that, is perhaps, with molecular imaging, or at least, in some small populations. Or with analyzing pulmonary arterial endothelial cells in the blood, and their molecular phenotype, to see if they are a distinct group, which I suspect they may be. So further genotyping of this exercise induced pulmonary hypertension in this population, will be important as well.

Dr. Greg Hundley:

Thank you. Well, listeners, we've had a great discussion today, from Dr. Sanjiv Shah, from Northwestern University in Chicago, our editorialist, Dr. Evangelos Michelakis, from Edmonton, Alberta, and our own associate editor, Dr. Justin Ezekowitz from Edmonton, who brought us this study, demonstrating that in patients with heart failure and preserved ejection fraction, or heart failure and mildly reduced ejection fraction, the presence of pulmonary vascular disease, uncovered by invasive hemodynamic exercise testing, identifies patients who may worsen with atrial shunt therapy. Whereas, those without pulmonary vascular disease may, at least in the short term, benefit. And of course, as Evangelos has pointed out, the long term findings really warrant further study.

Dr. Greg Hundley:

Well listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the Run.

Dr. Greg Hundley:

Circulation May 17, 2022 Issue

16 maj 2022 | 19 min

This week, please join author Andrew Stokes as he and Greg Hundley discuss the Research Letter "E-Cigarette Use and Risk of Cardiovascular Disease: A Longitudinal Analysis of the PATH Study (2013–2019)."

Dr. Greg Hundley:

Well, listeners, welcome to this May 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, associate editor, director of the poly heart center at VCU Health in Richmond, Virginia. And this week, Carolyn is away out on vacation and we are going to go through the summaries together. We have a great feature today on e-cigarette use and the risk of cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And the first one comes to us from the world of clinical science and Dr. Jiaqi Huang from the National Cancer Institute. Listeners, the objective of this study was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption through the prospective analysis of 27,000 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC Study, and also a systematic review and meta-analysis of several other cohort studies.

Dr. Greg Hundley:

So, what did the investigators find? Well, first, based on 482,000 person-years of follow-up, the authors identified 22,000 deaths, including 9,110 deaths from cardiovascular disease. Now, greater dietary cholesterol and egg consumption were associated with increased risk of overall and cardiovascular disease mortality. Now, second, from the meta-analysis component of the study, overall consumption of one additional 50-gram egg per day was associated with an increased cardiovascular disease risk with a pooled relative risk of 1.04 with a higher risk of cardiovascular disease among those from us cohorts where their pooled relative risk ratio was 1.88, a borderline higher cardiovascular disease risk in European cohorts with a pooled relative risk of 1.05, but not an increased cardiovascular disease risk in the Asian cohorts. So, the results from this study, which includes an updated meta-analysis, suggest that there is support for restricted consumption of dietary cholesterol as really a means to improve long-term health and longevity.

Dr. Greg Hundley:

Well, let's go to our next article. So, in this next study, we are going to move from cholesterol risk now to salt substitution. And this article comes to us from Professor Maoyi Tian from the Harbin Medical University. Listeners, the Salt Substitute and Stroke Study, or SSaSS is a five-year cluster randomized controlled trial and demonstrated that replacing regular salt with a reduced sodium added or potassium salt substitute reduced the risk of stroke, major cardiovascular events, and premature death among individuals with prior stroke or uncontrolled high blood pressure that lived in rural China. So, this particular study, a substudy, assessed the cost-effectiveness profile of this particular intervention.

Dr. Greg Hundley:

So, listeners, what did the study find? Well, there was a mean follow-up of 20,995 participants that was conducted a little over four years, and over the period, replacing regular salt with salt substitute reduced the risk of stroke by 14% and the salt substitute group had on average 0.054 more quality-adjusted life years per person. The average costs were lower in the salt substitute group, and this intervention was dominant. That is better outcomes at a lower cost for prevention of stroke as well as for quality-adjusted life-years gained. Now, interestingly sensitivity analyses showed that these conclusions were robust except when the price of the salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95% probability of being cost-saving and a greater than 99.9% probability of being cost-effective. A really interesting article.

Dr. Greg Hundley:

Well, now, let's turn our attention to the world of population science. And in this study, these authors led by Dr. Steven Lubitz from Massachusetts General Hospital performed a Genome-Wide Association Study or GWAS of the QT corrected interval among 84,630 United Kingdom Biobank participants. And they created a polygenic risk score. Now, among 26,976 participants with whole-genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine or TOPMed program, they identified 160 carriers of punitive pathogenic, rare variants in 10 genes known to be associated with the QT interval.

Dr. Greg Hundley:

So, the authors here examined the QTC corrected associations with the polygenic risk score and with rare variants from the TOPMed cohort. So, what did they find? They found 54 independent loci by GWAS in the UK Biobank. 21 loci were novel of which 12 were replicated in TOPMed. The polygenic risk score comprising over a million common variants was significantly associated with the QTC in TOPMed, and carriers of punitive pathogenic rare variants had longer QTC intervals than non-carriers. Now, 23.7% of individuals with a QT corrected of greater than 480 milliseconds carried either a monogenic rare variant or had a polygenic risk score in the top decile. 3.4% for monogenic and 21% for the top decile of the polygenic risk score.

Dr. Greg Hundley:

So, listeners, the findings of this study indicate that the QTC duration in the population is influenced by both rare variants in genes, underlying cardiac repolarization and polygenic risk, with a sizeable additional contribution from polygenic risk. And therefore, comprehensive assessment of the genetic determinants of QTC prolongation should include incorporation of both polygenic and monogenic risk.

Dr. Greg Hundley:

Well, listeners, let's turn our attention to the world of preclinical science. And this next article comes to us from Professor Junbo Ge from the Department of Cardiology in Zhongshan Hospital in Fudan University. Well, listeners, after myocardial infarction, cardiac resident macrophages, which are self-maintaining in that they originate from embryonic hematopoiesis are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes. And that process is called efferocytosis. Now, efferocytosis is required for inflammation resolution and tissue repair. However, the underlying molecular mechanisms of this process really remain unknown.

Dr. Greg Hundley:

So, as such, listeners, these authors sought to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Well, what did Dr. Ge and colleagues find? Several things. First, they identified legumine as a gene specifically expressed by cardiac resident macrophages, and legumine deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in-vivo efferocytosis in the border area of infarcts. Furthermore, the formation of LC3 to dependent phagosome around secondary encountered apoptotic cardiomyocytes was disabled. In addition, legumine deficiency increased infiltration of MHC to high CCR2+ macrophages, and the enhancement of recruitment of MHC to low CCR2+ monocytes with downregulation of anti-inflammatory mediators, such as IL10 and TGF-beta, and upregulation of pro-inflammatory mediators, including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6, and IFN-gamma.

Dr. Greg Hundley:

So, listeners, in summary, the results of this study directly link efferocytosis to wound healing in the heart and identify legumine as a significant link between acute inflammation resolution and cardiac function after infarction. Well, listeners, also in this issue, we have a wonderful On My Mind feature from Professor Camlet entitled “A Role for the Vascular Endothelium in Post-Acute COVID-19.” Well, next, we're going to head to our feature article on e-cigarette use and the risk of cardiovascular disease.

Dr. Greg Hundley:

Well, listeners, welcome to our feature discussion today. A very interesting topic. E-cigarette use and the risk of cardiovascular disease. And we have with us today the senior author of this particular manuscript, Dr. Andrew Stokes from the Boston University School of Public Health in Boston, Massachusetts. Welcome, Andrew. Andrew, to get started, can you describe some of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Andrew Stokes:

Absolutely, and thank you for having me on the podcast. Despite the increasing popularity of electronic cigarettes, the long-term health effects of habitual e-cigarette use remain unclear. Most of the studies that have been conducted to date are either cross-sectional or they pertain to small clinical samples. The goal of the present study was to develop a longitudinal design to see if e-cigarette use at a point in time was linked to cardiovascular events over a multi-year follow-up period.

Dr. Greg Hundley:

Very nice. So, your specific hypothesis really pertained to e-cigarette use, correct?

Dr. Andrew Stokes:

That's right. As a novel product, information on e-cigarette use and its health effects is lacking, and so our goal was to see if e-cigarette use was associated with the incidence of clinical events.

Dr. Greg Hundley:

And so, can you describe for us your study population and your study design?

Dr. Andrew Stokes:

Absolutely. Data come from the Population Assessment of Tobacco and Health Study or the PATH Study, which is a nationally representative cohort study of the non-institutionalized population containing five annual waves of self-reported data collected between 2013 and 2019. The initial sample included over 30,000 US adults ages 18 years and older with oversampling of tobacco users. We excluded respondents who were lost to follow-up or who had a previous diagnosis of CVD or were missing baseline exposure information. Ultimately, we ended up with a sample of just over 20,000 individuals.

Dr. Greg Hundley:

Very nice. And so, what were your study results?

Dr. Andrew Stokes:

So, we had several key findings. One key finding was that, compared to people who only smoke cigarettes, people who smoke both traditional cigarettes and used e-cigarettes had no significant reduction in risk for heart attack, heart failure, or stroke, nor any cardiovascular disease outcome. This is significant because many e-cigarette users use both e-cigarettes and cigarettes in combination. Very few move to exclusive e-cigarette use. Additionally, we found that those who do move to e-cigarette use exclusively though, representing a very small fraction of the cohort, had some evidence of reduction in cardiovascular harm. However, these results for exclusive e-cigarette users were not statistically significant, indicating that additional studies with longer follow-up will be required before we can make any definitive conclusions about this group.

Dr. Greg Hundley:

Very nice. And did you notice any discrepancy in your results between either men versus women or between individuals that were younger in age versus those that may say be 50 years or older?

Dr. Andrew Stokes:

I think both sources of effect modification will be valuable directions for future research. Unfortunately, samples of e-cigarette users are quite small and incident events over follow-up are quite limited. Therefore, the present study did not pursue or explore these types of stratifications.

Dr. Greg Hundley:

Very good. So, sounds like more research to come forward. Well, Andrew, how do we put your results really in the context with other studies evaluating the harmful effects of e-cigarettes?

Dr. Andrew Stokes:

Of course. So, we know from toxicological studies that there are many constituents of e-cigarette aerosols that are concerning and have substantial toxicity. We know that the inhalation of e-cigarette aerosols among young healthy adults induce inflammation and oxidative stress. Population-based studies from cross-sectional data sources also suggest evidence of harm. What's needed are more longitudinal studies with longer follow-up periods and more incidence events so we can really parse this risk and identify the magnitude of these harms. Finally, we also need to understand better whether there's any harm reduction potential associated with e-cigarette use. E-cigarettes are currently not an FDA-approved cessation product. Therefore, we do not recommend their use despite preliminary evidence of potential harm reduction. We'll need further evidence before we can make any such conclusions.

Dr. Greg Hundley:

And Andrew, describe for us, and you've started to already, what series of studies are needed next to be performed in this sphere of research?

Dr. Andrew Stokes:

Right. So, it's difficult to really identify definitively the effects of e-cigarette use in the absence of randomized control trials. However, we can use observational data with target trial approaches to emulate the clinical trial that we would like to do if we were able to. So, the next step is really to look at transitions across products between cigarette and e-cigarette use and to associate those who switch products, such as from e-cigarettes to cigarettes or vice versa, to see if those switches are associated with any harm or harm reduction.

Dr. Greg Hundley:

Very good. Any specific racial or ethnic groups or even social determinants of health that may need to be targeted with some of these future studies?

Dr. Andrew Stokes:

That's a great question. So, what we know so far from preliminary research is that some groups are more likely to switch to e-cigarettes than other groups. Particularly among current combustible cigarette users, the rates of switching do vary by race and ethnicity. Thus, we need further research to understand why these patterns differ across subgroups and what their implications may be for health.

Dr. Greg Hundley:

Do you foresee any difficulty in trying to enroll participants from those other groups as you plan these studies moving forward?

Dr. Andrew Stokes:

The advantage of the current research design is that we're using a large secondary data set of survey participants who are enrolled in the Population Assessment of Tobacco and Health study. Therefore, we are not enrolling patients ourselves and the response rates are quite high in these surveys.

Dr. Greg Hundley:

Well, Andrew, we hear that some of the inhalants that are mixed with the inhaled nicotine can be flavors and perhaps have been approved by the FDA for consumption in the GI tract where, whatever these additives are, you would think might be broken down by the digestive system. But if they're inhaled and get into the lung tissue and the parenchyma, the alveoli, et cetera, do they perhaps have harmful effects that maybe we're not aware of?

Dr. Andrew Stokes:

Absolutely. E-cigarettes come in thousands of characterizing flavors including sweet flavors, tobacco flavors, and many other miscellaneous flavors. As we saw with the outbreak of lung injury associated with the use of e-cigarettes in 2019, inhaling flavors can have health effects that are unanticipated based on research in the GI tract, and therefore, as a next step in this research, we really need more work to investigate how different flavors are associated with the incidence of clinical events, whether cardiovascular or pulmonary conditions.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Andrew Stokes from the Boston University School of Health for bringing us this data from the PATH study, suggesting that combining smoking with e-cigarette use does not reduce cardiovascular events and that quitting both products is needed to ensure overall cardiovascular disease risk reduction.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation May 10, 2022 Issue

9 maj 2022 | 18 min

This week, please join Guest Host Mercedes Carnethon and Author Brendon Neuen as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data from Randomized, Controlled Trials."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, this week's feature paper is on one of my favorite topics, SGLT2 inhibitors. And this time, looking at their association with the risk of hyperkalemia in people with type-two diabetes. Now this is something we've all been waiting to look at. It's a meta-analysis of individual participant data from randomized controlled trials, so a very important, clinically applicable discussion coming right up. But first, I'm actually going to talk to you about text messages.

Dr. Greg Hundley:

Wow, Carolyn. I can't wait to hear about this article.

Dr. Carolyn Lam:

Well, specifically the TEXTMEDS randomized clinical trial, which is our first paper today. It is a trial that examined the effectiveness of text-message delivered cardiac education and support on medication adherence following an acute coronary syndrome.

Dr. Carolyn Lam:

This is from Dr. Clara Chow from University of Sydney and her colleagues, who performed a single blind multi-center randomized controlled trial of post-ACS patients across 18 rural and urban centers and three time zones in Australia. The control group received usual care, and the intervention group additionally received multiple motivational and supportive weekly text messages on medications, and healthy lifestyle, with the opportunity for two-way communication.

Dr. Greg Hundley:

Wow, Carolyn. So text messaging to facilitate medication adherence. I can't wait to hear. So what did they find?

Dr. Carolyn Lam:

I think the design, it's such a neat study. However, the study found no significant impact on the primary outcome of medication adherence at six and 12 months, nor on LDL cholesterol or blood pressure.

Dr. Carolyn Lam:

However, intervention participants were more likely to achieve a normal body mass index and to eat guideline-recommended servings of fruit and vegetables. Qualitative analysis demonstrated a high level of acceptability, utility in being a unified source of information, high program engagement, and emotional support, especially during times of uncertainty.

Dr. Greg Hundley:

Interesting, Carolyn. Sounds like an impact on diet, so what did we learn from this study?

Dr. Carolyn Lam:

Well, customized and personalized text message-based prevention programs are indeed a scalable and low-cost means of delivering consistent education and support to patients following hospitalization for ACS. So this study shows it's feasible. The lack of impact, however, on medical adherence, though with better adherence to healthy lifestyle practices, suggests that maybe external factors, such as cost, may strongly influence medical adherence. These need to be addressed, in addition to education programs, to improve medical adherence. But all of this is discussed in a beautiful editorial entitled, "Opportunities and Challenges of Mobile Health Tools to Promote Health Behaviors" by Drs. Sharma and Avram.

Dr. Greg Hundley:

Very nice. Carolyn, what a great summary. Well, my paper comes to us from Professor Mario Delmar from New York University School of Medicine, and Carolyn, exercise training as well as catecholaminergic stimulation increases the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy or ARVC, and this correlates with plakophilin-2 mutations. Now, Carolyn, separate data show that reduced abundance of plakophilin-2 leads to dysregulation of intracellular calcium homeostasis, and Carolyn, these authors studied the relation between exercise and or catecholaminergic stimulation, intracellular calcium homeostasis, and arrhythmogenesis in plakophilin-2 deficient murine hearts.

Dr. Carolyn Lam:

Ooh. So what were the effects?

Dr. Greg Hundley:

Right, Carolyn. For training, the mice underwent 75 minutes of treadmill running once per day, five days each week, for six weeks. And the authors observed that exercise disproportionately affected calcium intracellular homeostasis in plakifilin-2 deficient hearts, in a manner facilitated by stimulation of intracellular, beta-adrenergic receptors or hyper-phosphorylation of phospholamban.

Dr. Greg Hundley:

Now these cellular changes created a pro-arrhythmogenic state that can be mitigated by plakophilin receptor blockade. Additionally, Carolyn, these authors' data unveiled an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of a deficit in plakophilin-2. They suggest that membrane-permeable beta blockers are potentially more efficient for ARVC patients.

Dr. Greg Hundley:

And also they highlight the potential for ryanodine-receptor channel blockers as treatment for the control of heart rhythm in this population at risk, and propose that plakophilin dependent and phospholamban-dependent, ARVC-related arrhythmias have a common mechanism.

Dr. Carolyn Lam:

Wow, thanks again, Greg. That was really, really a nice explanation. Well, for this next original paper, it looks at the question of the association between major bleeding and non-major clinically relevant bleeding, with subsequent mortality in hospitalized patients, and authors did this by exploring this relationship in the MAGELLAN and MARINER trials of extended thrombo-prophylaxis in hospitalized medical patients.

Dr. Greg Hundley:

Wow. Carolyn. I can't quite remember, and maybe for our listeners, remind us of the design of the MAGELLAN and the MARINER trials.

Dr. Carolyn Lam:

These trials evaluated, whether rivaroxaban compared with enoxaparin or placebo, could prevent venous thromboembolism without increased bleeding. The authors, led by Dr. Spyropoulos from the Feinstein Institute of Medical Research in New York, hypothesized that patients with major bleeding, but not those with non-major clinically relevant bleeding, would be at an increased risk of all-cause mortality. So Greg, would you like to guess what they found?

Dr. Greg Hundley:

Oh, Carolyn, you've put me on the spot here. I'm not sure.

Dr. Carolyn Lam:

Maybe just, did the authors get it right or wrong? Just....

Dr. Greg Hundley:

I'm saying, they got it right.

Dr. Carolyn Lam:

Oh, always clever. They found that compared to patients with no bleeding, the risk of all-cause mortality for patient with non-major clinically relevant bleeding was not increased in MARINER, but was increased in MAGELLAN. Major bleeding, however, was associated with a higher incidence of all-cause mortality in both studies, while trivial bleeding was not associated with mortality in either study. These results really inform the risk benefit calculus of extended thromboprophylaxis in medically ill patients.

Dr. Greg Hundley:

Wow. Carolyn, great presentation. We've got some other articles in this issue. And let me tell you about two that I have. First is a Research Letter from Professor Frankel entitled "Trends in Opioid Use after Cardiac-Implantable Electronic Device Procedures in the United States, between the years of 2004 and 2020." And Tracy Hampton, from the National Association of Science Writers, presents some very recent news in the world of cardiology.

Dr. Carolyn Lam:

Nice. Well, there's an exchange of letters as well between Drs. Yang and Nagareddy regarding the article "Retention of NLP3 Inflammasome-Primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-Induced Granulopoiesis." And finally, in the Editor’s Page, a nice piece from Drs. Joe Hill, Darren McGuire, and James de Lemos on “Circulation: Best Papers, 2021.” Gosh, really, really nice issue. Now let's go on, though, to the feature discussion, yeah?

Dr. Greg Hundley:

You bet.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run podcast. My name is Mercedes Carnethon, one of the associate editors, and I'm a professor of preventive medicine at the Northwestern University Feinberg school of Medicine. I'm really excited today to have a guest with us. Dr. Brendon Neuen, who has shared with us his really outstanding research on SGLT2 inhibitors and the risk of hyperkalemia in people with type-two diabetes, a meta-analysis. So welcome to our podcast today, Brendon.

Dr. Brendon Neuen:

Thanks very much for having me Mercedes. It's a real pleasure to be here.

Dr. Mercedes Carnethon:

Well, thank you for joining us. We're really pleased that you chose Circulation to share with us your really important findings. Can you tell us a little bit about the rationale for your study and how you carried out your work?

Dr. Brendon Neuen:

Yeah, absolutely. So we know that in people with diabetes and people with CKD, hyperkalemia is a common occurrence, and it's a problem for two reasons as you'd be aware. Firstly, it is associated with cardiac dysrhythmias and secondly, perhaps at least as importantly, it limits the optimal use of treatments that reduce kidney disease progression and heart failure events. So that is, agents that block the renin angiotensin aldosterone system.

Dr. Brendon Neuen:

We now know, and we've got robust evidence from large outcome trials, that SGLT2 inhibitors reduce the risk of heart failure and kidney disease progression in people with and without diabetes, but we haven't really, up and until now, systematically evaluated their effect on potassium outcomes, particularly hyperkalemia. And so we set out to assess whether these agents affect serum potassium levels and alter the risk of hyperkalemia as well as hypokalemia.

Dr. Mercedes Carnethon:

Thank you. That sounds like a really excellent and well needed study, given how much we've heard within the field about the benefits of SGLT2 inhibitors. It's nice to see a careful evaluation of what some of the considerations are in their use. So tell us a little bit about how you carried out this study and what you ultimately found.

Dr. Brendon Neuen:

What we did was, we identified clinical trials that enrolled people with type two diabetes at high cardiovascular risk or with chronic kidney disease. And what we did is, we approached the investigators of each of these trials and asked them to collaborate on a large meta-analysis using individual participant data.

Dr. Brendon Neuen:

What that allowed us to do was, then, standardize across all of the trials of different outcome definitions, and allowed us to assess the effective SGLT2 inhibitors on a primary outcome of time to first serum potassium greater than or equal to six, defined as serious hyperkalemia, as well as hypokalemia, investigator-reported hyperkalemia events, and a range of other potassium-related outcomes in a broad population, including people with chronic kidney disease, people with heart failure, and people using different concomitant medications, such as diuretics and MRAs in the background.

Dr. Mercedes Carnethon:

So thank you, Brendon, for the explanation of the use of the meta-analytic design and the entry criteria of type-two diabetes and chronic kidney disease. Can you tell us, what were the outcomes across these studies?

Dr. Brendon Neuen:

The primary outcome we evaluated was time to first serious hyperkalemia, defined as a serum potassium greater than or equal to six, as well as a range of other potassium-related outcomes, including investigator reported hyperkalemia, change in potassium over time, as well as hypokalemia, defined as a serum potassium less than 3.5.

Dr. Brendon Neuen:

What we found was that overall SGLT2 inhibitors reduce the risk of serious hyperkalemia by about 16%. And that effect was consistent across the agents within the class, and across different subpopulations and trials. This effect was supported by a 20% risk reduction in investigator-reported hyperemia events and importantly, there was no difference in risk of hypokalemia, that is a serum potassium less than 3.5, between SGLT2-treated and placebo-treated participants.

Dr. Mercedes Carnethon:

Thank you for that summary. You know, one of the very impressive aspects of this clinical trial is certainly the size and the number of participants. Brendon, I was really struck by your description of the consistency of findings across the subgroups. And in particular, when I reviewed the findings in the paper, I noticed that serious hyperkalemia was higher in those with poorer kidney function. Did you find that surprising?

Dr. Brendon Neuen:

From clinical practice, we know that one of the major determinants of hyperkalemia risk is kidney function. It's a major problem that we run into in people with more advanced CKD. And what that means is that for people with more advanced chronic kidney disease, who are at high risk of hyperkalemia, the absolute benefits of SGLT2 inhibition on hyperkalemia risk are likely greater in these individuals, because they're at high risk of this outcome.

Dr. Brendon Neuen:

Other patients who might be at increased risk of hyperkalemia include those with heart failure or those taking mineralocorticoid receptor antagonists at baseline. And so you'd expect that if the relative effects are consistent across many subgroups, then the absolute risk reductions are likely to be larger in people taking MRAs or people with more advanced CKD.

Dr. Mercedes Carnethon:

Thank you so much for summarizing the importance of these findings and what they mean for our clinical audience. It's wonderful to have this sort of information from a meta-analysis because it allows us large sample sizes, where we can do things like you describe, such as describing subgroup effects.

Dr. Mercedes Carnethon:

It also presents us with very robust evidence that can be taken into clinical practice for our clinical audience to use. Based on what you found, how do you anticipate that these findings can be used by our clinicians?

Dr. Brendon Neuen:

Well, thanks, Mercedes. I think the reduction in risk of hyperkalemia that is observed in these data suggests that SGLT2 inhibitors might enable better use of other proven therapies that reduce cardio-renal risk in people with chronic kidney disease and people with heart failure. We all know that in treating these high risk patients, hyperkalemia is a problem. And by reducing the risk of hyperkalemia with SGLT2 inhibitors, it might enable better use of renin angiotensin system blockade and mineralocorticoid receptor antagonists in people with chronic kidney disease and heart failure.

Dr. Mercedes Carnethon:

So you've provided a really excellent overall summary of the impact of these finding for clinical practice and the possible next steps. I wanted to end on a note of asking you what surprised you about these findings that might lead to further future investigations.

Dr. Brendon Neuen:

Thanks, Mercedes. I think that's a really interesting question. What was somewhat surprising, but also reassuring, was the consistency of the treatment effect on hyperkalemia, regardless of how we defined it, whether that was defined based on investigator-reported hyperkalemia events or central laboratory-measured serum, potassium levels, the treatment effect was very consistent. And I think that gives us some confidence about the robustness of these findings and their application to clinical practice.

Dr. Mercedes Carnethon:

Well, thank you so much, Brendon. I have really enjoyed this discussion with you today and this really important paper that is describing an important safety outcome for SGLT2 inhibitors in patients with type two diabetes. And again, I really want to thank you for sharing your excellent work with us here at Circulation. I anticipate that our readership, when they leave this podcast and pick up their journals, will be thrilled to read about all of the details about the excellent work that you and your team have carried out. So thank you very much for joining us today.

Dr. Brendon Neuen:

Thanks very much for having me, Mercedes. It was a real pleasure.

Dr. Mercedes Carnethon:

Thank you, and thank you again to our audience for joining us for this episode of Circulation on the Run.

Speaker 5:

Circulation May 3, 2022 Issue

2 maj 2022 | 27 min

This week, please join author Guest Host Mercedes Carnethon, Author Brian Bergmark, and Associate Editor Parag Joshi as they discuss the article “Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.”

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this week's feature, non-high density lipoprotein cholesterol levels in statin treated patients with elevated cholesterol. We're going to hear from the TRANSLATE-TIMI 70 study. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I would. And by the way, that feature is going to be all exciting. It was discussed at the American College of Cardiology. But okay, how about from cholesterol to vitamins? Let's start with the Greg quiz. Greg, which vitamins have been associated with arterial calcification? Is it A, B, C, D, E?

Dr. Greg Hundley:

I'm going to pick E and K.

Dr. Carolyn Lam:

You’re smart. Indeed. Vitamin K2, also known as menaquinone-7 is the most effective co-factor for the carboxylation of proteins involved in the inhibition of arterial calcification. Furthermore, combined low vitamin K and low vitamin D have been associated with increased all-cause mortality risk. And so, today's paper is from Dr. Diederichsen from Odense University Hospital in Denmark and colleagues really present the first double-blind, randomized controlled trial to test whether vitamin K2, a drug-targeting processes of calcification in addition to vitamin D, could slow the progression of aortic valve calcification and stenosis. So, in a randomized double-blind multicenter trial, men from the community with an aortic valve calcium score above 300 arbitrary units on cardiac non-contrast CT were randomized to daily treatment with 720 micrograms of vitamin K2 plus 25 micrograms of vitamin D or matching placebo for 24 months. And the primary outcome was the change in aortic valve calcium score.

Dr. Greg Hundley:

Carolyn, so menaquinone-7 and aortic valve score. So, what were the results?

Dr. Carolyn Lam:

Menaquinone-7 had no major effect on the progression of aortic valve calcification as assessed by CT or echo. High-dose menaquinone-7 was, however, safe and well tolerated. Now, some limitations is that this external validity is limited to men aged 65 to 74 with aortic valve calcification scores of greater or equals to 300 arbitrary units. Thus, caution is needed if we extrapolate these findings and other pathways need to be explored in order to identify an effective therapy for this unmet clinical need.

Dr. Greg Hundley:

Wow, very nice Carolyn. Well, my first article comes to us from Dr. Michael Laflamme from the University Health Network. And Carolyn, human pluripotent stem cell-derived cardiomyocytes or hPSC-CMs exhibit promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. So Carolyn, this research team hypothesized that large scale manufacturing of mature hPSC-CMs could be achieved via culture on polydimethylsiloxane, and we're going to call that PDMS, lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes then with conventional immature hPSC-CMs populations.

Dr. Carolyn Lam:

Oh, that's neat, Greg. So, what did they find?

Dr. Greg Hundley:

Right, Carolyn. So, these authors demonstrated the economic generation of greater than one times 10 to the eighth mature hPSC-CMs per PDMS line roller bottle. And compared to their counterparts, PDMS matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More importantly, intracardiac graphs formed with PDMS matured myocytes showed greatly enhanced structured alignment, better host graft electromechanical integration, less pro arrhythmic behavior, and greater beneficial effects on contractile function. So in summary, Carolyn, this team describes practical methods for the scale generation of mature human pluripotent stem cell-derived cardiomyocytes and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo. And there's a wonderful editorial by Professor Murray entitled Flexing Their Muscles: Maturation of Stems Cell-Derived Cardiomyocytes on Elastomeric Substrates to Enhance Cardiac Repair.

Dr. Carolyn Lam:

Wow! That's really significant. Thank you, Greg. Well, the next paper is the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals. And this is from Dr. Xia Chen from Fudan University and Dr. James Wilson from University of Edinburgh in UK, and their colleagues. And guess what, it focuses on severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID 19. And we know that that enters human cells using the ACE2 protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems.

Dr. Greg Hundley:

Wow, Carolyn. ACE2, and also a very important topic here with SARS-COVID-2. So, what did they find?

Dr. Carolyn Lam:

First, the overall heritability of ACE2 level is 16% of which 30% can be explained by 10 protein quantitative trait loci identified in this study. ACE2 level is genetically correlated with both COVID-19 and cardiovascular. Elevated ACE2 levels show a causal relationship with COVID-19 severity, hospitalization and infection as shown by Mendelian randomization analyses. ACE2 regulatory variants are enriched on DNA methylation sites in immune cells.

Dr. Greg Hundley:

Wow, Carolyn. So, elevated ACE2 and a causal relationship with COVID-19 severity. So tell us, what are the clinical applications of this really nice study?

Dr. Carolyn Lam:

The causal evidence of ACE2 suggests that pharmacological inhibition of circulating ACE2 may be a promising approach for treating COVID-19 or its comorbidities. Transcription factors that play essential roles in ACE2 generation could provide alternative paths to pharmacological modulation of ACE2 plasma levels. The genetic correlations between ACE2 and both COVID-19 and cardiovascular disease imply that the cardiovascular complications seen in COVID-19 patients may be intrinsic to the disease and mechanically or/and mechanistically-driven by ACE2. Isn't that neat?

Dr. Greg Hundley:

You bet, Carolyn. Boy, what an exciting issue. And we've got other articles in this issue.

Dr. Carolyn Lam:

Yeah. Now, let me start this time. There's an exchange of letters between Drs. Duan and Chang regarding the article “Therapeutic Exon Skipping Through a CRISPR-Guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy in Vivo.” There's a Perspective piece by Dr. Morris, “The Updated Heart Failure Guidelines: Time for a Refresh.” Love that piece! There's an AHA Update piece (AHA President’s Page) by Dr. Elkin on The Road to Equity in Brain Health, and ECG challenge by Dr. Kolominsky, Electrical Extremists in a Critically ill Patient, and an On My Mind Paper by Dr. Paulus entitled “Border Disputes Between Heart Failure Phenotypes.”

Dr. Greg Hundley:

Wow, Carolyn. And I've got two Research Letters. The first from Professor Groeneveld entitled “Prevalence of Short-Coupled Ventricular Fibrillation in a Large Cohort of Dutch Idiopathic Ventricular Fibrillation Patients.” And then a second Research Letter from Professor Yamashita entitled “Single Cell RNA Sequence Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome.” Well Carolyn, now, we get to go onto our feature, vupanorsen on non-high-density lipoprotein cholesterol levels and catching up with TIMI 70.

Dr. Carolyn Lam:

Let's go.

Dr. Mercedes Carnethon:

So, good morning listeners. I'm really pleased to invite you to this episode of our Circulation on the Run podcast. For those of you who don't hear me often, I'm stepping in as a guest host today. My name is Mercedes Carnahan from the Northwestern University Feinberg School of Medicine. And I'm really excited to be joined today by Dr. Brian Bergmark, and associate editor, Dr. Parag Joshi. And we will have today Dr. Bergmark discussing his new article published with us on the effects of vupanorsen on non-HDL cholesterol levels in the TRANSLATE-TIMI 70 trial. We're really thrilled to have you with us here today, Brian, to talk about the really important findings coming from this trial. So to start us off, just tell us, what did you find?

Dr. Brian Bergmark:

Great. Thank you so much. It's really a pleasure to be here and I'm grateful for the opportunity. So, in the big picture, despite numerous agents to reduce lipid-mediated cardiovascular risk, obviously, residual risk remains and there are novel targets to address that risk. One of them is angiopoietin-like 3, which is a protein made in the liver. Angiopoietin-like 3 or ANGPTL3 inhibits lipoprotein lipases among other lipases, and thereby interferes with metabolism of triglyceride-rich lipoproteins. And so, the idea here was that if ANGPTL3 could be inhibited that LPL or lipoprotein lipase function could be augmented and metabolism of these lipoproteins could be augmented. And so, what we did is we took patients with an elevated non-HDL cholesterol, at least 100 milligrams per deciliter, and elevated triglycerides, 150 to 500 milligrams per deciliter, and randomized them to placebo or one of seven doses of vupanorsen, which is an antisense oligonucleotide, which inhibits the synthesis of ANGPTL3 in the liver. We then follow them to see what the impact was on their non-HDL cholesterol, as well as other lipid parameters through 24 weeks.

Dr. Mercedes Carnethon:

Thank you so much. It's a wonderful design, and I'm really excited to hear a little bit more about what you found.

Dr. Brian Bergmark:

Great. So, the primary endpoint was the change in non-HDL cholesterol from baseline to 24 weeks. And we did find that all vupanorsen regimens reduced non-HDL cholesterol in a statistically significant manner. The magnitude of that effect was up to 27.7% in one of the dose arms or about 28%. We also saw a statistically significant reductions in the target ANGPTL3 up to about a 95% reduction in the highest dose arm, as well as statistically significant reductions in triglycerides at all of the dose regimens. The effect on LDL cholesterol and on apolipoprotein B or apo B was variable across regimens and only statistically significant in a few of the dose arms. We also found several safety signals. One, there appeared to be higher rates of injection site reactions in the skin at higher total monthly doses. We also found higher rates of elevation in liver enzymes, AST and ALT at higher total monthly doses. And we also found significant increases in hepatic fat fraction or the fat content of the liver at higher total monthly doses.

Dr. Brian Bergmark:

In the end, we found that while statistically significant, the magnitude of the reduction in non-HDL cholesterol was modest as was the reduction in apo B. And so, the goal here was to find a dose that might have a reduction of a magnitude that would be clinically meaningful for cardiovascular risk reduction. We were underwhelmed by the magnitude of that reduction, and then it was paired with these safety signals, which if there's interest, we could get into more detail in our thinking about why those occurred, what the implications are, but suffice it to say that there were medically meaningful safety concerns paired with a modest reduction in non-HDL cholesterol.

Dr. Mercedes Carnethon:

Thank you for that excellent summary. Before I turn it over to the associate editor, I read this with great interest, and in particular, looking at one of the first figures in the paper, which is demonstrating the adjusted change at 24 weeks across different doses and based on how frequently the doses were given the four week as compared with the two week. And one thing that really stood out to me was the clear dose response with the four week regimens with the higher doses appearing to demonstrate the greatest reductions but a less clear signal with the two week regimens. Do you have any hypotheses about why these patterns appeared so different?

Dr. Brian Bergmark:

Yeah. It's a great question. So, the responsiveness of this is something of interest here I think. So, if you look at the effect of the drug on its target, ANGPTL3, there is a very clear dose response, so there's no doubt that higher doses were impacting the target ANGPTL3 to a greater extent. So, one of the most direct effects would be on triglycerides, one of the most direct lipid effects, and that appears pretty close to a dose response relationship within each of these frequencies of administration. But once you start getting to non-HDL cholesterol, it starts to break down a bit. And is it simply because of random chance or is there actually something distinct going on with how the lipids are being metabolized?

Dr. Brian Bergmark:

That is something we are diving into. So, the hope would be that we actually reduce apo B, the number of these actually circulating lipoproteins as has been demonstrated with the monoclonal antibody. It's possible that with this other different mechanism in the antibody, this antisense oligonucleotide, perhaps, we're simply shifting the content of these lipoprotein molecules and decreasing the triglyceride content but not actually meaningfully modifying the amount of apo B, LDL cholesterol. And that might be part of what we're seeing with the more muted relationship between dose and the effect on non-HDL cholesterol. I don't know for certain we are diving into this a bit more with other lipid fractions, et cetera.

Dr. Mercedes Carnethon:

Oh, well, thank you so much for that explanation. I know that a number of people, this was extremely well received when shared at the recent American College of Cardiology meetings, and so I was really thrilled to find that this was appearing in the journal circulation. So Parag, I'm really interested in hearing your perspectives on why we knew that this was certainly a priority paper for us.

Dr. Parag Joshi:

Yeah. Let me first start, Brian, congratulations. Fantastic work. And we were excited to receive the paper. I think really hard to pull off trials right now or in the last couple years, so kudos to you. And I echo the sentiments from Mercedes. This is great work. Really important space, the residual risk space I think is very important of course and is critical to moving forward with improving cardiovascular health. So, one of the big picture questions and as we get to this triglyceride-rich lipoprotein lowering space, certainly, there's strong associations with residual risk, but can we impact that risk? And here, we're starting to explore that. And I think when you think of the lipoprotein space, many of us are interested in what is the effect on these lipoproteins as opposed to the cholesterol content or the triglyceride content. And non-HDL cholesterol or apo B, clearly, the better, stronger markers for that risk, so we were really excited to see this paper.

Dr. Parag Joshi:

And as Brian mentioned, unfortunately, not the strongest impact here on those measures. And I want to dive into that a little more because I think that carries significant implications for the space, and I'd love to hear your thoughts on that. But overall, really fantastic work. I think my first question really is around the apo B aspect of this and the less than anticipated lowering of those levels. You hinted at this in terms of, is this shuffling cholesterol and triglycerides across particles, or do you think this could be the mechanism by which this happens through ANGPTL3? You do inhibit the levels quite a bit. Did we just miss that... Is this not the right target? What do you think?

Dr. Brian Bergmark:

Yeah, it's a great question. I do think the target itself holds great promise. Obviously, a monoclonal antibody against this same target results in major reductions in apo B, LDL cholesterol, and the latter through a mechanism that is not really known but is not dependent on the LDL receptor, and therefore has real clinical utility that's approved for people with familial homozygous hypercholesterolemia. Beyond that, of course, in genetic studies, there's a clear association with loss of function in the ANGPTL3 gene and lower levels of all of these lipids, lower rates of coronary artery disease, et cetera.

Dr. Brian Bergmark:

So, I think it's not that this pathway is not promising and actually already being taken advantage of, I think it's that this particular agent acting through this mechanism was not able to achieve a necessary efficacy with reasonable safety. Some genetic data suggests that there is not actually a dose response between a reduction or loss of function in ANGPTL3 and reduction in apo B or lower levels of apo B and non-HDL cholesterol, but it really requires your complete elimination of ANGPTL3 function, which is probably, likely achieved with the monoclonal antibody. And so, even though we had quite large reductions with the antisense oligonucleotide, perhaps, we just didn't cross that threshold that's needed to modify the lipid panel in the way that would've been clinically meaningful.

Dr. Parag Joshi:

Yeah. I think that's fantastic as you allude to with evolocumab and the impact that has on apo B levels. I didn't think of it as a threshold effect, but that makes a lot of sense as maybe that just getting to that tipping point is where the issue is here. In terms of the liver signal, what were your thoughts on that? And is that something that we should expect to see in ASOs or do you think it's specific to this compound?

Dr. Brian Bergmark:

Yeah, I don't know. That was unexpected. Right, there are two liver signals and it's unclear how related they are. One is the inflammation of the liver as indicated by the elevation in enzymes, and then the other is the fat accumulation. So with respect to the fact, if anything, genetic data suggests perhaps loss of function in ANGPTL3 might result in lower rates of hepatic steatosis. In animal models, the antisense oligonucleotide reduces liver fat, and so there's, there was promise going into this that this could actually be beneficial for non-alcoholic fatty liver disease. And additionally, there's not data to suggest that the monoclonal antibody increases liver fat. So, there's not a lot to support this as being an on-target effect that by inhibiting ANGPTL3, by that pathway, the liver fat was increased. So, I think a reasonable person might wonder whether this was an off-target effect of the drug.

Dr. Brian Bergmark:

By what mechanism that occurred, I don't know, what the implications would be for other related agents, I don't know. And then similarly, the liver enzyme elevations, is that related to this? I'm not exactly sure, but also unexpected and I think off-target. But that sort of intrinsic to this mechanism of hepatic targeting, is this something we need to be worried about for other agents in this class or not? I don't know. Obviously, we can't answer that from this single study. We are going to dive into it a bit more to try to overlay patients with hepatic fat accumulation, liver enzymes, et cetera. Of course, both of those happen more at higher doses. How much we can really parse this? I'm not sure yet.

Dr. Parag Joshi:

Yeah. That's really fascinating. I think the appeal of this paper to the circulation audience is that you have a really exciting novel target and pathway to explore here but somewhat divergent results from what's existing in this space. And I think that raises a lot of questions, really interesting questions going forward for this space. For the ANGPTL3 pathway, what do you see there coming down the line or what are your thoughts on that going forward for this target and ways to approach risk related to it?

Dr. Brian Bergmark:

Yeah. Great. Thank you. Yeah. No, so I agree. I think moving into this other end of the spectrum of triglyceride-rich lipoproteins, et cetera, I think this is where we're headed and this is why we do the trial. We weren't expecting these things that's why you do this experiment, and this is what we found. So now, where do we go from here? So there are, of course, other ways beyond the monoclonal antibody of targeting ANGPTL3 specifically. There's siRNA, there is gene therapy being investigated. So, I think all of them hold an great promise. And of course, we will need to see as those therapies move along what the actual trials show. And then there are, of course, other pathways that are of interest, APOC3, for instance. So, I think there's a lot more in this space that's coming down the line.

Dr. Parag Joshi:

Yeah, absolutely. I think it's a really exciting space, and we're really happy to get this paper as one piece of that whole puzzle. So, thank you.

Dr. Mercedes Carnethon:

Yes. And I echo that as well. And as a methodologist myself, I'm always really pleased to see such well-designed studies. I think this was sophisticated in many aspects in testing different dosing and different timing of the dosing. And also, I'm really impressed by your inclusion criteria, particularly when I noted that 44% of the participants were female, and that you reported those stratum-specific effects. I just had a final question as we wrap up. You acknowledge a nominally significant interaction by sex and I see, for example, that it appears that the magnitude is larger possibly in the relatively smaller subset of females as compared with males. Is this something to pay attention to or do you think this is just some type of an artifact related to greater variability because the group is smaller?

Dr. Brian Bergmark:

Yeah, it's a good question. So, this is the burning question. We had no a priority reason to suspect that biologically and we are not adjusting for multiple testing in the key value of 0.04. So just to put my money down, I would say, I would guess it's random chance. We found it. It's worthy of looking into a bit more. There were, of course, the important implications for other drugs, et cetera. So, I think it's worth diving into as we will, but are we likely to uncover some biological difference? I doubt it. I wouldn't guess. There are other subgroups where I think at least upfront, you might expect there could be a difference. So, there are thoughts about insulin's effect on LPL. Could diabetes status have an interaction with the drug? I think though not statistically significant, it's also something worth looking into that group and the subfractions of the lipid panel and all of that stuff. So, I think it's all worth looking into but cautiously with the constraints.

Dr. Mercedes Carnethon:

Well, thank you so much for that explanation. And I've really enjoyed this discussion with you today, Brian, and you, Parag. I've certainly learned a lot and I'm really excited to see this excellent work coming out in the journal circulation. So, thank you very much for your time this morning and thank you to our listeners. Wrapping up this episode of Circulation on the Run.

Dr. Greg Hundley:

Circulation April 26, 2022 Issue

25 april 2022 | 22 min

This week, please join author Vasan Ramachandran and Associate Editor Mercedes Carnethon as they discuss the article "Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about today's feature paper. You see, I trained at the Framingham Heart Study and today's feature paper talks about the temporal trends in the remaining lifetime risk of cardiovascular disease among middle aged adults across six decades in the Framingham Heart Study. Truly a landmark study and a discussion nobody wants to miss. But first, let's talk about the other papers in today's issue, and I understand that you've got one ready.

Dr. Greg Hundley:

You bet Carolyn. I'll get started first. Thank you. So my first paper comes from Dr. Daniel Mark from Duke University and it refers to the ISCHEMIA trial.

Dr. Carolyn Lam:

Ooh, could you please first remind us what is the ISCHEMIA trial and are you presenting a substudy, is that correct?

Dr. Greg Hundley:

Right, Carolyn. So the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, or ISCHEMIA, compared an initial invasive strategy with an initial conservative strategy in 5,179 participants with chronic coronary disease and moderate or severe ischemia. And this sub study of the ischemia research program included a comprehensive quality of life analysis.

Dr. Carolyn Lam:

So very interesting. What did they find Greg?

Dr. Greg Hundley:

Right, Carolyn. So this study included 1,819 participants. 907 in the invasive, 912 in the conservative. And collected a battery of disease specific and generic quality of life instruments by structured interviews at baseline. And then at three, 12, 24 and 36 months post randomization, and then finally at study closeout. Now Carolyn, these assessments included an angina related quality of life assessment from the 19 item Seattle Angina Questionnaire, a generic health status assessment, an assessment of depressive symptoms, and for North American patients, cardiac functional status from the Duke Activity Status Index, or DASI. In this study, Carolyn, in terms of results, the median age was 67 years and about 20% were women and about 16% were nonwhite. So Carolyn, getting to the results. The estimated mean difference for the SAQ 19 summary score favored invasive therapy. And remember the SAQ 19 was the Seattle Angina Questionnaire.

Dr. Greg Hundley:

Next, no differences were observed in patients with rare or absent baseline angina. Next, among patients with more frequent angina baseline, those randomized to invasive had a mean point higher score on the SAQ 19 summary score than the conservative approach, with consistent effects across all of the SAQ subscales including physical limitations, angina frequency and quality of life health perceptions. For the DASI, and remember DASI refers to the Duke Activity Status Index, no difference was estimated overall by treatment. But in patients with baseline marked angina, DASI scores were higher for the interventional arm. Whereas patients with rare or absent baseline angina showed really no treatment related differences.

Dr. Carolyn Lam:

Oh, okay. So a lot of results. What's the take-home message, Greg?

Dr. Greg Hundley:

Right, Carolyn. Glad you asked. So in the ISCHEMIA comprehensive quality of life substudy, patients with more frequent baseline angina reported greater improvements in the symptom physical functioning and psychological wellbeing dimensions of quality of life when treated with an invasive strategy. Whereas patients who had rare or absent angina baseline reported no consistent treatment related quality of life differences.

Dr. Carolyn Lam:

Wow. Thank you, Greg. Very interesting indeed. Now from angina to now cholesterol. Now, cholesterol guidelines typically prioritize primary prevention statin therapy based on 10 year risk of cardiovascular disease. Now the advent of generic pricing may in fact justify expansion of statin eligibility. Moreover, 10 year risk may not be the optimal approach for statin prioritization. So these issues were looked at in this next paper by authors led by Dr. Kohli Lynch from Northwestern University and colleagues who estimated the cost effectiveness of expanding preventive statin eligibility, and evaluated novel approaches to prioritization from a Scottish health sector perspective. A computer simulation model predicted long term health and cost outcomes in Scottish adults, age 40 years or more.

Dr. Greg Hundley:

So Carolyn, what did they find?

Dr. Carolyn Lam:

The advent of generic pricing has rendered preventive statin therapy cost effective for many adults. Absolute risk reduction guided statin therapy, which is based on 10 year cardiovascular disease risk and non HDL cholesterol levels, is cost effective and would improve population health. Whereas age stratified risk thresholds were more expensive and less effective than alternative approaches to statin prioritization. So guidelines committees may need to expand statin eligibility and consider new ways to allocate statins based on absolute risk reduction rather than 10 year risk thresholds.

Dr. Greg Hundley:

Very nice Carolyn. Always important, new information regarding statin therapy. Well Carolyn, my next paper comes to us from the world of preclinical science. And Carolyn, as you know, the regenerative capacity of the heart after myocardial infarction is limited. And these authors led by Dr. Tamer Mohamed from University of Louisville previously showed that ectopic introduction of Cdk1, CyclinB1 and Cdk4, CyclinD1 complexes and we'll refer to those now as 4F, promoted cardiomyocyte proliferation in 15 to 20% of infected cardiomyocytes in vitro and in vivo and improved cardiac function after MI in mice. So Carolyn, in this study using temporal single cell RNA sequencing, the investigative team aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. And also using rat and pig models of ischemic heart failure, they aim to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia induced heart failure.

Dr. Carolyn Lam:

Oh, wow Greg. So what did they find?

Dr. Greg Hundley:

Several things, Carolyn. First, temporal bulk and single cell RNA sequencing and further biochemical validations of mature HIPS cardiomyocytes treated with either LAcZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours post-infection with 4F. Which was mainly associated with sarcomere disassembly and metabolic reprogramming. Second Carolyn, transient overexpression of 4F specifically in cardiomyocytes was achieved using a polycistronic non-integrating lentivirus encoding the 4F with each driven by a TNNT2 promoter entitled TNNT2-4F polycistronic-NIL. Now this TNNT2-4F polycistronic-NIL or control virus was injected intra myocardial one week after MI in rats, so 10 per group, and pigs, six to seven per group.

Dr. Greg Hundley:

And four weeks post-injection the TNNT2-4F polycistronic-NIL treated animals showed significant improvement in left ventricular injection fraction and scar size compared with the control virus treated animals. And four months after treatment, the rats that received TNNT2-4F polycistronic-NIL still showed a sustained improvement in cardiac function without obvious development of cardiac arrhythmias or systemic tumorigenesis. And so Carolyn this study advances concepts related to myocellular regeneration by providing mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell factors, thanks to the use of a novel transient and cardiomyocyte specific viral construct.

Dr. Carolyn Lam:

Wow. What a rich study. Thanks so much, Greg.

Dr. Greg Hundley:

Well, Carolyn, how about if we see what else and what other articles are in this issue. And maybe I'll go first. So there's a research letter from Dr. Wu entitled Modeling Effects of Immunosuppressive Drugs on Human Hearts Using IPSC Derived Cardiac Organoids and Single Cell RNA Sequencing. Carolyn, there's an EKG challenge from Dr. Yarmohammadi, entitled “Fast and Furious, A Case of Group Beating in Cardiomyopathy.” And then finally from Dr. Tulloch, a really nice Perspective entitled “The Social Robots are Coming, Preparing For a New Wave of Virtual Care in Cardiovascular Medicine.

Dr. Carolyn Lam:

Oh, how interesting. Well, also in the mail back is an exchange of letters of among Drs. Lakkireddy, Dhruva, Natale, and Price regarding Amplatzer Amulet Left Atrial Appendage Occluder versus Watchman Device for stroke prophylaxis, a randomized control trial. All right. Thank you so much, Greg. Shall we go on to our feature discussion now?

Dr. Greg Hundley:

You bey. Welcome listeners to our feature discussion today. And we're so fortunate we have with us today, Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. Welcome to you both. And Vasan, let's start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Vasan Ramachandran:

Thank you, Greg, first of all for having me. So we know two facts. One is that heart disease and stroke disease death rates and incidents are declining over the last six decades in the United States. Juxtapose against that is also the observation that there is rising incidence of obesity and overweight, and also a rising burden of diabetes. There are a lot of advances in our ability to treat high blood pressure, high cholesterol, as well as high blood sugar. So we wanted to ask the question, given the historic trends in control awareness of risk factors and their control, interrupted by this escalating burden of obesity, overweight, and diabetes, what is the lived experiences of people over time in terms of the risk of developing heart disease or stroke using a metric we call as the remaining lifetime risk of developing heart disease or stroke.

Dr. Greg Hundley:

The hypothesis you wanted to address?

Dr. Vasan Ramachandran:

The hypothesis we wanted to address was that perhaps the decline in the incidence of heart disease and stroke may have decreased over time given the escalating burden of overweight, obesity and diabetes.

Dr. Greg Hundley:

Very nice. And can you describe for us your study population and your study design?

Dr. Vasan Ramachandran:

Thank you, Greg. So the Framingham Heart Study is one of the oldest running epidemiological studies in the world. We have multiple cohorts. The study began in 1948 with the original cohort, the offspring cohort enrolled in 1971, third generation cohort in 2002, and two minoritized cohorts in the 1990s and 2002. So we have an observation period of different cohorts over a six decade period. So we asked the question, if you were a participant in the Framingham study between 1960 and 1979 and then 1980 to 1999, and then 2000 to 2018, what was your lifetime risk of experiencing a heart disease or stroke in the three different time periods? Is it going down, is it steady or is it going up?

Dr. Greg Hundley:

Very nice. And so, Vasan, describe your study results.

Dr. Vasan Ramachandran:

Look, what we found was if you look at the first, the 20 year period from 1960 to 1979, and compare that with the latest, which is 2000 to 2018, in the initial time period, the lifetime risk of developing heart disease or stroke in a man was pretty high. It was about one in two. And that for a woman was about one in three. So when you come to the latest epoch, what we find that the risk of one in two men had dropped to about one in three men in the latest decade. For women, the risk declined from what was one in three in the earlier epoch to one in four. So approximately there was about a 36% reduction in the lifetime probability of developing heart disease or stroke across the six decade period of observation.

Dr. Greg Hundley:

Very nice. And so help us a little bit, put the context of your results into what that might mean for us today as we are managing patients with atherosclerotic disease.

Dr. Vasan Ramachandran:

Yes, Greg. What it means is that the permeation of the advances in science in terms of the screening of risk factors, awareness of risk factors, medications to lower these risk factors effectively, the clinical trials that have given us these new medications, they may have translated into a reduction in risk over time. That the lived experience of people in the later decades is better in terms of having a lower risk of heart disease or stroke as the consequence of multiple advances that have happened in heart disease and stroke.

Dr. Greg Hundley:

Well, thank you so much Vasan. Well listeners, now we're going to turn to our Associate Editor, Mercy Carnethon. And Mercy, you have many papers come across your desk. What attracted you to this particular paper and how do you put these results really in the context of other science pertaining to risk associated with populations that may have atherosclerotic cardiovascular disease?

Dr. Mercedes Carnethon:

Thanks so much for that question, Greg. And again, Vasan, I really thank you and your team for bringing forth such outstanding research. You know, as cardiovascular disease epidemiologists, we were all raised and taught that what we know about risk factors for cardiovascular disease are based on the Framingham cohort. And so I was really excited to see this very comprehensive piece of work that characterized what the Framingham study has identified and also leverages the unique characteristics of a study that started in 1948.

Dr. Mercedes Carnethon:

So, you know, we're almost 75 years in and actually has the ability that cross sectional studies don't have to look over longer periods of time at risk. And you know, when we think about papers that excite us, that we really want to feature in circulation, they are papers that teach us something new. And I will say there were aspects of this work that confirmed what I had heard but had not seen using empirical data. Namely that the remaining lifetime risks for developing cardiovascular disease were going down over time, and they were going down secondary to better management and recognition of the risk factors that the Framingham cohort study had really been instrumental in identifying in the first place.

Dr. Mercedes Carnethon:

There were surprising elements of the paper. The surprising elements being that I think as you brought up earlier, we were concerned that risk factors that were on the rise, such as obesity, were threatening these increases in life expectancy. And it was really nice to see that the findings held, even in the face of rising risk factors. And just to summarize, what I really like about this piece when we situate it within circulation, where we are addressing clinical treatment factors, where we're also featuring clinical trials and even other epidemiologic studies, is that your work identifies for us the overall context in which the clinicians who read the journal are thinking about managing patients and where we're going. It highlights our successes, but it also really brings up what we need to do next. And I look forward to hearing from you about where you think this may be headed.

Dr. Greg Hundley:

Well, Mercy, you're teeing us up for that next question. Vasan, what do you think is the next study or studies that need to be performed in this space?

Dr. Vasan Ramachandran:

Thank you, Greg and Mercy, for your kind comments. Like I shared, this is a success story for a predominantly white population in the Northeast. We are very much aware about the heterogeneity and the geographic variation in heart disease burden in our country. So one of the success stories interpretation might be this represents the upper bound. What can happen to a population that is compliant with screening of risk factors, awareness of risk factors, treatment and healthcare access. I think the next set of studies should broaden the study population to bring in additional populations that are more diverse, that are also followed up over a period of time to assess and put the current observations in the appropriate context. Do we see similar findings longitudinally in other cohorts with non-white participants? Is it different, is their lived experience different? If so, why? And that could inform us how we can reach the success story and replicate it across the entirety of our country.

Dr. Greg Hundley:

And Mercy, do you have anything to add?

Dr. Mercedes Carnethon:

I do. You know, I really like that focus on broadening to whom these results are applicable. We've undergone a lot of shifts within our country and also around the world. You know, circulation, we have a worldwide readership. I would love to see this sort of work replicated across different countries to the extent that we have the data to do so, recognizing that limitation. But I'd love to see work focus on comparing how these things change in low income countries, middle income and high income countries, so that we can really think about resource allocation and find strategies to try to replicate the successes that we are seeing based on the data from the Framingham heart and offspring studies.

Dr. Greg Hundley:

Excellent. Well listeners, we really appreciate the opportunity to get together today with Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. And really appreciate them for bringing us these epidemiologic data from the Framingham cohort, indicating that over the past decades, mean life expectancy increased and the remaining lifetime risk of atherosclerotic cardiovascular disease decreased across individuals in the cohort, even after accounting for increasing incidences of other cardiovascular risk factors like obesity and smoking. Well on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley

Circulation April 19, 2022 Issue

18 april 2022 | 24 min

This week, please join author Andrew Chapman and Guest Editor Harvey White as they discuss the article "Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Greg Hundley:

Well, Carolyn, this week's feature on April 19th refers to coronary artery and cardiac disease in patients with type two myocardial infarction. And we will have more to learn about that, but how about we grab a cup of coffee and get started with some of the other articles in the issues.

Dr. Carolyn Lam:

Please? You first.

Dr. Greg Hundley:

Thanks Carolyn. So Carolyn, this team investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity based proteomic assays to estimate their association with incident heart failure. And so to accomplish this, the team, led by Dr. Thomas Lumbers from University College of London, utilized a fixed effect meta-analysis of four population-based studies comprising a total of 3,000 plus participants with 732 heart failure events. Now, the causal effects of heart failure associated proteins were then investigated by Mendelian randomization using CIS protein, quantitative loci, genetic instruments identified from genome-wide association studies or GWAS and over 30,000 individuals.

Dr. Carolyn Lam:

Wow! Big study, important stuff. So what did they find?

Dr. Greg Hundley:

Right Carolyn, several things. So 44 of 90 proteins were positively associated with the risk of incident heart failure. Now, among these eight proteins had evidence of a causal association with heart failure that was robust to multiverse sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney injury molecule one were positively associated with the risk of heart failure, whereas higher adrenomedullin chitinase-3 like-protein-1, cathepsin L1, and fibroblast growth factor 23, and matrix metalloproteinase 12 were protective. And so Carolyn in summary, the team identified 44 circulating proteins that were associated with incident heart failure of which eight showed evidence of a causal relationship, and seven were identified as being drugable, including adrenomedullin, which represents a particularly promising drug target.

Dr. Greg Hundley:

Additionally, Carolyn, this is a really interesting study as the teams approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

Dr Carolyn Lam:

Wow! Super cool. Yeah, indeed the methodology is significant there too. Thanks Greg. Well, this next paper deals with hypertrophic cardiomyopathy and we know that familial hypertrophic cardiomyopathy is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. But how exactly is the dysregulated sarcomeric force production sensed and how does that lead to pathological remodeling?

Dr. Carolyn Lam:

Well, today's authors and they are Dr. Qyang from Yale University School of Medicine and colleagues gained insights from a severe phenotype of an individual with hypertrophic cardiomyopathy and a second genetic alteration in a sarcomeric mechanosensing protein. They derived cardiomyocytes from patient specific induced pluripotent stem cells and developed robust, engineered heart tissues to study human cardiac mechanobiology at both cellular and tissue levels. They further used computational modeling for muscle contraction and rescue of disease phenotype via gene editing and pharmacological interventions to identify a new mechanotransduction pathway in hypertrophic cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn! Tell us more about this new pathway.

Dr. Carolyn Lam:

The study presents a novel biomechanical mechanism by which enhanced myofilament contractile force generation due to sarcomeric mutations, destabilize the muscle limb protein Z-disc mechanosensory complex, and this leads to disinhibition of calcineurin nuclear factor of activated T-cells or NFAT signaling and consequently leads to hypertrophy. Normalization of hypercontractile force in proband cardiomyocytes either with gene editing approaches or with ectomyosin crossbridge inhibitor mavacamten, resulted in an increase in Muscle Lim Protein levels, a decrease in that calcineurin and fat activity and a rescue from the hypertrophic cardiomyopathy defects.

Dr. Carolyn Lam:

The authors provided evidence that the common Muscle Lim Protein W4R variant is an important modifier that worsens the disease severity of hypertrophic cardiomyopathy, but alone does not appear sufficient to cause disease. All in all, these data established a foundation for developing innovative mechanism-based treatments for hypertrophic cardiomyopathy that stabilize the Z-disc Muscle Lim Protein mechanosensory complex.

Dr. Greg Hundley:

Oh, wow Carolyn! What a really nice mechanistic study and important new information too. Well, Carolyn, my next paper comes to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital at the Harvard Medical School and Carolyn the LV myocardium increases in mass in response to pathological as well as physiological stimuli. The former or pathologic hypertrophy, often proceeds cardiomyocyte loss and heart failure. The latter or physiologic, paradoxically protects the heart enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Now, while long non-encoding RNAs are important in cardiac development and disease associated with pathologic hypertrophy, less is known about their roles in physiologic hypertrophy or cardiomyogenesis.

Dr Carolyn Lam:

Oh, interesting! So what did these authors find about link RNAs and physiologic hypertrophy?

Dr Greg Hundley:

Right, Carolyn. So in this study of mice, the authors identified exercise regulated cardiac link RNAs termed lncExACT and lncExACT1 was evolutionarily conserved and decreased in exercised hearts, but increased in experimental heart failure. Cardiac lncExACT1 over expression caused pathological hypertrophy and heart failure while lncExACT1 inhibition induced physiologic hypertrophy and cardiomyogenesis protecting against cardiac fibrosis and dysfunction.

Dr. Greg Hundley:

Now, lncExACT1 functioned by regulating microRNA 222 calcineurine signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCH2 over expression in zebra fish induced pathological hypertrophy and impaired cardiac regeneration promoting scarring after this injury. In contrast mirroring DCH2 deletion, induced physiological hypertrophy and promoted cardiomyogenesis.

Dr. Carolyn Lam:

Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take home message?

Dr. Greg Hundley:

You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch, toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the benefits of exercise.

Dr Carolyn Lam:

Oh, thank you, Greg. Well, also in this issue is an In-Depth paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro Exhale Flow Pump Support in Cardiology.” There's a Research Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.”

Dr. Greg Hundley:

Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter to the Editor from Dr. Gronda entitled “The Failing Heart and SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in Business?” We also have from Dr. Viskin, an ECG challenge entitled “Sinus Node Dysfunction with a Nice Twist.” And finally, Carolyn, there's a Perspective piece from Dr. Schulman entitled “The Price and Quality of the Generic Pharmaceutical Market.” Well, how about at Carolyn we get on our feature discussion involving type two myocardial infarction.

Dr. Carolyn Lam:

Yay! Let's go.

Dr. Greg Hundley:

Well, listeners, welcome to our feature discussion on this April 19th and we have with us today, Dr. Andrew Chapman from Edinburg, Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome gentlemen. And we'll start with you, Andrew. First, could you describe for us some of the background information that went into the preparation of your study?

Dr Andrew Chapman:

Good morning and good evening and thank you very much for the invitation. So type two myocardial infarction is an interesting diagnosis. It was first introduced in around 2007 in recognition that patients could have heart injury when they were in hospital with other problems that led to an imbalance in myocardial oxygen supply, or an unmet need in myocardial oxygen demand, without the presence of atherothrombotic coronary artery disease. We don't know a great deal about these patients.

Dr. Andrew Chapman:

There have been a number of observational cohort studies, including from ourselves in Scotland, which have demonstrated the outcomes for this patient group are poor. We know only around one-third of patients with type two MI, survive to five years after diagnosis. And we also know, and previously demonstrated from patients in Scotland that those with underlying coronary artery disease actually had the worst outcomes and were at increased risk of future myocardial infarction events due to plaque rupture. So we hypothesized that patients with type two myocardial infarction may have failed a physiological stress test due to another illness and we wanted to investigate what the prevalence of underlying coronary artery disease and/or structural heart disease was, using a panel of different imaging modalities.

Dr. Greg Hundley:

And so Andrew tell us the hypothesis that you wanted to address?

Dr. Andrew Chapman:

So we believed that observational evidence suggested that coronary artery disease was important in patients with type two myocardial infarction and we felt that this was increasing their susceptibility to these events. Our primary hypothesis was that the majority of patients with type two myocardial infarction would have underlying coronary artery disease, which was previously quiescent undetected.

Dr. Greg Hundley:

Tell us a little bit about the study design and the study population that you use to answer this question.

Dr. Andrew Chapman:

Demand MI is to our knowledge, the first prospective observational cohort study in which patients who were in hospital with evidence of myocardial injury, so a raised cardiac troponin, were screened for the presence of supplier demand imbalance and the clinical diagnosis of type two MI. Now, in those patients that we were able to recruit, we did obviously have important exclusion criteria, but we designed a series of different investigations depending on individual patient risk factors and the appropriateness of such, but the primary goal was to undertake coronary angiography, ideally using an invasive coronary angiogram, which would allow us to undertake additional testing, such as plaque imaging and pressure wire study, to look for the functional consequences of stenosis. In those not fit for an invasive angiogram, we undertook CT coronary angiography. And in all patients we undertook structural imaging and we aimed to do cardiac MRI in all. Due to the coronavirus pandemic and for other reasons, we used echocardiography where MRI was not available.

Dr. Greg Hundley:

And so the total number of subjects here was how many?

Dr. Andrew Chapman:

We recruited 100 patients with a clinical diagnosis of type two myocardial infarction.

Dr. Greg Hundley:

Very good. And so now, Andrew, what were your results?

Dr. Andrew Chapman:

It's a really fascinating study, obviously, in my opinion. So we recruited 100 patients with a clinical diagnosis of type two myocardial infarction who had evidence of supplier demand and balance, a raised cardiac troponin concentration and evidence of symptoms and/or signs of myocardial ischemia. So in line with the universal definition criteria. Of 100 patients after undertaking coronary imaging, we reclassified the diagnosis in seven.

Dr. Andrew Chapman:

In five patients, we found that there was evidence of either plaque rupture or a stent thrombosis. And in two patients, we found evidence of myocarditis and stress cardiomyopathy respectively. The first principle finding is that actually despite careful characterization and really detailed screening, we were correct in 93 of 100 patients and we got the diagnosis wrong in seven. The principle hypothesis related to the prevalence of coronary artery disease and this was, as alluded to, undertaking with invasive and noninvasive imaging. But overall, the prevalence of coronary artery disease was 68% of those with type two myocardial infarction and this was obstructive in 30%.

Dr. Andrew Chapman:

We also undertook structural imaging as mentioned. We observed evidence of left ventricular systolic dysfunction in 34% of patients, of around a third, and perhaps most surprisingly, although we had a clear diagnosis of myocardial infarction in these patients, we only found imaging evidence of in part pattern late gadolinium enhancement, which is considered the gold standard for its diagnosis of myocardial infarction. We only observed that in 42%, which raises some interesting questions.

Dr. Andrew Chapman:

One of the principle clinical findings of the study is that these underlying conditions of coronary artery disease and left ventricular impairment, both of which are readily treatable with secondary prevention. These conditions were previously unrecognized in 60% of patients and only one-third were on appropriate evidence-based treatment, which gives me some cause for optimism, that there may be a role here for targeted treatment, which could plausibly, plausibly impact on outcomes.

Dr. Greg Hundley:

And Andrew, just a clarification point, maybe a subgroup analysis, any differences in your findings in regarding men versus women?

Dr. Andrew Chapman:

Excellent question. And in most studies of type two myocardial infarction, it's thought that this condition is more prevalent in women than men, but undoubtedly in all observational cohorts, there is selection bias as you will only diagnose a type two myocardial infarction if a clinician requests to test troponin in the first place. In our study, interestingly, we recruited more men than women. We had 56% men and we did not find any differences by sex in our analysis.

Dr. Greg Hundley:

Well listeners, what an excellent description from Dr. Chapman. A very interesting study. And we now want to turn to one of our editors, guest editors, Dr. Harvey White, and Harvey, we want to thank you for your work here with us at the American Heart Association and Circulation, and you receive many articles to review. What attracted you to this particular article and how do we put in context, these results with others that have been published pertaining to type two myocardial infarction?

Dr. Harvey White:

Thanks, Greg, it's a pleasure to work for Circulation. This paper is very close to my heart because I introduced the typing system in 2007 and it had minimal support and people said, "Why do we need a typing system? We've got killer class and Canadian class and you've done a troponin release system as well". And people stood up and then I laid out the type one plaque rupture. We know the pathophysiology and we know the treatment. Type two, I'd worked on beta blockers, supply and demand and I thought we should define the pathophysiology and define the treatment. That's 2007, which is 15, 16 years ago. And Andrew's paper is really lovely. As I said, it's close to my heart and he inches things forward. I've written an editorial, which I call "Zooming in on the enigmas of type two MI" and enigma means mystery or it's unclear, uncertain.

Dr. Harvey White:

And that's for sure we don't have full support for the diagnosis. It's become very practical, used in clinical trials and clinically, but we don't know how to manage it and we don't know how to define the groups. Andrew and colleague study is very nice. It's prospective and it has set out to define the coronary artery disease. I've tried for about 10 years to subdivide type two and to those without coronary disease and those with coronary disease. And you could also have a type C, which hasn't been investigated or unknown. And Andrew has answered one of the enigmas and it's really interesting. Large proportion, normal coronary arteries, diagnosis was changed a little bit based on the finding of thrombus. We're challenged with that finding because all MIs have thrombus at PM and really type one should be ruptured plaque. But Andrew changed the diagnosis in a few where one was an OTC, a marvelous case with marvelous pictures, changed the diagnosis. So I like the study and I like the findings. Thanks.

Dr. Greg Hundley:

Very nice. Well, Andrew, what a perspective and listeners getting just to listen to Dr. White is really quite exciting for me. Andrew, what do you see as the next study to be performed in this sphere of research?

Dr. Andrew Chapman:

I think we've gone some way to provide some insights into the underlying pathophysiology of this condition and these coexistent conditions of coronary artery disease and left ventricular impairment, which might increase an individual's susceptibility to a type two myocardial infarction. The question is what can we do about it and does targeted treatment with secondary prevention therapies for coronary disease and treatment for heart failure left ventricular impairment, does that improve outcomes?

Dr. Andrew Chapman:

The next study for me is clear. The next study for me, needs to be a randomized controlled trial, whereby patients with type two myocardial infarction are randomized to current best practice or risk stratification by a cardiologist with an interest in this condition, followed by targeted investigation for coronary disease and LV impairment and thereafter treatment as appropriate. This will be a trial of a complex intervention. I'm very grateful that we've received funding in Scotland already for this pilot phase of this trial, which we've called Targets Type Two and we'll begin recruitment for that trial in August of this year.

Dr. Andrew Chapman:

I must acknowledge colleagues in this area are looking at coronary disease and type two myocardial infraction. Professor Derek Chew is leading a study called Act Two, which is already recruiting and that will also provide invaluable information as to the prevalence of coronary disease and the potential benefits of treatment of that coronary disease in patients with this condition.

Dr. Greg Hundley:

And Harvey. How about your, what is your perspective in terms of the next series of studies perhaps that need to be performed in this space?

Dr. Harvey White:

There's a number and I like very much, Andrew's suggestion. The study that we're doing is randomizing to angiography or not angiography working with Derek Chew. I think all patients with MI should have coronary angiography. It's simple, it takes about 10 minutes. There's obviously some contraindications, but the information as Andrew has pointed out is really so useful. He found dissection, he found an embolus. Normal coronary arteries that in my view changes the management. Whether you should do an angiogram is very important. Randomization to various treatments. That's important. I would like to get more information about the objective evidence of type two MI, the criteria for low hemoglobin, shortness of breath, low blood pressure, high blood pressure, and so forth. There's a lot to do. As Andrew pointed out, the outcome may be worse than type one that's becoming more common and I think these studies will be very, very important.

Dr. Greg Hundley:

Very nice well listeners. We want to thank Dr Andrew Chapman as lead investigator and Dr Harvey White as guest editor for bringing us this study using advanced imaging of patients with type two myocardial infarction, which identified coronary artery disease in two-thirds and left ventricular dysfunction in one-third, and also highlighting that unrecognized and untreated coronary or cardiac disease occurs in many patients with type two MI and gives us pause for thought on a series of studies that may be performed in the future.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

Circulation April 12, 2022 Issue

11 april 2022 | 27 min

This week, please join author Enrico Ammirati and Guest Editor Stephane Heymans as they discuss the article "Prevalence, Characteristics, and Outcomes of COVID-19–Associated Acute Myocarditis."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature on this April 12, we are going to review COVID-19–associated acute myocarditis, looking at the prevalence and the outcomes. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other articles in the issue, and maybe there could be a quiz in there somewhere.

Dr. Carolyn Lam:

Oh, yikes.

Dr. Greg Hundley:

But before we get to that quiz, Carolyn, would you like to go first?

Dr. Carolyn Lam:

I would, and we're starting with a topic that we rarely talk about, it's about neurodevelopmental impairment. We know that it's common in children with congenital heart disease, yet postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedence for neuro development disabilities might begin in utero, these authors, led by Dr. Rollins from Boston Children's Hospital and Harvard Medical School, analyzed whether fetal brain volume predicted subsequent neuro development outcome in children with congenital heart disease. To do this, the authors studied fetuses with isolated congenital heart disease and social demographically comparable healthy controlled fetuses, all undergoing fetal brain MRI and two year neurodevelopmental evaluation.

Dr. Greg Hundley:

Ah, Carolyn, wonderful, interesting article that we're taking on here in Circulation. What did this group find?

Dr. Carolyn Lam:

In children with congenital heart disease, a smaller total brain volume on fetal MRI correlated with worse neurodevelopmental outcome at two years of age, across all domains of development and adaptive function. A predictive model, including total brain volume, along with sociodemographic and medical data, accounted for up to 45% of the variance in neurodevelopmental outcome within the congenital heart disease group. Fetal brain volume was the most consistent predictor of outcomes across neurodevelopmental domains compared with other sociodemographic and medical or surgical variables.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my first paper comes to us from the world of preclinical science. Okay, Carolyn, we're going to start it with the infamous Carolyn's quiz. Here we go.

Dr. Carolyn Lam:

Wait a minute, we should put a rule here, no quizzes on preclinical basic science, especially stuff we can't pronounce.

Dr. Greg Hundley:

Ah, yes, but seems to me, there's a heart failure expert on the team. Always remember, you can phone a friend because we have our wonderful Augie Rivera, our production manager, who is available and you can call on him at any time. Okay, here's the quiz, is Cam Kinase II helpful to cure or harmful to exacerbate heart disease?

Dr. Carolyn Lam:

Oh goodness, Greg. Okay. Cam Kinase II, I know it's Calcium-calmodulin Kinase II. I know there are different isoforms, and I'm cheating here a bit because last week we talked about targeting CaM Kinase II in heart disease. I'm going to guess harmful, I'm going to guess dealing with something with calcium overload, but I'm sure there's more to the story.

Dr. Greg Hundley:

Carolyn, getting onto to the article, cardiac ischemia-reperfusion injury really has emerged as an important therapeutic target for ischemic heart disease, the leading cause, as we know, of morbidity and mortality worldwide. Currently, there is no effective therapy for reducing ischemia-reperfusion injury. Calcium II Calmodulin dependent Kinase II, or CaM Kinase II plays, a pivotal role in the pathogenesis of severe heart conditions, including ischemia-reperfusion injury. Therefore, pharmacological inhibition of CaM Kinase II could be an important strategy in the protection against myocardial damage and cardiac diseases. But to date, however, there is no drug targeting CaM Kinase II for the clinical therapy of heart disease. Furthermore, currently, there is no selective inhibitor of CaM Kinase II Delta, the major CaM Kinase II isoform, in the heart.

Dr. Carolyn Lam:

Wow. What did the authors do?

Dr. Greg Hundley:

Okay, Carolyn. A small molecule kinase inhibitor library, and a high throughput screening system for kinase activity of CaM Kinase II Delta9, the most abundant CaM Kinase II Delta splice variant in the human heart, were used to screen for CaM Kinase II Delta inhibitors. Using cultured neonatal rat ventricular myocytes and human embryonic stem cell derived cardiomyocytes, as well as in vivo mouse models, in conjunction with myocardial injury induced by ischemia-reperfusion or hypoxia-reoxygenation and CaM Kinase II Delta9 over expression, this team, led by Professor Yan Zhang, from Peking University, sought to investigate the protection of Hesperidin against cardiomyocyte death and cardiac diseases.

Dr. Carolyn Lam:

Oh, wow. Please tell us, so what happened?

Dr. Greg Hundley:

Right, Carolyn. Several important findings. First, Hesperidin, the Aurora B kinase inhibitor, with antitumor activity in vitro directly bound to CaM Kinase II Delta and specifically blocked its activation in an ATP competitive manner. Second, Carolyn, functionally, Hesperidin ameliorated both ischemia-reperfusion and over express CaM Kinase II Delta9 induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell derived cardiomyocytes. And then, finally, Carolyn, in an in vivo BALB/C nude mouse model, with xenografted tumors of human cancer cells, Hesperidin delayed tumor growth without inducing cardiomyocyte death or cardiac injury.

Dr. Carolyn Lam:

Wow. Goodness, Greg, that's impressive. Okay, what's the take home message?

Dr. Greg Hundley:

Well, Carolyn, these results suggest that Hesperidin is a specific small molecule inhibitor of CaM Kinase II Delta with dual functions of cardioprotective and antitumor effects. These findings not only suggests that Hesperidin is a promising leading compound for clinical therapy of cardiac ischemia-reperfusion injury, and heart failure, but also could provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anti-cancer treatment.

Dr. Carolyn Lam:

Wow, Greg, that is an amazing summary. Thank you. Well, for my last paper, I'd like to tell you about a study in which authors led by Dr. Lubo Zhang from Loma Linda University in California, and the colleagues, tested the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion injury by controlling mitochondrial bio energetics and reactive oxygen species flux. Myocardial infarction in an acute setting of ischemia-reperfusion was examined via comparing loss versus gain of function experiments in microRNA-210 deficient and wall type mice.

Dr. Greg Hundley:

Ah, Carolyn, another really interesting paper from the world of preclinical science. What were the results here?

Dr. Carolyn Lam:

MicroRNA-210 deficiency induced an ischemic sensitive phenotype and exaggerated acute myocardial infarction and cardiac dysfunction after MI in males in a gender dependent pattern in a murine model of myocardial infarction. The study identified a novel mechanism of MicroRNA-210 targeting mitochondrial glycerol-3-phosphate dehydrogenase in controlling mitochondrial energy metabolism, and reactive oxygen species flux, and improving cardiac function in the setting of acute ischemic-reperfusion injury. Thus, the present findings reveal new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.

Dr. Greg Hundley:

Oh, beautiful descriptions, Carolyn. Well, my next papers come from the mail bag, and there is a great Research Letter from Professor Downing entitled “Critical Illness Among Patients Hospitalized With Acute COVID-19 With and Without Congenital Heart Defects.” Carolyn, there's a second Research Letter from Professor Zhao entitled “Dual Genetic Lineage Tracing Reveals Capillary to Artery Formation in the Adult Heart.”

Dr. Carolyn Lam:

Nice. There's also an On My Mind paper by Dr. Mintz on “Prioritizing Quad Therapy and the Path Forward in Guideline-Directed Medical Therapy for Patients with Heart Failure with Reduced Ejection Fraction.” Cool, Greg, thank you. Now, let's go to our feature discussion, shall we?

Dr. Greg Hundley:

You bet. To learn more about the prevalence and outcomes in COVID-19–associated acute myocarditis.

Dr. Carolyn Lam:

Acute myocarditis is thought to be a rare cardiovascular complication of COVID-19, or is it? Well, we have minimal data available in case reports, but really not a large scale study until today's issue and today's feature paper, which really aims to look at the prevalence, baseline characteristics, in hospital management and outcomes for patients with COVID-19–associated acute myocarditis.

Dr. Carolyn Lam:

I'm so pleased to have the first author with us, Dr. Enrico Ammirati from Niguarda Hospital in Milano, Italy, as well as our guest editor, Dr. Stephane Heymans from Maastricht University Medical Center in The Netherlands. Welcome, gentlemen. Enrico, thank you, thank you, thank you for this very important study. Could you please tell us what you did and what you found?

Dr. Enrico Ammirati:

Carolyn, it's a pleasure to be here with you and Stephane. We performed, let's say, large study on myocarditis associated with the COVID-19. That is a multicenter study, including 23 centers in the United States and in Europe. The senior author is Professor Marco [Metra], from Brasia, and the co first author is Dr. Laura Lupi, again, from Brasia. What we have done was to better characterize the prevalence of in-hospital myocarditis among the patients hospitalized with the COVID-19 diagnosis.

Dr. Enrico Ammirati:

And then, we tried to describe the outcome and the clinical characteristic at presentation. First of all, we define the myocarditis as a definitive or probable. That was based on the presence of cardiac magnetic resonance imaging consistent with myocarditis plus increase in troponin plus presence of symptoms that are compatible with an acute myocarditis. Alternatively, the patients must have a positive endomyocardial biopsy.

Dr. Enrico Ammirati:

The first result was that among more than 56,000 patients hospitalized in these hospitals, the rough prevalence of myocarditis was around 2.4 among 1000 hospitalized patients. The second main message was that the prognosis, we divided the population, we spitted the population in two groups. Patients with an ongoing and concurrent pneumonia and patient with myocarditis, but without evidence on CT of pneumonia. What we have found it was that among 57% of cases of COVID patients, you can have a myocarditis without pneumonia. So this is an interesting and new finding, and we compare the clinical characteristic of this patient comparing with the patient with the pneumonia. And we found that generally patient with pneumonia were older comparing with the patient with the isolated myocarditis and the prognosis of patients was worse comparing with the patient with just myocarditis.

Dr. Enrico Ammirati:

The outcome was around, overall, the outcome of this population that had median age of 38 year was an incidence of 6% of death. And if we look at the patient with the concurrent pneumonia, the outcome was worse. Then we have other findings that are of potential interest. And that is, for instance, that in 55% of patients, corticosteroids were used, and that is consistent with the idea that corticosteroids can work in this setting. We have also data on the presence of such Coronavirus, two in the heart, in patient that undergo vital search. And it was just in 21% of cases that underwent genome research in the myocardium. So I would say that these are the main findings of this research.

Dr. Carolyn Lam:

Oh, wow. First of all, heartfelt congratulations more than fifth, almost 57,000 hospitalized patients with COVID-19 and 23 hospitals across us and Europe. Stefan, you really appreciate that you served as guest editor here. Could you tell us some of your initial reactions, put the findings in context, perhaps?

Dr. Stephane Heymans:

Yes, yes. For sure. Enrico, indeed, I would like to concur with this congratulations on this beautiful study. It's a lot of work to collect this data and also to try to distinguish myocarditis from all other possible cause of cardiac injury. When I first saw this data, I think, oh, how difficult should be to make a diagnosis of myocarditis. And, of course, increased troponins are often seen in those COVID-19 hospitalized patients. Cardiac MRI is quite a specific for any non-ischemic myopathy. Yeah, I was wondering, so are these cardiac MRI images suggestive of acute myocarditis, but a really specific, sensitive enough to make a definite accurate diagnosis of COVID 19 related myocarditis, or could also be severe illness related to COVID-19 sepsis of pneumonia, give similar images on cardiac MRI?

Dr. Enrico Ammirati:

Stephane, this is a very good point. We haven't studied so in detail the cardiac injury in patients with the viral pneumonia, with the other viruses, so we cannot say that this kind of cardiac involvement is specific for such Coronavirus too. But what I can say is that this population is a population of highly likely acute myocarditis because if you look at simple clinical characteristics, and you can find that the median age is 38 years. This is the first reassuring a clinical characteristic because if we compare with the age of the population, of the laboratory registry of acute myocarditis we published in 2018 in Circulation, the media age was 36.

Dr. Enrico Ammirati:

Then, another point in support of our finding is that in the end, we have both present of edema and positive LG in patients with consistent myocarditis on magnetic resonance imaging. So, I know that probably edema can be associated with either other form of myocardial injury that are not necessary so specific for myocarditis. But if you look at troponin increase in this population, the median increase was 55 folds above the upper reference limit, so it was not just a small increase. It was a huge increase in troponin.

Dr. Enrico Ammirati:

Specifically, in patients that were above 45 years, we have a confirmation that was no coronary artery disease associated, to assure the readers that likely these are myocarditis. But as you said, we cannot be 100% sure about that. And you mentioned an important point, we cannot say that, also, in other form of viral disease, we can have a myocardial injury that can be very similar to myocarditis.

Dr. Stephane Heymans:

Yes. Thank you so much for your clear answer. It just underscores how sick a COVID-19 can make you because the numbers you're getting is two [in] 1000, you would say, okay, that's a small number, but still, there's so many more patients with a cardiac injury related to COVID-19. Indeed, to put it into context, so common viral myocarditis occurs in one to 10, 100,000, so the COVID-19 related myocarditis is up to 100 times more with your numbers. And of course, the common viral myocarditis, it's at the same age, similar age around 36, means a young, relatively young age.

Dr. Stephane Heymans:

Indeed, this COVID-19 is probably a trigger in immune and maybe genetic susceptible, young persons had to get myocarditis upon COVID-19 disease. Whereas, the COVID-19 vaccination related myocarditis, which is getting much more media attention, at least, previous months, only occurs in one to five in 100,000 people. And those patients are completely recover and transplant free. Survival is over 99%. To put it in context, it's still quite severe at this COVID-19 related myocarditis.

Dr. Carolyn Lam:

Thank you so much. Stephane.

Dr. Enrico Ammirati:

Can I add some comments? First of all, we have to say that these patients that died with myocarditis associated with the COVID-19, died to complication related to ECMO. For instance, we had a patient with a brain hemorrhage, and we had one patient who had a complication related septic shock. So, myocarditis can be something on top of a severe disease. We have a condition that is as background that is quite severe, and we a further complication related to myocarditis, so what we have seen is that, generally, even comparing with the previous Lombardy Registry I referred before the outcome of this patient was worse. Of course, it's very difficult to compare studies that have been performed in different centers during a different time period. But, of course, if you think that most of viral myocarditis are secondary to cold or flu, so the background condition is really mild.

Dr. Enrico Ammirati:

The main focus is the myocarditis. While in this patient, we have a subpopulation where you have in a great proportion of them, a severe myocarditis associated with a pneumonia. So you have the double component and that can explain why this patient had a worse outcome. Referring to them, vaccination, my thought is that for the first time we have a large vaccine campaign in this range of age, between 15 and 30 years or 35 years, that is the population at higher risk for myocarditis, where we do not generally perform large campaign for vaccination.

Dr. Enrico Ammirati:

In the end, it can be that we have seen more myocarditis related to vaccination because it was the first time that we vaccinate this kind of population. We have seen something similar with a smallpox vaccination in the military population. And that's the case because for other reason, that are not really related to the health reason, we vaccinated a high-risk population for myocarditis by itself. And we found that smallpox is more associated with myocarditis. Probably, there are, as you said, genetics per count that can explain in some patients an increase risk of myocarditis, but that can be possible that is there is also hormonal or epigenetics phenomena that can explain the higher risk in this population for myocarditis, both for COVID related or for vaccine related.

Dr. Stephane Heymans:

Ah, yeah. Enrico, could you remind me, was this incident of prevalence of COVID-19 myocarditis more prevalent in male patients compared to female when correcting for the background numbers?

Dr. Enrico Ammirati:

In our population, the main population was exactly was about 60%. There was just a slight increase in the number of cases in the male population, but it was not such a large prevalence as you expect in, let's say, uncomplicated myocarditis, where you can find an 80% of male prevalence or in vaccine.

Dr. Stephane Heymans:

Indeed. In the common or the vaccine related myocarditis, it's mainly young male, hetero sex, hormonal factors are being involved, so probably, as you say, these COVID-19 patients have a change in their immune background. And some of those, might some of those also have already background cardiomyopathy or myocarditis, maybe cardiomyopathy, that was not known yet. And then with the COVID-19 might have developed a clinical myocarditis/cardiomyopathy.

Dr. Enrico Ammirati:

When we look at the endostolic diameter of the left ventricle, I can say that the diameter was in the normal range, so that can support the idea that generate this patient did not have a previous dilated cardiomyopathy, but I cannot say that this patient had a known dilated cardiomyopathy before this event.

Dr. Carolyn Lam:

You know, once in a while, Augie, I get to do some of these interviews, and it just takes off on its own. And I love it. And there's nothing I need to do except to sit and listen, and to be grateful that you are publishing this and having such a lovely discussion on this podcast. Thank you, both of you. And, if I could, just very quickly, do you have any take home clinical messages now, from what you've seen, for someone who may be managing one of these COVID-19 patients and suspecting anything?

Dr. Enrico Ammirati:

Can I add that, in the end, what I can, say based on this research, is that likely myocarditis associated with COVID-19 is worse compared with myocarditis associated to vaccine. So even if we see that probably the prevalence is, again, high year with COVID-19, but the most important point is that it's even worse with myocarditis is associated with COVID-19 comparing with the vaccine, so please get the vaccination.

Dr. Carolyn Lam:

Thank you. And you've been listening to Circulation on the Run. From Greg and I, thank you for joining us today. I'm sure you're so grateful, and have learned so much, as I have. And don't forget to tune in again, next week.

Dr. Greg Hundley:

Circulation April 5, 2022 Issue

4 april 2022 | 21 min

This week, please join author Zdenka Pausova and Associate Editor Svati Shah as they discuss the article "Circulating Metabolome and White Matter Hyperintensities in Women and Men."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, have you ever wondered what white matter hyperintensities in a brain are made of? Well, guess what? The feature discussion is going to give us a little clue. Believe it or not from the circulating metabolome, interesting, huh? Well, I'm going to keep you in suspense, as we first discuss other papers in the issue. And I want to go first, may I?

Dr. Greg Hundley:

Absolutely, but let's all grab a cup of coffee.

Dr. Carolyn Lam:

All right. You got yours. And here goes. This first paper reviews the results of endovascular aneurysm repair in patients from the Japanese Committee for Stent Graft Management registry, to determine the significance of persistent type II endoleak and the risk of late adverse events, including aneurysm sac enlargement.

Dr. Greg Hundley:

Ah, Carolyn, a very clinically relevant question. So what did this study show?

Dr. Carolyn Lam:

Of more than 17,000 patients who underwent endovascular aneurysm repair for abdominal aortic aneurysm from 2006 to 2015, 29% had persistent type II endoleak. The cumulative incidence rates of abdominal aortic aneurysm related mortality, rupture, sac enlargement, and reintervention were higher in patients with persistent type II endoleak. Specifically, the cumulative incidence rates of rupture and abdominal aortic aneurysm related mortality increased to 2% at 10 year follow up, which is dissimilar to the previously reported frequency of only about 1%. Cox regression analysis revealed older age, female sex, proximal neck diameter, and chronic kidney disease as independent, positive correlates of sac enlargement.

Dr. Carolyn Lam:

So these wonderful results are from Dr. Hitoshi Matsuda and colleagues from the National Cerebral and Cardiovascular Center in Osaka Japan, and really suggests that persistent type II endoleaks are not always benign.

Dr. Greg Hundley:

Beautiful summary, Carolyn. Well, my paper comes from the world of pre-clinical science. And Carolyn, in most eukaryotic cells, the mitochondrial DNA is uniparenterally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mitochondrial DNA. All copies are therefore, nearly identical or, as we would call homoplasmic.

Dr. Greg Hundley:

Now Carolyn, the presence of more than one mitochondrial DNA variant in the same cytoplasm can arise naturally or as a result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH.

Dr. Greg Hundley:

Now Carolyn, these investigators led by Professor Jose Enriquez from the Centro Nacional de Investigaciones Cardiovasculares hypothesized that DNPH is maladaptive and usually prevented by the cell.

Dr. Carolyn Lam:

Wow, that's really interesting, investigations from the world of preclinical science. What did the investigators find?

Dr. Greg Hundley:

Right, Carolyn. So, the investigative team engineered and characterized divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, as we've talked about before, mice throughout their lifespan. The authors found that DNPH impair mitochondrial function with profound consequences in critical tissues that did not resolve heteroplasmy, particularly within cardiac and skeletal muscle. Progressive metabolic stress in these tissues led to severe pathology results, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. And finally, Carolyn, symptom severity was strongly modulated by the nuclear context.

Dr. Greg Hundley:

So in conclusion, Carolyn, these findings suggest that medical interventions that could generate divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, so to address potential incompatibility between donor and recipient mitochondrial DNA.

Dr. Carolyn Lam:

Oh wow. That is fascinating. Well guess what? My next paper is also about mitochondria, but this time looking at the role of the mitochondrial calcium uniporter. So we know that calcium is a key regulator of energy metabolism and impaired calcium homostasis damages mitochondria, resulting in cardiomyocyte death, pathological hypertrophy, and heart failure.

Dr. Carolyn Lam:

This study by Dr. Wang from University of Washington and colleagues investigated the regulation and the role of the mitochondrial calcium uniporter in chronic stress induced pathological cardiac remodeling. In a series of elegant experiments in the mitochondrial calcium uniporter knockout or transgenic mice infused with isoproteronol, the authors found that the mitochondrial calcium uniporter is up regulated in the stressed heart to orchestrate mitochondria sarcoplasmic reticulum, and cytosolic calcium handling, preventing cytosolic calcium overload induced cardiomyocyte death.

Dr. Carolyn Lam:

Lack of mitochondrial calcium uniporter mediated mitochondrial calcium uptake is detrimental. Whereas, transgenic over expression is beneficial to the heart during chronic beta adrenergic stimulation. The nuclear translocation of calcium/ calmodulin kinase II delta beta via calcineurin mediated dephosphorylation of serine 332 activates CAMP response element binding protein to promote mitochondrial calcium uniporter gene expression in adult cardiomyocytes.

Dr. Greg Hundley:

Well, Carolyn, what's the take home here? What are the clinical implications?

Dr. Carolyn Lam:

Ah, thought you might ask. Well, this study indicates that enhancing mitochondrial calcium uptake could be a new approach to prevent chronic beta adrenergic stimulation induced heart remodeling. Targeting this cam kinase two delta beta KREB mitochondrial calcium uniporter pathway could be a therapeutic option for pathologic cardiac remodeling associated with chronic adrenergic stress.

Dr. Greg Hundley:

Excellent description, Carolyn, and thank you for walking us through that wonderful paper. Well, we've got some other papers in the issue and from the mail bag, Professor Lusis has a Research Letter entitled Identification of DNA Damage Repair Enzyme, ASK II as Causal for Heart Failure with Preserved Ejection Fraction. And Carolyn there's a cardiovascular case series from Professor Barrett entitled, “The Unrepairable Infant Mitral Valve, an Unexpected Case of Decompensated Heart Failure.”

Dr. Carolyn Lam:

Interesting. There's an exchange of letters between Doctors Matrougui and Wang regarding the article, “Integrated Stress Response Couples Mitochondrial Protein Translation with Oxidative Stress Control” and a Perspective piece by Dr. Fatkin on “Fishing for Links between Omega-3 Fatty Acids and Atrial Fibrillation.” Wow. Super cool. Greg, let's go on now to a feature discussion, shall we?

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

For our feature discussion today, we are talking about white matter hyperintensities. Now that's the most common brain imaging marker of small vessel disease. That may be known, but there's a lot more to it. For example, what are they made of? Well, you're going to so enjoy today's feature paper, and I'm so proud to have the corresponding author with us, Dr. Zdenka Pausova from Hospital for Sick Kids in Toronto, Canada, as well as our associate editor, Dr. Svati Shah from Duke University. So welcome ladies. And Zdenka, if I could start with, could you explain the rationale for your study and what you did?

Dr. Zdenka Pausova:

Yeah. Thank you. Thank you for having me. Well, we were thinking that it is important to know what the metabolic variables that associate with white matter hyperintensities might be, simply because we know that there are other studies that have shown that whatever circulates in blood is in some way related to brain health. For example, different lipids associated with Alzheimer Disease, cognitive functioning and with structural properties of the brain. So we were wondering what the metabolics that are associated with white matter hyperintensities might be, simply because we would like to know a little bit more about the pathogenesis of the disease, because that's what metabolomic profiling can provide. And also if one can identify biomarkers that potentially could be used in the clinical setting.

Dr. Carolyn Lam:

Wow. Thank you. And Zdenka, this may be a very basic question, but we hear a lot about the metabolome and sometimes it's not very clear what metabolome profiling actually is. And could you just say a little bit about the technique and your study population and then your findings? Thanks.

Dr. Zdenka Pausova:

Yes. Sure. So we actually studied over 9,000 individuals from eight different population based studies and all of those individuals had metabolomic assays done with two main platforms. It's mass spectrometry and nuclear magnetic spectroscopy. Mostly these platforms are actually commercially available and altogether across all platforms, there were over 2,200 different metabolites. And from those we could study about 1200 that we had at least in two populations. And what the metabolites are, these are different metabolites of lipids, sugar, proteins, amino acids that people put on those platforms or that designers put on the platforms, in order to test some of their hypotheses, that they were actually these metabolites of interest for different sorts of diseases, including cardiovascular and cerebrovascular disease.

Dr. Carolyn Lam:

Wow. So this is really large scale, massive, big data, if I may, and if I'm not wrong, it's the first large scale study to identify circulating metabolomic measures associated with white matter hyperintensities. So could you please summarize the main findings?

Dr. Zdenka Pausova:

Well, overall we actually found that there were 416 metabolites that were nominally associated with white matter hyperintensities, but as it is in epidemiology, you have to correct for multiple comparisons. So when we did DR correction, there were only 30 variables associated with white matter hyperintensities. And when we wanted to check whether those associations are independent of the risk factors for white matter hyperintensities, such as hypertension, type two diabetes, smoking, obesity, we actually ended up with seven markers, seven metabolites that were significantly associated in the fully adjust model.

Dr. Zdenka Pausova:

And the main one was actually a derivative of amino acid hydroxyphenol that probably is a marker of ischemia in the brain. And what actually I am coming to is, and one of the main findings was, that many of those metabolites were associated with white matter hyperintensities in a sex specific manner. That is that they were detected in the pool sample, but essentially the signal came from only one of the sexes. And so this one that was the most significant was detected only in males essentially, and not really in females.

Dr. Zdenka Pausova:

And that I think is an interesting, one of the most interesting findings that we can expect that there are really sex specific pathways, biochemical pathways, that accompany white matter hyperintensities.

Dr. Carolyn Lam:

Wow. Zdenka, thank you so much. I have to bring Svati in right now to share some perspective, Svati, especially to put these findings into context, please.

Dr. Svati Shah:

Yes. Dr. Pausova, really wonderful paper. This is an incredible study, if you think about it. The largest scale study that really is trying to understand metabolic by biomarkers, but the biomarkers actually tell us about the potential biology of what's going on with these white matter hyperintensities. We know that these hyperintensities in the brain are associated with increased risk of stroke, increased risk of cognitive decline, but we don't really understand stand what the risk factors are. There's been some studies suggesting that there's genetic risk factors, but this is really the first large scale study to say, "Hey, what's in the blood that we can measure?" And just to be clear, these technologies are measuring these biomarkers that are very, very, very low levels in the blood, really granular snapshot of what's going on with the human being.

Dr. Svati Shah:

And by looking at these blood markers that the authors were able to find biomarkers that are associated with these brain abnormalities, but really highlighting some of the important biology as Dr. Pausova started to talk about. So I think what it gets us to is we get to have our cake and eat it too. We get to learn about biomarkers that might have clinical utility, but we also have discovered, they've discovered new biology that could lead to new therapies, for example, and a better understanding of the mechanisms of why some people develop these hyperintensities as they age. And some people do not.

Dr. Carolyn Lam:

Wow, Svati, you put that so eloquently and just to put it out there for everyone, that significant metabolite hydroxyphenol pyruvate explain 14% of the variants of white matter hyperintensity volumes in males. Whereas, the proportion of variants explained by hypertension is only 1% or type two diabetes is only 1 to 3%, or smoking is even less than 0.1%. So this is, as you said, Svati, it's a significant discovery as well. Zdenka, though, how do we apply this clinically?

Dr. Zdenka Pausova:

Well, it could be a marker that is measured in circulation and it is a marker that can be measured in blood and can indicate early stages of white matter hyperintensities. But I think before we get there, it would be of high value to actually carry out some longitudinal studies, because it would be really interesting to know if it is an early marker before the white matter hyperintensities extent is enlarged. And so that would one thing. But other than that, I think if that would be the case, we can just measure it in blood and see how predictable it is.

Dr. Carolyn Lam:

Can I ask what about the women? Did anything predict it in women?

Dr. Zdenka Pausova:

That's a good question. There was only actually one variable. To our surprise, only one variable that was significantly associated with white matter hyperintensities in women. And it is really surprising because the sample size was the same. The extent, the volume of white matter hyperintensities was quite similar. They were of similar age, similar adiposity. So there were no huge differences, yet we could not actually detect too many metabolized associated with white matter hyperintensities in women. Really surprising. And I don't have a good answer for it now.

Dr. Carolyn Lam:

Wow. Thank you. Svati, did you have further thoughts on the clinical applications and implications of these tremendous data?

Dr. Svati Shah:

Yeah. I think the ability to have a biomarker as Dr. Pausova nicely articulated that would potentially prevent people from having to get an MRI. And we would be able to identify people hopefully at an earlier stage in the process. In this lovely study, they were looking at biomarkers in people who already had the hyperintensities. I think the next step as Dr. Pausova outlined to be able to identify whether these predict high risk people who will develop them in the future and then try to target therapies. A potential advance in precision medicine in the neurologic space, that we could use this biomarker to say, "You need this particular medication."

Dr. Svati Shah:

Some of the biomarkers that Dr. Pausova's group discovered were actually just cholesterol measures. So maybe we need to be instituting more aggressive cholesterol therapies in these patients who are at high risk. I'm not saying we can do that yet, but these provocative results suggest that this could lead to a more personalized approach to high risk individuals who may have consequences and develop these white matter hyperintensities.

Dr. Carolyn Lam:

And Zdenka, did you have anything to add to that?

Dr. Zdenka Pausova:

Perhaps one interesting aspect of the study that I actually was nicely surprised at the end of the study that the markers, one could the different lipids or the different derivatives of amino acids, the literature provided actually a possible pathways, how those could be involved in the development of white matter hyperintensities. Some of them actually, we could possibly link to impairment of myelination of a neuronal axons, or actually the axons themselves could be the metabolized could reflect damage of those axons.

Dr. Zdenka Pausova:

And also, one suspicious pathway or one pathway that is suspected to be big part of the development of white matter hyperintensities is the disruption of blood brain barrier and some of the markers could be actually linked to that vascular dysfunction.

Dr. Carolyn Lam:

Aw, that's wonderful. Thank you so much, Zdenka, for publishing this beautiful work with us in Circulation. And thank you, Svati, for taking this paper through and inviting this beautiful editorial. In fact, it quite summarizes our discussion. It's entitled, What Turns White Matter White? Metabolic Clues to the Origin of Age-Related White Matter Hyperintensities and it's by Dr. Eric Smith from University of Calgary and I invite everyone to read this.

Dr. Carolyn Lam:

So thank you once again for joining us today on Circulation on the Run. From Greg and I, it's been wonderful having you. Don't forget to join us again next week.

Dr. Greg Hundley:

Circulation March 29, 2022 Issue

28 mars 2022 | 19 min

This week, join authors Steven Lubitz and Associate Editor Mark Link as they discuss the article "Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Huntley, Associate Editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Well, guess what we have for the featured discussion today, Greg. It's about screening for atrial fibrillation in older adults at primary care visits. Very, very important topic. And what we'll be looking at is the vital AF randomized control trial. Ooh, we're going to keep everyone in suspense here as we carry on and discuss today's papers. Can I start?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

Alright. This first paper is about infective endocarditis. Now, we know that cardiac surgery often represents the only treatment option in patients with infective endocarditis. However, infective endocarditis surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. So, authors Dr. Doesnst from Friedrich Schiller University of Jena in Germany, and colleagues, decided to investigate the impact of hemo absorption during infective endocarditis surgery on post-operative organ dysfunction.

This multicenter, randomized, non-blinded controlled trial assigned 288 patients undergoing cardiac surgery for infective endocarditis to hemo absorption, which is integration of cytosorb to the cardiopulmonary bypass or control. The primary outcome was defined as the difference between the mean total postoperative sequential organ failure assessment score, calculated maximally to the ninth postoperative day, and the difference with the basal score. Secondary outcomes were 30 day mortality, durations of mechanical ventilation, basal presser and renal replacement therapy. Cytokines were also measured in the first 50 patients.

Dr. Greg Hundley:

Interesting study, Carolyn. Wow. So, what are the results?

Dr. Carolyn Lam:

Yes, this trial involved a lot of work and results showed, however, that there was a failure to demonstrate a reduction in postoperative organ dysfunction, 30 day mortality, or any of the clinically relevant secondary outcomes through intraoperative hemo absorption. Although hemo absorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcomes.

Dr. Greg Hundley:

Great description, Carolyn. Well, my first paper comes to us from the world of preclinical science. And Carolyn, the ascending thoracic aorta, site of aneurysm formation, is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field, or the cardiac neural crest. Second heart field derives cells, populate areas that coincide with the spatial specificity of thoracic aortopathies that are often associated with aneurysms. And so, this study, led by Dr. Alan Daugherty, from the University of Kentucky. Its purpose was to determine whether and how second heart field derived cells contribute to as sending aortopathies.

Dr. Carolyn Lam:

Wow, an important topic, Greg. What did the authors find?

Dr. Greg Hundley:

Okay. So, Carolyn, first, ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin 2 infused mice. And so, the investigators found several things. First, second heart field derived smooth muscle cells and fibroblasts associate with angiotensin 2 induced aortic pathologies. Second, angiotensin 2 induced a distinct fibroblast sub-cluster that was less abundant for messenger RNAs related to major extracellular components and TGF beta-ligands and receptors, but more abundant for proliferative genes.

Third, TGFBR2 deletion in second heart field derived cells were embryonically lethal, with significant dilatation of the outflow tract in the mice. And finally, second heart field specific deletion of LRP1 led to aortic pathologies in mice, supporting the importance of second heart field derived cells in maintaining ascending aortic wall integrity.

Dr. Carolyn Lam:

Wow. Could you just sum up the clinical implications for us, Greg?

Dr. Greg Hundley:

Well, Carolyn, I knew you were going to ask me that. So, these results indicate that heterogeneity of the embryonic origins of smooth muscle cells and fibroblasts contributes to complex mechanisms of vasculopathy formation, which should be considered when investigating the pathogenesis of thoracic aortopathies.

Dr. Carolyn Lam:

Wow, thanks Greg. Well, my next study is also a translational study, and this one provides a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type one diabetes. So, this is from Dr. Biddinger from Children's Hospital Boston and colleagues. In order to define the mechanisms by which insulin controls plasma cholesterol levels, the authors knocked down the insulin receptor, FOXO1, and the key bioacid synthesis enzyme, CYP8B1, in mice. They measured bioacid composition, cholesterol absorption, and plasma cholesterol. In parallel, they measured markers of cholesterol absorption and synthesis in humans with type one diabetes treated with ezetimibe and statins in a double blind crossover study.

Dr. Greg Hundley:

Oh, wow, Carolyn. So, experiments in both animal models and in human subjects. So, what did they find?

Dr. Carolyn Lam:

Insulin, by inhibiting FOXO1 in the liver, reduces 12 alpha hydroxylated bio acids, reduces cholesterol absorption and reduces plasma cholesterol levels. Thus, type one diabetes leads to a unique set of derangement in cholesterol metabolism with increased absorption rather than increased synthesis. These derangements are reversed by ezetemibe, which is a cholesterol absorption inhibitor, but not simvastatin, which is a cholesterol emphasis inhibitor. So, taken together, these data suggest that a personalized approach to lipid lowering in type one diabetes may be more effective, and highlight the need for further studies specifically in this group of patients.

Dr. Greg Hundley:

Nice, Carolyn. Well, we've got some other really interesting or articles in the issue. And first, from the mail bag, there's a Research Letter from Professor Bers, entitled "Empagliflozin Reverses Late Sodium Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murray Model of Heart Failure with Preserved Ejection Fraction." Carolyn, there's another research letter from Professor Shu entitled, "Activation Of INKY Cells at the Maternal Fetal Interface that Predisposes Offspring to Cardiac Injury." Also, there's a really nice, in depth article entitled, "Takasubo Syndrome Pathophysiology Emerging in Concepts and Clinical Implications." And it's from Dr. Trisha Singh.

Dr. Carolyn Lam:

Nice. We also have an ECG challenge by Dr. Mugnai on “A Tachycardia in Disguise” and a Perspective piece by Dr. Alexander on “Equipoise in Clinical Trials: Enough Uncertainty [but] in Whose Opinion?” Isn't that interesting? Wow, thanks, Greg. Now, though, let's go on to this super exciting feature discussion on screening for atrial fibrillation in older adults' primary care.

Dr. Greg Hundley:

You bet.

Well, listeners, we are here for the feature discussion, now, on this March 29th issue. And we have with us Dr. Steve Lubitz, from Mass General and Boston, and our own associate editor, Dr. Mark Link, from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen.

So, Steve, we're going to start with you. Can you describe for us some of the background information that went into the construct of your study, and then what was the hypothesis that you wanted to address?

Dr. Steven Lubitz:

Sure. Well, thanks for the opportunity to talk with you today about our work. So, as we know, AFib is a common and more bitter arrhythmia. And the first manifestation of AFib can be stroke in a substantial number of individuals. Strokes from atrial fibrillation or debilitating, but they can be prevented using oral anticoagulants if we know who has atrial fibrillation.

But atrial fibrillation can be a symptomatic and it's possible, therefore, that screening pre-AFib could lead to new diagnoses and ultimately improve outcome by enabling stroke prevention. Point of care screening for AFib has been embraced by some guidelines for individuals age 65 or older, such as those in Europe, and mobile technology has now evolved and enables rapid mask screening using handheld ECGs, single lead ECGs, which obviates the need and expense of performing 12-lead ECGs to screen for AFib.

Nevertheless, though, some guidelines have suggested that data are insufficient to recommend screening AFib using ECGs, such as those from the United States Preventative Services Task Force. We tested whether screening individuals age 65 or older at the time of a primary care clinic visit using a single lead ECG would lead to an increased rate of detection of AFib in contemporary United States practices.

Dr. Greg Hundley:

Very nice. And so, maybe describe for us this task force, and also what was your study design and, again, your study population?

Dr. Steven Lubitz:

Sure. So, specifically our study design, we performed a cluster randomized control trial in which primary care practice clinics were randomized to the screening intervention or to usual care, and patients aged 65 or older arriving for a primary care visit with their provider were eligible for participation. Patients were offered screening by practiced medical assistants at the time of their vital sign assessments, and screening was performed, if they consented, within a live core cardio mobile single ECG device, which was affixed to an iPad and stationed in the clinic.

The results of the screening were made available to the providers at the time of the visit, and then the provider was able to make any and all decisions about subsequent management, confirmation or treatment. The primary outcome was a new diagnosis of Afib made in the medical record at one year following the start of the screening intervention, and the outcome was ascertained using the electronic health record and then manually adjudicated. We powered the study to detect a difference of nearly 0.5% in the rate of atrial fibrillation diagnoses at 12 months between the screening and usual care arms.

Dr. Greg Hundley:

And how many patients did you enroll? And then what were your study results?

Dr. Steven Lubitz:

Well, eight practices were randomized to the screening arm and eight practices to the usual care arm. And in total, that equated to about 15000 patients without a history of atrial fibrillation in the screening arm and 15000 patients in the control arm without a history of atrial fibrillation. The mean age was about 74, about 60% were female, 82% were white. And the mean chad-vad score was 3.4.

We observed several main findings. The first is that, of the individuals in the screening arm, 91% were screened at least once. And this is the largest point of care screening study to date. The rate of screening in the intervention arm was substantially greater than any other contemporary trial, point of care, single ECG screening. We think that high rate of compliance with the intervention reflects patient enthusiasm for screening and a widespread feasibility of incorporating single ECGs into the routine vital sign practice workflow.

Secondly, the primary endpoint, however, incidence of new AFib diagnoses at 12 months, was 1.72% in the screening arm, and 1.59% in the usual care arm, which equates to a risk difference of .13%. That was not statistically significant in the overall sample. We observed a substantial difference in new AFib diagnoses among those aged 85 or older in pre-specified subgroup analyses, 5.56% in the screening arm and 3.76% in usual care arm, which corresponds to a risk difference of 1.8%, where a number needed a screen of about 55, raising the possibility that point of care single ECG screening among the oldest and highest risk individuals might be effective. But this finding warrants future study.

Third, we observed a shift in the location of diagnosis. So, they fit with a higher likelihood of diagnosis at a primary care practice encounter in the screening arm, as compared to the usual care arm, which is as expected. And the implications on downstream management pathways, cost of care, other downstream work flows is unknown at the moment.

And lastly, we observed it in anticoagulation use was high, even among those with AFib diagnosed in the screening arm, which is a reassuring finding, suggesting that clinicians recognized that AF detected using this single lead point of care screening is likely to represent high burden, persistent AF that carries a substantial risk of stroke.

Dr. Greg Hundley:

Very nice. Well, Mark, I know you review many papers for us here at Circulation. What attracted you to this particular paper?

Dr. Mark Link:

This issue of point of care screening for AFib is a very hot topic. We all know that clinically diagnosed AFib carries with it a high risk of stroke, but what we don't know is incidentally found Afib, or nonclinically found Afib, what does that mean? This was one of the largest, if not actually the largest, study of point of care screening. And the i-cors are a very accurate device, or reasonably accurate device. So, we thought it's an important contribution to the literature. I think it surprised the authors, as well as us, there wasn't a difference in the diagnosis of AFib between the two arms. I think all of us would've expected to see that. But we're still learning a lot about point of care screening, and we're not to the point where we know what to do yet.

Dr. Greg Hundley:

And Mark, what are some of your thought? Steve raised the point that, in that subgroup, greater than age 85, any additional insights there?

Dr. Mark Link:

Yeah. I think that, if you can enrich your group with people that are more likely to have AFib, and the older you get, the more likely you are to have AFib, you are more likely to find Afib. But then treating people over age 85 also becomes a little bit riskier, with both anticoagulants and antirhythmic drugs and ablation.

Dr. Greg Hundley:

Great points. Well, Steve, coming back to you, what do you see as the next study to be performed, really, in this sphere of research?

Dr. Steven Lubitz:

Thanks. I think I proposed two additional lines of inquiry. At first, I think our hypothesis generating observation to the point of care screening with a single EDCG can lead to higher rates of AFib detection among the oldest individuals, age 85 or older, with a small number needed to screen warrants, replication, and the downstream implications of that on stroke and bleeding merit further evaluation.

I think secondly, given the proliferation of wearable technology, future studies should examine the effectiveness of detecting perccismal atrial fibrillation for preventing downstream adverse events, including stroke. This point of care screening is likely to detect the highest burden persistent forms of atrial fibrillation in contrast to some of the wearable technology, like consumer wearable technology, that might detect paroxysmal atrial fibrillation, more commonly.

Dr. Greg Hundley:

Ah, great point. And Mark, how about you? Anything to add? What future study do you see needs to be performed in this space?

Dr. Mark Link:

It's clear from a number of studies that the longer that you monitor someone, the more likely you are to get a diagnosis of AFib. And that's pretty clear. This was a 30 second monitor. We have a number of studies that have shown two week and ILS monitoring is far more likely to get a diagnosis of AFib. But what we don't know is, if making that diagnosis of AFib makes any difference on ultimate outcomes. That's the studies that we need to see, is does treatment of incidentally found AFib improve clinical care.

Dr. Greg Hundley:

Very good. Well, listeners, we want to thank Dr. Steve Lubitz from Mass General in Boston, and also Dr. Mark Link from UT Southwestern in Dallas, bringing us results from this study indicating that screening for atrial fibrillation using a single lead EKG at a primary care visit did not affect new atrial fibrillation diagnoses among those that were aged 65 years or older. There was, perhaps, a difference in those aged greater than 85 years, but more research is to come in that space. And, of course, looking for peroxisomal AFib with handheld devices is another area you yet to be investigated.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week, On the Run.

Dr. Greg Hundley:

Circulation March 22, 2022 Issue

21 mars 2022 | 27 min

This week, join authors Maryjane Farr and Josef Stehlik as they discuss their Perspective article "Heart Xenotransplant: A Door That Is Finally Opening."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, at VCU Health in Richmond, Virginia.

Dr. Greg Hundley:

Well, Carolyn, this week's feature, very interesting, xenotransplantation, where organs from other species are transplanted into humans. And it's a perspective piece. And so, we're going to get a weighted conversation from two different individuals that have a different perspective on the topic.

Dr. Greg Hundley:

But, before we get to that, how about we grab a cup of coffee, and start with some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

Absolutely, Greg. Although man, that is a big hook you just gave us. Xenotransplantation is seriously, seriously, a hot topic. Can't wait to learn more.

Dr. Carolyn Lam:

But, for this first paper I want to talk about, well, we know that sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing, can identify carriers of pathogenic, or lightly pathogenic, variants. However, to what extent do these variants associate with clinically meaningful phenotypes, and what do we know about variants of uncertain significance?

Dr. Carolyn Lam:

So to answer this question, Dr. Dan Roden, from Vanderbilt University, and his colleagues, looked at 10 arrhythmia susceptibility genes, that were sequenced in more are than 20,000 participants without an indication for arrhythmia genetic testing in the eMERGE III study, which is a multi-center prospective cohort. Variants, previously designated pathogenic, or likely pathogenic, were identified in 120 individuals, or 0.6% population. And electronic health records revealed an over-representation of arrhythmia phenotypes. Some variants of uncertain significance were also found in individuals with arrhythmias and patch clamping, confirmed reclassification, to likely pathogenic.

Dr. Greg Hundley:

Really interesting results from this eMERGE III study, Carolyn. So what's the take home message?

Dr. Carolyn Lam:

As genetic testing becomes more common, the combination of electronic health records and in vitro testing, will help classify variant pathogenicity. Population screening has the potential to identify patients with undiagnosed Mendelian rhythm disorders. However, we need to consider the pros and cons of such an approach. And this is discussed in an accompanying editorial by doctors, Walsh, and Bezzina, and Wilde, from Amsterdam University Medical Center.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my first paper comes to us from Professor Karl Heusler from the University of Wurzburg. Carolyn, this study was a pre-specified analysis of the anticoagulation using the direct factor Xa inhibitor, apixaban, during atrial fibrillation catheter ablation comparison to vitamin K antagonist therapy, or the AXAFA–AFNET 5 trial. And it randomized 674 patients with atrial fibrillation, in a one-to-one fashion, to uninterrupted apixaban, or vitamin K antagonist therapy, prior to first time ablation, with a goal to assess the prevalence of magnetic resonance imaging detected ischemic brain lesions, and their association with cognitive function, three months after first time ablation, using the continuous oral anticoagulation in patients with paroxysmal atrial fibrillation.

Dr. Carolyn Lam:

Huh. Nice. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. They found that brain MRI detected chronic white matter damage, as well as, acute ischemic lesions, were frequently found after first time ablation for paroxysmal atrial fibrillation, using uninterrupted oral anticoagulation. Including, 27.2% of those receiving apixaban, and 24.8% of those receiving the vitamin K antagonists. So Carolyn, no difference there. MRI detected acute ischemic brain lesions were not associated with cognitive function at three months after ablation. And then, Carolyn, the lower Montreal Cognitive Assessment scores, both before and after ablation, were associated with older age only, highlighting the safety of atrial fibrillation ablation on uninterrupted oral anticoagulation.

Dr. Carolyn Lam:

Oh, thank you, Greg. Well, my next paper talks about basilar artery occlusion, which we know is a devastating condition without definitive evidence to guide treatment. Now, while we do know that faster treatment times with endovascular therapy is associated with better outcomes in the anterior circulation of the brain. What about this relationship for basilar artery occlusion? See? So that's the question that this paper sought to answer, and it's led by Dr. Smith from University of Calgary in Alberta, Canada, and colleagues. They used individual level patient data from the Get With The Guidelines-Stroke nationwide US registry, prospectively collected from January 2015 to December 2019, and identified 3015 patients with basilar artery occlusion treated with endovascular therapy.

Dr. Greg Hundley:

Ah, Carolyn. And so what did they find here?

Dr. Carolyn Lam:

So, here are the results. Treatment of basilar artery occlusion with endovascular therapy, within six hours of last known well, is associated with better outcomes, compared to treatment after six hours. Including, lower odds of mortality and higher odds of reperfusion, independence, and discharge home.

Dr. Carolyn Lam:

There was a non-linear association between, faster treatment with endovascular therapy for basilar artery occlusion, and better outcomes, with the greatest per hour improvement in outcomes seen within six hours of the last known well. In summary, results indicate that, faster treatment with endovascular therapy may improve outcomes in basilar artery occlusion. Efforts should therefore be made, to optimize workflow, including pre-hospital, inner-hospital, intra-hospital processes, to achieve rapid treatment with endovascular therapy in acute stroke with basilar artery occlusion.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science. And Carolyn, as we know, pulmonary hypertension can be caused by chronic hypoxia, leading to hyperproliferation of pulmonary arterial smooth muscle cells, and apoptosis-resistant pulmonary microvascular endothelial cells. And then, upon re-exposure to normoxia chronic hypoxia induced pulmonary hypertension in mice, is reversible. So in this study, the authors led by Dr. Christine Veith, from Justus Liebig University in Giessen, aimed to identify novel candidate genes involved in pulmonary vascular remodeling, specifically, in the pulmonary vasculature.

Dr. Carolyn Lam:

Ah, a very interesting and important topic. So what, or how, did they do this, Greg?

Dr. Greg Hundley:

Right, Carolyn. So following a microarray analysis, the investigative team assessed the role of secreted protein, acidic, and rich in cysteine, or SPARC, using lung tissue from idiopathic pulmonary arterial hypertension patients, as well as from chronic hypoxic mice. In this experiment, the mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia, at different time points

Dr. Carolyn Lam:

Okay, so what were the results?

Dr. Greg Hundley:

Okay, Carolyn, the big drum roll. So the microarray analysis of the pulmonary vascular compartment, after laser micro dissection, identified SPARC as one of the genes down-regulated at all reoxygenation time points that were investigated. Intriguingly, SPARC was vice versa, up-regulated in lungs, during development of hypoxia induced pulmonary hypertension in mice, as well as in idiopathic pulmonary hypertension. Although, SPARC plasma levels were not elevated in pulmonary hypertension.

Dr. Greg Hundley:

Transforming growth factor, or TGF-beta 1, or hypoxia induced factor to a signaling pathways, induced SPARC expression in human pulmonary arterial smooth muscle cells. In loss of function studies, SPARC silencing enhanced apoptosis, and reduced proliferation. And so Carolyn, in conclusion, these authors provide evidence for the involvement of SPARC in the pathogenesis of human pulmonary hypertension, and chronic hypoxia induced pulmonary hypertension in mice, most probably, by affecting vascular cell function.

Dr. Carolyn Lam:

Wow. Thanks for that, Greg. Well, let me give a tour of what else there is in today's issue. There's a letter from Dr. Ng on could cardiologists support, improve, the cardiovascular risk of GnRH agonists. There's a Case Series, by Dr. Blumer, on [entitled] Hemophagocytic Lymphohistiocytosis Associated with Endocarditis: A Case Years in the Making.” There's a Perspective piece by Dr. Hillis on [entitled], Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game?”

Dr. Greg Hundley:

And Carolyn, from the mailbag, we have a Research Letter, from Professor McFadyen entitled, Inherited Thrombophilias are Associated with a Higher Risk of COVID-19 Associated Venous Thromboembolism, a Prospective Population Based Cohort Study.

Dr. Greg Hundley:

Well, now onto that perspective and discussion from two viewpoints on xenotransplantation.

Dr. Carolyn Lam:

Xenotransplantation. Cool. Let's go.

Dr. Greg Hundley:

Well welcome everyone, to this feature discussion. And today, we're taking a little bit of a, different tact, and we are going to discuss a perspective piece. As you know, usually we will discuss an original article, but we have a perspective. And we have with us, the two authors that created this perspective. Dr. Jane Farr from UT Southwestern, in Dallas, Texas, and Dr. Josef Stehlik, from University of Utah. Welcome to you both.

Dr. Greg Hundley:

And listeners, our discussion today is on cardiac xenotransplantation, taking a heart from another species and implanting it in a human subject. So Josef, we'll start with you. Could you tell us a little bit about the history of cardiac xenotransplantation, and what are some of the obstacles that have to be overcome, if we're considering performing this procedure in a patient?

Dr. Josef Stehlik:

Greg, thank you for that question. The concept of xenotransplantation has been around for a long time, with the biggest attraction being, a large and ideally safe source of organs for our patients. As far as cardiac xenotransplantation, the first human art xenotransplant was done in 1964, in a man with terminal heart failure, who received a chimpanzee heart at the University of Mississippi.

Dr. Josef Stehlik:

The patient didn't survive the surgery, and the way it was done back then, brought up a number of ethical issues, and other issues as well. And so, the next xenotransplant was not done until 1984, in a neonate with hypoplastic left heart syndrome, at Loma Linda University. You might have heard the term, Baby Fae, before. And this infant survived about 20 days, and so we couldn't consider it, long term success. However, these two first xenotransplant brought up some important issues that would be studied for years to come. And I think, that the biggest lesson was that, the intra-species immune barriers were a formidable obstacle, and that really, new technologies, and then new medications, would probably have to come into the clinical arena, before we could do it again.

Dr. Greg Hundley:

Very nice. Well listeners, now we're going to turn to our second author on this particular paper. And Jane, can you describe some of the circumstances pertaining to this most recent cardiac xenotransplantation? What transpired, and what's been the outcome with that individual?

Dr. Maryjane Farr:

Thanks, Greg. And thanks for having us here on this program today. So the circumstance around this particular groundbreaking transplant was such that, there was a critically ill patient. This man who was in cardiogenic shock. Both sides of his heart were not working. He was on life saving temporary mechanical support with VA ECMO. And he unfortunately, despite his cardiogenic shock, he was not eligible for standard allotransplantation.

Dr. Maryjane Farr:

Part of that story was really about, not meeting standard criteria for organ transplantation, probably just about anywhere, in terms of a long history of, maybe not taking his meds, or taking care of himself. And there's, certain criteria that he didn't fit into. And he actually had been assessed, as I understand it, by a number of programs, before the University of Maryland approached him with this possibility.

Dr. Maryjane Farr:

One other option that could have been taken, was a mechanical circulatory assist device. But as I say, both sides of his heart were not working, and so really, total cardiac replacement was really his only option.

Dr. Greg Hundley:

And so Jane, do we know anything about what happened? How did the surgical procedure go? Do we know anything about the outcomes?

Dr. Maryjane Farr:

This is of course, patient privacy. So what we know is really, what's in the public arena. And it's actually, there's been a lot of transparency, which has been terrific, by the patient, and the family, and the doctors, because this is such groundbreaking information. But this patient was truly critically ill. There was some paperwork done to try to get FDA approval for emergency experimental surgery, with xenotransplantation. And of course, all the research at University of Maryland, and in many other centers, nationally, and internationally, have been done over the years. And so finally, there was an approval to do this, and it was basically a scheduled surgery.

Dr. Maryjane Farr:

And as I understand it, it went just like any other transplant surgery. There was obviously, a procurement team for the genetically modified pig. There was cold storage of the device. Transport, at least as far as to the next operating room, or however it went. And then, standard implantation, and release of cross clamp, and perfusion. And at least by what you can read about, the heart started to work almost immediately. And then of course, I think that's the easy part. It was really all the intense and multi blockade immunosuppressive therapy, which is really, the challenge of this type of therapy.

Dr. Greg Hundley:

Very nice. Well, Josef, Jane's alluded to this a little bit, but who would be a candidate for this therapeutic, this form of therapy?

Dr. Josef Stehlik:

Greg, so that's an excellent question. And I would like to address it. Before I do that, maybe we should also mention, very briefly, a little bit of the science behind the genetically engineered pig, that Jane mentioned.

Dr. Josef Stehlik:

There were three main things that have been done, and what enabled that is gene editing. And here, I would like to actually mention Dr. Mario Capecchi, who received a Nobel Prize in 2007, for his groundbreaking work at the University of Utah, by describing mouse gene knockout. That has been part of what has been used for engineering, of course, in newer approaches, like CRISPR.

Dr. Josef Stehlik:

Some of the things that have been done is that, the highly antigenic carbohydrates that pigs have on their cell surface, have been edited out. There have been genes that have been edited out and in, connected to coagulation and compliment, to prevent clotting and bleeding in the organ and the recipient after transplant.

Dr. Josef Stehlik:

And of course, one thing that it's very relevant also to our COVID pandemic, there has always, with xenotransplantation, been a question. Could there be trans-species infection? And pigs do have endogenous retroviruses that are parts of their genome, and those have been edited out as well. And so in this way, some of the previous obstacles have been removed.

Dr. Josef Stehlik:

So to your question, who might be a candidate? And I absolutely agree with Jane, that in the first step, it should really be patients who are not candidates for other clinically approved approaches, like allotransplantation from human donors, or mechanical assist, that can be durable, and those are the characteristics that the patient met. And I think, the next patients that will come now, hopefully, will probably be in the same category.

Dr. Josef Stehlik:

Now, I believe, and again, this is a little bit of a speculation, that the next step will be patients who are not eligible for transplant, but who may be eligible for durable ventricular assist devices. And our goal will be to show, that survival and quality of life after xenotransplantation can approach survival and quality of life, on LVADs. And of course, LVADs are evolving, as well.

Dr. Josef Stehlik:

And then, to some degree, it might be the choice of the recommendation of the team, of the multidisciplinary team. What is the best match for the patient? And to some degree, I think patient preference, to really share decision making in patient preference.

Dr. Josef Stehlik:

And in the next step, I believe, that's what we are hoping for, that at some point, we will achieve is that, xenotransplant will rival the outcomes of human allotransplantation. And so, that will be probably, the next group of patients. How long this will take is to be seen. But I think, that it addresses your question, who could be the candidates for xenotransplant in the future?

Dr. Greg Hundley:

Very good. And Jane, Josef was touching on a topic here. How do the anti-rejection treatments differ in xenotransplantation, as compared to allograft transplantation?

Dr. Maryjane Farr:

And so, that's been the thing for all these decades. And so, the first thing is, genetically engineered xenotransplant organs, that can mitigate some of the anticipated xenoantigenic responses.

Dr. Maryjane Farr:

So first, these carbohydrates that we do not see, so they are foreign to us, so there can be acute fulminant rejection. So that's, one step, and the gene knockout can take care of that mostly, but not completely. And then there's humeral rejection, and then, cellular rejection.

Dr. Maryjane Farr:

The cocktail that gets put together for a xenotransplant includes, some of the things that we standardly use, like steroids, ATGAM, or antithymocyte globulin, which is a generalized T and B-cell depleting therapy. What's nuanced, and there's also some role for anti-CD20 B-cell therapy, but what it is nuanced in xenotransplant is anti-CD40 monoclonal antibody therapy. And that was specifically developed, and then studied in heterotopics, or non-human primate pig transplant. Because what turns out is that, the robust T-cell responses, by what's called the indirect pathway, really requires significant costimulatory blockade, where anti-CD40 therapy has been critically important, and well studied by these scientists and others at the University of Maryland, and elsewhere.

Dr. Maryjane Farr:

And as I understand it, anti-CD40 was really, is the basis, the backbone, of this therapy. And then there's one last thing. And that is, temsirolimus, which is a pro drug of proliferation signal inhibitor therapy, that we standardly use in transplant. That's utilized to arrest the further growth of the xenotransplant. So that sounds like it's the cocktail, and there's some published reports, on these scientists using just such cocktail in their non-human primate transplant models.

Dr. Greg Hundley:

Well, listeners, we've heard a really interesting story here. But now, let's ask these experts, first, Josef, and then, Jane. Josef, moving forward, what are the concerns that you really see in this aspect of research?

Dr. Josef Stehlik:

Greg, I think, one of the issues that will have to be addressed, are ethical considerations. And we've seen, that after the news of xenotransplant was made public, there has been a lot of discussion among public about ethics of xenotransplant. I think it will be important to really proactively address that.

Dr. Josef Stehlik:

One aspect from the past is, we knew that primate xenotransplant have not been embraced by the public, just because of the closeness of primates to humans. I think, some of that will be mitigated, now that we are using pigs. But of course, there are many who feel strongly about humane treatment of animals. And so I think, regulation will need to be established that will address that, and that will make both the professionals and the wary public, comfortable with this approach.

Dr. Josef Stehlik:

And another thing that will need to be addressed, and Jane talked about it a little bit is, what parts of care for xenotransplant will be different from human allotransplant. Right? So how do the assessment of the biopsies differ? Right? We'll probably have a new grading scheme looking at xenotransplant. Should the antimicrobial prophylaxis be different? So we do prevent the possibility of trans-species infections we haven't seen before, et cetera. So there would be a lot of work for the transplant teams to do, as well.

Dr. Greg Hundley:

And, Jane.

Dr. Maryjane Farr:

Yes. One thing that's hard, this is amazing science, and this is a huge opportunity to transplant more patients, many of whom die on the wait list every year. But what really needs to be understood also, as we move into this area, and this is where us, as clinicians, get involved in some of these conversations in particular, is that this patient actually wasn't eligible for transplant. And these are very, very difficult decisions that centers are tasked to make.

Dr. Maryjane Farr:

It can get really tricky, and there's lots of patients who say, "Okay, I'm not a transplant candidate.", because of this or that, or the other reason. And there's, some reasons that are more important than others. They'll say, "Transplant me anyway. Give me a heart that you might turn down. Just give me a chance." And we don't do that. And insurance companies don't pay for that. And we have to actually find a way to be rational in our approach.

Dr. Maryjane Farr:

But truly, acknowledging that, if we had more resources, we could probably expand transplant even with the organs that we do have, because we turn down about, probably about 40% of organs, and maybe even more, every year, because we want to match the best organs. So it's really important that xenotransplant, in centers that can do this, demonstrate that this therapy works, and it provides a good quality and quantity of life, for at least, to be reasonable. And once you get there, then you can start to talk about, whether you need to think about allocation, and all that. So you can see how the conversation's going to go on for the next 10 years, about how this fits in.

Dr. Greg Hundley:

You both alluded to the fact, we need more research. And so, incrementally, for maybe each of you in 30 seconds. What do you see as the next research study that needs to be performed in this space? First, Josef, and then again, Jane.

Dr. Josef Stehlik:

That's a tough question, but I'll try to address it. I think, it will be a little bit in parallel to the first human allotransplant. Now that we've figured out the procedure and the organ that we can use, I think, it will be research focused on the care of the transplant recipient. And the task, number one, will be to identify immunosuppression that will be safe and effective, to protect this heart from dysfunction for many years after transplant.

Dr. Greg Hundley:

And Jane?

Dr. Maryjane Farr:

Yeah. You need to do a case series. The handful of centers in this country, and maybe the world, but I only know about this country, that have been studying and working towards this day, should take the lead. University of Maryland has taken the lead, and there are other centers who have been thinking hard about this, and preparing for this time for a long time, and they should lead the way, and try to do this with all the expertise that they've already built. And then as time passes, we can see what their outcomes are, and then we can start to think about, should there be a randomized controlled clinical trial? What should we compare it against? Who should be offered the opportunity? But at first, we need to find that there's safety and efficacy in the patients that are selected, and also, they themselves select, to go through this operation and therapy.

Dr. Greg Hundley:

Well listeners, we want to thank Dr. Jane Farr and Dr. Josef Stehlik, for providing their perspective on a recent procedure, involving the xenotransplantation of a genetically engineered porcine heart, into a human subject with advanced biventricular heart failure, that was not well suited for human heart allograft transplantation.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily, those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

Circulation March 15, 2022 Issue

14 mars 2022 | 28 min

This week, join author Tristram Bahnson and Associate Editor Changsheng Ma as they discuss the article "Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results from the CABANA Trial."

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Guess what, Greg? For today's feature paper, we are going to be looking at a very interesting analysis from the CABANA trial, this time, looking at the association between age and outcomes of catheter ablation versus medical therapy for atrial fibrillation. Cool, huh? Okay, but first, let's go through some other important papers in today's issue. Why don't I let you go first?

Dr. Greg Hundley:

Well, Carolyn, my first paper pertains to the cost effectiveness of coronary artery bypass surgery, and it comes to us from the STICH trial.

Dr. Carolyn Lam:

Ah, very important question, but please remind us what the STICH trial is again.

Dr. Greg Hundley:

Right, Carolyn. So the Surgical Treatment for Ischemic Heart Failure trial, or STICH demonstrated that coronary artery bypass grafting reduced all-cause mortality rates out to 10 years compared with medical therapy alone in patients with ischemic cardiomyopathy and reduced left ventricular function, defined as an ejection fraction of less than or equal to 35%. Now in this study, the authors led by Dr. Derek Chew at University of Calgary examined the economic implications of these results using a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG versus medical therapy alone, using patient-level resource use and clinical data collected from the STICH trial.

Dr. Carolyn Lam:

Again, really important study. And what did they find?

Dr. Greg Hundley:

Right, Carolyn. So first, using their patient-level simulation model incorporating resource use and clinical data collected from the STICH trial, they found that coronary artery bypass grafting was estimated to cost $63,989 per quality-adjusted life year gain compared to medical therapy alone. Second, in STICH eligible patients with left ventricular ejection fraction of less than 35% in coronary artery disease amenable to CABG, routine use of CABG increased the quality-adjusted life expectancy compared to medical therapy alone for an increased cost within current benchmarks for good value in healthcare within the United States. Then finally, Carolyn, together with the improved clinical outcomes seen in the 10 year extended follow-up of STICH, the findings in this study provide additional economic support for the use of coronary artery bypass grafting in patients with ischemic cardiomyopathy eligible for STICH.

Dr. Carolyn Lam:

Wow, thanks Greg. Well, this next study contributes to the understanding of the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease. Interesting? Well, listen up. This is from Dr. deVries from UT Health Science Center at Houston and colleagues who aimed to quantify remaining lifetime risk and years free of coronary heart disease according to polygenic risk and the AHA's Life's Simple 7 guidelines in the population base cohort of ARIC. As a reminder, the Life's Simple 7 by the AHA consists of smoking status, body weight, total cholesterol, blood glucose, blood pressure, physical activity, and diet.

Dr. Greg Hundley:

Ah, Carolyn. So genes versus lifestyle. So what did they find?

Dr. Carolyn Lam:

Participants with high polygenic risk may offset their lifetime risk of coronary heart disease by up to 50% through managing their health according to the Life's Simple 7's recommendations, depending on ancestry. Individuals with high polygenic risk scores and ideal Life's Simple 7 scores had 4.5 to 20 more coronary heart disease free years than individuals with high polygenic risk scores, but low Life's Simple 7 scores and again, depending on ancestry. Appropriate management of lifestyle and clinical risk factors of coronary heart disease play larger roles in the overall lifetime risk of coronary heart disease than presently available genetic information. Thus, communicating the effects of Life's Simple 7 measures and polygenic risk on coronary heart disease in terms of absolute risk may have important implications for education, policy, and environmental changes, which can benefit not only high risk individuals, but the whole population.

Dr. Greg Hundley:

Wow, Carolyn, really informative study and so nicely summarized. So Carolyn, my next paper comes to us from the world of preclinical science and it's from Professor Yan from Shanghai, Ruijin University School of Medicine. So Carolyn, previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure. However, the underlying mechanisms often remain unclear. Now since kinases have been reported to modulate mitochondrial function team investigated the effects of dual specificity tyrosine regulate kinase one B on mitochondrial, bio energetics, cardiac hypertrophy, and heart failure.

Dr. Carolyn Lam:

Wow. Okay. So what did they find Greg?

Dr. Greg Hundley:

Right, Carolyn. So this team found that Dual Specificity Tyrosine-Regulated Kinase 1B, our DYRK1B expression was clearly up regulated in failing human myocardium as well as in hypertrophic mirroring hearts and cardiac specific DYRK1B over expression resulted in cardiac dysfunction, accompanied by a decline in the left ventricular ejection fraction, as well as the fraction shortening. And it increased left ventricular myocardial fibrosis. Carolyn in striking contrast to DYRK1B over expression, the deletion of DYRK1B mitigated tack-induced cardiac hypertrophy and heart failure. In addition, the authors found that DYRK1B was positively associated with impaired mitochondrial bio-energetics by directly binding with stat three to increase its phosphorylation and nuclear accumulation. Thereby ultimately contributing toward the down regulation of PG C one alpha. Now, furthermore, the inhibition of DYRK1B or stat three activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bio-energetics.

Dr. Carolyn Lam:

Cool, Greg. So could you give us a take home?

Dr. Greg Hundley:

Right. So in summary then, Carolyn, taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1 beta in mitochondrial bio-energetics and the progression of cardiac hypertrophy in heart failure.

Dr. Carolyn Lam:

Fantastic. Thanks, Greg. Well, other papers in today's issue include an exchange of letters between Doctors Nie and Wollert on the article myeloid derived growth factor protects against pressure overload induced heart failure by preserving sarcoplasmic reticulum calcium, ATPase expression in cardiomyocytes. There's an AHA update [AHA Advocacy Page] paper by Dr. Churchwell on improving heart health through value-based payment. An ECG Challenge by Dr. Murphy on a “Curious ECG Morphology of a Cardiac Device.” An On My Mind paper by Dr. Figtree on “Sublingual Nitrates for Patients as a Default in the Post ACS Discharge Pack. Is the Time for a Rethink?”

Dr. Greg Hundley:

Right? Carolyn. Boy, this issue is really packed with great articles. There's a Perspective piece from Professor Stewart entitled “Myocardial Edema Provides A Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.” There's a wonderful Frontiers in medicine piece from Professor Kandzari entitled “A Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document from the Hypertension Academic Research Consortium.” And then finally, Carolyn, there's a Research Letter from Professor Wold entitled “E-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice. Well, Carolyn, how about we get onto those results from the CABANA trial?”

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we are now here for our feature discussion and we have with us today, Dr. Tristram Bahnson from Duke University and one of our own Associate Editors, Dr. Changsheng Ma from Beijing. Welcome gentlemen. Tristram, we will start with you first. Could you describe for us some of the background pertaining to this particular research study and what was the hypothesis that you wanted to address?

Dr. Tristram Bahnson:

Sure. Being an active electrophysiologist, a challenge we've had over the years is to try to figure out for whom catheter ablation would be a preferred therapy. I've had the privilege of being part of the CABANA study team over the last several years. As listeners might recall, the CABANA trial was a very large trial looking specifically at hard endpoints, including mortality, to try to determine whether or not catheter ablation provides significant benefits to patient. Apart from what we already knew over the years, which is the catheter ablation was more effective than drug therapy to reduce AFib recurrences. That study, the CABANA proper study was published in 2019.

Dr. Tristram Bahnson:

In the course of that study, pre-specified subgroup analyses were done initially reporting unadjusted outcomes for important clinically relevant subgroups. We found in that initial study that patients with heart failure, minorities, and patients of young age in particular appeared to do better with catheter ablation than with drug therapy. So with that as background, the CABANA study team embarked to focus on each of those subgroups and the heart failure paper was published in 2021, the minorities paper also in 2021 and the subject of our discussion now, the relationship between age and outcome in the CABANA study cohort is a subject of study today.

Dr. Greg Hundley:

Describe just quickly Tristram the hypothesis you wanted to test here and then in order to test that hypothesis, what was the study population that you included and what was your study design?

Dr. Tristram Bahnson:

So the focus was on the relationship between age and outcome in CABANA, and this was pre-specified substudy of the CABANA population. So it's probably worthwhile going over who got into the CABANA trial and to remind folks the CABANA trial enrolled 2,204 patients across 126 sites at 10 countries and randomized them one to one to a treatment strategy of either catheter ablation or drug therapy for simple traumatic atrial fibrillation that in the judgment of the treating physicians warranted therapy, patients had to have had at least two episodes of PAF or one episode of persistent AFib documented by ECG or ambulatory recordings within the six months prior to enrollment and they hadn't have failed more than one anuric drug. In other words, they would have to have been reasonable candidates for drug therapy, should they be so randomized.

Dr. Tristram Bahnson:

In addition, patients that were less than 65 years of age, had to have some additional factors that would increase the likelihood that outcome events would occur. They had to have a CHADSVASC score greater than one. That was not required of the older subjects follow up was 48 and a half months for the population at large, with the interportal range of follow up between 30 and 62 months. The patients had regular follow up every three months for the first year and then six months thereafter. In addition, 1,240 patients received a recording device that allowed them to provide either prescribed episodic recordings or recordings for when they were symptomatic and they also provided 96 hour holters every six months throughout the duration of the trial.

Dr. Tristram Bahnson:

So that's the population that we were working with. The study design, as I said, focused on trying to tease out the relationship between age and outcomes and the primary outcomes of the CABANA trial included the primary outcome, which was a composite. It included all cause mortality, disabling, stroke, serious bleeding or cardiac arrest, and the key secondary endpoints that were looked at included mortality and cardiovascular hospitalization and AF recurrence.

Dr. Greg Hundley:

Very nice. Describe for us your results.

Dr. Tristram Bahnson:

So we actually took a deeper dive into the subgroup of age, and we did a couple things that we thought would be valuable. One was to consider age as a continuous variable because after all, it's pretty arbitrary to bin people into age groups. I think the initial analysis did so with the CABANA proper publication in 2019 to correspond with the break points that we use for CHADSVASC scoring, but we elected to consider age as a continuous variable and we also elected to do adjusted Cox proportional hazard models to account for the various clinical factors that of course varied with age, such as their CHADSVASC score, the occurrence of structural heart disease, like valvular heart disease or coronary disease, the proportion of women, which typically increases with age and did so in this population. The key endpoints that we examined were the CABANA endpoints, including the primary composite endpoint of total mortality, mortality, or CB hospitalization and AF recurrence.

Dr. Tristram Bahnson:

So at the end of the day, we had 766 patients who were less than 65, 1,130 that were between 65 and 74 and 308 that were greater than 75. Mind you, CABANA admitted patients with any kind of AFib. As a matter of fact, more than half of the study population had persistent or longstanding persistent atrial fibrillation, which is not typical of many studies that have been published, looking at the relative benefits of catheter ablation. We had an unexpected finding that was hinted at, at the initial CABANA study and that was the benefit of catheter ablation was greatest in the younger patients and the benefits of catheter ablation relative to drug therapy seemed to decrease with advancing age at enrollment, which was the age criterion that we based the analysis this on and that this effect was primarily driven by changes in mortality.

Dr. Tristram Bahnson:

For the composite endpoint in CABANA, which was total mortality, serious stroke, serious bleeding and cardiac arrest, we saw that the adjusted hazard ratio increased average of 27% for every decade in advancing age, where the age was defined as that at enrollment, and for the total mortality endpoint, the adjusted hazard ratio increased an average of 46% for every 10 year increment in age at enrollment. For all age groups, catheter ablation was superior to drug therapy, a relative to a reduction in AFib consistent with many other studies. The benefit was a reduction in the adjusted hazard ratio of about 50%. So catheter ablation was agnostic to age in terms of the benefit of reducing AFib, but was not agnostic to age with result to these mortality inclusive endpoints. We did notice that there was a trend towards a relative benefit of drug therapy for the oldest age group, but we interpreted that result with caution for a variety of reasons. The oldest age group was least well represented and comprised less than 10% of the CABANA population and less than half of the next best well represented age group, which was the less than 65's.

Dr. Tristram Bahnson:

In looking carefully at the data, we could find no plausible explanation for why the older age group might do better with drug therapy. Again, it was not significant by an intention to treat analysis, but there was a trend towards drug therapy getting better with the oldest age group. We noticed that there was no excess mortality in the old age group within six months of treatment, so it didn't seem like it was related to some adverse procedural effect. We saw no evidence of more advanced forms of AFib in the oldest age group, because they had as good AFib suppression as others, and had the same distribution of paroxysmal versus persistent forms of AFib as the other age groups. There was no difference in crossover after all, if more patients in the old age group crossed over from drug to ablation therapy, who might expect that to be a confounder.

Dr. Tristram Bahnson:

We did see something that was very unusual and unexpected, which is that the mortality of the oldest age group treated with drugs was actually less than their mortality in catheter ablation, which is the issue at hand, but also less than the other age groups, which was unexpected and even less than all but the youngest age group treated with catheter ablation. So we can't explain this finding. It was not statistically significant. At the end of the day, we don't believe that elderly patients who have drug refractory AFib that is symptomatic should be denied ablation.

Dr. Greg Hundley:

Well, thank you so much, Tristram, for these very intriguing results. Changsheng, you have many papers that come across your desk. What drew you to this particular paper?

Dr. Changsheng Ma:

Yes. Dr. Bunch and colleagues should be commanded for the understand and taking important subgroup analysis of CABANA study. There has also been interest in whether the risk and the benefit of ablation may be modulated by patient age. The current analysis suggests that the related benefit of ablation was characterized for those less than 65 years of age are a tiny bit by the increasing age. It is important to emphasize that the current analysis result should not be interpreted to suggest that the cancer ablation has less value in idly patients. As a casual ablation must treated before recurrence across all age groups.

Dr. Changsheng Ma:

The current analysis is assuming we should know age related increase in safety constant in patients and taking ablation therapy. So we must be cautious not to over incorporate the result of the sub-group analysis, especially in the context of CABANA trial, treating in the permanent effect of ITT analysis. So I think it can be a possible that reach age related gradings in the relatively treatment benefits of the ablation is finding a challenge. Secondly, the CABANA trial was not a oral subgroup analysis. So the variation of treatment effect across the different age group were in the further resource. That's my opinion.

Dr. Greg Hundley:

Thank you very much. Well, gentlemen, what do you see is the next study that needs to be performed in this sphere of research and Tristram, we'll start with you.

Dr. Tristram Bahnson:

Well, clearly the clinical task at hand, for those of us who treat patients is to advise patients about relative benefits of therapy when there are choices at hand. And in the case of atrial fibrillation, the fundamental choice obviously is whether or not to pursue catheter ablation or to pursue medical therapy, either for rhythm or rate control. An important part of that decision making is to understand which patients would derive the most benefit from one versus the other therapy. And that need is perhaps the genesis of why we embarked on these subgroup analysis, which admittedly need to be interpreted with caution are not powered to give definitive results, but can certainly help guide future research. So we have noted in the CABANA trial that heart failure patients might do better and that's consistent with other studies looking specifically at heart failure with reduced ejection fraction. So we're contemplating additional studies to help tease that population out since in CABANA, in particular, our heart failure population was mostly those with a preserved ejection fraction and clinical heart failure.

Dr. Tristram Bahnson:

With regard to age, I think it'll be important to do studies to try to understand what factors resulted in the young patients apparently doing better with ablation. Again, this is hypothesis generating in terms of our result with this paper. So it'd be very interesting to find out whether there are some subsets of patients with younger ages or patients who have the relevant characteristics of the young age patients who would derive particular benefit from catheter ablation. This would obviously require a variety of approaches, including prospective randomized studies and carefully done population studies. So this issue about which patients really derive a significant mortality benefit it from catheter ablation is an important one that has not yet been teased out completely.

Dr. Greg Hundley:

Thank you. And Changsheng, do you have anything to add?

Dr. Changsheng Ma:

Yes. I think two streams say it's a very important topic for, you know, who have more and more, the older patients. So we need to answer the question, how about the real influence of age on the outcomes of the atrial fibrillation patients with ablation. So in future, we should consider randomized trial, but I think it's very difficult. So maybe we have to wait more and more, you know, other study to have a trend, how about the outcome for all the patients. It becomes too difficult for a new randomizedtrial.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Tristram Bahnson from Duke University and Dr. Changsheng Ma from Beijing for bringing us the results from this substudy of the CABANA trial indicating that the mortality related benefits of catheter ablation for atrial fibrillation appeared to decrease for every 10 year increment in age, above the age of 65 years. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation March 8, 2022 Issue

7 mars 2022 | 18 min

This week, join author Marco Valgimigli and Associate Editor Mark Link as they discuss the original research article "Amulet or Watchman Device for Percutaneous Left Atrial Appendage Closure: Primary Results of the SWISS-APERO Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage fast as a journal and editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor, Director of Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I've got a personal interest in this feature paper that's coming up. I've always been very intrigued with the left atrial appendant closure. Well guess what? This is the results of the Swiss-Apero Randomized Clinical Trial, comparing the Amulet with the Watchman device for percutaneous left atrial appendage closure, really interesting stuff coming right up, but let's hold everyone in suspense. As we go through some of the other favorite papers in today's issue. Would you like to go first?

Dr. Greg Hundley:

You bet Carolyn, this first paper really pertains to driving restrictions and earlier arrhythmia is in patients receiving a secondary prevention, implantable cardioverter defibrillator, and it comes to us from Dr. Christian Steinberg. So Carolyn, regulatory authorities of most industrialized countries recommend six months of private driving restriction after implantation of a secondary prevention ICD and these driving restrictions result in significant inconvenience in social implications. And so Carolyn, the purpose of this study was to assess the instance rate of appropriate device therapies in contemporary recipients of a secondary prevention ICD using a retrospective across three Canadian tertiary care centers enrolling 721 consecutive patients with new secondary prevention ICD implants between the years of 2016 and 2020. And they were followed for a median of 760 days.

Dr. Carolyn Lam:

Nice. An important question. So what did they find Greg?

Dr. Greg Hundley:

Right Carolyn. So they found that the cumulative incidents of arrhythmic syncope resulting in sudden cardiac incapacitation was 1.8% within the first 90 days, and subsequently dropped to 0.4% between 91 and 180 days after ICD insertion. So Carolyn the incidence rate of appropriate therapies resulting in sudden cardiac incapacitation in contemporary recipients of a secondary prevention ICD is much lower than previously reported and significantly declines after the first three months, lowering driving restrictions to months after the index cardiac event seems safe and revision of the existing guidelines should be considered in countries still adhering to a six month period.

Dr. Carolyn Lam:

Oh, love it Greg. Elegant study with clinically impactful results as with the next paper, I'm going to talk about a post talk analysis of the Danish trial in which authors led by Dr. Boas from Denmark and Dr. Bower from Austria and their colleagues. And what they did is they tested whether periodic repolarization dynamics or P R D, which is a marker of repolarization instability associated with increased sympathetic activity. Could indeed identify patients with non-ischemic cardiomyopathy that may benefit from prophylactic ICD implantation. So, 748 patients were included in this P R D sub-study. And they were included if they had a 24 hour whole term monitor recording at baseline with technically acceptable ECG signals during the night hours. P R D as a reminder of periodic repolarization dynamics was assessed using wavelet analysis according to previously validated models.

Dr. Greg Hundley:

Very interesting, Carolyn. So what did they find?

Dr. Carolyn Lam:

Periodic repolarization dynamics was independently associated with mortality. More over P R D was significantly associated with mortality in the control group, but not in the ICD group in this Danish trial. There was a significant interaction between P R D and effect of ICD implantation on mortality, such that patients with higher P R D had greater benefit in terms of mortality reduction with the ICD. Based on P R D the investigators could identify a new group of patients where prophylactic ICD implantation was associated with a significant absolute mortality reduction of 17.5% after eight years corresponding to a number needed to treat of only six. So this is the first sub-study of Danish to identify a marker on top of age, that can predict the treatment effect of prophylactic ICD implantation in patients with nonischemic cardiomyopathy.

Dr. Greg Hundley:

Very nice Carolyn. Well, my next paper comes to us from Dr. Kory Levine from the Washington University School of Medicine. And Carolyn recent studies have established that cc chemokine receptor type two are CCR2 marks the pro inflammatory subsets of monocytes, macrophages and dendritic cells that contribute to adverse left ventricular remodeling and heart failure progression. Now elucidation of the effector mechanisms that mediate adverse effects of CCR2 plus monocytes, macrophages and dendritic cells could yield important insights into therapeutic strategies to suppress myocardial inflammation.

Dr. Carolyn Lam:

Hmm, indeed. And so what did these author determine regarding the suppression of myocardial inflammation?

Dr. Greg Hundley:

So Carolyn this team utilized mouse models of re perfused myocardial infarction, and angiotensin two and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate cc chemokine ligand 17. They found that cc chemokine ligand 17 serves as a pro-inflammatory mediator of CCR2 macrophages and dendritic cells, and their results suggest that inhibition of cc chemokine ligand 17 may serve as an effective strategy to promote T-cell regulation recruitment, and thereby suppress myocardial inflammation.

Dr. Carolyn Lam:

Wow, thanks, Greg. That was beautifully summarized great stuff. Well, there are other exciting articles in today's issue. There's an exchange of letters between Doctors Nagareddy and Spear on “Interleukin One Alpha as a Central Regulator of Leukocyte Endothelial Adhesion in Myocardial Infarction and Chronic Kidney Disease. There's an ECG challenge by Dr. Yang entitled, “A Fatal Case of Y QRS tachycardia following Sintilimab treatment for lung cancer. It can happen.” There's an On My Mind paper by Dr. Faed on “CYP2C19 Genotyping in Anticoagulated Patients Post PCI: Should it be Routine?”

Dr. Greg Hundley:

Great, Carolyn and I've got a Research Letter from Professor Poo entitled “Efficient in Vivo Hemology- Directed Repair within Cardiomyocytes.” Well, how about we get onto that feature, discuss and learn more about Watchman devices and left atrial appendage closure.

Dr. Carolyn Lam:

Ooh, let's go.

Dr. Greg Hundley:

Well, listeners. Now we are onto the feature discussion today, and we're so privileged to have with us, Dr. Marco Valgimigli from Bern, Switzerland and our own Associate Editor, Dr. Mark Link from UT Southwestern. Welcome gentlemen. Well, Marco, we will start with you. Can you describe for us a little bit of the background material as to why you wanted to perform this study and what was the hypothesis that you wanted to address?

Dr. Marco Valgimigli:

But thank you so much for having me left atrial appendage closure is a therapeutic option for a patient who have formal indication to oral anti-population because of atrial fibrillation yet have some relative or absolutely contraindication to the treatment because mainly of high bleeding risk features, mainly because of previous bleeding complications. The two most frequently use device to accomplish that procedure are from one side Watchman, which is FDA approved. And on the other hand, the Amulet, which has been historically the device, which has been most frequently used in Europe, these two devices have been formally compared in one head to head study, which is Amulet IDE and also reported in the journal some month ago. However, it was important also to compare the new Watchman iteration, which the Watchman Flex, which was not part of the original Amulet IED, which only compared Amulet with Watchman 2.5.

Dr. Marco Valgimigli:

Before we set up this multicenter study, which recruited patients across eight centers and four European countries, we roughly screened 450 patients. And we ended up randomizing 222 to either of these two device being Amulet or Watchman. We set up this study to answer a superiority hypothesis, actually, of Amulet versus Watchman and we assume that Amulet would be superior compared to Watchman with the respect to the need for crossover to a known randomly allocated device or LA Patency at 45 day SCCTA.

Dr. Greg Hundley:

Very nice Marco. And so now describe for us your study design. And then what was your study population?

Dr. Marco Valgimigli:

That was an investigate initiated and conducted multicenter study, which took place across eight centers in four European countries. We screened roughly 450 patients to be able to randomize. Finally, 222 were evenly allocated to either of these two device. We selected patients with either fibrillation and form lead for oral anti-regulation to with relatively high chat box score on average four and very high has bled at least three or greater. In fact, 95% of our patient had prior bleeding before being considered for the study.

Dr. Greg Hundley:

Very good. And describe for us your results.

Dr. Marco Valgimigli:

So the superiority that we assumed was actually not met. The primary point, which was again, crossover to a known allocated device or patency rate at 45 day SCCTA was pretty much similar with rates being 68% in the Watchman group and 70% in the Amulet group. So basically no real difference. We did see though some interesting differences with respect to some key secondary endpoints.

Dr. Greg Hundley:

And describe those.

Dr. Marco Valgimigli:

So for example, the type of leaks that was recorded was actually different with respect to the two devices with intra device leaks, being much more frequent with Amulet and peri device leak, being much more frequent with Watchman. Also the rate of any or major procedure complications were slightly yet significantly higher in the Amulet group. And interestingly as well, we had some minor differences with respect to the device related thrombosis, which was numerically slightly higher in Watchman as compared to Amulet also, we performed at 45 day TEE, Transesophageal Echo and with that respect, we did see a slightly, yet numerically and significantly higher rate of peri device leak, detected at Transesophageal Echo with Watchman as compared to Amulet, which is in a way reflecting our SCCTA findings.

Dr. Greg Hundley:

Very nice. And so lots of results comparing these two devices for a left atrial appendage closure. So Mark, you see many papers come across your desk. What attracted you to this particular paper?

Dr. Mark Link:

Yeah, this is a very important clinical paper. The left atrial occlusion devices are going to continue to be used and with increasing frequency and there can be very beneficial. The Amulet is not approved in the United States. And so comparison between Watchmen and the Amulet are very important, both for the US and for Europe and the rest of the world. And that's why we were attracted to this paper, it's a nice randomized paper comparing the two most commonly use devices.

Dr. Greg Hundley:

Help us put the results of this study into the context in really how we might manage patients and how we're considering these devices, both from the European perspective and then also here in the US.

Dr. Mark Link:

I think what this study shows is that they're more or less equivalent and there may be theoretical reasons why one may be better than the other, but in this trial it didn't really come out. So I think the Amulet used more in Europe. The Watchman is used exclusively here, but I think this opens a window for the Amulet to come to America also and be approved by the FDA.

Dr. Greg Hundley:

Very good, well, coming back to you, Marco, where do you see is the next study that needs to be performed in this arena of research?

Dr. Marco Valgimigli:

I think now we have relatively effective device in accomplishing what we would like to accomplish. Namely sitting the LAA for preventing subsequent thromboembolic events. However, the procedure despite operators have been growing in terms of interest and experience is still associated with some degree of complications. Some of them are minor, but some of them are not. I think the next future, we should try to minimize those complication to the lowest possible event so that this procedure can potentially be also offered to a broader patient population, perhaps not just as a replacement of oral anticoagulation, but perhaps in association with oral anticoagulation to further minimize the stroke and other thrombotic events.

Dr. Greg Hundley:

And Mark, do you have anything to add here?

Dr. Mark Link:

Yes. I think what we need more information on is two things. One is procedural complications, procedural complications were higher with the Amulet device. And is that because it was a newer device and people are just learning how to use it, or is there something there that's really important? So that's one and then the really important one is long term clinical outcomes. This was a relatively short term trial when you're talking about strokes and anticoagulation. And so what I'd like to see is longer term follow up with both devices in the future.

Dr. Greg Hundley:

Well, thank you Mark. So now Marco, do you have any additional studies that you're performing really on this same dataset?

Dr. Marco Valgimigli:

Well, I actually fully agree with Mark, very long term follow up is absolutely mandatory in this patient population. And I'm very glad to announce that this Swiss Apero study that we have been discussing will actually continue. Continuing patients follow up five years so that we will have much more clinical information, at least comparative effectiveness, clinical information between two devices. And also we'll be performing at 13 months, a second SCCTA to better understand the dynamic nature of these peri device or inter device list, whether they actually do see over time and which of them may or not play a clinical role.

Dr. Greg Hundley:

Very nice well listeners, we want to thank Dr. Marco Valgimigli from Bern, Switzerland and our own associate editor, Dr. Mark Link from UT Southwestern for really bringing us this very important paper that compared the results of the Watchman, which is for primarily used in the US versus the Amulet, primarily used in Europe, a left atrial appendage closure device. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Speaker 5:

This program is copied right of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation March 1, 2022 Issue

28 februari 2022 | 21 min

This week, join author Makoto Hibino and editorialist Christoph Nienaber as they discuss the article "Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies" and accompanying editorial "Taming Hypertension to Prevent Aortic Dissection: Universal Recognition of a "New Normal" Blood Pressure?"

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week's feature discussion. Oh, very interesting. We are going to delve into results from the Japan specific health checkup study, as well as the UK Bio bank study and also a meta-analysis of several cohorts and investigate the relationship between hypertension and the future risk of aortic dissection. Well, Carolyn, but first, how about we grab a cup of coffee and delve into some of the other articles in this issue, and I'll go first?

Dr. Carolyn Lam:

Please do.

Dr. Greg Hundley:

I'm going to discuss with you the AVATAR trial.

Dr. Carolyn Lam:

Hold on, Greg, remind us, the AVATAR trial?

Dr. Greg Hundley:

Right, Carolyn. So the aortic valve replacement versus conservative treatment in asymptomatic, severe aortic stenosis or the AVATAR trial is an investigator initiated international prospective randomized control trial that evaluated the safety and efficacy of early SAVR or surgical aortic valve replacement in the treatment of asymptomatic patients with severe aortic stenosis, according to common criteria.

Dr. Greg Hundley:

So for example, the valve area is less than one centimeter squared with an aortic jet velocity of greater than four meters per second, or a mean trans aortic gradient of greater than 40 millimeters of mercury. They also, all of the patients had normal LV function and negative exercise testing was mandatory for inclusion.

Dr. Greg Hundley:

And so these authors, led by professor Marco Banovic from the University Clinical Center of Serbia, tested the primary hypothesis that early SAVR would reduce the primary composite endpoint of all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure as compared to a conservative strategy, according to guidelines. And the trial was designed as event driven to reach a minimum of 35 pre-specified events. The study was performed across nine centers in seven European countries.

Dr. Carolyn Lam:

Wow. A big important study. What did they find?

Dr. Greg Hundley:

Right, Carolyn? So they had 157 patients and they age average, 67 years and 57% were men and they were randomly allocated to early surgery, so 78 were in that group, or conservative treatment, and 79 were in that group. The follow-up was completed in May of 2021 and the overall medium follow was 32 months, 28 months in the early surgery group and 35 months in the conservative treatment group.

Dr. Greg Hundley:

There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment arm. So Carolyn, in asymptomatic patients with severe aortic stenosis, early surgery reduced the primary composite all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared to the conservative treatment. And so, Carolyn, this randomized trial provides preliminary support for early SAVR once aortic stenosis becomes severe, regardless of symptoms.

Dr. Carolyn Lam:

Wow. Interesting. Well, this next paper that I'm looking at describes a novel therapeutic target that, listen up, can lower plasma cholesterol and prevent thrombosis simultaneously.

Dr. Greg Hundley:

What? Are you sure about this? All right, Carolyn. All right. Describe this for us.

Dr. Carolyn Lam:

Well, I'll tell you what that target is. It is the coagulation factor prekallikrein, which I'm going to call PK, prekallikrein. Okay. Now, as a reminder, coagulation cascades are activated by tissue factor initiated extrinsic pathway and the contact system initiated intrinsic pathway. Both of which converge into the common pathway. Plasma kallikrein is a serine protease playing a crucial regulatory role in the intrinsic pathway and is generated from the liver expressed prekallikrein, a pro enzyme encoded by the KLKB one gene.

Dr. Carolyn Lam:

Now that was the background. In the current study, Drs. Song and Luo from Wuhan University in China and their colleagues identified that the plasma coagulation factor prekallikrein or PK interacts with the LDL receptor and induces its degradation in the lysosomes. In young Chinese Han adults serum PK concentrations positively correlate with LDL cholesterol levels. In hamsters genetic ablation of the KLKB one decreases plasma lipid levels through up-regulating LDL receptor in a manner additively to the PCSK nine inhibitor cyclocumarol.

Dr. Carolyn Lam:

Injections of the anti PK neutralizing antibody in mice and knock down of the KLKB one gene in rats also increased hepatic LDL receptor levels and reduced plasma cholesterol levels. Furthermore, in mice with ample E deficient background PK absence arrested the progression of atherosclerotic lesions. So in totality, these results suggest that PK, remember that's prekallikrein, regulates both LDL and thrombosis, and that PK inhibition can be an attractive therapeutic strategy to lower plasma cholesterol and prevent thrombosis simultaneously.

Dr. Greg Hundley:

Very nice, Carolyn. Well, before we get to our feature discussion on aortic dissection, I've got a paper that pertains to preclinical science and involves the study of aortic dissection. And it comes to us from Professor Aijun Sun from the Shanghai Institute of Cardiovascular Diseases at the Song Hang Hospital in Futon University, the Institute of Biomedical Science in Futon University.

Dr. Greg Hundley:

So Carolyn, the development of thoracic aortic dissection is closely related to the extracellular matrix degradation and the vascular smooth muscle cell transformation from contractile to synthetic type and legumin degrades the extracellular matrix components directly, or by activating downstream signals. However, the role of legumin in the vascular smooth muscle cell differentiation and the occurrence of thoracic aortic dissection, that remains elusive or unsolved.

Dr. Carolyn Lam:

Oh, so what did this study show?

Dr. Greg Hundley:

Right, Carolyn. So these authors found that the elevation of legumin is observed in thoracic aortic dissection tissues of both human subjects and in mice and deletion or pharmacologic inhibition of legumin rescues BAPN induced thoracic aortic dissection development in mice by alleviating extracellular matrix degradation and the vascular smooth muscle cell transformation. Carolyn, legumin depletion may represent a novel therapeutic strategy for thoracic aortic dissection and further studies are required to explore the diagnostic value of serum legumin as a novel biomarker for thoracic aortic dissection.

Dr. Carolyn Lam:

Wow. That's cool. Thanks, Greg. Well, there are other really cool papers in today's issue. There's a Cardiovascular Case Series by Dr. Bockus on a “Heart of Gold: A Scintillating Leading Pericardial Effusion. And I'll give you a hint, it's a case of cholesterol pericarditis. There are letters by Drs. Lucas and Taegtmeyer regarding the article “One Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage B HFpEF” with a response by Dr. Levine. There are highlights from the Circulation Family of Journals by Sara O'Brien.

Dr. Greg Hundley:

Well, Carolyn, I have some other papers to discuss in this issue as well. First, there's an On My Mind piece from Professor Lawler entitled, “What Are Adaptive Platform Clinical Trials, and What Role May They Have in Cardiovascular Medicine?” Next, there's an In Depth piece from Professor Damman entitled Evidence Based Medical Therapy in Heart Failure Patients With Reduced Dejection Fraction and Chronic Kidney Disease. And then finally, Professor Yoshida has a Research Letter entitled The Efficacy and Safety of Edoxoban 15 Milligrams According to Renal Function in Very Elderly Patients With Atrial Fibrillation, a Sub-Analysis of the Elder Care AF Trial. Wow, Carolyn, how about now we get onto that feature discussion.

Dr. Carolyn Lam:

Oh, let's go Greg.

Dr. Carolyn Lam:

For our feature discussion today, we are talking about aortic dissection and the association with hypertension or elevated blood pressure. Now at first sight, you may think, well, we all know that hypertension and elevated blood pressure is an important risk factor for aortic dissection, but I'd like you to question, do we really know?

Dr. Carolyn Lam:

Surprisingly few prospective studies have been published. We know that aortic dissection is an extremely important and serious complication, but it's low incidence means we need huge numbers to be able to answer questions such as, what blood pressure does the start taking off at? For example, is it systolic or diastolic blood pressure and so on? Well, guess what? We finally, I think, have some of the best evidence on this topic published in today's issue of Circulation.

Dr. Carolyn Lam:

And I'm so proud to have the first and corresponding author with us, Dr. Makoto Hibino from the University of Toronto to discuss his fantastic paper. As well as an editorialist, Dr. Christoph Nienaber from Imperial College, London, who will discuss the significance of this paper. Well, let's start with you, Dr. Habino or Makoto, if you don't mind, could you please tell us what you did and what you found?

Dr. Makoto Hibino:

Thank you, Carolyn. So it's my honor to be here to present my case in this podcast. So first, some of the recent data shows that the number of aortic dissection operation and this increasing trend, depending on countries and given the critical nature of aortic dissection preventive strategy against aortic dissection is expected. On the other hand, hypertension is still global issue and is responsible for constant number of deaths from cardiovascular diseases, including aortic dissection, but due to the relatively rare instance of dissection and acute critical nature of the disease, the available epidemiological evidence has been limited. So this time we wanted to investigate how the relationship of hypertension and blood pressure with the instance of the aortic dissection is, in terms of strengths association and the shape of the association.

Dr. Makoto Hibino:

We also hypothesized that association may not be leading a relationship. And what we did is our study is consist of three parts. The first two parts are original cohort studies using a Japanese specific health checkup study and UK Bio bank study in both of which we prospectively followed about half a million general population and analyzed the hazard risk of other aortic dissection instance for hypertension and systolic and diastolic blood pressure using Cox proportional analysis. And the last part is meta-analysis including eight cohort studies and examine the robustness and shape of the association between hypertension and systolic and diastolic blood pressure and the risk of aortic dissection.

Dr. Carolyn Lam:

Wow. So a huge study across diverse cohorts. What did you find?

Dr. Makoto Hibino:

Yes. So in both of our cohort studies, there was significant risk of aortic dissection for hypertension and systolic and diastolic blood pressure as a continuous variable. Also, there was increasing trend in hazard ratios for categorical systolic and diastolic blood pressure with two to five, for higher risk in the highest systolic blood pressure category and four to 12 for higher risk in the highest diastolic blood pressure category in the meta-analysis. The summary relative risk shows that those with hypertension has threefold risk of aortic dissection and the robustness of the result confirmed with the sensitivity and subgroup analysis. Lastly, in the non-linear dose response, meta-analysis, there was very strong dose response relationship between systolic blood pressure and aortic dissection with evidence of non-linearity. And similar, but still, those response relationship was found between diastolic blood pressure and aortic dissection. This analysis showed that the risk of aortic dissection was significant at systolic blood pressure more than 132 millimeter mercury, and diastolic blood pressure more than 75 millimeter mercury suggesting a risk of aortic dissection, even in non-hypertensive population.

Dr. Carolyn Lam:

Wow. That last part really grabbed me. And I think I should repeat that the risk was significant at the systolic blood pressure of only 132 and a diastolic blood pressure of 75. That's really striking. Chris toff, would you agree with me when I said, I think this is like the best data that we have now, sort of correlating blood pressure and hypertension with aortic dissection. I loved your editorial by the way.

Dr. Christoph Nienaber:

Thank you very much. I'm pleased to have the chance to write this editorial. Because, when I reviewed the article, I was thrilled of the data and the fact that somebody some consortium had managed to pool data from two different, let's say population studies in two different gene pools in Japan and in the UK together. And finding in a very granular way, that even within the normal spectrum of blood pressures, up to let's say 140 systolic, we find an increasing risk of dissection with a high normal blood pressure as compared to a low normal blood pressure. This has been very convincingly shown by Makoto's analysis. The entire group has to be congratulated for that fantastic idea. Collaboration from two different ends of the world, and then coming up with a similar conclusion in both populations, tells us that this is a general principle at work, that works in both gene pools in both Asian, as well as European populations, and tells us how important it is to keep an eye on blood pressure and even manage blood pressure within the normal range to a low normal in the future.

Dr. Carolyn Lam:

And I love the way you articulated that in that beautiful editorial, but could I now ask your thoughts, both of you, what are the clinical implications of this? I love Chris toff, that you discussed in your editorial, well, do we now lower the thresholds for treatment? Because aortic dissection is not the most common of incidences, right? So does lowering the blood pressure even more or targets come at a price? Or what should we be thinking of now, clinically?

Dr. Christoph Nienaber:

We are not treating dissection. We are trying to prevent dissection by gauging or gouging to a low normal blood pressure with various drugs and combinations of drugs in patients that are considered to be at risk with a slightly elevated blood pressure. So in the future, it's not enough to accept 140 systolic or 90 diastolic we should really pay attention to strictly lowering blood pressure in the idea of preventing vascular events.

Dr. Christoph Nienaber:

And that was considered to come at a price, but we have of course, reassuring data from Hope, from Sprint recently published that showed that even the low normal doesn't hurt. I mean, you have a lower risk of cardiovascular events, generally speaking, shown in Sprint with a low normal blood pressure. It comes a little bit at the expense of watching renal function, but that doesn't contribute to kind of prognostic sequelae. You just have to pay attention to it. You would not run any additional risk by lowering the blood pressure to a normal low blood pressure. And that's, I think, the convincing message, and even with a low incidence of the most important vascular accidents, such as dissection, you could prove that, or the group could prove that in almost 3000 patients that suffered from dissection, that whole pool of analyzed data. So again, I have to congratulate to this fantastic and convincing results.

Dr. Carolyn Lam:

Thank you. And Makoto, what do you think are the most important clinical take home messages from your study?

Dr. Makoto Hibino:

Yes. So let me, a little bit, step back to the summary of our findings. So our findings is so that this is a study is a fast summary of the evidence from the prospective stakeholder studies on the association of blood pressure and hypertension with the risk of aortic dissection. And this study improves the evidence base from being based on the case studies or single study to actual estimate of the relative risk. So also, with further study are needed, the current results suggests that the reducing blood pressure either through a healthier lifestyle or medication may reduce the instance of aortic dissection and furthermore the optimal target blood pressure may even lower than the current cut for hypertension. So from my perspective given the little rare instance of aortic dissection, intensive blood pressure management may be more effective or efficient in high risk population, such as those with bicuspid aortic valve or those with very ill medical follow for aortic aneurysm and those with genetic background. So further study in a specific subgroup, is warranted.

Dr. Carolyn Lam:

Thank you. And Chris toff, that's very interesting because I buy your argument too, that on the other hand, going lower, even in non-high risk, doesn't really come at a price as far as we can see. So what do you think Chris toff, what do you think are the further studies that are needed?

Dr. Christoph Nienaber:

Well, I was intrigued to see in their analysis that even the subgroups of patients, including patients with hereditary connective tissue disorders, survivors of previous dissection, patients with other conditions, including diabetes, et cetera, they're all across the board, benefited from low blood pressure adjust or adjustment to a low blood pressure. That gives me confidence to recommend to my colleagues, not only here, but in my further environment to follow those patients that are identified either as risk groups or with a slightly elevated blood pressure to definitely lower the blood pressure to lowest, lower to blood pressure with those side effects.

Dr. Carolyn Lam:

Nice. These are association studies just to take a step back rather than sort of treatment target studies, although we've discussed some of the treatment target studies, but I have to really agree that it's some of the strongest association data that I can frankly think of for blood pressure and aortic dissection. We're just so grateful that it has been published in Circulation. And thank you so much, Chris toff, for your elegant editorial, that really puts things in perspective with a very important final key take home message.

Dr. Carolyn Lam:

And with that, well listeners, you heard it right here on Circulation on the Run from Greg and I thank you for joining us this week. And, don't forget to tune in again next week.

Speaker 5:

This program is copyright of the American heart association in 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more, please visit ahajournals.org.

Circulation February 22, 2022 Issue

21 februari 2022 | 31 min

This week, our very own Carolyn Lam is in the author role along with author Vlado Perkovic, Associate Editor Naveed Sattar, and Guest Editor John McMurray as they discuss the articles "Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial" and "Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: A Pooled Analysis of SUSTAIN 6 and LEADER Trials."

Dr. Carolyn Lam:

Dr. Greg Hundley:

I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

I have a confession. I am nervous because right after this, Dr. Greg Hundley is going to interview me and, thank goodness, not just me, but really, really interesting other authors and editors with feature papers, all about GLP-1 receptor agonists and the SGLT-2 inhibitors. Very, very, very hot topic. Do listen up! But for now, Greg, you're going to be nice, right? How would you start?

Dr. Greg Hundley:

Well, thank you, Carolyn. I am really looking forward to that. Maybe we'll have a few quiz questions in there. Before we get started, how about we grab a cup of coffee? I am going to bring to our listeners a paper from the world of preclinical science. It's from Professor Vincent Christoffels from Amsterdam. Carolyn, there's a pathogenic variant in the fifth exon of TBX-5 entitled PG125R. It's found in a Dutch atypical Holt-Oram syndrome family with early onset atrial fibrillation. These investigators modeled this in a mouse. Carolyn, this is the first human pathogenic variant based on a patient family in this key cardiac transcription factor that's been explored in an in-vivo animal model.

Dr. Carolyn Lam:

Wow, that's interesting. So, what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. The investigative team identified widespread electrophysiological transcriptional and epigenetic changes including coding and non-coding RNA, chromatin accessibility, and H3K27ac associations in the atria of TBX5-PG125R heterozygous mice distinct from the changes in the atria of TBX5 insufficient animals.

Dr. Carolyn Lam:

Okay. Could you give us the clinical take home message, Greg?

Dr. Greg Hundley:

Right, Carolyn. What these authors really have found is that the characterization of the TBX5-BG125R mouse model... it indicates that a patient-specific pathogenic variant in TBX5 induces changes in regulatory element activity, an altered balance in the regulatory network of atrial cardiomyocytes, and clinically relevant changes in cardiomyocyte function. So therefore, Carolyn, this work may provide insight into the epigenetic changes and transcriptional underpinning of arrhythmias in the general population caused by small increases in TBX5 expression also caused by common variants predisposing ones to atrial fibrillation.

Dr. Carolyn Lam:

Wow. Thanks Greg. Well, guess what? I've got an interesting mouse model to share about as well. This next paper comes from co-corresponding authors, Drs. Chen, Fu, and Wu from UCSD. What they do is provide insights into possible underlying factors in a molecular mechanism responsible for left ventricular noncompaction cardiomyopathy. Now, we know this condition, but... It was discovered half a century ago, yet owing in part to the lack of a suitable mouse model that faithfully mirrors that selective left ventricular vulnerability in patients, the actual mechanisms underlying susceptibility of the left ventricle to dilatation dysfunction in this condition actually remain unknown. Well, until now.

Dr. Greg Hundley:

Wow, Carolyn. So, what actually did this investigative team do, and what did they find?

Dr. Carolyn Lam:

At the basis of their study is a transcription factor. This is PRDM16. This transcription factor has previously been implicated in this condition through characterization of defects associated with the 1P36 syndrome. What the authors did this time, though, is they generated two new conditional knockout mouse models of PRDM16. Their subsequent characterization of the phenotype is a tour de force of gene expression analysis that uses a myriad of functional genomic approaches, including RNA-seq, ChIP-seq, single cell RNA-seq spatial transcriptomics.

What they found is cardiomyocyte specific ablation of PRDM16 in mice indeed caused left ventricle specific dilation and dysfunction, as well as biventricular non-compaction. In other words, fully recapitulating the left ventricular noncompaction syndrome in patients. Mechanistically, PRDM16 functions as a compact myocardium enriched transcription factor which activated compact myocardial genes while repressing trabecular myocardial genes in the left ventricular compact myocardium. Consequently, PRDM16 knockout cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes and/or neurons and chamber specific transcriptional regulation by PRDM16 was in part due to its cooperation with left ventricular and rich transcription factors.

Dr. Greg Hundley:

Carolyn, wow. Mechanistic understanding now for cardiovascular noncompaction. This is really exciting research. Clinically, how can we interpret this work from this animal model?

Dr. Carolyn Lam:

Thought you may ask. This study provides a unique left ventricular noncompaction mouse model for developing therapeutic interventions for any person with a left ventricular dilation and dysfunction, which emerge as the most important disease features in this condition. Improper specification of compact or trabecular cardiomyocytes is likely the common mechanism in the pathogenesis. Spatial single cell gene expression profiles in normal or disease conditions can be shown in this example to facilitate future studies for identifying new targets. This paper is accompanied by an editorial by Drs. Mably, Joe Wu, and Dr. Wang.

Dr. Greg Hundley:

Very nice Carolyn. Well, there are some other articles in this issue, and before we get to that feature forum let's go through those with our listeners. First, Carolyn, I've got a Research Letter from Professor Cornel entitled "Long Term Efficacy of Colchicine In Patients With Chronic Coronary Disease With Insights From LoDoCo2."

Dr. Carolyn Lam:

Wow. There's an exchange of letters between Drs. Wang and Ji regarding the article "Histidine Triad Nucleotide Binding Protein-1 Attenuates Cardiac Hypertrophy Via Suppressing Homeobox A5 Expression," Global Rounds paper by Dr. Indolfi on the universal healthcare system and cardiovascular disease burden in Italy. There's a cardiovascular case series by Dr. Raber on a pacemaker red herring and a hypertrophic cardiomyopathy copycat. Finally, there's a Perspective piece by Dr. Drakos on a mechanical bridge to recovery as bridge to discovery learning from few and applying to many.

Dr. Greg Hundley:

Well, Carolyn, I can't wait to get to this feature forum discussion, and I get a chance to interview you.

Dr. Carolyn Lam:

Ah! All right, let's go.

Dr. Greg Hundley:

Welcome listeners. We have on this February 22nd a forum feature discussion where we have two papers that we are going to present, and oh, what an honor it is. Guess who I get to interview first? Dr. Carolyn Lam from the National Heart Center of Singapore, along with a guest editor, Dr. John McMurray from Glasgow University in Scotland, followed by another paper from Dr. Vlado Perkovic from the Georgia Institute for Global Health in Sydney, Australia. Then lastly, Dr. Naveed Sattar, one of our associate editors who also comes to us from Glasgow, Scotland. Welcome to all of you.

Well, Carolyn, we're going to start with you today. I know you've got a paper combining the use of GLP-1 receptor agonists with SGLT-2 receptor antagonists. Can you tell us, Carolyn, a little bit about the background that went into this study? What was the hypothesis that you wanted to test?

Dr. Carolyn Lam:

Happily, Greg. First of all, what a pleasure to be sitting on the opposite side of the mic, if I might say so, and a real privilege to be speaking on behalf of the AMPLITUDE Executive and Steering Committee about this paper. The whole idea is that we know that SGLT-2 inhibitors and GLP-1 receptor agonists are the rage being recommended for their reduction in cardiovascular events in patients with Type 2 diabetes. However, they appear to do this by complimentary mechanisms. That really raises the tantalizing question of, "Can we combine them?"

Now, What do I mean by that? Well, GLP-1 receptor agonists are known for their reduction in the risk of atherosclerotic ischemic events, particularly like stroke, that benefit being greater, whereas a relatively modest effect on kidney function, perhaps heart failure. Whereas SGLT-2 inhibitors more impressively reduce the risk of heart failure, kidney function decline, kidney outcomes, and so on with a modest effect on myocardial infarction and perhaps no effect on stroke. So, you see, very complimentary. The whole question was, "What would it be like to combine these treatments?" And, in the absence of a trial that actually does a two by two randomization perspective or anything, we decided to look back at the AMPLITUDE-O trial, which was a large multinational trial of patients with Type 2 diabetes randomized to the GLP-1 receptor agonist efpeglenatide versus placebo, but was unique in including the largest proportion thus far of concurrent SGLT-2 inhibitor use in these prospective GLP-1 receptor agonist trials to date.

Dr. Greg Hundley:

Very nice. And so, you've told us a little bit about your study design. How about specifically your study population? And then, Carolyn, what did you find?

Dr. Carolyn Lam:

All right. So, of the 4,076 participants in the AMPLITUDE-O trial, 618 reported SGLT-2 inhibitor use at baseline. They were fairly similar to those not receiving SGLT-2 inhibitors. They had similar age and body mass index, but were less likely to be women, they had a longer duration of diabetes, similar history of cardiovascular disease, but lower prevalence of prior heart failure and lower blood pressure, HB A1C, LDL cholesterol, and albuminuria, but similar GFR.

When we looked at the effect of efpeglenatide in the presence or absence of baseline SGLT-2 inhibitor use, we basically found no difference. The P for interaction for each of these outcomes was basically not significant, whether we were looking at MACE and expanded MACE, which included revascularization and angina on top of standard MACE, whether we were looking at a renal composite or a composite of MACE and death, or whether we were looking at heart failure hospitalization. Which, by the way, all of these were significantly reduced by efpeglenatide, and so, similarly, whether or not there was a baseline SGLT-2 inhibitor. Very importantly, side effects were also similar whether or not patients were on an SGLT-2 inhibitor concurrently. This bodes really well for the combination.

Dr. Greg Hundley:

Very nice Carolyn. Well, John, as a guest editor to Circulation, several papers often come your way each year. What in intrigued you about this particular manuscript?

Dr. John McMurray:

Well, exactly as Carolyn said, Greg, this asks a question and gives some of an answer to a question that all of us are asking which is, "Should we be using these two drugs together? Do they have complimentary additive benefits, or are those benefits independent of each other?" I think, as Carolyn said, her data from the AMPLITUDE-O trial, which was a fantastic trial, go some way towards addressing that.

And, Carolyn, I wondered... Maybe to give some more context to these really interesting data... I think this question was asked the other way around. I think our colleagues in the DECLARE–TIMI 58 trial looked at it in reverse. They were able to look at adding of an SGLT-2 inhibitor to the subset of patients who were in a GLP-1 receptor agonist. What... Can you remind us what they found, because I think that's an interesting alternative approach to this?

Dr. Carolyn Lam:

Excellent point, John, thank you. Because DECLARE was so big a trial that even though the percentage of patients on a concurrent GLP-1 receptor agonist was a bit smaller if you look at percent, it was still a very large subgroup. Thankfully, those results were extremely consistent with what we are seeing, too.

In a trial of an SGLT-2 versus placebo, the SGLT-2 inhibitors benefits were regardless of concurrent GLP-1 receptor agonist, and we showed the mirror image of that. Again, I think with the totality of evidence, it's very reassuring and also very important because to truly answer this, we would need a huge prospective randomized two by two trial, or... Which, I think will not be feasibly accomplished except in a pragmatic trial.

Dr. John McMurray:

Carolyn, maybe one very last point to make again about context, which Greg asked about. Here, we're talking about the primary, secondary prevention of cardiovascular events. You mentioned heart failure, which we're both very interested in. That's intriguing, because it looks to me like the heart failure was largely the prevention... perhaps the incident heart failure. I think there is still a question mark about the role of GLP-1 receptor agonists as a treatment for prevalent heart failure. Do you agree? Do you think that's still an unanswered question? Or, do these results in some way make you more comfortable about using GLP-1 receptor agonists in patients with established heart failure?

Dr. Carolyn Lam:

Wow. Again, an excellent question. These data reassure me that if I had a patient with Type 2 diabetes who developed heart failure and still required glucose control I would be very comfortable continuing a GLP-1 receptor agonist, because many of these patients in this trial who got heart failure obviously didn't drop out of the trial. They continued on the GLP-1 receptor agonist and the safety profile looks okay. However, I do not agree that the GLP-1 receptor agonists have become a treatment for heart failure the same way the SGLT-2 inhibitors have. That would require, in my mind, evidence in a prospectively defined validated population of heart failure, with known ejection fraction or not. And, to be even more provocative, I suppose, even perhaps without diabetes. Now, that would really put the nail in the coffin, if I may. Basically exactly what you did, John, in DAPA HF.

Dr. John McMurray:

All right, to finish on a provocative comment for the audience just before we leave this segment, it may of course depend on the heart failure phenotype type as well. In all of these trials, we're never really sure whether the patients have HFpEF, HFrEF, or a combination. So, lots of questions still.

Dr. Greg Hundley:

Very nice. Well, thank you so much, Carolyn and John.

Listeners, next we want to turn to our second feature article. This one is from Dr. Vlado Perkovic. Vlado, welcome. You have a paper involving GLP-1 receptor agonists and focusing on renal disease. Can you describe for us a little bit about the background pertaining to your paper, and what was the hypothesis that you wanted to address?

Dr. Vlado Perkovic:

Thanks so much, Craig, and thanks for having me here. It's such a joy to be part of this conversation. Our paper was a post hoc analysis of two completed clinical trials, the LEADER and SUSTAIN trials that looked at liraglutide and semaglutide, respectively, compared to placebo in people at high cardiovascular risk. We wanted to ask the question of... in more detail, the effects of these agents collectively and individually on important kidney outcomes to try and understand whether the GLP-1 receptor agonist, which, as Carolyn says, have clearly had significant benefits for MACE in particular, might also have the sorts of benefits that we've seen, for example, with SGLT-2 inhibitors on renal outcomes recognizing the massive burden of ill health, premature mortality, morbidity, economic, and social costs that go along with kidney disease as a complication of diabetes. What we've done here is we've pulled the data from the two trials and looked at them collectively and individually to try and unpack the effects of GLP-1 receptor agonists on a range of kidney outcomes.

We've looked at different thresholds of loss of kidney function. Traditionally we've used doubling of creatine, which equates to a 57% loss of kidney function. More recently, we've moved to a 40% loss of kidney function as being a good outcome in kidney trials. There's been a push for 30 and 50% outcomes to be used. Here we wanted to look really comprehensively at all of those outcomes, as well as the outcomes of change in albuminuria and change in EGFR slope, where we had more power, perhaps, to detect differences between the agents. Our hypothesis was that GLP-1 receptor agonists would have evidence of kidney protection. We thought up front that the likelihood was the kidney protection would be consistent at different levels of kidney function and might be similar between different agents. But, that wasn't what we ended up finding.

Dr. Greg Hundley:

Very nice. So, you mentioned the SUSTAIN and the LEADER trials. Can you describe for us a little bit more, and some of the specifics, perhaps, to your study population? And then, walk us through your study results.

Dr. Vlado Perkovic:

Yeah, so very happy to do that. Thank you. As I say, these trials were primarily cardiovascular outcome trials that were designed to assess the cardiovascular effects of the GLP-1 receptor agonists and therefore the populations reflect that intent with people who had preexisting cardiovascular disease primarily. What we found when we looked at the results was evidence of perhaps modest reduction in some of the renal outcomes based on different thresholds of loss of kidney function of the order of 10 to 20% overall when we looked at the pooled study population. Of course, that compares to a much more significant 30 to 40% reduction in the risk of these same outcomes when we look at drugs like SGLT-2 inhibitors.

Overall, they didn't appear to be quite as effective. But, we were somewhat surprised when we started to dig into the data in more detail in that we found that people who had reduced kidney function based on a lower EGFR, particularly an EGFR below 60, or those who had either micro or macro albuminuria, the benefits of treatment appeared to be greater in absolute and proportional terms. It also was much clearer, such that in people who had both had reduced EGFR and an increased level of albuminuria, there were reductions in the risk of the constant renal outcomes of approximately 40%, suggesting that these drugs may be particularly effective in people with established kidney disease, which... there's a novel finding today.

We were able to dig into that in more detail, looking at albuminuria and EGFR slope and effectively found consistent results for those outcomes as well, giving us some confidence that the findings perhaps were more likely to be real. We, in addition, looked at the different drugs and found some evidence that high dose semaglutide... in particular, one milligram weekly dose, and appeared to be more effective than the lower dose of semaglutide or liraglutide for some of those intermediate markers, if you like.

Dr. Greg Hundley:

Very nice. Naveed, now, as the associate editor, what intrigued you about this particular study? What drew your attention to it and caused you to bring it through that review process to our readers?

Dr. Naveed Sattar:

Yeah. Thanks Greg, and thanks Vlado. Now, I think this is a lovely study. I think we've been familiar with the effect of GLP-1 and albuminuria for a long time. I think that's fine, but not... that doesn't really float everyone's button. You know, albuminuria is not necessarily a hard endpoint. But, EGFR and EGFR slopes are becoming something that people are starting to become interested in as a marker of future diabetic kidney disease in end stage kidney disease. Vlad could probably comment on that. I think there was a suggestion if you meta-analyze all the GLP-1 trials, which we did recently on the back of efpeglenatide, both Carolyn and John were co-authors.... that there's a suggestion that GLP-1 may actually improve hard kidney outcomes. This paper, on the back of that, with a detailed look at EGFR slopes and different thresholds, does further support the fact that liraglutide and semaglutide do slow kidney outcome progression, particularly in those who've already got a degree of kidney damage.

Now, the context of that is actually really important in the sense that Vlado and colleagues and nephrologists around the world are very excited about the SGLT-2 inhibitors. But, also having another drug on top of that would might further slow kidney damage is excellent, particularly in a population which also has more atherosclerotic cardiovascular disease. These drugs could therefore have a double benefit, not only slowing kidney damage, but also preventing atherosclerotic cardiovascular disease and the population at high risk of both conditions. Of course, the future then also, as John mentioned, will be, "what about the benefit on top, and going forward in heart failure as well?" I think this study looks... well, adds to the support that GLP-1 receptor agonists actually improve hard kidney outcomes. I think that's the realization. But, going back to Vlado, I'd be interested to get his comment of, "Well, does this study and associated evidence now lead you to think when should we be using these drugs in our patients with chronic kidney disease?" That probably is the question, Vlado.

Dr. Vlado Perkovic:

Yeah. That's an important question. I think, Naveed, for us as a community. I think one of the nice things is that we can use these drugs in people with kidney disease already. They're approved, and we don't have the same sort of EGFR restrictions as we've had with SGLT-2 inhibitors. But, what we really want to know is, "What are the benefits that we're offering to our patients, and at what price might that come? Is there an increased risk of adverse events in this very sensitive population?"

Of course, the only way to answer those questions is to test it prospectively, which we're now doing in the FLOW trial, where we're randomized three and a half thousand people on semaglutide and placebo. So, over the next couple of years we will answer that question more definitively I hope. We're particularly focused on people with kidney disease in that trial. But of course it also... These data, if they're confirmed in that trial, raise important questions, I think, about the mechanism of the renal effect that needs teasing out. If they're truly more effective in relative terms, as well as absolute terms, in people who've got established kidney disease what does that tell us about the way that they might be providing that renal benefit? And its relative interaction, not only with SGLT-2 inhibitors, but also with mineralocorticoid receptor antagonists, which have recently additionally been shown to be beneficial on the kidney in the FIDELITY and the FIGARO trials.

Dr. Greg Hundley:

Very nice. Well, Naveed, you have led us and Vlado into our next very quick rapid fire question for our listeners, in working through each of you, both as authors and editors, what do you see is the next study to be performed in this sphere of research? Carolyn, we'll start with you, then John, then Vlado, and then Naveed.

Dr. Carolyn Lam:

Well, I think I alluded to it a little bit earlier that what we'd, of course, really love is a prospective randomized trial looking at the combination of the treatments versus placebo and versus one of each only. That sounds like pie in the sky, though. Maybe a pragmatic trial. Maybe an... Oh, John, shut your ears, but maybe looking back at real world data to look at this a little bit better. We're going to need a little bit more, at least I think, also to reassure ourselves that the combination is really safe in these patients.

Dr. Greg Hundley:

John?

Dr. John McMurray:

I think we need to know about GLP-1 receptor agonists in patients who don't have Type 2 diabetes because I think it's going to be critically important going forward to know whether this is just about dysglycemia and glucose lowering, which it seems probably isn't. Because my interest is in heart failure, of course, I would like to see these drugs tested in patients with symptomatic heart failure and both the major heart failure phenotypes with and without Type 2 diabetes.

Dr. Greg Hundley:

Vlado?

Dr. Vlado Perkovic:

Yeah, I'd support what John says and add people with and without diabetes in kidney disease as well to that group, as we've seen with DAPA-CKD study. I think the other really big opportunity for us here that's been highlighted by work done by John and others is the possibility that we might dramatically reduce the prevalence of these terrible complications of diabetes by using combination therapy and multi-drug combination therapy. Potentially, we've got not just the GLP-1 receptor agonist and the SGLT-2 inhibitors, but we've got MRAs and other drugs, depending on which outcome we're talking about. If these drugs are truly independent, as Carolyn's important work suggests, we could have a major impact at a population level on the prevalence of these terrible disorders in our patients.

Dr. Greg Hundley:

And finally, Naveed.

Dr. Naveed Sattar:

Yeah, thanks. I'm glad I'm not the only one who upsets John McMurray now and again, but it's probably good for him. What I would say is I agree with all the comments thus far. I would love the fact that with the newer stronger GLP-1s giving us additional weight loss, and, perhaps, with the combined GLP-1 GIP drugs, I would love if we could test them early in diabetes, actually, to actually reverse diabetes, as it were. And, can we delay these complications for 5-10 years, and perhaps with combination SGLT-2? Of course, we can't really do that now because of the costs, but going forward... And, John and I have had lots of conversations about multi-morbidity and obesity is being a big driver to all of that. Now we've got class of drugs coming that actually could cause significant weight loss and improve multiple outcomes that we've discussed: kidney, heart failure, atherosclerotic cardiovascular disease, and also possibly improve patients quality of life, particularly if the weight loss is quite substantial. I would love if we target that, but I think that's partly linked to some of the answers that've already been heard.

Dr. Greg Hundley:

Well, listeners, we want to thank our investigators, Dr. Carolyn Lam and Dr. Vlado Perkovic, and also our editors, Dr. John McMurray and Dr. Naveed Sattar for bringing us these two papers. The first highlighting that the efficacy and safety of GLP-1 agonists appear independent of concurrent SGLT-2 inhibitor use. And the second paper, emphasizing that GLP-1 receptor agonists offer renal protection, particularly in those with advanced renal disease.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.

Speaker 7:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

Circulation February 15, 2022 Issue

14 februari 2022 | 26 min

This week's episode is special: Circulation is proud to present the 6th annual Go Red for Women issue podcast. Please join Sana Al-Khatib and James de Lemos as they welcome authors Michelle Albert and Sadiya Khan as they discuss their articles "Shining a Light on the Superwoman Schema and Maternal Health" and "Geographic Differences in Prepregnancy Cardiometabolic Health in the United States, 2016 Through 2019." Then Sana presents an overview of the other exciting articles in this important issue.

Dr. Sana Al-Khatib:

Hello, and welcome to this special Circulation on the Run podcast, focused on the sixth Go Red For Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I have the pleasure of co-leading the sixth Go Red for Women issue with, my friend and colleague Dr. Biykem Bozkurt. Very excited to introduce Dr. James de Lemos, the executive editor for Circulation, who will co-host this part of the podcast with me. Welcome, James.

Dr. James de Lemos:

Well, Thanks. I'm delighted to be here.

Dr. Sana Al-Khatib:

The theme of our podcast today is social determinants of health. We will discuss a perspective article in the issue, titled The Interplay of Sex with Social Determinants of Health in Cardiovascular Diseases, led by Dr. Michelle Albert, who is a cardiologist at the University of California in San Francisco. We will also discuss a research letter on geographic disparities in pre-pregnancy cardiometabolic health in the United States from 2016 to 2019, led by Dr. Sadiya Khan, a cardiologist at Northwestern Medicine in Chicago. Welcome, Doctors Albert and Khan.

Dr. Michelle Albert:

So pleased to be here. An honor to be part of the Go Red issue.

Dr. Sadiya Khan:

Thank you for having us.

Dr. Sana Al-Khatib:

Wonderful. So we'll start with the discussion and turn it over to you, Dr. de Lemos, to ask the first question.

Dr. James de Lemos:

Well, thanks, Sana. Michelle, let's start with you. I love the title of your essay. I'd like you to sort of orient our listeners as to why this title, why the topic and what you write about in your piece.

Dr. Michelle Albert:

Thank you, James. The title of the essay or Perspective is “Shining a Light on the Superwoman Schema and Maternal Health.” We felt, along my coauthors, Dr. Rachel Bond and Dr. Annette Ansong--Dr. Ansong is a pediatrician, actually. Dr. Bond is also a cardiologist. We felt that it was really important to put forward the psychological parts of the maternal health crisis as a major social determinant of health. Most often, the focus is only on the other risk factors that we know of, like hypertension, diabetes and obesity. And while those are also extremely important, it is actually the interplay between those risk factors and social factors, including racism, including access to care, that actually drive the maternal health crisis for women of color. Particularly for black women, who have about three to four times the mortality and pregnancy complications, compared to white women.

Dr. James de Lemos:

Michelle, one thing that you've really defined your career by is moving to the biology of adversity. I thought the figure in your paper was striking. Can you expand a little bit on what you mean by this, and how these social determinants and the pernicious effects of things like racism and psychological stress, translate into the biology that I think Sadiya will tell us about, even in her research letter?

Dr. Michelle Albert:

Yes, James. As you know, I've had a longstanding research history and portfolio, looking at the interplay between biology and social factors, coined the biology of adversity. The adversity part of this is something, we often think about the ACEs, adverse childhood experiences, and think about how those relate to health outcomes, including cardiometabolic and cardiovascular health outcomes. But as we think about adults, actually, it's the adult environment that actually defines adversity for children. Certainly, as it pertains to black women and other women of color, there are certain special circumstances that get embedded into the whole framework of the biology of adversity, that lead to poor overall cardiovascular outcomes, but also maternal and non-maternal health outcomes. So conceptually speaking, the framework of the biology of adversity is the incorporation of stressors into the brain. That then results in a hyper inflammatory milieu, combined with dysregulation of the hypothalamic pituitary access, as well as the flight or fright hormones or the up-regulation of the sympathetic nervous system. And actually importantly, the down-regulation of the parasympathetic nervous system, which is an area that is actively under research currently, that then results in the downstream cascade of health effects. For black women, this is characterized by, in part, the Superwoman Schema, which includes several major themes. The first major theme is the history of oppression and racism and sexism. Also, a history of disappointment, the influences of spiritual values and form other influences, interplayed. These are stressors that incorporate with other stressors. And then there's an interplay with subscales, that focus on the ability to succeed, despite limited resources. Putting others ahead of yourself. So less self-care for yourself, but putting self-care of others ahead of your self-care, the lack of showing vulnerability, as well as suppressing one's emotions. So, all of these things interact with behavior and genetics, as well as epigenetics, to flow into that cascade of the biology of adversity. For me, I gave this presentation four years ago now, at American Heart Association, where I sort of reformatted this whole biology of adversity to incorporate the Superwoman Schema, which was first defined or characterized by Cheryl Woods-Giscombé, who is a PhD scientist in the United States.

Dr. Sana Al-Khatib:

Now, that was very helpful and insightful, Michelle. Could you tell us about, what are the main next steps that need to be done in this area, that you think are going to be important to move this line of research forward, so that we can actually change this situation and really improve healthcare for these women?

Dr. Michelle Albert:

Well, I like to think of the answers to that question on several levels. So, I think one of the first levels is ensuring that women, especially women of color and specifically black women, are aware of the fact that hypertension, preeclampsia and eclampsia are risk factors, not only for their pregnancy, but also for cardiovascular disease later on, and for their children developing hypertension and cardiovascular disease later on. So, I think education is really important, on one level. On the next level is, actually having a continuum of care, where women are asked to get early prenatal care, even when they're contemplating pregnancy. So that they can be screened for hypertension, diabetes and their stressors, assessed and put in contact with resources. Having doulas, midwives involved in this process, as well as cardiologists who are involved in the pregnancy setting, as well as post-pregnancy for these women. Then, there's an advocacy initiative that has to take place, that focuses on getting aid. Kamala Harris has put forward a bill to actually do just that for maternal health, focusing on racism and bias in healthcare, because black women across the spectrum of socioeconomic status, experience poor maternal health outcomes. So, this is not only an access to care issue. It's not only a socioeconomic status issue. It is an issue that pertains to the women not being listened to, with racism and other stressors. I can't stress those first two things more, the whole discrimination part of it, and dumbing down the concerns of black women. Then, I think on a research perspective, certainly the American Heart Association has got now this HERN Network, which is a network that's going to focus on research around maternal health. So in that context, figuring out the best care models for women. Understanding the biology and how it interplays with poor outcomes later on, is also very important. One point around the biology that I want to point out for, let's say, African American women and actually Asian women as well, is that there's a higher prevalence of fibroids. There's very little research focusing on fibroids and its importance on maternal health outcomes and even the care for those women. Frankly, in my mind, a lot of that has to do with bias and how we value the healthcare of certain groups of women over other groups of women. So, those are some of the things, in terms of the solutions.

Dr. Sana Al-Khatib:

Absolutely. Before we move on to the presentation by Dr. Khan, are there any final words Michelle, that you'd like to share with the group, in terms of any final wisdom, so to speak, that you want to leave the listeners with?

Dr. Michelle Albert:

Yeah. I would just say that the maternal health crisis is preventable and it is tied into... Much of our audience are going to be healthcare providers. To the healthcare providers, I'm going to say, you really, really need to listen to these women when they tell you that they're experiencing certain symptoms. You also need to dig deeper to find out about their concerns, especially their stressors, in addition to making sure their blood pressure is controlled and that their weight is managed.

Dr. James de Lemos:

Well, thank you, Michelle. We'll turn to Sadiya now, and her team's research letter on geographic differences in pre-pregnancy cardiometabolic health in the US. For our listeners, I think what you'll see, if you read this paper, is how remarkable the research letter format is, and how much information Dr. Kahn and her team have conveyed in this really, really powerful letter, that I think has major public health implications. Sadiya, do you mind orienting our listeners to what you studied and how you did it?

Dr. Sadiya Khan:

Thanks, James. And again, thank you for the opportunity to join you guys in this podcast. I think Michelle very eloquently set up the preface for this research letter, which was understanding that health in pregnancy begins before conception. That was really the reason we wanted to focus on health factors, particularly cardiometabolic health factors, like body mass index, diabetes status and hypertension status in the pregnant individual, prior to pregnancy. The second piece of this that we were really interested in, is that we had observed that there are significant differences across the United States, in maternal morbidity and mortality outcomes. There are much higher rates of pregnancy-related deaths occurring in the South and Midwest, compared with other states in the US. That led us to ask this question, if we're able to better describe or define health prior to pregnancy, will we see similar patterns? We used the Centers for Disease Control Natality database, which includes all live births in the United States. So, the strength of this dataset, is that this is a surveillance system employed by the CDC, to monitor and record health outcomes of the pregnant individual and the newborn in the United States. Using this dataset, we were able to display maps for pre-pregnancy cardiometabolic health and look at changes from 2016 to 2019. Unfortunately, there's not much positive news, in that we've seen continued declines in favorable or optimal pre-pregnancy cardiometabolic health, which we defined as having a normal BMI and the absence of diabetes or hypertension. In addition, we saw that the levels of favorable pre-pregnancy cardiometabolic health were lower in the South and Midwest. It starts to set up some questions about upstream social determinants of health, that may be playing an important role as we start to address this problem at the individual level, but also at the societal and population level.

Dr. Sana Al-Khatib:

Very interesting and important findings there, Sadiya. Are you planning to work on additional research, to build on the research that you were publishing in this issue?

Dr. Sadiya Khan:

One of the most important questions that came from this are, what are the potential ways to start to address and support care for pregnant individuals, or as I think is Michelle really nicely put it, is for preconception care. So, thinking more about the reproductive life course before pregnancy, as well as during and after pregnancy. For that, one of the things that seems to be potentially really important, could be how Medicaid expansion has helped in states that have expanded, and differences between states that have or have not expanded Medicaid. Knowing that, that probably isn't sufficient, but it has that been helpful.

Dr. James de Lemos:

Yeah. I was struck, Sadiya. I mean, Michelle's essay and your research project really shine a bright and distressing light on maternal health in the US, I think and the crisis that we're under, that many of us don't even maybe recognize is happening. The time trends you showed were, to me, striking, giving over such a short period of time, how much maternal cardiovascular health has declined. It seems, indirectly at least maybe, that declining at a higher rate than overall cardiovascular health. I first applaud you for writing on this topic because I think it brings this issue to light, in terms of a public health crisis, frankly. But I wonder if you have any thoughts on why specifically, things are declining at such a higher rate for pregnant women or pre-pregnant women, maybe relative to national trends? Maybe they're not. Maybe this is what's happening across all age and gender demographics.

Dr. Sadiya Khan:

It's a really important observation. I agree with you. It seems like it's much more striking in this concentrated and focused group of individuals, that are pregnant and giving birth. It's possible because of the age range that we focus on, the 20 to 44 year old age range, that there are potentially more significant declines happening during this time period. We know cardiovascular health in general, appears to have some age-dependent dips, generally around adolescence. That early adulthood, college age period seems to be where a lot of cardiovascular health decline happens. So, I think that's what we're observing, as we're seeing these more striking trends in this age group. But it would be interesting to know, compared to non-pregnant individuals and across the life course, if that is in fact, the case.

Dr. Sana Al-Khatib:

Then I'll ask you what I asked Michelle, Sadiya. Any final words of wisdom that you'd like to share with our listeners?

Dr. Sadiya Khan:

I don't know if I'll be able to speak as eloquently as Michelle did. I think her responses really capture both of these papers and thinking about ways forward, about how we can dress the maternal health crisis. But I think that the word that she used, that really sticks with me and is one of the reasons that I'm so passionate about this work, is that this is preventable. That there are so many different things that could be in place, whether it's at the individual clinician and patient level, at the individual health system level, at the state level, as we looked at here, but really at the national level as well. I think we have a lot of work to do, but there's a lot of things that we know can help.

Dr. Sana Al-Khatib:

Great. Wonderful. James, any final words from you before we wrap up this part of the podcast?

Dr. James de Lemos:

First, Sana and the rest of the Circulation team, I congratulate you on another spectacular Go Red issue, that really is such an important endeavor. You and Biykem have done an incredible job leading this. I thank Michelle and Sadiya for coming on today, but also for their work. I think raises the stakes here, that we've got a public health crisis affecting women, and disproportionately affecting black women in the United States. It's underappreciated. I think you both point out that it's preventable. So, I think it's a call to action. It's a really well stated and an important topic.

Dr. Sana Al-Khatib:

Wonderful. Well, thank you so much, James and Sadiya and Michelle. Thank you so much for submitting your excellent work to us. Thank you for being with us today. This concludes this part of the podcast. Thank you. Next, I'm excited to provide you with a brief overview of the issue. We have two original articles. One is on genes that escape X-chromosome inactivation, modulate sex differences in valve myofibroblasts. This one was submitted to us by Dr. Kristi Anseth and her team. The study elucidated sex dependencies in myofibroblasts activation pathways and transcriptome analyses and small molecule interventions, implicating genes that escape X-chromosome inactivation, in regulating sex differences in the progression of aortic valve stenosis. The authors highlight the importance of considering sex as a biological variable, to understand molecular mechanisms underlying aortic valve stenosis and help guide sex-based precision therapies. The second original article is by Dr. Elena Aikawa and her team. It is on Prothymosin Alpha, a novel contributor to estradiol receptor alpha-mediated CD8+ T-cell activation and recognition of collagen cross-reactive epitopes in rheumatic heart valve disease. This paper provides novel findings that will likely have clinical impact down the road. As the authors pointed out, understanding the Prothymosin Alpha and estrogen sensitivity mechanisms to control the CD8 T-cell function may indeed provide insights into treatment for rheumatic heart valve disease. In this issue, we have three research letters. One letter was on the geographic disparities in pre-pregnancy cardiometabolic health in the US. You just heard about this paper in the first part of the podcast. Another letter, by Dr. Pradeep Natarajan and his team, offers information on the microvascular outcomes in women with a history of hypertension in pregnancy. It highlights that hypertensive disorders of pregnancy, especially preeclampsia, are independently associated with reduced microvascular indices. The investigators called for further research, to translate these findings into cardiovascular risk reduction strategies for women with these conditions. The third research letter, by Dr. Androulakis and his team, provides insights from cardiac magnetic resonance and angiography screening on spontaneous coronary artery dissection, also known SCAD. Theirs was the largest cohort of SCAD patients screened for peripheral vascular pathology by magnetic resonance and geography, to date and one of the largest to assess the SCAD-related impact size and relevant associations. They concluded that cardiac magnetic resonance has valuable contribution to the investigation of SCAD patients. In this issue, we have six perspective papers. In addition to the Perspective paper that you heard about from Dr. Michelle Albert, there are five perspective articles that span topics of great clinical and research relevance and importance. One perspective article, led by Dr. Carolyn Lam, tackles incorporating sex and gender into the design of cardiovascular clinical trials, a very important topic. Dr. Lam highlights the importance of sex and gender to the optimal interpretation, validation and generalizability of cardiovascular clinical trial results. Another perspective by Dr. Kathryn Lindley presents a call for action to address increasing maternal cardiovascular mortality in the US. This actually ties in with the initial part of the podcast. Dr. Lindley offers insightful suggestions, regarding strategies that could improve maternal cardiovascular care. Another perspective by Dr. Anne Curtis, addresses sex differences in response to rhythm management devices. Dr. Curtis reminds us that the conclusion that should be drawn from the many studies that have been conducted on cardiac rhythm management devices, is that these devices are indeed effective in both men and women, but they're still significantly underutilized in women eligible for those therapies. Dr. Curtis calls on us to be ever vigilant, to provide sex-neutral medical care to all patients, when clinical trials don't provide a strong rationale to do otherwise. I'm quoting her here. Another perspective paper by Doctors Mauricio and Khera, addresses statin use in pregnancy. They raise the of whether it is indeed time for a paradigm shift. This article was prompted by the FDA's request to remove the pregnancy Category X label for statins that was issued in July of 2021. The authors encouraged clinicians to use shared decision making. They add that those with atherosclerotic cardiovascular disease events, especially recent ones, should be encouraged to continue statins during pregnancy or resume them as soon as possible, if they're withheld. For those with heterozygous familial hypercholesterolemia, previously reasonable LDL control and no manifest vascular disease, there may be more tolerance for statin deferral during pregnancy, but they definitely highlight the need for dedicated research in this area. The last perspective, led by Doctors Okwuosa and Zaha tells clinicians what they should know about sex differences in cardio-oncology. They highlight sex differences in cancer and cancer treatment, cardiovascular diseases and the intersection of these conditions, that are likely to be quite helpful for clinicians taking care of such patients. Don't forget to check out the Pathways to Discovery section, where you will find a very interesting and motivating dialogue between Dr. Maryjane Farr and Dr. Biykem Bozkurt in which Dr. Bozkurt describes her career journey. I personally enjoyed reading that interview and found it quite inspiring. In closing, I want to express my deepest gratitude to my co-editor Dr. Bozkurt, the Editor-in-Chief for Circulation, Dr. Joseph Hill, the Executive Editor for Circulation, who was with us at the beginning of the podcast, Dr. James de Lemos and all the authors who submitted the research for this issue. I also want wholeheartedly thank and acknowledge the Circulation Associate Editors and Staff, who work tirelessly to enable us to produce an excellent Go Red for Women issue. I am very excited about this issue and hope that you will like it as much as I do. This concludes our Go Red for Women issue, Circulation on the Run podcast. Thank you for listening.

Dr. Greg Hundley:

Circulation February 8, 2022

7 februari 2022 | 21 min

Please join author David Webb and Editorialist Steven Smith as they discuss the original research article “Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?"

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries.

Dr. Carolyn Lam:

The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death.

Dr. Carolyn Lam:

The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment.

Dr. Carolyn Lam:

The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada.

Dr. Carolyn Lam:

The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction.

Dr. Carolyn Lam:

So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] “Why Are We Still Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion.

Dr. Carolyn Lam:

For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that.

Dr. David Webb:

So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure.

Dr. Carolyn Lam:

Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found?

Dr. David Webb:

So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer.

Dr. Carolyn Lam:

And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension?

Dr. David Webb:

Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated.

Dr. Carolyn Lam:

So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be?

Dr. Steven Smith:

Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results.

Dr. Steven Smith:

As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen

Dr. Carolyn Lam:

Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David?

Dr. David Webb:

Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures.

Dr. David Webb:

And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects.

Dr. Carolyn Lam:

And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most important unanswered questions?

Dr. Steven Smith:

Yeah, it's a great question. If I could piggyback on David's answer, I think one of the really interesting findings from this study is that we see these blood pressure changes even after only two weeks of therapy, so this is not something that requires some chronic, very high dose of acetaminophen to start experiencing these blood pressure changes. Obviously a lot of people are on acetaminophen, as David mentioned all over the world. Many of those patients, of course, are on it for chronic therapy, for example, for osteoarthritis, but a lot take it much more sporadically or for short term use. And I think it's telling that we see these blood pressure changes pretty rapidly after starting therapy.

Dr. Steven Smith:

As far as unanswered questions go, I think Dr. Webb summarized some of those already, but I guess what I would add is we still lack some clarity on what the ultimate outcomes of these blood pressure changes are. Obviously we know that blood pressure is highly correlated with adverse cardiovascular outcomes, as well as other outcomes, but the data showing an increased cardiovascular risk with acetaminophen is a little bit more murky. And so I do think there's still some question as to how this translates to increased cardiovascular risk, and I totally agree with David that the evidence supporting efficacy of acetaminophen is so weak at this point for most things, it may be a moot point. We may want to just move on from acetaminophen to the extent that we can, because it seems to have some risks, or at least some concern for risks, without a lot of evidence.

Dr. Carolyn Lam:

Wow. Thank you so much, gentlemen, for this. It's just amazing discussion, but even more so for publishing such an important study and such an elegant editorial in our journal. I think this is one that not only may change practice, but changes my personal perception and things that I'm going to do immediately.

Dr. Carolyn Lam:

Thank you very much audience. I'm sure you agree. This was incredible. Do tune in again next week for another episode of Circulation On The Run.

Dr. Greg Hundley:

Circulation February 1, 2022 Issue

31 januari 2022 | 22 min

Please join senior author Louise Olde Nordkamp, Editorialist Sana Al-Khatib, and Associate Editor Mark Link as they discuss the original research article Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in "Transvenous and Subcutaneous Implantable Defibrillators: An Analysis of All Appropriate Therapy in the PRAETORIAN trial" and the editorial "Just When We Thought the Debate About the Value of Anti-Tachycardia Pacing Was Over Perplexing Results from the PRAETORIAN Trial Emerged."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, your host and Associate Editor from the National Heart Center and Duke National University of Singapore. And as you can tell, I am sorely missing my co-host, Dr. Greg Hundley, who cannot make it today, but yet I am so excited to tell you about the wonderful papers in today's issue. Now, right after these summaries, we will be discussing appropriate shocks and anti-tachycardia pacing in transvenous and subcutaneous implantable defibrillators. A really interesting analysis from the PRAETORIAN trials. The results may surprise you as they did for me. I really highly recommend you listen to the discussion, important clinical take home messages there. Now, though, let me tell you about some original papers in today's issue. We know that symptomatic children with catecholaminergic polymorphic ventricular tachycardia and that's a mouthful.

Dr. Carolyn Lam:

So, I'll abbreviate it as CPVT. They are at risk for recurrent arrhythmic events, beta blockers decreases risk, but are some types of beta blockers better than others in this regard? That's what coauthors and corresponding authors, Dr. Peltonberg and van de Werf from University Medical Center, Amsterdam and colleagues looked at. Studying 329 patients with RYR2 variant carrying symptomatic children from two international registries of patients with CPVT, these authors found that beta-1 selective beta blockers were associated with a higher risk for arrhythmic events, defined as syncope, appropriate ICD shock, sudden cardiac arrest, or sudden cardiac death. And this was compared with non-selective beta blockers. The difference in non-selective versus beta-1 selective beta blockers was driven by a significantly lower risk for arrhythmic events in patients treated with nadolol compared with metoprolol, bisoprolol, and atenolol. So, what are the clinical implications? Well, symptomatic children with catecholaminergic polymorphic ventricular tachycardia should preferably be treated with nadolol or another non-selective beta blocker such as propranolol should nadolol be unavailable.

Dr. Carolyn Lam:

The next paper deals with the super hot topic of myocarditis-related COVID-19 vaccination in adolescents and young adults. Now, suspected myocarditis temporarily related to COVID-19 vaccination has been reported in adolescents above 12 years old and young adults since the emergency use authorization of the Pfizer COVID-19 vaccine. And this is particularly in male adolescents and young adults. Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccine, of course, has important public health implications in the decision to vaccinate youth. So, these authors led by corresponding author, Dr. Truong from University of Utah and Primary Children's Hospital from Salt Lake City in Utah, retrospectively collected data on patients younger than 21 years old presenting before July 2021 with suspected myocarditis within 30 days of COVID-19 vaccination. And they found that in 139 adolescents and young adults with 140 episodes of suspected myocarditis, 49 of which were confirmed and 91 were probable.

Dr. Carolyn Lam:

And these were at 26 centers. Most patients were male and white with a median age of 15.8 years. Suspected myocarditis occurred in 98% following mRNA vaccine with 94% following the Pfizer vaccine, 91% occurring after the second dose. Symptoms started a median of two days after vaccination. The most common symptom was chest pain. 26 patients or 19% were in the ICU. Two were treated with inotropic vasoactive support and none required ECMO or died. The median hospital stay was two days. So, while the majority of patients with suspected vaccine associate myocarditis had normal ventricular systolic function on echocardiogram, many had abnormal findings suggestive of myocarditis on cardiac MRI in the setting of elevated troponin and electrocardiographic changes. The take home message is that despite lab and cardiac MRI evidence of cardiac injury, the majority of adolescents and young adults with suspected myocarditis following COVID-19 vaccination have rapid recovery of symptoms and a mild clinical course. Further studies are needed to better understand the timing of resolution of myocardial injury, mechanisms of myocardial injury, and the long term outcomes.

Dr. Carolyn Lam:

The next paper is the first study to look at examining the genetic architecture of the plasma protein using whole-genome sequencing in persons of African ancestry and really provides a chance to look at rare ancestry specific variation. Authors led by corresponding author, Dr. Gerszten from Beth Israel Deaconess Medical Center in Boston, Massachusetts performed proteomic profiling of 1,301 proteins in 1,852 black adults from the Jackson Heart Study using aptamer-based proteomics or the SOMAscan. Whole-genome sequencing association analysis was ascertained for all variants with minor allele count of five or greater. Results were validated using an alternative antibody-based proteomic platform, the Olink platform as well as replicated in the multiethnic study of atherosclerosis or MESA, and the HERITAGE family study. A huge amount of work. So, this large study added 114 novel genomic [inaudible 00:07:00] associated with protein levels and an additional 217 novel sentinel variant protein relationships. Novel cardiovascular findings included genetic variant associated with amyloidosis in persons with African ancestry shown to be associated with retinol binding protein four levels, even in those without cardiomyopathy implicating it as a potential biomarker.

Dr. Carolyn Lam:

Taken together, these results provide evidence of the functional importance of variants in non-European populations and suggest new biological mechanisms for ancestry specific determinants of lipids, coagulation, and myocardial function. And this is discussed in an excellent editorial by Professor Dr. Schunkert from German Heart Center, Munich. And the final original paper deals with high-salt intake, which we know to be the leading dietary risk factor for cardiovascular disease. We also know that clinical evidence suggests that high-salt intake is associated with non-alcoholic fatty liver disease. Now, could the two be linked, in other words, could hepatic steatosis induced by high-salt diet mediate cardiovascular damage and how? This is exactly what these authors did. Corresponding author, Dr. Zhu from Army Medical University in Chongqing, Institute of Hypertension in China and their colleagues in an elegant series of mouse experiments demonstrated that reduced SERT three expression in the liver is an important mediator of salt-induced hepatic inflammation and steatosis.

Dr. Carolyn Lam:

High-salt diet inhibits the transcription of SERT three through epigenetic modification mechanisms resulting in the persistence of hepatic inflammation in the liver. Notably, the over expression of SERT three in the liver using an adeno-associated virus eight vector or activation of SERT three by metformin effectively relieved the progression of persistent hepatic damage in mice and thus counteracted salt-induced cardiovascular damage. Taken together, these findings suggest that the MK SERT three pathway may be a promising interventional target for treatment of persistent cardiovascular damage in populations exposed to high-salt diet, and finally rounding up the other papers in today's issue, there's an AHA Update by Dr. Lloyd-Jones on the power of patient stories to inspire us to prevent cardiovascular disease and death, personal reflections on AHAs scientific sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30 years of no-touch saphenous vein harvesting, a timely jubilee gift.

Dr. Carolyn Lam:

There's a Frontiers paper by Dr. Rivard on a tremendous contribution on atrial fibrillation and dementia, a report from the AF Screen Interventional Collaboration. And finally a research letter from Dr. Joe on genetic proliferation tracing revealing a rapid cell cycle withdrawal in pre-adolescents cardiomyocytes. Well, that wraps it up for the summaries. Now, let's go on to our feature discussion.

Dr. Greg Hundley:

Welcome listeners to our feature discussion today on this February one. And we're very excited because we have three individuals that will be discussing this paper, Dr. Louise Olde Nordkamp from Amsterdam, Netherlands, the primary author. Dr. Sana Al-Khatib, who is our editorialist for this paper. And finally, Dr. Mark Link, who is our associate editor. Welcome to you all. Louise, we're going to start with you. Can you describe for us some of the background pertaining to why you formulated this study and then what was the hypothesis that you wanted to address?

Dr. Louise Olde Nordkamp:

Yes. Thank you very much for joining this podcast on our study. Our study was designed because in ICD therapy, antitachycardia pacing, ATP has been developed as a painless method to terminate ventricular arrhythmias, and it might decrease the number of appropriate shocks. But on the other hand, ATP might also be given unnecessarily for VTs that would've been ended spontaneously and might even accelerate VTs. The reported efficacy ranges from 52 to 81%, and some studies have observed even higher mortality in patients treated with ATP. The subcutaneous ICD has been developed 10 years ago approximately, and it's completely extra thoracic. And due to this extra thoracic design, it is incapable of providing pacing therapy including ATP. And this was a pre-specified analysis from the PRAETORIAN trial, which was a randomized trial comparing the transvenous and the subcutaneous ICD. And in this pre-specified secondary analysis, we're aimed to determine the efficacy of ATP, the safety of ATP and shocks by comparing appropriate therapies in both arms. So, both the SICD and transvenous ICD, and specifically, we investigated whether ATP reduced the number of appropriate ICD shocks.

Dr. Greg Hundley:

Very nice. And so describe for us a little bit more the study population and the design particularly of the PRAETORIAN trial.

Dr. Louise Olde Nordkamp:

Yeah. So, we published at PRAETORIAN trial in August 2020, in The New England Journal of Medicine and it was the first randomized trial to compare the subcutaneous ICD with the transvenous ICD in patients with a regular ICD indication, but without a pacing requirement. And in 39 census throughout Europe and US of 849 patients were randomized to either the subcutaneous and transvenous ICD in a one-to-one ratio. And during a median follow up of 49 months, the rate of the primary endpoint composite of device related complications and inappropriate shocks were similar between the subcutaneous ICD and the transvenous ICD arm. But here we looked at the appropriate therapy in the study. So, it was defined as both ATP or shock therapy and appropriate therapy was also defined as therapy for ventricular arrhythmias. The PRAETORIAN trial population in overall was, as I said before, regular ICD population with a median age of 63 years, 20% were female. Two-third of patients had an ischemic cardiomyopathy and 20% of patients had a secondary prevention indication.

Dr. Greg Hundley:

Very nice. And so tell us your study results.

Dr. Louise Olde Nordkamp:

Our findings were that in this trial, there was no significant difference in number of patients with appropriate therapy, so shocks and ATP. There were 86 patients in the SICD group and 78 patients in the transvenous ICD group. But patients in the subcutaneous ICD group were one and a half times more likely to be treated with at least one shock. So, if we look at shocks only, and that has a hazard ratio of 1.52 and that was statistically different of significance between the groups. The first shock efficacy was similar in the SICD and in the transvenous ICD. And the first ATP attempt successfully terminated 46% of all monomorphic VTs, but it accelerated through arrhythmia in 9.4%. And although, ATP successfully terminated 46% of all monomorphic VTs, the total of number of shocks, as I said before, was not statistically different between the two groups.

Dr. Louise Olde Nordkamp:

So, we looked at discrete episodes where ATP does reduce the number of appropriate shocks. But when we looked at storm episodes, which was defined as more than three shocks within 24 hours, we saw that there was a higher number of shocks in the transvenous ICD arm, despite a randomized design of the trial and the distribution of shocks between the discrete and the storm episode was there for opposites in the SICD, in the transvenous ICD. So, there was a high number of shocks in storm episodes in the transvenous ICD group, which can partly explain by the number of patients and electrical storms in this group, because there was 10 patients with an SICD who had an electrical storm and there were 18 patients with a transvenous ICD who had an electrical storm. So, patients with appropriate therapy had therefore almost twofold increased risk of an electrical storm in the transvenous ICD arm.

Dr. Greg Hundley:

Very nice. Listeners, next, we're going to turn to the associate editor for this paper, Dr. Mark Link, and Mark, you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Mark Link:

Thanks, Greg. And thanks, Louise for contributing this papers. We were really very happy to have it. And the reason that we were happy to have it is that this is a very important question in our clinical practice. That is, should we give a patient a subcu ICD or a transvenous ICD? Then, there are risk and benefits of both. It's a discussion that I have multiple times a week with patients. And so getting data on the efficacy of shocks and the efficacy of ATP is very, very important for us as we will discuss this with our patients. So that's why we really like this paper, because we thought it was very clinically relevant to our readership and to the practicing EP community.

Dr. Greg Hundley:

Very nice. Next listeners, we're going to turn to our editorialist, Dr. Sana Al-Khatib from Duke University and Sana, help us put the results of this study in perspective with other research in the field of both subcutaneous and transvenous pacing.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. I'd like to start by congratulating the authors on this paper, I really enjoyed reading it and thank you for sending it to circulation. I also enjoyed writing the editorial. So, certainly this paper provided results that have challenged some of the findings of prior studies, in the sense that several prior studies had shown that antitachycardia pacing reduces the risk of shocks, improves patients outcomes. And that's not at the expense of them having syncope or having adverse events. And this was the case in those trials even for faster ventricular tachycardia. So in this particular study, they excluded patients with slower ventricular tachycardia, but I would also say that several of the prior studies had looked at antitachycardia pacing for faster VT and showed better outcomes.

Dr. Sana Al-Khatib:

And so, this study certainly makes us question some of those findings, but really I feel like it will be a great impetus for different researchers to look at this question in relation to the newer generation of transvenous ICDs as well as even potentially looking at the combination of the subcutaneous ICD with perhaps leadless pacemakers that could deliver antitachycardia pacing, which is an area of research that we're going to hear more about.

Dr. Greg Hundley:

Very nice. And Sana, that really leads us into our next round of questions with our panelists. We'll start with you first, Louise, what do you see is the next focus of research that'll be performed in this space?

Dr. Louise Olde Nordkamp:

So, I think the efficacy and also the potential harm of ATP should be studied more thoroughly. So, I think a randomized trial with ATP as a main focus, because this was a secondary analysis, is the first step to do. And moreover as Dr. Al-Khatib already mentioned is that new innovations are ongoing with a leadless pacemaker in addition to a subcutaneous ICD and these clinical results will be gathered in the coming months and years. And that is really interesting to look at as well.

Dr. Greg Hundley:

And Mark, can you share your thoughts?

Dr. Mark Link:

Yeah. This study brings up many questions, tying in the leadless pacemaker with the subcu ICD is certainly one that's being explored by a number of manufacturers right now, ways to make shocks less painful also would be very critical. I mean, I think that the storms often are because of the catecholamine surges that occur with shocks, if you could make shocks less painful, that would be very keen. And that's been a focus of some researchers for quite some time without good results at the time. And then, increasing the efficacy of ATP because there was a signal here that ATP could, what did generate faster VPs and VFs. And so, the prevention of that I think is very crucial.

Dr. Greg Hundley:

Very nice. And Sana, do you have anything to add?

Dr. Sana Al-Khatib:

Yeah, no, absolutely. I completely agree with what was said. I truly feel that this is an area where we're going to see a lot of research being done. We have new algorithms of antitachycardia pacing, Greg, that are being developed and incorporated into devices that use machine learning, which is really exciting. So, trying to look at hard outcomes related to those and comparing them with, as I mentioned, the subcu ICD combination with a leadless pacemaker would be really interesting. And then, this whole question about the electrical storm, I commend the authors for looking at that, but as they pointed out this was a secondary analysis and the numbers that they had were pretty small. So, trying to look at those findings in a larger population of patients really designed to look at that question would be important.

Dr. Greg Hundley:

Very nice. Listeners, we want to thank our electrophysiology panelists today, Dr. Louise Olde Nordkamp, Dr. Sana Al-Khatib, and Dr. Mark Link for bringing us the results from this trial indicating that really there was no difference in observed shock efficacy of the subcutaneous compared with the transvenous ICDs. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinion expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation January 25, 2022 Issue

24 januari 2022 | 24 min

Please join authors Christopher Granger and Anthony Carnicelli, as well as Associate Editor & Editorialist Shinya Goto as they discuss the article "Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex" and accompanying Editorial "Patient Level Meta-Analysis: End of the Era for DOAC Developmental Trial in AF Patients?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about our feature discussion today. It is about DOACs versus warfarin in patients with atrial fibrillation, a really important patient-level network meta-analysis of randomized control trials with interaction testing by agent six. So you can already tell something very, very clinically relevant and important discussed by not only the authors, but our dear associate editor and editorialist.

Dr. Carolyn Lam:

Okay. You just got to tune in, but first I'm going to start us off with some coffee, as well as a description of this first paper in today's issue. The 2018 AHA ACC multi-society cholesterol guidelines states that statin therapy may be withheld or delayed among intermediate risk individuals in the absence of coronary artery calcium.

Dr. Carolyn Lam:

However, two traditional cardiovascular risk factors associate with incident atherosclerotic cardiovascular disease events among individuals with zero coronary artery calcium over the long term? Well, this is the question that investigators decided to answer in today's paper and they're led by Dr. Virani from Baylor College of Medicine in Houston, Texas.

Dr. Carolyn Lam:

They studied 3,416 individuals with coronary artery calcium score of zero at baseline from the MESA study, which is a prospective cohort study of individuals free of clinical atherosclerotic cardiovascular disease at baseline. Among these individuals with zero coronary artery calcium, cigarette smoking, diabetes and hypertension were found to be independently associated with incident atherosclerotic cardiovascular disease events over long-term follow up.

Dr. Greg Hundley:

Ah, very interesting. Another piece of information relating to how we might use coronary artery calcium scores in, it sounds like, a high-risk patient population. So, Carolyn, what's the take-home message here?

Dr. Carolyn Lam:

Well, even if individuals have a coronary artery calcium of zero, if they are current smokers, if they have diabetes melitis or hypertension, initiation and long-term use of statin therapy, along with a heart healthy lifestyle and risk factor modification may still be warranted as part of the patient/clinician risk discussion.

Dr. Greg Hundley:

Very interesting Carolyn. Well, I've got a clinical study to tell you about. And, Carolyn, as you know, obesity and diabetes are associated with a higher risk of heart failure and the inner relationships between different measures of adiposity, including overall obesity, central obesity, fat mass, and diabetes status for heart failure risk, are not well established.

Dr. Greg Hundley:

And so this investigative group, led by Dr. Ambarish Pandey, from UT Southwestern Medical Center, looked at the ARIC, the visit five in ARIC and CHS, the visit one, and cohorts together, and they were obtained from the NHLBI BioLINCC. They were harmonized and pooled for the present analysis, excluding individuals with prevalent heart failure.

Dr. Greg Hundley:

So using multi-variable adjusted fine-grade model models were created to evaluate the associations of body mass index, waist circumference, and fat mass with risk of heart failure in the overall cohort, as well as among those with, versus without, diabetes at baseline.

Dr. Greg Hundley:

And the population attributable risk of overall obesity with BMI greater than 30 kilograms per meter squared, abdominal obesity with waist circumference greater than 88 and 102 centimeters in women and men, respectively, and high fat mass above the sex-specific median for incident heart failure, was evaluated among participants with and without diabetes.

Dr. Carolyn Lam:

Ooh, I'm so in interested in this topic. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So a large study, it included 10,387 participants, about 53% from ARIC, 25% had diabetes, and the median age was 74 years. And higher levels of each adiposity measure were significantly associated with higher heart failure risk. The population-attributable risk percentage of overall obesity, abdominal obesity, and high fat mass for incident heart failure was higher among participants with diabetes versus those without diabetes.

Dr. Greg Hundley:

And so, Carolyn, we can conclude from this research that higher BMI, higher waist circumference and higher fat mass, are strongly associated with greater risk of heart failure among older adults, particularly among those with prevalent diabetes.

Dr. Carolyn Lam:

So, so nicely done. Thank you, Greg. Well, the next paper talks about common ancestry-specific ion channel variants and how they predispose to drug-induced arrhythmias. Now, we know that multiple reports associate the cardiac sodium channel gene Scn5a variants, and these are the specific variants, S1103Y and R1193Q, with Type 3 congenital long QT syndrome and drug-induced long QT syndrome.

Dr. Carolyn Lam:

These variants are, however, two common in ancestral populations to be highly arrhythmogenic at baseline. The S1103Y allele frequency, for example, is 8.1% in Africans and the R1193Q is 6.1% prevalent in East Asians. So the investigators, led by Dr. Roden from Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues, determined the effect of the S1103Y variant on QT intervals among 1,479 Africans from a large electronic health record with no confounding medications or diagnosis of heart disease.

Dr. Carolyn Lam:

Now, while both the specific variants generated increased late sodium current, baseline action potential durations in cardiomyocytes from induced pluripotent stem cells carrying these variants were unexpectedly normal. The re-polarizing potassium current, IKR, was markedly increased in these induced pluripotent stem cells with the variants, accounting for normal baseline action potential duration but, with exposure to an IKR blocker, they displayed exaggerated action potential duration prolongation and after depolarizations.

Dr. Greg Hundley:

Wow, Carolyn, interesting. So tell us, what are the clinical implications of this really exciting research?

Dr. Carolyn Lam:

Yeah. So here's the take-home message. These common ancestry-specific variants do not affect baseline re-polarization, despite generating an increased late sodium current. So the authors propose that increased re-polarizing potassium current, IKR, serves to maintain normal re-polarization, but increases the risk of manifest QT prolongation with IKR blocking in these variant carriers. So we need to be aware of that and, further, these findings highlight the need to include ancestral diversity in genomic and pharmacogenomic studies.

Dr. Greg Hundley:

Oh, wow. Beautifully described, Carolyn. I really appreciate that. Just excellent discussion. Well, Carolyn, my next paper comes to us in an investigation regarding doxorubicin or anthracycline-associated induced cardiotoxicity. So, Carolyn, multiple pharmacogenetic studies have identified the synonymous genomic variant rs7853758 and the intronic variant rs885004 and SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity.

Dr. Greg Hundley:

However, the true causal variant, or variance, of this cardioprotective mechanism at this locus, the role of SLC28A3 and other solute carrier transporters in anthracycline-induced cardiotoxicity and the suitability of solute carrier transporters as targets for cardioprotective drugs has not been investigated.

Dr. Carolyn Lam:

Wow. Got it. So what did these investigators do and find, Greg?

Dr. Greg Hundley:

Right. So Paul Burridge and his colleagues at Northwestern University found that the patient-specific cardiomyocytes recapitulate the cardioprotective effect of the cGAS-identified SLC28A3 locus, and the authors functionally confirmed for the first time, the role of SLC28A3 in doxorubicin-induced cardiotoxicity.

Dr. Greg Hundley:

And a novel genetic variant, the rs11140490, is the potential causal variant in the SLC28A3 cardioprotective locus. And finally, Carolyn, the solute carrier transporter inhibitor desipramine protects against doxorubicin-induced cardio toxicity through decreasing the intracellular uptake of doxorubicin into the heart.

Dr. Carolyn Lam:

Wow. That is a lot of data. Could you summarize it for us, Greg?

Dr. Greg Hundley:

Right, Carolyn. So these investigators provide two potential therapeutic options to attenuate doxorubicin-induced cardiomyopathy, either repurposing FDA-approved desipramine, or therapy with long non-coding RNA SLC28A3-AS1. Also, Carolyn, they propose that a simple clinical test to detect the presence of rs11140490 can be used to predict that a patient will be less likely to experience doxorubicin-induced cardiomyopathy, and that, perhaps with future clinical trials, it may be possible for these patients to be treated with a longer duration, that is a higher accumulative dose of doxorubicin, to enhance the efficacy of their chemotherapy.

Dr. Carolyn Lam:

I love the way you took that home for us. Thank you, Greg. Well, also in today's issue is a Research Letter by Dr. Chen on multifaceted spacial and functional zonation of cardiac cells in an adult human heart.

Dr. Greg Hundley:

Right, Carolyn. And Professor Constantine has a Letter to the Editor entitled Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia. Well, Carolyn, how about we get onto that feature article and learn about DOACs versus warfarin in this very large network meta-analysis?

Dr. Carolyn Lam:

Yes, yes, yes. Let's go, Greg. Thanks.

Dr. Greg Hundley:

Welcome, listeners, to our feature discussion today. And we're very fortunate. We're going to review the utility of DOACs in patients with atrial fibrillation. And we have with us two of the authors of this original research, Dr. Anthony Carnicelli from Duke University, and Dr. Chris Granger from Duke University.

Dr. Greg Hundley:

Additionally, we have with us our associate editor, Dr. Shinya Goto, from Japan. Welcome, gentlemen. Anthony, we'll start with you. Describe for us a little of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Anthony Carnicelli:

Yeah, thanks so much, Greg, for having us here to discuss this. I started working in the DOAC space when I was a resident at Brigham and Women's Hospital with mentorship from Dr. Bob Guigliano there, and was really fortunate to connect with Dr. Granger when I came to Duke for a fellowship, and we had this unique opportunity to take data out of the four largest trials of anticoagulants in the atrial fibrillation, and take individual patient data from these international centers and combine them to form the combined AF database from which we did this analysis.

Dr. Anthony Carnicelli:

So a very unique opportunity here to have individual patient-level data from over 70,000 patients, and perform this analysis. And, really, what we aimed to do was to do the kind of highest quality meta-analysis using network meta-analysis methods to investigate the relative safety and efficacy of DOACs versus warfarin and a broad and diverse, but randomized, population of patients with atrial fibrillation.

Dr. Greg Hundley:

Very good. So you started to describe for us your study population and your study aligns. So tell us a little bit more, who were these patients, and then maybe specifically give us a little bit of the outline of your meta-analysis.

Dr. Anthony Carnicelli:

Yeah, so these were, again, a very broad patient group, but from kind of 10,000 feet, this was a population of patients with atrial fibrillation who were at risk of stroke, from CHADS score perspective. So there are some nuances from each of the included studies, of course, regarding the individual risk of stroke from one study to the next. But largely, as I mentioned, in patients with non-valvular atrial fibrillation randomized to either DOAC or warfarin.

Dr. Anthony Carnicelli:

And, from a method standpoint, we are fortunate at Duke and at DCRI, to have an expert in the network, meta-analysis methodology, whom we've worked with, Dr. Bonnie Huang, who helped to put together the analysis here and to proceed with this kind of network methodology.

Dr. Anthony Carnicelli:

And so, again, our goal was to evaluate the overall safety and efficacy of DOACs versus warfarin, but then also to dive into some specific subgroups, both from a categorical covariant perspective, and then also to evaluate some continuous covariants, specifically age, and to assess gender across the entire spectrum of continuous age in our population, which, of course is a unique opportunity in the individual patient-level data.

Dr. Greg Hundley:

And, Anthony, you had, gosh, it looks like over 70,000 patients in this particular analysis. Tell us a little bit about the results.

Dr. Anthony Carnicelli:

Yeah, so interesting, actually, and I agree that the biggest strength of our meta-analysis is the individual patient-level data and also the profound number of randomized patients included. So I think, from a high level, the most important results to highlight are the fact that there is a 19% relative risk reduction in stroke or systemic embolism among patients who are randomized to DOACs compared to warfarin, with an 8% reduction in all-cause death and a 55% reduction in intracranial hemorrhage.

Dr. Anthony Carnicelli:

So a massive reduction in the most feared complications of both atrial fibrillation and then also those associated with systemic oral anticoagulation. We also found a trend towards less bleeding in patients randomized to the standard-dose DOAC group, as well.

Dr. Greg Hundley:

Very good. Well, Chris, we're going to turn to you. What an exciting discovery here, and beautiful methodology. I wonder, in addition to what Anthony has shared with us, were there particular outcomes that were pertinent to men versus women or perhaps related to age?

Dr. Christopher Granger:

Yeah, Greg. So, again, we're proud of this as being really the state-of-the-art ability to evaluate safety and efficacy in this incredibly important population of patients with Afib and at risk for stroke, and to be able to dive into the subgroups and to the individual outcomes, even the less common outcomes. And one of the most striking things, and this really reinforces prior data, but with the greatest confidence of any study ever done, there was this 55% at reduction in intracranial hemorrhage and 19% reduction in total stroke and systemic embolism, really highlighting that these drugs are clearly better than warfarin, from reinforcing the guidelines.

Dr. Christopher Granger:

And the message with the subgroups is there was really a remarkable amount of consistency. And specifically in the older population where people are really concerned about anticoagulation, there was a clear and consistent major advantage of DOACs over warfarin. Men versus women, clear, clear, compelling benefit of DOACs over warfarin across each of these outcomes, including mortality, by the way, 8%. But highly statistically significant reduction in total mortality.

Dr. Christopher Granger:

A couple of the interesting ones, there was some effect modification. In other words, some evidence of an even greater benefit in patients who were not previously on a vitamin K antagonist or who had lower creatinine clearance, really important group, right? The renal impairment group.

Dr. Christopher Granger:

And then there was a greater benefit of lower risk of bleeding for patients with low body weight. And, in fact, the younger population, if anything, had a greater benefit with respect to less bleeding. And the bleeding is so important, Greg and Shinya, right? Because that's the major reason that people are not using anticoagulation, warfarin or DOACs, for this large population of patients who are untreated. And I hope this meta-analysis will be viewed as evidence that have really safe and effective treatments that are underused for this population that we're concerned about bleeding.

Dr. Greg Hundley:

Excellent. Thanks so much, Chris. Well, Shinya, you see a lot of papers come across your desk. What attracted you to this particular paper? And then can you help us put these results in the context with others that have evaluated the utility of DOACs in patients with atrial fibrillation?

Dr. Shinya Goto:

Thank you, Greg. Let me congratulate for Anthony and Chris and also group for conducting this great work. I mean, combine AF with amazing success for sharing the clinical trial database. So that all the four with a DOAC available is approved by each country based upon individual trial. Individual trial itself, large enough, right? Include more than 10,000 patient, but this time the [OSA 00:19:49] accumulated all four DOAC trial database together so that it is easy to say clinical trial data sharing provided robust evidence.

Dr. Shinya Goto:

But it is difficult, actually, to conduct it. I really commended OSA to conduct this success. So the data is predicted, I would say. Individual clinical trial itself shows lower risk of bleeding in DOAC as compared to warfarin. But this paper really provides the first time standard dose of DOAC reduce the risk of stroke and systemic embolism and death as compared to warfarin.

Dr. Shinya Goto:

So I really commented OSA. So this paper have a strong impact on the medical care. DOAC rapidly change the standard of care already. But superior efficacy was shown only in a few dose of DOAC, like 150 milligram BID of dabigatran, 60 milligram QD edoxaban, and five milligram apixaban. But this combined AF provides a stronger and a trustable robust evidence DOAC is better than warfarin.

Dr. Greg Hundley:

Very nice. Well, gentlemen, I want to turn back to you. I'll start with Anthony and then Chris, and then Shinya. Anthony, what do you think is the next study to be performed, really, in this space?

Dr. Anthony Carnicelli:

Well, it may be a bit of a pitch, but I mean, we have many opportunities in the combined AF data set to perform additional analyses, but I think that one of the most important next steps in this space that I'm most excited about is with respect to the newer oral anticoagulants that are coming down the pike.

Dr. Anthony Carnicelli:

For example, the Factor 11 inhibitor space. I mean, I think that there is another opportunity in the near future to potentially revolutionize the systemic anticoagulation space. And I think that data from combined AF could potentially be used to help continue moving the ball forward, again in the development of newer agents. So I think that's probably the thing that I'm most excited about in this space.

Dr. Greg Hundley:

Very good. And, Chris?

Dr. Christopher Granger:

Greg, I think there's so many unanswered questions and I think, as Tony points out, this highlights the fact that we know a lot, but there's a lot of unanswered questions. And those, some of the ones that I'm most interested in are low burden AFib, this AFib that we're detecting now with smart watches and devices, and what we do with that. And patients with renal impairment, including all the way down to renal failure, where those are relatively underrepresented, including in the combined AF data set.

Dr. Greg Hundley:

Very good. And, Shinya?

Dr. Shinya Goto:

Yeah. Yeah, Anthony and Chris talked about a little bit the plans to space, but I insist there is a lot of space that also could do with the combined AF database. We can expect a lot of sub-analysis, like you conducted as a continuous variable in this paper, but you can do that with eGFR as continuous variable, PMI as continuous variable. So we can expect a lot of sub-analysis. Probably, this is the end of publication from the individual DOAC development trial. You change the game with the combined AF data set.

Dr. Greg Hundley:

Very good. Well, listeners, we want to thank Dr. Anthony Carnicelli, Dr. Christopher Granger and our own associate editor, Dr. Shinya Goto, for bringing us this very interesting result from the meta-analysis that, compared to warfarin, DOACs have a more favorable efficacy and safety profile among patients with atrial fibrillation. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation January 18, 2022 Issue

18 januari 2022 | 20 min

Please join author Mohamed Abdel-Wahab and Associate Editor Stefan James as they discuss the article "Comparison of a Pure Plug-Based Versus a Primary Suture-Based Vascular Closure Device Strategy for Transfemoral Transcatheter Aortic Valve Replacement: The CHOICE-CLOSURE Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, a very interesting topic, looking at closure devices at the sites of access for patients that are undergoing TAVR procedures. But before we get to that, how about if we grab a cup of coffee and start with some of the other articles in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would love to and I would like to describe not just one, but two articles from recent SGLT2 inhibitor trials. So, the first paper is an analysis of the DAPA-HF trial. Now we know that circulating high sensitivity, cardiac troponin T predominantly reflects myocardial injury. And higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction or HFrEF. But what about the prognostic significance of changes in high sensitivity troponin T over time and the effects of Dapagliflozin and on clinical outcomes in relation to baseline levels, as well as the effect of dapagliflozin on the high sensitivity troponin T levels? Well, this is what this study answers. It's a biomarker substudy of the DAPA-HF trial from Dr. Berg of the TIMI study group at Brigham women's hospital and colleagues.

Dr. Greg Hundley:

Wow. Carolyn, very interesting. So remind us about the DAPA heart failure trial. What was it about?

Dr. Carolyn Lam:

Ah, well, DAPA-HF was a randomized double blind placebo control trial of dapagliflozin in patients with symptomatic HFrEF defined by injection fraction 40% or less wherein dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure events. And in today's biomarker substudy increases in high sensitivity, cardiac troponin T over a one year interval of time were highly predictive of subsequent risk of worsening heart failure and cardiovascular death. The effect of dapagliflozin on the primary endpoint was consistent irrespective of baseline troponin T concentration with no evidence of attenuated treatment benefit in those with very high troponin T concentrations.

Dr. Greg Hundley:

Very interesting Carolyn. Now you've got another study. Is this one on EMPA?

Dr. Carolyn Lam:

You are right. Thank you. The next paper is and analysis of the Emperor-Preserved trial. As a reminder, Emperor-preserved study the SGLT2 inhibitor empagliflozin in patients with HFpEF this time, which is a left ventricular ejection fraction above 40, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. The current paper evaluated the efficacy of empagliflozin on health related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varied according to baseline health status.

Dr. Greg Hundley:

Very nice, super review Carolyn. So what were the results of this study?

Dr. Carolyn Lam:

In Emperor-Preserved, baseline health status and quality of life did not influence the magnitude of effect of empagliflozin on the risk of cardiovascular death or hospitalization for heart failure. Empagliflozin improved health status and quality of life as assessed by the Kansas city cardiomyopathy questionnaire across all domains and at all measured time points. Thus an effect that appeared early and was sustained for at least one year.

Dr. Greg Hundley:

Very nice. So two really informative papers on SGLT2 inhibitors. Well Carolyn, I'm going to turn the conversation to the world of preclinical science and talk about Titin. So Carolyn, titin truncation variants are the most common inheritable risk factor for dilated cardiomyopathy and their pathogenicity has been associated with structural localization. The A-band variants with overlapping myosin heavy chain binding domains appear more pathogenic than the I-band variants and the mechanisms for this are not well understood. So these investigators led by Dr. Hinson at the Jackson Laboratory for genomic medicine, performed a study demonstrating why A-Band variants are highly pathogenic for dilated cardiomyopathy and how they could reveal new insights into dilated cardiomyopathy pathogenesis. Titin functions and therapeutic targets were assessed.

Dr. Carolyn Lam:

Wow, interesting. So what did they enroll in? How did they do this? what did they find?

Dr. Greg Hundley:

Great Carolyn, so human Cardiomyocytes and cardiac micro tissue functional assays revealed that highly pathogenic A-Band Titin truncation mutations generate four shortened titin poisoned peptides and diminish full length, titin protein levels. While less pathogenic I-band titin mutations only diminish titin protein levels. And so Carolyn, the authors developed a one and done, genome editing therapeutic approach using CRISPR technology to repair the reading frame of Titin truncation mutations in cardiomyocytes. And therefore these genome editing therapeutics could correct the underlying genetic lesion responsible for dilated cardiomyopathy due to these Titin mutations.

Dr. Carolyn Lam:

Wow. Interesting. One and done genome editing. You learn something new every day with circulation. You've got another paper?

Dr. Greg Hundley:

Yes, Carolyn. Thank you. And so this paper comes to us from Dr. Beiyan Zhou From the Yukon health, school of medicine and again, from the world of preclinical science. So Carolyn, while several interventions can effectively lower lipid levels and people at risk for atherosclerotic cardiovascular disease, cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to this cardiovascular event risk. Now monocytes and macrophages play central roles in atherosclerosis, but previous work has yet to provide a detailed view of macrophage populations involved in increased atherosclerotic cardiovascular disease risk.

Dr. Carolyn Lam:

Huh? Okay. Well, I'm super excited to hear what these investigators did Greg.

Dr. Greg Hundley:

Right, Carolyn. Well these authors developed a novel computational program. They call AtheroSpectrum, which identified a specific gene expression profile associated with inflammatory macrophage foam cells. And additionally, a subset of 30 genes expressed in circulating monocytes jointly contributed to the prediction of symptomatic atherosclerotic vascular disease. So therefore Carolyn, in the future, perhaps incorporating this new pathogenic foaming gene set with known risk factors may significantly strengthen the power to predict atherosclerotic cardiovascular disease risk.

Dr. Carolyn Lam:

Wow. Super interesting and well summarized. Thank you, Greg. Well also in today's issue, there's a Perspective by Dr. Kirtane on “The Long-Awaited Revascularization Guidelines are Out. What's In Them?” A Research Letter by Dr. Laffin on rise in blood pressure observed among us adults during the COVID 19 pandemic.

Dr. Greg Hundley:

Very Nice Carolyn. Well in our Cardiovascular News Segment, there's a piece on metabolic risk factors and how they drive the burden of Ischemic heart disease. Well, what a great issue here and now, how about we get onto that feature discussion?

Dr. Carolyn Lam:

Very Cool. Closure devices after TAVR. Here we go.

Dr. Greg Hundley:

Well, listeners welcome today to our feature discussion and we have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we are going to discuss some issues pertaining to transcatheter aortic valve replacement, in terms of access to the arteries in the lower extremity. Welcome Mohamed. And can you start with, what was some of the background that led you to perform your study and what was the hypothesis that you wanted to address?

Dr. Mohamed Abdel-Wahab:

Thank you, Greg. And thank you for having me here. So as you mentioned, there are several cardiovascular procedures that currently require large-bore arterial access. The most common of these procedures is transcatheter aortic valve replacement. But there are other procedures as well, like endovascular aortic repair, mechanical circulatory devices. All of these require large-bore arterial access and of course, closure afterwards. And what we were interested in looking at was whether different types of vascular access site closure devices or strategies behave differently in the setting. Particularly in the setting of transcatheter aortic valve replacement. The reason behind this is that for many years, we only had one technique, to percutaneously close arterial access sites after these procedures. And these were mainly based on suture based devices or suture based techniques. Very recently, alternative techniques based on collagen plugs have been introduced.

Dr. Mohamed Abdel-Wahab:

And we know these types of devices or closure techniques from usual coronary intervention procedures for smaller access sites or for smaller sheath size. But they have been developed a step further for these large-bore procedures. These newer devices, particularly what we call the MANTA device, which is based on the collagen plug has been shown in initial visibility studies and also in registry based analysis to be very safe and effective. It leads to a very rapid hemostasis. And data from observational studies have suggested that it may be even superior to the suture based techniques, largely based on what we call the ProGlide device or the [inaudible 00:10:56]. And this is actually what we were aiming to look at. To compare these two different strategies based on two different devices. The suture based, the classical suture based technique using two ProGlides compared to the newer plug based technique using the MANTA in a population treated with TAVR.

Dr. Greg Hundley:

Very nice. And describe for us, your study design. And then also maybe explain a little bit more about the study population. Who did you include in this study?

Dr. Mohamed Abdel-Wahab:

So the design was more or less, very inclusive. So we designed the trial to more or less represent real word population. More or less [inaudible 00:11:40] population receiving transcatheter aortic valve replacement. So we included patients, of course where the procedure is being thought to be indicated and feasible by a multidisciplinary heart team. And also where the heart team thought that the transfemoral access route, which is the main route for the majority of patients, is obtainable and use of a percutaneous closure device is also possible.

Dr. Mohamed Abdel-Wahab:

Of course we had some exclusions. For example, patients where the use of a surgical access technique was necessary. They couldn't be naturally included in the trial. Patient that already had complications related, for example, to previous coronary angiogram PCI at the access site, they couldn't be included. But we were more or less, very inclusive in this trial. The trial population reflects the patients that are currently being treated with TAVR, so more or less an elderly population. More or less equally split-by males and females, which is very particular, again to the TAVR population. So this is a little bit different than the population that receives PCI, where we usually have a predominantly male population. This is not the case here. So these are the broad lines. Also reflecting current practice, the population that has been included in the trial is more or less overall, an intermediate risk population, when you look at the surgical scores.

Dr. Greg Hundley:

Very nice. So this was multicenter and then also patients were randomized to each of the two therapies, I believe. And was that a one to one randomization?

Dr. Mohamed Abdel-Wahab:

Exactly. So it was a multicenter trial. Patients were randomized between these two techniques. We mentioned the ProGlide based and the MANTA based in 1:1 fashion. And steering committee of course was more or less dominated by interventional cardiologists. Of course, in the context of this particular trial setting, the trial was only performed in Germany and it was an investigative initiated trial, not sponsored by the industry.

Dr. Greg Hundley:

Very nice. And can you describe for us, Mohamed, your results?

Dr. Mohamed Abdel-Wahab:

Yes. We actually hypothesized based on the observational data we have, that we will have less vascular complications with the MANTA based technique or the collagen based technique. At the end of the day, what we observed is completely the opposite. So the primary endpoint of the trial, which was what we call major and minor vascular complications defined according to the standardized criteria provided by the valve academic research consortium. These events occurred significantly more common in patients that were randomized to the MANTA based technique, as opposed to the ProGlide based technique, which was statistically significant.

Dr. Greg Hundley:

And did you observe those results across both the men and the women? And also, were there any differences in the results related to participants' age?

Dr. Mohamed Abdel-Wahab:

Yeah. So there were no interactions with various subgroups, both the predefined ones, including age and sex, as you mentioned. But also we looked at some post hoc subgroups, including for example, whether this is being affected by the size of the access vessels or by the presence and location of calcification, for example. But there were no interactions in all subgroups we looked at, with one exception which was chronic renal insufficiency. But all other subgroups showed actually no significant interaction, favoring the suture based, ProGlide based technique in all subgroups.

Dr. Greg Hundley:

Very good. And so can you describe in terms of, for individuals performing TAVR procedures and obtaining access, how do we use the results of your study to inform how we might move forward with closure of the artery in the future?

Dr. Mohamed Abdel-Wahab:

I mean, the first thing I would like to stress is the importance of doing randomized trials in general. Because I think this is not the first time we see opposite results when we are comparing randomized evidence with the evidence from observation studies, with the known limitations of observational comparative analysis. The second thing I think is really reassuring that the suture based technique that we know and that we have been using for many years now is safe and appears to be even more effective than the newly developed plug based technique. So this is one important information I think from this trial. The third piece of information is that the recently developed plug based technique, although being inferior in the study, it still may have some advantages in selected patients. And this is what we probably need to look at in a little bit more details in the future.

Dr. Mohamed Abdel-Wahab:

For example, what we realized from the study is that it could be a good option as a bailout device. So in some cases where the suture based technique has failed in the study, the crossover to the MANTA device was successful in the majority of cases. And may lead or help avoid complex endovascular interventions and implanting for example, stents or covered stents or even doing surgery. So this is something that is a nice observation from the dataset we have, but of course needs validation in larger studies.

Dr. Greg Hundley:

Very nice. And so really you've answered, kind of one of our key questions is, your thoughts on the next study that you see needs to be performed really in this area of research?

Dr. Mohamed Abdel-Wahab:

Yeah, so I think there are several things. One thing is, again, to look at potential patient subgroups that may benefit from the plug based device from the beginning. So probably it's not something that we should be using as a default strategy based on the results of this trial. But there could be certain subgroups we need maybe to dig a little bit more into the details or subgroups, if you wish to say so. Look a little bit more granularly at some patient groups that could benefit. But as mentioned, I think that the bailout indication is a very interesting one and needs to be looked at.

Dr. Mohamed Abdel-Wahab:

Not only in the TAVR setting, but also in the setting of other procedures. Such as for example, the use of mechanical circulatory assist device or ECMOs, where it may be difficult to apply these sutures post hoc. So the sutures that we apply during a TAVR procedure and what we use in this trial, this is the so-called preclosure technique. So you apply the sutures after gaining access. Then you insert your large-bore sheaths through the procedure. And then the sutures are already there and you can close the access site, usually without problems. Which is difficult, if you obtain access, for example, with an ECMO or an Impella. And then after a couple of days, you need to close it. So the sutures are not yet in place. In this particular scenario, it may be beneficial to use a plug afterwards. Or as a bailout device as previously Mentioned.

Dr. Greg Hundley:

Very nice well listeners. We want to thank Dr. Mohamed Abdel Wahab from Leipzig Germany for bringing us this study indicating that among patients treated with transfemoral TAVR, this pure plug based vascular closure technique using the MANTA VCD was associated with a higher rate of access site or access related vascular complications. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more, please visit AHA journals dot org.

Circulation January 11, 2022 Issue

10 januari 2022 | 33 min

This week's Feature is a Panel Discussion. Circulation invited the Young Investigator Finalists who had a Simultaneous Publication for AHA's 2021 Sessions. Please join authors Amgad Mentias, Matthew Burrage, Shaan Khurshid, Sevedeh Maram Zekavat, and Neel Butala as they discuss their articles.

Dr. Greg Hundley:

Welcome listeners to this very special January 11th issue of Circulation on the Run. And I'm going to tell you why it's special. I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia and also associate editor at Circulation. Why is this issue special? Because we have the opportunity to speak with finalists for several of the awards that were presented or that these investigators presented for at the American Heart Association sessions. And so we have with us today, five early stage investigators and we are going to hear about each of their research projects and the manuscripts that are coming out and are published in this issue. Want to welcome all five of you and we'll introduce one at a time as we work through their research projects. And the first is Dr. Amgad Mentias from Cleveland Clinic and he was in the session competing for the Elizabeth Barrett-Connor Research Award for early career investigators in training. Welcome Amgad. And we'll start with you. Can you tell us a little bit about the background for your study and what was the hypothesis that you wanted to address?

Dr. Amgad Mentias:

Hi, Dr. Hundley. How are you? Thank you so much for inviting me today. A little background, we know that community economic distress affects outcomes in patients with heart failure. It actually affects both short term and long-term outcomes. What was not studied on a nation level before is how is that impact different or if it's actually different between different races. In White patients and Black patients and Hispanic patients, what would be the differentiated effect of community economic distress on their short and long-term outcomes with heart failure after a heart failure admission?

Dr. Greg Hundley:

Absolutely. And so that hypothesis that you were going to address, what were you hypothesizing here?

Dr. Amgad Mentias:

We were hypothesizing that each race has probably some shared risk factors but also some specific risk factors. We were hypothesizing that the community level economic distress effect on heart failure outcomes is not homogeneous or not exactly the same between all races.

Dr. Greg Hundley:

Very nice. And so what was your study design? And describe a little bit for us the study population.

Dr. Amgad Mentias:

We included the Medicare population. We included patients who were admitted with a primary diagnosis of heart failure from the years 2014 till 2019. We included patients from Black and White and Hispanic races or ethnicities. And we only included the first admission for a patient if the patient was admitted more than once during these years. That was the study population. And we had about 1.6 million White patients and about 205,000 Black patients and around 89,000 Hispanic patients.

Dr. Greg Hundley:

Great. And so was this a cohort design?

Dr. Amgad Mentias:

Yes, it was a cohort design. The study start date was when they were admitted to the hospital for our mortality outcome and when they were discharged from the hospital for readmission outcomes. And then we followed them in time up to one year.

Dr. Greg Hundley:

Very nice. And so tell us, what did you find?

Dr. Amgad Mentias:

Our primary exposure of interest, like we said, was economic distress and race and our primary outcome was three things, mortality, the second thing is readmission burden, which is number of admissions over time the patient is alive and third thing is home time how many days the patient spends at home, out of the hospital and out of skilled nursing facilities and LTACs. And we looked at these outcomes at three different points, at 30 days, at six months and at one year follow up. Initially we did an interaction and that is to see whether our hypothesis, that the effect is different or not between a race and term and the economic distress term. And the interaction was significant, in all three outcomes. Then we went deeper and we started to study each race separately and see how economic distress affects their outcomes. We defined economic distress by distress score called the distressed community index, which is a composite measure of seven things, including education of the people in the zip code, unemployment, poverty rate and income in the zip code compared to the state level and that stuff.

Dr. Amgad Mentias:

We actually found that in White patients, economic distress was actually associated with adverse outcomes in the short and long term. In Black patients, it was affecting the outcomes more robust and more evident in the long term, not in the short term. We also found the geographic location and their approximate location, whether it's urban or rural, residential zip code also affected outcomes. We found that in all races being in a rural distressed community had the highest posterity and the highest admission burden and the worst home time compared to other communities. In fact, people in distressed urban communities had comparable outcomes. People in rural, non-distressed communities had comparable outcomes to urban distressed. We found that the rural location and approximate location near resources affected outcomes in all races but specifically also in Black patients.

Dr. Greg Hundley:

Very nice. And how do you put your results in context with others that are doing research in this area?

Dr. Amgad Mentias:

We show that the interplay between economic distress and societal factors and different things for heart failure is very complex and there is a complex interplay between different factors. I think it's very important for health policies that targeting improvements in community with economic distress and access to care, they are key to improving outcomes and reducing racial disparities among patients with heart failure.

Dr. Greg Hundley:

Beautiful. Well, Amgad, we want to congratulate you on this just excellent work in identifying associations between community level economic distress and risk of adverse outcomes across different race ethnic groups. Congratulations to you.

Dr. Greg Hundley:

Well listeners, next we're going to turn to Matthew Burrage from University of Oxford. And Matt was a finalist for the Melvin Judkins Early Career Clinical Investigator Award. Matt, just like with Amgad, could you tell us a little bit about the background that went into your research project? And what was the hypothesis that you wanted to address?

Dr. Matthew Burrage:

Yeah, certainly. And thank you very much for the invitation to take part in this discussion. Really it's a pleasure to be here. The inspiration for this study was really driven by the difficulties that we've been having in trying phenotype heart failure with preserved ejection fraction or HFpEF, given that until very recently, there were really no therapeutic agents that have significantly improved outcomes for this population. This is despite the fact that around half of all heart failure is classified as HFpEF. And so the thought is that this is a very heterogeneous population but when you dig down into the physiology, there seems to be a central mechanism which involves impairment of myocardial relaxation and in a subsequent rise in intracardiac filling pressures. And this is something that's often unasked by exercise and typically this then results in pulmonary congestion and symptoms of breathlessness. And so some recent translational studies suggests that abnormal cardiac mitochondrial function and energetics may be a unifying feature in the pathogenesis of HFpEF.

Dr. Matthew Burrage:

And given that we know myocardial contraction is dependent on cardiac energy metabolism and that diastolic relaxation is even more energy dependent, we hypothesized that impairment of myocardial energetics may underpin a lot of the physiological changes in the heart that occur during exercise and thus could potentially present a metabolic basis that underlies symptoms in patients with HFpEF, with the hope that this could then lead to new translational drug targets for HFpEF in the future. But then alongside this as well, there's been some really pivotal work on pulmonary congestion during exercise in HFpEF that's been led by Barry Borlaug's group at the Mayo Clinic as the main determinant of patients' symptoms. This has been very well validated against invasive hemodynamics. The second component of our study was to see if we could noninvasively assess pulmonary congestion during exercise and HFpEF. And so to do this, we developed and implemented a new MRI sequence that could quantitatively assess changes in lung water.

Dr Greg Hundley:

Very nice. How did you address the hypothesis in terms of your study design and your methodology?

Dr. Matthew Burrage:

This was a prospective study that followed essentially a basket trial design, where we recruited four distinct groups of participants that were felt to really encompass the spectrum of worsening diastolic dysfunction in HFpEF, which was based on clinical scoring systems, blood biomarkers and echocardiography. We recruited 43 participants split across this group and so we had a cohort of age matched, healthy controls. We had patients with cardiometabolic risk factors for HFpEF like diabetes and obesity who were included essentially if you think of it like a pre-HFpEF group, patients with carefully clinically phenotyped HFpEF and then a cohort of patients with cardiac amyloidosis. And the amyloid group was recruited really as a positive control, that the proof of principle lung imaging sequences, as the presence of restrictive physiology in those patients meant they would be the group that would be far most likely to develop pulmonary congestion during exercise.

Dr. Matthew Burrage:

And so each participant underwent blood sampling, a targeted echocardiogram, they had magnetic resonance spectroscopy to assess myocardial energetics and cardiac metabolism. We do this by measuring the phosphocreatine to ATP ratio and also a cardiopulmonary exercise MRI. The exercise protocol for the study was a fixed low intensity workload of 20 Watts for six minutes with the patient supine within the MRI scanner using an ergometer. And then during exercise, we did whole heart free breathing cine stacks to assess cardiac volumes at rest and exercise, as well as performing our custom proton density weighted lung imaging sequence to look at changes in pulmonary congestion. And if you're interested, the whole rest and stress protocol together can be done within about 15 minutes.

Dr. Greg Hundley:

Wow. Boy, very exciting. Exercise during an MRI scan. Matt, we're very anxious to hear, what did you find?

Dr. Matthew Burrage:

The key findings from this study is that there really is a clear gradient myocardial energetic impairment that exists across the spectrum of diastolic dysfunction and HFpEF phenotypes of increasing clinical severity and worsening diastolic function. And this gradient of impaired myocardial energetics was associated with progressively abnormal exercise responses compared to normal physiology in the age matched controls. And so a greater degree of energetic deficit was linked to impaired left ventricular systolic and diastolic functional reserve. It was also linked to altered right ventricular reserve and abnormal RV-PA coupling and also to exercise induced pulmonary congestion.

Dr. Matthew Burrage:

And we also showed that the pulmonary congestion or changes in lung water could be quantitatively assessed using our new proton density lung imaging sequence and that there is a subgroup of patients with HFpEF who do demonstrate transient pulmonary congestion during exercise that we can assess noninvasively. Overall, the findings suggest a pathway where impaired energetics are linked to patient symptoms and they do this by limiting cardiac reserve during exercise and promoting pulmonary congestion. There seems to be a really important role of resting cardiac energetics in signaling the abnormal ability of the heart to perform high energy consuming processes like active diastolic relaxation and augmentation of contractility and then this leads of course to the downstream effects that we see.

Dr. Greg Hundley:

Very nice. And you were able to even also observe the lung water. It sounds like, help us put this in context for our listeners of how do your results really advance some of the understanding of the pathophysiology of heart failure with preserved ejection fraction?

Dr. Matthew Burrage:

I think one of the key impacts of this study is the fact that the heterogeneity of clinical HFpEF syndromes has been such a major challenge to efforts to develop new therapies to improve symptoms and prognosis in these patients. Pathophysiological phenotyping may represent an important step towards targeting the right therapies to the right patients and specifically targeting myocardial energy metabolism may be a promising therapeutic strategy to improve cardiac reserve and potentially reduce pulmonary congestion in patients with HFpEF. And this really builds on all the translational studies that exist today and have gone before it.

Dr. Matthew Burrage:

Hopefully the mechanistic insights that we get from this could lead to some new translational drug targets, which can be tested against myocardial energetics in patients to see if this metabolic substrate is modifiable. And if this then leads to improvements in symptoms and outcomes. The second aspect very quickly, relates to the evaluation of patients with breathlessness, particularly because invasive hemodynamic assessments may not be possible in all patients who have breathlessness on exertion. The lung water imaging represents a potentially new diagnostic tool that can help to differentiate HFpEF from other causes of dyspnea and I think this is some something that may have a lot of direct clinical applications for patient diagnostics for a wide range of conditions in future.

Dr. Greg Hundley:

Very nice. Well, thanks so much for what outstanding work, identifying this myocardial energetic deficit and then linking that to both cardiac performance, as well as the development of pulmonary congestion.

Dr. Greg Hundley:

Well listeners, we are going to switch to our third author today, Dr. Shaan Khurshid from Mass General and Shaan was a finalist for the Samuel A. Levine Early Career Investigator Award. And so, Shaan, can you give us a little bit of the background information pertaining to your study? And what was the hypothesis that you wanted to address?

Dr. Shaan Khurshid:

Thanks for having me, it's a pleasure to be here. A little bit of background that predicting the risk of atrial fibrillation or AF, may increase the efficiency of AF screening and effectively prioritize individuals for preventive interventions that are designed to reduce the risk of incident AF in the first place. And to that end, risk of AF can be estimated with reasonable accuracy using clinical factors. We already know that. And for example, the CHARGE-AF score is a well validated score that been used in multiple settings. More recently, work suggests that artificial intelligence or AI enabled analysis of the 12 lead electrocardiogram can extract latent information that may be relevant for predicting AF risk. Past models however, have had some limitations. They've utilized very short time intervals. They have not incorporated survival time and censoring with is important for prognostic models. They are kind of a black box and therefore difficult to interpret and they haven't undergone a broad external validation.

Dr. Shaan Khurshid:

Therefore, in this current study, we sought to develop a deep learning model, utilizing the 12-lead ECG to predict risk of incident AF at five years. We call this model ECG-AI quote unquote and compared the performance of ECG-AI directly to the CHARGE-AF clinical risk score that I was mentioning. We also sought to assess a model that combines both ECG-AI and CHARGE-AF to each score alone. We hypothesized that the ECG-AI model utilizing 12-lead ECG could improve the ability to predict five year AF risk as compared to clinical risk factors alone. And we felt that such a model may have practical applications, particularly since wearable devices like smart watches are increasingly able to provide single lead ECGs.

Dr. Greg Hundley:

Really nice. Sounds like a very interesting application of artificial intelligence with electrocardiograms in assessing patients with atrial fibrillation. Can you describe for us your study population and your study design?

Dr. Shaan Khurshid:

Of course. We trained our models utilizing a retrospective cohort. The training population was 45,000 individuals receiving regular primary care at Massachusetts General Hospital or MGH. We then validated our models in three completely independent samples, an MGH internal test set, so individuals from MGH but were not included in training, a separate set of primary care patients at Brigham and Women's Hospital and the UK Biobank Prospective Cohort Study in the UK. The total population in which the models were validated was over 83,000. ECG-AI itself was trained as a convolutional neural network, which was inputted with 10 seconds of the 12-lead ECG and utilized a specialized loss in encoding function that incorporated survival time and censoring in order to produce a five year risk estimate for each individual. We trained models utilizing all ECGs available for each person but evaluated the models utilizing a single ECG alone. We compared each model, ie. ECG-AI, CH-AI and CHARGE-AF by incorporating risk estimates into analogous Cox proportional hazards model so we could compare them apples to apples and calculated traditional epidemiologic metrics of prognostic model performance, including discrimination, calibration and reclassification.

Dr. Greg Hundley:

Very nice. And so what did you find, John?

Dr. Shaan Khurshid:

From our study, we had two major findings. First, the ECG-AI model consistently discriminated five year AF risk comparably to the CHARGE-AF 11 component clinical risk score with C statistics ranging from 0.7 to 0.8. Second, the CH-AI model, which was the combination of ECG-AI and CHARGE-AF, consistently offered greater discrimination than either model alone. Both AI models were very well calibrated across the three test sets with calibration error consistently less than 1%. The ECG-AI and CHARGE-AF scores were moderately correlated, suggesting that the AI model is able to leverage clinical risk factor information extracted from the ECG, yet also adds something further.

Dr. Shaan Khurshid:

Saliency analyses, which are a method of determining which areas of the ECG are most relevant for the model's prediction, highlighted the P-wave and surrounding regions, which provides important evidence of biologic plausibility in our models. Importantly, in sub-analyses assessing the AI models, including only one lead of the 12-lead ECG, we found that model performance was similar, suggesting that AI models utilizing only single lead ECGs may also be effective. We also found that the models performed reasonably well in individuals with prevalent heart failure and stroke, which are populations in whom AF risk destination is particularly relevant.

Dr. Greg Hundley:

Very nice. And so clinically, moving forward, how do we put your results in the context of really where you see this field moving and how we might use it to identify patients at risk of atrial fibrillation?

Dr. Shaan Khurshid:

We're excited. Our work we think provides an important demonstration that ECG-AI based models can utilize a 12-lead ECG to estimate future risk of AF up to five years. And importantly, the AI models were generalizable, providing good discrimination across three large and independent datasets spanning two continents. We're most excited about this finding that models perform well when utilizing single lead ECG data alone, which has important ramifications for wearable devices. In particular, one could imagine a future application of AI in which a wearable device is able to not only be used to screen for atrial fibrillation or AF, but also stratify an individual's risk for AF utilizing ECG based analysis and therefore potentially prioritizing that individual for preventive interventions and also potentially determining how intensely to screen that individual all in a single closed group.

Dr. Greg Hundley:

Excellent. Wow, Shaan, just beautiful presentation, listeners. Really discussing how the artificial intelligence assessment of these EKGs may enable efficient quantification of the future risk of developing atrial fibrillation.

Dr. Greg Hundley:

Well listeners, we're going to turn now to our fourth presenter, Maryam Zekavat from the Bird Institute, Yale University. And Maryam was a finalist for the Genomic and Precision Medicine Council's Early Career Investigator Award. Welcome Maryam. And can you describe for us some of the background pertaining to your study? And what was the hypothesis you wanted to address?

Dr. (Sevedeh)Maryam Zekavat:

Absolutely. And thank you for the invite to be part of this podcast. The title of the work that we presented and that was published in Circulation is Deep Learning of the Retina Enables Phenome and Genome-wide Analyses of the Microvasculature. And so as a little bit of a background, we know that the microvasculature has key roles in maintenance of organ health and that microvascular disease is implicated in conditions across all organ systems. Here, to study the human microvasculature noninvasively, we used data across about a 100,000 retinal fundus photographs. And the purpose of our work was really to address two main things.

Dr. (Sevedeh)Maryam Zekavat:

First, an unbiased assessment of the phenotypes associated with the retinal microvasculature had yet to be performed and that motivated us to ask our first question, namely, what information can the retinal vasculature provide on future ocular and systemic disease risk? And then secondly, therapies such as anti-VEGF, which pharmacologically influence vascular density, are the mainstay of treatment for multiple ocular conditions, including wet AMD, proliferative diabetic retinopathy, as well as many cancers. However, an unbiased screen of genetic targets for other treatments that may influence the microvascular has yet to be performed. And so that motivated us to ask for our second question, namely, what genes influence the retinal vasculature? And so from there, I'll go to our hypothesis, which was that analyses of retinal fundus photos may enable an understanding of the connection between microvascular geometric indices, diseases and genetics.

Dr. Greg Hundley:

Very nice. And so boy, I heard you had almost a 100,000 participants involved in this study. Tell us a little bit about your study design and clarify for us, where did you get all these patients from? What was your study population?

Dr. (Sevedeh)Maryam Zekavat:

Yeah, of course. The study list we utilized the UK Biobank, which is a cohort of half a million individuals, including over a 100,000 fundus photographs from about 50,000 individuals. We first implemented deep learning to remove poor quality images and then to segment out the vasculature fundus photos. And then from there, we went on to quantify two vascular features, branching complexity as measured using fractal dimension and also vascular density. And lastly, we performed phenome and genome-wide association studies to understand how these vascular geometric indices influenced disease risk and what genetic factors influence the vasculature.

Dr. Greg Hundley:

Excellent. And tell us, what did you find?

Dr. (Sevedeh)Maryam Zekavat:

Yeah. First using deep learning, we were able to successfully perform image quality control and vessel segmentation to extract two geometric features of the retinal vasculature. Next through phenome-wide analyses, we identified that lower retinal vascular fractal dimension and density were significantly associated with higher risk for incident mortality, as well as cardiometabolic conditions, including hypertension and type 2 diabetes, heart failure and renal failure among others. And also multiple incident ocular conditions, including future risk of retinal detachment. Thirdly, genome-wide association of these two geometric indices identified seven and 13 novel loci associated with vascular fractal dimension and vascular density respectively. And these were enriched in pathways linked to angiogenesis, such as VEGF, angiopoietin and WNT signaling pathways, as well as inflammation via interleukin and cytokine signaling. And then fourth, through Mendelian randomization for genetic causal inference analysis, we identified that a genetic risk for hypertension and type 2 diabetes is associated with lower microvascular density and that a genetic risk for lower microvascular density is associated with increased risk of retinal detachment.

Dr. Greg Hundley:

Wow. Really interesting. The intersection of this beautiful phenotype characterization of the retina with this genetic information. Where do you see this research moving forward in the future?

Dr. (Sevedeh)Maryam Zekavat:

Yeah, so clinically these findings may support the use of retinal microvascular indices for risk prediction and disease monitoring of systemic and ocular conditions. And of course, further assessment of the identified biological pathways influencing the microvasculature can potentially lead to therapies for not only retinopathies but also other conditions linked to microvascular disease, including oncologic, renal and cardiovascular conditions. And more broadly, our results illustrate the potential for using deep learning on retinal imaging to understand the microvasculature with wide applications across diseases. And of course, more research is needed to evaluate the added benefit, in addition to existing clinical predictors and the feasibility for incorporation into clinical workflows.

Dr. Greg Hundley:

Just beautiful. And thank you so much Maryam and for highlighting for us, the results of your study, indicating that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights on genes and biological pathways that influence microvascular indices.

Dr. Greg Hundley:

Well listeners, now we are going to turn to our last speaker today and it's Dr. Neel Butala from Mass General, Beth Israel. And he also was a finalist for the Samuel A. Levine Early Career Investigator Award. Welcome, Neel. And could you describe for us the background pertaining to your study and what hypothesis did you want to address?

Dr. Neel Butala:

I appreciate the opportunity to be here and chat with you. And so there's conflicting evidence on the optimal duration of dual anti-platelet therapy, which is DAPT, after drug eluting stent implantation. Older studies, such as the DAPT study show fewer ischemic events with more bleeding, with longer DAPT duration and our site and the guidelines for DAPT duration after PCI but newer studies show similar ischemic events and actually less bleeding with shorter DAPT, even among those with high ischemic risk at baseline. We wondered whether the DAPT study, which is the only study powered to detect ischemic endpoints and still influences a major cardiovascular guidelines still applies to contemporary practice.

Dr. Neel Butala:

And so we asked two key questions. Now, number one is a US contemporary real world population of patients receiving PCI, different from the DAPT trial population. And again, the DAPT trial enrolled between 2009 and 2011. And here we hypothesized that the populations are probably a little different. And number two, we asked how would trial treatment effects change if a real world population had been enrolled instead? And here we hypothesized that perhaps the ischemic benefit of longer DAPT would actually go away, would be similar to the newer trials that have been done.

Dr. Greg Hundley:

Very nice. And describe for us your study design and your study population.

Dr. Neel Butala:

Yeah. We compared characteristics between DAPT study patients, with those of a more contemporary real world cohort of NCDR cath PCI registry patients. And to do this, we used novel transportability methods to really create a propensity score model to predict an individual's likelihood of trial participation based on patient characteristics. And this type of propensity score model actually gives us inverse probability weights, which we used to reweight the DAPT study patients based on the distribution of characteristics in the real world patients. The intuition here is really to up weight the trial patients with characteristics more common in the real world and down weight trial patients with characteristics less common in the real world. We then compared treatment effects in the DAPT study patients with those of the reweighted DAPT study patients to understand whether DAPT study results would change if a real world population had been enrolled instead.

Dr. Greg Hundley:

Very nice. And what were the results associated with these comparisons?

Dr. Neel Butala:

First, we found that trial and real world populations were different. We found that the contemporary real world population was older, less likely to be White, more likely to have comorbidities and then more likely to present with ACS. Additionally, nearly a 100% of real world patients received a second generation drug eluting stent versus only 58% of trial patients. And then these differences led to differences in the estimated average treatment effects of DAPT, to the results of the DAPT study. And the real world treatment effect in reducing ischemic endpoints is actually no longer present but the increase in bleeding persisted. And so we found that the average top line treatment effect in the DAPT study may not be applicable to contemporary practice. We did find however, the DAPT score in the subgroup did still identify subsets of patients who may benefit from prolonged DAPT beyond one year after PCI in the contemporary population.

Dr. Greg Hundley:

Very nice. And so clinically as we're managing patients, how would we interpret your results and help us with clinical management today?

Dr. Neel Butala:

Yeah, great question. These results really harmonize the DAPT trial with results of newer clinical trials of DAPT duration, which all demonstrate the safety of shorter duration DAPT to reduce bleeding risk and these results more broadly illustrate the importance, the nuance interpretation of clinical trials to guide clinical decision making and really highlight the risk of simply applying the top line trial results to all patients in contemporary practice, even beyond the study. These results emphasize the importance of accounting for patient specific factors and leveraging risk scores when available in deciding how clinical trials results actually apply to a particular patient. And finally, the results actually illustrate the importance of continually evaluating the generalizability of cardiovascular trials to ensure that the guidelines reflect treatment effects in contemporary clinical practice. And the methods that we use in the study can actually be used to do this in RCTs more broadly.

Dr. Greg Hundley:

Very nice, Neel. And thank you for really bringing us this study highlighting the differences between patients and devices used in contemporary clinical practice compared with those in the DAPT study. And how they were associated with attenuation of benefits and greater harms attributable to prolonged DAPT duration.

Dr. Greg Hundley:

Well listeners, what an exciting day. Getting to see these papers in print and also have these early stage investigators from the 2021 sessions that were finalists in many of these competitions, we're so grateful to Amgad Mentias, Matt Burrage, Shaan Khurshid, Maryam Zekavat and Neel Butala for their time today.

Dr. Greg Hundley:

On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation January 4, 2022 Issue

3 januari 2022 | 27 min

Please join author George Dangas and Associate Editor Brendan Everett as they discuss the article “Colchicine in Cardiovascular Disease.”

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley: Welcome, everyone, to 2022. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, oh, we're starting off the year with a twist on the feature article. It's a review article on colchicine and cardiovascular disease.

But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue?

Dr. Carolyn Lam: Absolutely. The new year is starting off with a bonanza issue. This first topic is so important. We know that various non-invasive, intermittent rhythm monitoring strategies have been used to assess arrhythmia recurrences in atrial fibrillation ablation trials. But the question is, what is the frequency and duration of non-invasive rhythm monitoring that accurately detects arrhythmia recurrences and approximates the atrial fibrillation burden derived from continuous monitoring using the gold standard, implantable cardiac monitor?

Now to answer this question, investigators Jason Andrade and colleagues from the Montreal Heart Institute, who looked at the rhythm history in 346 patients enrolled in the CIRCA-DOSE trial. They reconstructed the rhythm history using computer simulations and evaluated event-free survivals, sensitivity, negative predictive value, and AF burden in a range of non-invasive monitoring strategies including those used in contemporary AF ablation trials.

Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they find?

Dr. Carolyn Lam: Detection of arrhythmia recurrence following ablation was highly sensitive to the monitoring strategy employed between trial discrepancies and outcomes, in fact, may reflect these different monitoring protocols. Binary efficacy outcomes, such as time to AF recurrence, appeared to underestimate the true impact of catheter ablation on the burden of atrial arrhythmia.

The most commonly performed intermittent rhythm monitoring techniques, like short duration 24- or 48-hour ambulatory Holter, they do miss a substantial proportion of arrhythmia recurrences and significantly overestimate the true AF burden in patients with recurrences. So based on measures of agreement, serial long-term, that is four seven-day or two 14-day intermittent monitors accumulating at least 28 days of annual monitoring provide estimates of AF burden that are comparable with the implantable cardiac monitor.

However, implantable cardiac monitors outperform intermittent monitoring for arrhythmias and should be considered the gold standard for clinical trials.

Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of clarification on monitoring of AF burden. Well, my first paper comes to us from Dr. Prabhakara Nagareddy from The Ohio State University, The Wexner Medical Center.

Carolyn, acute myocardial infarction results in an overzealous production and infiltration of neutrophils in the ischemic heart, and this is mediated in part by granulopoiesis induced by the S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed neutrophils.

In this study, Carolyn, the investigators evaluated a hypothesis as to whether IL-1 beta is released locally within the bone marrow by inflammasome prime and reverse migrating neutrophils.

Dr. Carolyn Lam: Ah, okay. So what did they find, Greg?

Dr. Greg Hundley: Okay, Carolyn. In response to myocardial infarction, the NLRP3 inflammasome prime neutrophils upregulated CXCR4 and reverse migrated to the bone marrow, where they adhered to adhesion molecules like P-selectin on the bone marrow endothelial cells.

Second, Carolyn, in the bone marrow, the inflammasome prime neutrophils released IL-1 beta through gasdermin-dependent conduit pores without undergoing the mandatory pyroptosis.

Third, genetic and/or pharmacological strategies aimed at limiting reverse migration of inflammasome prime neutrophils to the bone marrow or release of IL-1 beta, both suppressed granulopoiesis and improved cardiac function in mouse models of myocardial infarction.

So Carolyn, therefore, strategies aimed at targeting specific signaling pathways within the neutrophils or reducing retention of the inflammasome prime neutrophils in the bone marrow may provide novel avenues to regulate inflammation and improve cardiac outcomes.

Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so nicely. Well, the next paper deals with my favorite topic, heart failure with preserved ejection fraction of HFpEF, and this time looks at mechanisms of sinoatrial node dysfunction.

The investigators, led by Dr. Cingolani from Smidt Heart Institute at Cedars-Sinai Medical Center, sought to investigate the role of the intrinsic pacemaker on chronotropic incompetence in HFpEF. They performed extensive sinoatrial node phenotyping, both at baseline and after stress in the well-characterized Dahl salt-sensitive rat model of HFpEF.

These rats exhibited limited chronotropic response associated with intrinsic sinoatrial node dysfunction, including impaired beta-adrenergic responsiveness and an alternating leading pacemaker within the sinoatrial node. Prolonged sinoatrial node recovery time and reduced sinoatrial node sensitivity to isoproterenol were confirmed in the two hit mouse model. Adenosine challenge unmasked conduction blocks within the sinoatrial node, which were associated with structural remodeling.

Finally, single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the membrane clock or iron channels and the calcium clock of the spontaneous calcium release events.

Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data here. So what were the clinical implications?

Dr. Carolyn Lam: Yeah, it's a really great study. Two models of HFpEF-consistent result in an important topic. Basically, here at the take-home messages. Provocative testing can be valuable to elicit functional abnormalities to facilitate HFpEF diagnosis and considering the exceptionally high clinical and epidemiologic convergence between AFib and HFpEF, sinoatrial node dysfunction may underlie the development of abnormal atrial rhythms in HFpEF.

Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF, again, one of your favorite subjects. Next, we're going to turn to a paper from Dr. Jian Li from the Peking Union Medical College Hospital. Carolyn, doxycycline has previously been demonstrated in a retrospective study to be associated with greater survival in patients with light chain AL amyloidosis.

Therefore, Carolyn, this group prospectively compared the efficacy of bortezomib, cyclophosphamide, dexamethasone, or cyclophosphamide B or D, and cyclophosphamide B or D combined with doxycycline for cardiac amyloidosis.

Dr. Carolyn Lam: Cool. So what did they find, Greg?

Dr. Greg Hundley: Carolyn, this was a multi-center, open-label, randomized controlled trial, and 140 patients underwent randomization. The primary outcome was two-year progression-free survival. Progression-free survival was defined as the time from randomization to death, hematologic progression or organ progression, and that's the heart, the kidney, or the liver.

And so Carolyn, these investigators in this trial demonstrated that doxycycline combined with cyclophosphamide B or D failed to prolong progression-free survival or cardiac progression-free survival compared with cyclophosphamide B or D alone in patients with cardiac AL amyloidosis.

So Carolyn, a negative study that's quite informative and a very nice editorial that accompanies this article pertaining to future directions for management of AL cardiac amyloid.

Dr. Carolyn Lam: Indeed important. Thank you. And there are other important papers in today's issue. There's a Research Letter by Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial.

Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got a big list today. First, Dr. Churchwell has an AHA update on the need for policy change to improve maternal cardiovascular health. Next, Dr. Piazza has a Perspective piece on expanding the role of coronary CT angiography in interventional cardiology. There's an ECG challenge from Dr. Yarmohammadi entitled “Dancing Bundles with Stable Sinus Rhythm.” And next, we have our own Darren McGuire who, in this issue for all of 2021, is really recognizing our outstanding reviewers.

And we want to thank all the listeners and everyone that reviews for us in this journal. Such an important feature and aspect to the publication of the wonderful articles that we receive. And then finally, there are some highlights from the circulation family of journals. Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and its use in cardiovascular disease.

Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone.

Dr. Greg Hundley: Welcome listeners to this January 4th feature discussion. This week, we're deviating a little bit because we are going to have an author discuss one of our in-depth reviews. As you know, we select those occasionally where they're is a topic that's very relevant in cardiovascular medicine and an investigator or team of investigators or authors will put together a very nice review of a topic.

This week, we're going to talk about colchicine, and we have with us Dr. George Dangas from the Icahn School of Medicine at Mount Sinai and our associate editor, Dr. Brendan Everett, who manages this paper and he is from Brigham and Women's Hospital. Welcome, gentlemen. George, we'll start with you. George, why colchicine? Can you tell us a little bit about mechanism of action? Tolerability? Why would we want to use this particular agent in patients with cardiovascular disease?

Dr. George Dangas: Thank you very much for the opportunity to join this interesting podcast. Colchicine is indeed an interesting drug. It's been around for centuries, in all honesty. In general, I would say it's a mild anti-inflammatory and in general, it's rather well tolerated. We'll go into those perhaps a little bit later.

The precise mechanism is actually interestingly not quite defined. It may have a few ways to act by blocking perhaps the chemotaxis of the leukocytes or the adhesion of the leukocytes or the ability to release their granules, et cetera, but there isn't a specific major one that is targeting. Perhaps, it's targeting more than one mechanism in a mild way, and I think that goes into each utility, as well as the absence of the major side effect that might limit it.

Dr. Greg Hundley: Very nice. So you started to mention the word utility, so maybe let's go through some clinical indications, or clinical uses perhaps rather than indications, can you tell us a little bit about its use in individuals with pericarditis?

Dr. George Dangas: I think this is where it started to enter the cardiovascular field because we all recognize that pericarditis is an inflammatory disease and inflammation of the pericardium of different reasons perhaps. And anti-inflammatory drug is rather fitted to treat an inflammatory disease and besides, it's not like we had any other drug, in all honesty. Clearly, recurrent pericarditis might be treated with steroids for example, but steroids is not something any cardiologist would jump as a first line and give high doses and all that.

Colchicine made its way to pericarditis like acute or recurrent pericarditis, post-cardiac cardiology syndrome, restless syndrome or the specific post-cardiac surgery, major inflammation. And indeed has a daily dosage perhaps with some loading dose or double the daily dosage or something initially and then we give it for a prolonged period of time in order to suppress.

I would say this is a reasonable choice rather than jumping to the steroid. And of course, you reserve the steroid for the, I would say, more severe or more recurrent cases. I think everybody understands this type of activity. There've been quite a few clinical studies in this aspect. Again, in the absence of a competitor, I think it's a winner in this area.

Dr. Greg Hundley: Very nice. And then, how about atrial fibrillation? Are there uses of this colchicine in patients with atrial fibrillation?

Dr. George Dangas: Well, again, it's very interesting that a lot of atrial fibrillation, it may be in some ways inflammatory in origin. And quite frankly, we had an interesting [inaudible 00:14:50] clinical trial in American Heart Association in 2021. I'd like to point out here, the study that postoperative atrial fibrillation was mitigated when, during cardiac surgery, there was a slicing of the posterior pericardial. This allowing the inflammation in some ways that's related there.

To me, that was a very interesting observation, though I related to colchicine because it validates the fact that there is something inflammatory in pericardial that related with the postoperative atrial fibrillation. So along these lines, let's go back to colchicine, Afib, and postop Afib, and post-ablation I would say patients. Again, there are risks of some inflammation and that's where the theory of a mild, rather well-tolerated, anti-inflammatory might come in. And there's been few studies, not a large definitive study, but several studies that are the, I would say, component with interesting results with colchicine in these patients.

Dr. Greg Hundley: Very good. Another area of cardiovascular disease that's emerging literally with some demonstrable results using colchicine is the realm of ischemic heart disease. Can you walk us through some of the utility myocardial infarction or maybe even post-percutaneous coronary artery intervention?

Dr. George Dangas: Again, the hallmark in this type of diseases, cardiovascular disease or coronary heart disease, is the hallmark of role of inflammation in this disease. And we know very well from the studies of the C-reactive protein, importance is a marker of inflammation. Very, very important in the CAD as well as in even the treatment with the antibody canakinumab a little bit earlier in the CANTOS trial a few years earlier at the very high level inhibited inflammation had a benefit and colchicine comes in maybe a milder anti-inflammatory about this agent, but at the same time with significantly less cause and significantly better recognition among the clinicians and a lot less, I would say, tolerability problems or issues are less unknowns. And I think that's where it comes in.

The difficulty has been that whenever you go to cardiovascular, the cardiovascular, I would say coronary artery disease specifically, ACS and all that, the level evidence required for the doctors to believe in a therapy is very different than the areas we discussed before where there's little bit of a pericardial disease, for example, not that many drugs, all of a sudden, coronary artery disease, the bar is so high, and that's where the difficulty has been.

There've been several studies. They've been interesting results with some benefits, particularly due to the decrease in inflammation and the secondary prevention, one can say. That is really the hallmark of where it aims to benefit in the secondary prevention, but there hasn't been one massive study with clearly superb results. I would say adequately powered single study that is missing in some ways.

But several studies have been, again, very, very encouraging, but we learned that there's no much point if loading a lot of doses of high doses of colchicine, and it's a little bit better, again, when you aim with a daily dose towards reduced recurrences, particularly if you started early after an acute event.

Dr. Greg Hundley: Very nice. Well, listeners, we're going to now turn to our associate editor, Dr. Brendan Everett, from Brigham and Women's Hospital. Brendan, you have a lot of papers come across your desk. First and foremost, what attracted you to this particular article?

Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and his team for putting together a really nice paper. It's great to have this kind of paper come into my inbox. That's specifically because colchicine, I think, has exploded as a really important novel therapy even though the therapy itself is perhaps hundreds of years old, as you heard George say a moment ago, but its role in treating cardiovascular diseases has really begun to emerge rapidly.

I think there's a tremendous amount of enthusiasm for other ways to treat our patients who have really a recalcitrant cardiovascular disease, whether that's pericarditis, atrial fibrillation or I think, importantly, ischemic heart disease, because that's such a common disease and something where we're always looking for new ways to help patients live longer with fewer recurrent events. And so this paper I thought did a really good job of capturing the existing evidence for these conditions and some others and giving us a sense of where the strengths of that evidence lay and where the weaknesses were.

I thought particular strength was in the tables where the authors laid out each of the trials and the results of the trial, their endpoints, where the benefit was potentially. And also importantly, where risks were seen because I think that's one of the really important questions that remains open with respect to colchicine therapy when we begin to talk about using it in a vast population of people with stable ischemic heart disease or post-myocardial infarction ischemic heart disease.

Dr. Greg Hundley: Brendan, tell us a little bit about those risks.

Dr. Brendan Everett: I'd be happy to do that. I want to emphasize before I dive in that I think the benefits that George has laid out are important, and I don't want to overshadow what the major trials have seen. But I think the thing that it is at least a little bit of the fly in the ointment, if you will, for colchicine in ischemic heart disease is that a couple of the large trials have shown an increased risk of non cardiovascular mortality or bad non-cardiovascular outcomes.

And that's of concern, I think, as we saw in the CANTOS trial, which was the monoclonal antibody trial for canakinumab that George mentioned earlier, there was an increase in infection-related mortality. And so whenever you use an anti-inflammatory drug, you're worried about whether or not you're blunting other compensatory mechanisms that the body has to protect against infection and other diseases.

I think it's likely that these findings are the play of chance, but we don't know for sure. For example, in the COLCOT trial, which I think is probably the largest and most interesting trial, which was designed and run in Canada, there was a slightly higher level of pneumonia in patients who got active therapy as compared to placebo.

And then, two of the trials that were published more recently including LoDoCo2, which was a trial of about 5,000 patients run in the Netherlands and Australia. There was actually a marginally increased risk of non-cardiovascular mortality. That didn't reach statistical significance, but it was awfully close, and I think it gave people some concern.

And then, there was also the COPS trial. Again, all these are really outlined in wonderful detail in the manuscript where there was a slight increase of total death and non-cardiovascular death. These events are few, but they're in a direction in two trials, and so they make people a little bit worried. I think the other thing that I noticed was the high prevalence of myalgia as a side effect.

I think, Greg, you're always interested in the clinical implications and yesterday I was in clinic and saw a young patient who had had pericarditis. He had been prescribed colchicine by his primary care physician, and he literally couldn't stand and walk up straight because of the amount of abdominal pain he had, which was unusual. To be honest, I've given colchicine to a hundred patients at least, and none of them have had that profound of a side effect, but it's at least worth considering that some patients will not tolerate the therapy because of adverse effects.

Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for each of you, first George and then Brendan. George, balancing some of the efficacy and then some of the concerns, what do you see is the next studies to be performed really in this sphere of research?

Dr. George Dangas: This is a great question. And indeed, the concerns one can say or the issues, I would say, regarding this drug, are indeed real because any drug that suppresses inflammation has this risk. There are two ways one can address those. One is with term administration. You don't prescribe it as an annuity forever, but you prescribe it in a three- to six-month or one-month or try to control the time. I think this is done in clinical practice, in all honesty.

I don't think that people are prescribing colchicine for life. Same way when we prescribe statins, for example. On the other hand or from investigational point of view, I think the two sets of information we need and, in all honesty, when you investigate issues regarding mortality or these are rare events, there's only one. You need a very large trial or a very large register. A very large trial preferably and colchicine being an often genetic drug, funding sources are rather limited, but we have NIH chipping in with some funding periodically and that might really be needed.

So I want to outline that in the last table of our very large, I would say large table of our manuscript but were very happily outlined many ongoing trials. There are, in atrial fibrillation, three coronary artery disease. One in PCI and two in stroke. Something we didn't touch up again. But again, there's the question of inflammation in stroke. I think there's a lot of work ongoing. Perhaps you can see some meta-analysis, again, in order to get a handle of those risks, but at a rather low rate. It's just a difficult thing to come around.

Dr. Greg Hundley: Very good. Brendan, anything to add?

Dr. Brendan Everett: I would just add I agree a hundred percent with George just said. I think the only missing piece there is heart failure, which I think is and many have shown that there's an inflammatory component to heart failure, whether it's heart failure with reduced ejection fraction or preserved ejection fraction.

And the timing of when that intervention might be, whether it might be before the development of symptoms or because there's a lot of trials out there that have struggled with this question and have unfortunately failed to show any benefit, I would just encourage the listeners of the podcast to look at this paper because it's a really marvelous compilation of the evidence for what is a really hot topic in cardiovascular medicine, a really important topic for a lot of the reasons that George mentioned. It's just very well done and comprehensive.

Again, kudos to the authors for making such a great effort at putting something together that has a lot of clinical relevance, I think, and also points the way forward for research as you ask, Greg.

Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. George Dangas from Icahn School of Medicine in Mount Sinai and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital for bringing us this data pertaining to colchicine benefits, as we know in acute and recurrent pericarditis, but also emerging indications related to post-procedural atrial fibrillation or coronary artery disease. And really, colchicine's targeting of cardiovascular inflammation is being helpful in those alleviating those processes.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley: This program, this copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Circulation December 28, 2021 Special

27 december 2021 | 28 min

In this week’s edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation.

Dr. Amit Khera:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do.

Dr. Amit Khera:

And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself.

Dr. Vanessa Blumer:

Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US.

Dr. Vanessa Blumer:

I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure.

Dr. Amit Khera:

Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself.

Dr. Pishoy Gouda:

Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training.

Dr. Pishoy Gouda:

Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome.

Dr. Amit Khera:

Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome.

Dr. Xiaoming (Ming) Jia:

Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology.

Dr. Amit Khera:

Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome.

Dr. Peder Langeland Myhre:

Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago.

Dr. Amit Khera:

Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please.

Dr. Sonia Shah:

Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now.

Dr. Amit Khera:

Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works.

Dr. Amit Khera:

And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing?

Dr. Vanessa Blumer:

Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media.

Dr. Vanessa Blumer:

So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way.

Dr. Amit Khera:

Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research.

Dr. Xiaoming (Ming) Jia:

Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts.

Dr. Amit Khera:

Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art.

Dr. Amit Khera:

And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet?

Dr. Pishoy Gouda:

Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content.

Dr. Pishoy Gouda:

So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future.

Dr. Amit Khera:

Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both.

Dr. Amit Khera:

And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians.

Dr. Peder Langeland Myhre:

Yes. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most.

Dr. Amit Khera:

Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all.

Dr. Amit Khera:

Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space?

Dr. Sonia Shah:

Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals.

Dr. Amit Khera:

Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months?

Dr. Xiaoming (Ming) Jia:

I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well.

Dr. Amit Khera:

We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes.

Dr. Amit Khera:

Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it.

Dr. Peder Langeland Myhre:

Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing.

Dr. Peder Langeland Myhre:

So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family.

Dr. Amit Khera:

Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media?

Dr. Pishoy Gouda:

Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me.

Dr. Amit Khera:

Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore.

Dr. Amit Khera:

So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit.

Dr. Vanessa Blumer:

Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out.

Dr. Vanessa Blumer:

I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it.

Dr. Amit Khera:

Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so.

Dr. Sonia Shah:

Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved.

Dr. Amit Khera:

Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal.

Dr. Amit Khera:

Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Circulation December 21, 2021 Issue

20 december 2021 | 22 min

Please join Guest Host and Associate Editor Mercedes Carnethon and author Christine Albert as they discuss the article "Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is such an important question clinically. It's something I've asked myself and so I cannot wait to discuss it in greater detail. It refers to the effect of long-term marine omega-3 fatty acid supplementation, and the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. So it talks about a systematic review and meta-analysis published in this week's issue.

Dr. Carolyn Lam:

All right. Okay. You got to wait in suspense, as do I, and let's discuss other papers, very important papers in today's issue too. I'd like to start with a bit of a quiz. So Greg, for converting atrial fibrillation, is the anterior-lateral or anterior posterior electrode position better? What's your guess?

Dr. Greg Hundley:

Oh, wow, Carolyn. That's interesting. We put these pads on and we kind of just follow the directions on whatever the particular device says. Interesting question. It's a guess, Carolyn, it's a guess. Antro-lateral?

Dr. Carolyn Lam:

Smarty pants. Well, let's see. Frankly I didn't know the answer. It's just such an elegant question, isn't it? To answer in a study. And this is exactly what Professor Løfgren from Randers University Hospital and Denmark and colleagues did. They performed a multi-center investigator initiated open label trial, where they randomly assigned 468 patients with atrial fibrillation scheduled for elective cardioversion to anterior-lateral versus anterior-posterior electrode position.

Dr. Carolyn Lam:

The primary outcome was the proportion of patients in sinus rhythm after the first shock. And so drum roll. The primary outcome occurred in 54% assigned to an anterior-lateral electrode position. And in 33% assigned to an anterior-posterior electrode position, a significant risk difference of 22% in favor of the anterior-lateral electrode position.

Dr. Carolyn Lam:

Cheers, Greg. There were no significant differences between groups in any safety outcomes and the superiority of the anterior-lateral electrode position was statistically significant both after the initial low energy shock and after a final high energy shock. So this study really suggests a practice change in the standard approach to electrode positioning for cardioversion in favor of anterior-lateral electrode position.

Dr. Greg Hundley:

Very nice, Carolyn. Very nice. Well, I'm going to come at you using your heart failure expertise and ask you a quiz here in just a second. But first I want to introduce this paper from Dr. Javier Barallobre-Barreiro from King's College London. Okay, Carolyn, here's your quiz. Do you think that the extracellular matrix fibrosis contributes to LV dysfunction in heart failure patients?

Dr. Carolyn Lam:

Absolutely.

Dr. Greg Hundley:

Very nice. I think, of course, you are correct. So Carolyn, remodeling of the extracellular matrix is a hallmark of heart failure and this team's previous analysis of the secretome of mirroring cardiac fibroblast returned ADAMTS5, a disintegrin and metalloproteinase with thrombospondin motifs 5 as one of the most abundant proteases. So ADAMTS5 cleaves chondroitin sulfate proteoglycans such as Versican. The contribution of ADAMTS5 and its substrate Versican to heart failure is unknown.

Dr. Carolyn Lam:

Ah, so what did the authors find, Greg?

Dr. Greg Hundley:

Well, first Carolyn, there was a methodologic advance here. Left ventricular tissues from 86 heart failure patients and non-failing controls were analyzed by quantitative mass spectrometry, constituting the largest proteomics analysis on human heart failure today. And so what did they find? Accumulation of proteoglycan Versican was regulated by ADAMTS5, that disintegrin and metalloproteinase with thrombospondin motifs 5, and was associated with the reduction in proteins involved in intercellular communication. And Carolyn, interestingly, proteoglycan accumulation in ischemic heart failure was attenuated by beta blocker administration.

Dr. Carolyn Lam:

Oh, that's very interesting. Could you put that all together for us? What's the clinical implications, Greg?

Dr. Greg Hundley:

You bet, Carolyn. So proteoglycan secretion by cardiac fibroblast constitutes an important component of cardiac fibrosis after ischemic heart failure, just like you stated at the beginning with your quiz answer. This contributes to impaired cardiac function and besides their negative chronotropic and inotropic effects, beta blockers may modulate extracellular matrix remodeling.

Dr. Carolyn Lam:

Wow, nice, Greg, thank you for that. I've got another original paper and it deals with the very important topic of endothelial to mesenchymal transition. Now it has been reported that cardiac endothelial cells contribute to a substantial proportion of myofibroblast through this process called endothelial to mesenchymal transition. Lineage tracing studies have demonstrated that myofibroblasts are derived from expansion of resident fibroblasts rather than from transdifferentiation from endothelial cells.

Dr. Carolyn Lam:

However, it remains unknown whether endothelial cells can transdifferentiate into myofibroblast reversibly or would these endothelial to mesenchymal transition genes just transiently activated in endothelial cells during cardiac fibrosis? So these authors, corresponding authors, Dr. Sun from Shanghai Jiao Tong University School of Medicine, Dr. Lui from Price of Wales Hospital and Chinese University of Hong Kong, as well as Dr. Zhou from the University of Chinese Academy of Sciences in Shanghai and their colleagues.

Dr. Carolyn Lam:

What they did is they used the dual recombination technology to generate a genetic lineage tracing system for tracking endothelial to mesenchymal transition in cardiac endothelial cells and their genetic fate mapping results basically showed that although mesenchymal gene expression was activated in cardiac endothelial cells throughout the endothelial to mesenchymal transition in the developing heart, the endothelial cells do not transdifferentiate into myofibroblasts, nor do they transiently express some known mesenchymal genes during homeostasis or fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblast by activating mesenchymal gene expressions are in fact the major contributors to cardiac fibrosis.

Dr. Greg Hundley:

Ah, Carolyn, very interesting. So can you put this together? What are the clinical implications?

Dr. Carolyn Lam:

So what it really says is that it's the resident fibroblasts that are converted to myofibroblast by activating mesenchymal genes. These are the ones that represent a major therapeutic target and really unraveling these mechanisms, driving endothelial to mesenchymal transition in such a detailed way, provided new insights into therapeutic development to target cardiac fibrosis.

Dr. Greg Hundley:

Wow, Carolyn. You know, two really good preclinical science articles speaking to us about myocardial fibrosis.

Dr. Carolyn Lam:

Well, there are other papers in today's issue too. There's a Perspective piece by Dr. Christopher Lamb on “Liver Cirrhosis and Hepatocellular Carcinoma After the Fontan Operation: Reaching Clarity in the Face of Uncertainty. And this is paired with a Research Letter by Dr. Toshio Nakanishi on incidents and expected probability of liver cirrhosis and hepatocellular carcinoma after the Fontan operation.

Dr. Greg Hundley:

Very nice, Carolyn, and I've got an “In the News” piece from Bridget Kuehn entitled “Centering Equity in Cardiovascular Care as Michelle Albert Lays Out a Roadmap for our Profession.” Well, Carolyn, how about we learn a little more about those long term marine omega-3 fatty acid supplementations and the risk of atrial fibrillation?

Dr. Christine Albert:

Oh, I can't wait. Let's go, Greg.

Dr. Mercedes Carnethon:

Thank you so much for joining us for today's episode of Circulation on the Run. My Lame is Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and Associate Editor at Circulation. And I have the great pleasure today of having a conversation with a long time friend, Dr. Christine Albert from the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles.

Dr. Mercedes Carnethon:

And today I've got the great pleasure of hearing directly from Christine about a wonderful original research piece that is being featured in Circulation about the effect of long term marine omega-3 fatty acid supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. And the exciting innovation of this piece that we'll dig into is what we're learning from the systematic review and meta-analysis that Dr. Albert and her team carried out. So, thank you so much for joining us today, Christine.

Dr. Christine Albert:

Well, thank you, Mercedes. It's really great to be here.

Dr. Mercedes Carnethon:

Great. Well, I'd just like to launch with you telling us a little bit about the study, what you found, why you decided to conduct this meta-analysis and review.

Dr. Christine Albert:

Yeah. Great. So my first author, Dr. Baris Gencer and I decided to do this because we actually had participated in a randomized trial called the Vital Rhythm Trial, where we actually randomized people to omega-3 fatty acids and atrial fibrillation, and found a slightly elevated risk, but it wasn't significant. And at that time, a number of other articles came out saying that there really was an increased risk of atrial fibrillation.

Dr. Christine Albert:

So we wanted to put together the data to see what the combined data, our data, that's been published before, on this sort of long term treatment with omega-3 fatty acids and atrial fibrillation. As you may know, there have been studies that have looked at short term treatment, and specifically for atrial fibrillation, and did not find benefit. So this is why we went ahead and did this study. And what we did is we were able to find seven randomized trials that collected data on atrial fibrillation that had randomized people to omega-3 fatty acids over an average of about five years of follow up between all the different trials. And we found that when you combine all these trials together, you actually see that there is a slightly elevated risk of atrial fibrillation in the participants that were randomized to the omega-3 fatty acids.

Dr. Mercedes Carnethon:

Thank you so much for that summary, Christine. I think the findings themselves surprised me. This is not my primary area of work, but we hear so much about supplements and their benefits that I thought it was really telling to actually have these data coming from a large number of studies, and particularly large studies that suggest that there is a risk to benefit ratio that we need to consider. How would you recommend that clinicians weigh this evidence that you've generated today?

Dr. Christine Albert:

So I think that it's got to be individualized. There are benefit, as you said, of these omega-3 fatty acids. And I think it's just awareness, awareness that this potentially is a risk. If you have a patient on omega-3 fatty acids and they start to have atrial fibrillation, there could be a link. Also when you talk about it with patients, I think it's reasonable, especially with the higher doses, we can just discuss that this is a potential side effect. Does it prevent you from using it? I don't think so. I think you have to look at what is, again, as you said, the risk benefit ratio for the individual patient. And as I alluded to, we did do a dose analysis and we found that the risk was primarily seen, and it was higher, in those that were given more than a gram of omega-3 fatty acid a day.

Dr. Christine Albert:

However, I will say that the trials are very different when you take a meta-analysis, it's really hard to say, "What is the cause of the differences between trials?" You know, these trials that had the higher dose, the reduce it trial that used just a purified EPA was very different than the dose of the medication that was used in vital, different than the type of medication that was used in strength. And as you know, there's the whole debate about the placebo and reduce it versus strength. And so there are other differences, but one thing that is pretty consistent is that most of the point estimates are on the side of harm. So there is the thought that I think this is potentially very real and we should be considering it when we use these supplements.

Dr. Mercedes Carnethon:

You know, that's a really nice summary which really launches me into two subsequent questions. The first would give you the opportunity to speculate beyond the findings in your particular study, and this is one of the benefits to me of this Circ on the Run podcast, because you, of course, produced excellent science and weighed all of your findings based on what you found. But can you tell me, based on your experience, could you speculate about what you think the mechanism of elevated risk of atrial fibrillation is, particularly with those higher doses?

Dr. Christine Albert:

Yeah, no, it's interesting. You know, if you look at the epidemiology for this, Mercedes, it was totally inconsistent. When I postulated doing the vital rhythm trial, I actually have to be honest with you, I thought that there might be an increased risk, because when you look at some of the data of what these omega-3 fatty acids do, they increase vegal tone, they lower heart rate. They can actually slow conduction. So potentially those electrophysiologic actions might, might allow atrial fibrillation to emerge in people who are susceptible.

Dr. Christine Albert:

On the flip side, all of those things might be good for ventricular arrhythmias. So you see, if you look at the literature, there's benefits for…sudden death and epidemiologic studies and in some of the randomized trials, but then when you look at atrial fibrillation, at least the short terms, really didn't show a benefit. And again, that point estimate was more towards harm.

Dr. Christine Albert:

And then when you look at epidemiologic studies, looking at fish consumption, there's actually a lot of studies that suggest that people who eat more fish get more AFib. So it is really paradoxical. And we know as electrophysiologist that atrial arrhythmias and ventricular arrhythmias are not the same, we give drugs to prevent atrial arrhythmias that then cause ventricular arrhythmias. So it is interesting. And I think it's something that hopefully some of our translational scientists will help us to figure out.

Dr. Mercedes Carnethon:

All those contradictions are so challenging, but you were certainly speaking my language in describing the hypothesized mechanisms. It calls to mind, back in the day, in your early research on sudden cardiac death that I was citing as part of my dissertation work in epidemiology. So thank you for that.

Dr. Christine Albert:

Yeah.

Dr. Mercedes Carnethon:

You know, the second question that builds off of that is I thought that the figure where you display the heterogeneity by the dosage of omega-3's really underscores the argument that you were just presenting. What I was wondering is, did you happen to study heterogeneity by any other characteristics, particularly sex or age?

Dr. Christine Albert:

That would be fantastic to be able to do, unfortunately, because it's a summary level meta-analysis, we really can't do that. And that's one of the things that we'd love to do in collaboration with some of these authors if they would like to do that, is to really get that sort of paid participant level data, so we could do those kinds of analysis.

Dr. Christine Albert:

But what we did do is sort of separate out studies that had like confirmed AF, studies that had incident AF versus recurrent AF, so things where the studies were completely different, we were able to look for heterogeneity and we didn't find anything that suggested that there was heterogeneity on that basis. But there's a number of things that I would love to look at and age is definitely one of them, and also sex. And actually looking at, which would be really interesting, is to look at the omega-3 or EPA and DHA levels in these individuals. And again, I think each study has sort of tried to do it on their own and you can't because there's just not enough data. So putting all this data together would be great to have a better understanding of what's going on.

Dr. Mercedes Carnethon:

Oh, it sounds speaks to a number really thoughtful future directions for this work. One of the benefits of me being able to speak with you today in my role as a guest podcast host, but I was also the Associate Editor for the piece and was really excited when it came in. The discussions that we had amongst the editors about this were really very stimulating and raised a number of questions that led to you responding and making some modifications and explaining certain things. Could you tell our audience, why did you select trials over a certain size? You know, quite often we do meta-analyses in order to pull together smaller studies, but why did you choose larger studies?

Dr. Christine Albert:

I think it was so that, there were two criterias, one was larger and one was long term, because we felt that the smaller studies had been merged together previously and we wanted to have at least some data on atrial fibrillation. One of the problems I think that I think I want to emphasize a little bit here about research in general in cardiovascular disease is that until now, most studies hadn't really measured atrial fibrillation, and I think it's really important. And I think you can see, you can find off target effects of some of the agents that we use for cardiovascular disease on atrial fibrillation. So for instance, the Statin Trials, everybody said, "Oh, well statins might lower atrial fibrillation," but then nobody measured atrial fibrillation, so we never knew. And then people went back and tried to measure it as a side effect or something that has all kinds of biases to it.

Dr. Christine Albert:

So I think that what is exciting about this work is that both reduce it and strength and vital, pre-specified that they were going to look at atrial fibrillation. And so if we do that, we may actually find other agents that are beneficial, not just harm, but beneficial, like the SGLT2 inhibitors, there's lots of hypotheses. So the reason that we did pick the bigger trials was that we wanted to find trials that really kind of looked at atrial fibrillation, had enough power to look at atrial fibrillation and then over a long term, a follow up to gather enough events.

Dr. Mercedes Carnethon:

Again, it has been such a pleasure to hear directly from you. I really hope that our listeners today and our readers of The Journal will dig into this in the same way that we have as editors and really appreciate the thoughtfulness with which you've presented this outstanding work. So I want to thank you so much, Dr. Albert for joining us today.

Dr. Christine Albert:

Thank you for having me.

Dr. Mercedes Carnethon:

I guess I will sign off now. This is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine and Associate Editor for Circulation.

Disclaimer:

This program is copyright of the American Heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart Association. For more, visit ahajournals.org.

Circulation December 14, 2021 Issue

13 december 2021 | 26 min

Please join Guest Host Mercedes Carnethon, author Jason Roberts, and Associate Editor Vlad Zaha as they discuss the article "Epigenetic Age and the Risk of Incident Atrial Fibrillation."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature we're going to learn more about the risk of incident atrial fibrillation, but as that pertains to epigenetics. But before we get to that feature, how about we grab a cup of coffee and get started on some of the other articles in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would love to. And the first paper I want to highlight asks the question, are social economic variables associated with 30 day survival after out of hospital cardiac arrest. And this comes from Dr. Jonsson from Karolinska Institute in Stockholm, Sweden, and colleagues. They linked data from the Swedish Registry of Cardiopulmonary Resuscitation with individual level data on social economic factors. In other words, educational level and disposable income, all from statistics, Sweden. And what they found was that both higher disposable income and higher educational level independently associated with better 30 day survival following out of hospital cardiac arrest. The relationship between disposable income and 30 day survival was more robust for mediating factors compared to educational level.

Dr. Greg Hundley:

Oh, wow Carolyn. Really interesting in a very, what I would call hot topic these days. So what are the clinical implications of this particular study?

Dr. Carolyn Lam:

Well, the results really highlight the importance of preventive efforts aimed at patients with lower social economic status. And these preventive actions could include both early recognition and warning signs and for example, CPR and AED training. So very lovely paper there.

Dr. Greg Hundley:

Absolutely. Very nice Carolyn. Well, my first paper comes to us from Dr. Nan Wang from Columbia University Medical Center. And Carolyn this paper focuses on a common genetic variant called link RS 3184504, and it is associated with increased platelet and neutrophil counts, coronary artery disease, thrombotic stroke, and autoimmune diseases. And so this research group previously has shown that hematopoietic link deficiency synergizes with hyperlipidemia to promote platelet production and activation, neutrophilia, platelet neutrophil aggregates, atherosclerosis and arterial thrombosis, all of those things. So platelet activation and platelet neutrophil interactions have been shown to promote neutrophil extracellular traps or net formations. So nets are formed when neutrophils release their contents leading to the formation web-like structures made of DNA, myeloperoxidase, citrullinated histone and proteases that entrap and kill bacteria. Now, while nets may help to suppress infection, the formation of nets called NETosis in blood vessels can promote atherosclerosis and thrombosis. And so this study was undertaken to investigate the hypothesis that linked deficiency might promote NETosis leading to formation of unstable atherosclerotic plaques, and arterial thrombosis.

Dr. Carolyn Lam:

Wow. What a really neat hypothesis and NETosis. I learn new things all the time. So what do they find?

Dr. Greg Hundley:

Right Carolyn. First of all, hypercholesterolemic mice with hematopoietic link deficiency displayed accelerated arterial thrombosis with nets in thrombi and these changes were reversed by PAD4 deficiency or OxPL antibodies. Second, linked deficient platelet from hyperlipidemic mice expose and release increased OxPL when activated promoting NETosis, when incubated with link deficient neutrophils. Third, an AntiOxPL antibody reduced OxPL levels, NETosis and arterial thrombosis specifically in link deficient mice, and finally Carolyn targeting atherothrombotic risk using OxPL antibodies might be particularly effective in genetically defined populations with reduced link function or increased JAK-STAT signaling.

Dr. Carolyn Lam:

Wow. Okay. So they proved their hypothesis. Could you sum it up for us, Greg?

Dr. Greg Hundley:

You bet Carolyn. So this foundational work suggests that perhaps future studies targeting NETosis and OxPL in patients carrying the common link loss of function variant, could reduce atherothrombotic risk.

Dr. Carolyn Lam:

Wow. Thanks, Greg. My next paper is super interesting in its approach. Listen up. Now the assessment of the relationship between myocardial ATP production and cardiac workload. We know is important for better understand disease development and choice of nutritional or pharmacological treatment strategies. So what Dr. Berndt from Charity University and colleagues did, was they developed a comprehensive physiology based mathematical model of cardiac energy metabolism. And this model is called cardiokine one. And what it does is it recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. The model encompassed all pathways along, which the possible energy delivering substrates like glucose, long chain fatty acids, keto bodies, acetate, branch chain, amino acids are utilized.

Dr. Carolyn Lam:

They use the proteomic space, the abundance of metabolic enzymes and cardiac tissue to generate individualized metabolic models of cardiac energy metabolism. And so to prove their case, they further applied this approach to the left ventricles of controls in patients with mitral insufficiency and aortic stenosis, and showed that despite overall preserved systolic function, the ATP producing capacity of these left ventricles of patients with valvular dysfunction was generally diminished and correlated positively with mechanical energy demand and cardiac output.

Dr. Greg Hundley:

So Carolyn really interesting findings. Sort of linking metabolism them with ventricular dysfunction in those with valvular heart disease. So what were the clinical implications here? What's the take home?

Dr. Carolyn Lam:

Well, this methodology is just awesome, but what they also found I think is a very important physiological principle. And that is, while metabolic capacity have a significant correlation with biomechanical properties like myocardial power and cardiac output, they can also vary considerably between individual patients and therefore help us to understand in future perhaps why some patients develop heart failure over time while others with similar hemodynamic conditions do not. So just interesting. I think it just opens the space to a lot more.

Dr. Greg Hundley:

Absolutely beautiful summary there Carolyn. Well, in the rest of the mailbag for this issue, we have an exchange of letters between Professors Hu and Trifon on the previously published paper, entitled “Short Term Treatment with Aspirin plus Clopidogrel Compared to Monotherapy of Aspirin May Not Significantly Decrease the Risk of Stroke Recurrence.” Also, there's a Research Letter from Professor Catalucci entitled, “Nano miR-133A Replacement Therapy, Blunts Pressure Overloaded Induced Heart Failure.” And then finally Carolyn, there's an In-Depth article from Professor Aengevaeren entitled, “Exercise-Induced Cardiac Troponin Elevations From Underlying Mechanisms to Clinical Science.” Well Carolyn, how about we get onto that feature discussion and learn more about incident atrial fibrillation and the age of epigenetics.

Dr. Carolyn Lam:

Let's go.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run, where we're going to have a very exciting discussion about a paper on epigenetic age and the risk of incident atrial fibrillation. We're extremely excited to have the lead author here with us, Dr. Jason Roberts from the Population Health Research Institute, McMaster University and Hamilton Health Sciences in Ontario Canada. And I am really excited to host this episode alongside the handling editor. My name is Mercedes Carnethon and I'm the professor and vice chair of Preventive Medicine at the Northwestern University School of Medicine. And I'm pleased to be hosting this with Dr. Vlad Zaha from UT Southwestern Medical School, who was the associate editor who handled the piece. So I'm really excited to jump right into this because I think there's a lot that we can all learn from this. So welcome Jason, and thank you so much, Vlad.

Dr. Jason Roberts:

Thank you so much for having me, it's a delight to be here.

Dr. Mercedes Carnethon:

So Jason, tell us a little bit about the rationale for this study, what you found and what it means.

Dr. Jason Roberts:

Absolutely. So as a cardiac arrhythmia specialist, I see a lot of patients with atrial fibrillation. And in 2021, our understanding of its underlying pathophysiology still remains modest. Our treatment strategies for the condition are also somewhat modest, although catheter ablation and antiarrhythmic drugs can potentially be very effective. In the context of these limitations, they're also exacerbated to some extent by the prevalence of atrial fibrillation, increasing dramatically in developed countries. Part of this is related to the obesity epidemic. Things like hypertension increasing becoming more common, but because atrial fibrillation is age dependent and because of our aging populations in developed countries, this is felt to have a major contribution to the growing prevalence of atrial fibrillation. Unlike obesity and hypertension and other risk factors, which are potentially modifiable, chronological aging is viewed as non-modifiable. It's not something that we can tackle. That said, we know within the population and just from personal experience that people age at different rates. There are some people that are 65 who behave more like they're 50, other people that are 50 who behave more like they're 65.

Dr. Jason Roberts:

And in that context, biological aging, we wondered whether or not, does biological aging independent of chronological aging potentially impacts the risk of atrial fibrillation. If that was the case, because there are gradually accumulating to suggest that biological aging is potentially modifiable, that could potentially open up the possibility of tackling aging as a respective for atrial fibrillation. So that drove us to ask this question. In terms of what we found in the approach that we used. So we used our biological marker of aging, was something called an epigenetic clock. So it's been found that modifications to DNA, specifically methylation at CpG at dinucleotides, they correlate with aging. This has been appreciated for a few decades. It was initially felt that with aging, methylation levels gradually reduced over time. But with more careful interrogation, it's shown that there's patterns. Some methylation areas increase, other methylation areas there's decreases.

Dr. Jason Roberts:

And Steve Horvath, who is a scientist at UCLA has found that using mathematical algorithms, you're able to very accurately ascertain chronological age based on the patterns of DNA methylation, he's called these things epigenetic o'clock. That said, even though they very accurately ascertain chronological age, they aren't perfect in each individual in terms of matching up to their chronological age, but that's actually turned out to be a good thing. So when people, their epigenetic age is older than their chronological age, they're said to have positive epigenetic age acceleration. They may be biologically older than their actual chronological age. And then the reverse also holds. So using this concept of epigenetic age acceleration, we ask whether or not do people that are older biologically on the basis of their epigenetic age, do they have an increased risk of atrial fibrillation? And then we tackle that using a few different core works that I'm certainly happy to elaborate on in terms of what we found.

Dr. Jason Roberts:

So we used three population based cohorts from the United States, the well known Framingham Heart Study, the Cardiovascular Health Study and Eric as well. There were approximately just under 6,000 people from those studies that had undergone genome wide methylation analysis that in the enabled us to calculate their epigenetic ages. The follow period for these people was just under 13 years. And then we look to see whether or not these epigenetic clocks associated with instant atrial fibrillation. In these cohorts, we look at five different clocks. So there's the Horvath Clock and the Hannum clock that were designed to predict chronological aging. The more recent clocks, things like DNAm PhenoAge and DNAm GrimAge are more designed to predict aspects of clinical phenotype and also mortality. We found that in unadjusted analyses, all of these clocks were associated with atrial fibrillation. When we then adjusted for multiple different clinical variables, we found that the DNAm PhenoAge clock and the DNAm GrimAge clock continued to exhibit statistically significant associations with atrial fibrillation.

Dr. Jason Roberts:

Interestingly, the multi-variable adjustment, one concern is, do these clinical factors, are they confounders where we should be adjusting, or are they potentially mediators. If we adjust for mediators that potentially masks the effect of the clock. But regardless of how we treat them both DNAm PhenoAge and DNAm GrimAge, we're associated with increased risks of incident atrial fibrillation. Alluding to the possibility that biological aging independent of chronological aging is important in terms of determining risk for atrial fibrillation. And it may be that if we're able to modify biological aging, we could potentially reduce the risk of atrial fibrillation. So that's the study in a nutshell.

Dr. Mercedes Carnethon:

No, that is really exciting. You said something early on about chronological age being immutable. And I would have to say, both Vlad and I are not aging. And in fact, we are going in the opposite direction. If only this were not just an audio podcast, you would see that I steadily gotten younger and younger and I'm suddenly about 25 now. But no, these are really important findings. I really like the innovation of using multiple different strategies to characterize epigenetic age and genetic aging. So tell me Vlad, I want to turn to you. When this came across your desk, what excited you about this particular piece and why did you think that it would be of great interest to our readership?

Dr. Vlad Zaha:

Good morning Merci and Jason. This is a great question. And as in associate editor at Circulation for the bridging discipline section, it was fascinating to see this topic coming on my desk, thinking about all the genome wide association studies in nature of fibrillation and predisposition to atrial fibrillation, that in that case would not be changed by interventions because of different loci that would be determined. This was coming as a completely new perspective that was opening some new potentials. And it was very interesting to see some of the findings.

Dr. Mercedes Carnethon:

Certainly. So Jason, I have a question. So what surprised you about the findings of this particular study?

Jason Roberts:

Yeah, that's a great question. So we had hoped that biological aging would be associated with atrial fibrillation. I think the concept of being able to tackle biological aging is exciting. In terms of what surprised us, I guess we were hoping for these results, I guess.

Dr. Mercedes Carnethon:

Yeah.

Dr. Jason Roberts:

But we were…Yeah. So I guess we were pleasantly surprised that our hypothesis was born out. It's important to note that the epigenetic clocks don't tell the full story with chronological aging. So after we insert the clock into the model, chronological age continues to remain associated with instant atrial fibrillation. So this measure biological aging is just part of the story. So I think that's very important. I had wondered whether or not inserting the epigenetic clocks would that potentially eliminate the subsequent association of chronological aging. So that finding suggests it's part of the story.

Dr. Jason Roberts:

I think that in terms of the overall concept, the idea of this being reversible really excites me. In terms of the approach of how to reverse biological aging. Right now healthy lifestyle seems to be very important. I think it provides more evidence to suggest to patients with atrial fibrillation, living healthy from a diet perspective, from exercise, keeping your weight under control, all of these things that seem to impact epigenetic aging and biological aging can be helpful for preventing atrial fibrillation. So I think that can help reinforce this message to our patients.

Dr. Jason Roberts:

I think ultimately in terms of where we'll be at in 15 to 20 years, it's possible that new therapies in the future are developed that are able to more powerfully address biological aging. As you alluded to, will it be possible to reverse biological aging as you and Vlad are experiencing that?

Dr. Mercedes Carnethon:

Most definitely. Yes.

Dr. Jason Roberts:

I think it may be possible. This is an intense area of investigation that's being pursued and it's still in its relative infancy. But I think that could it be small molecules? Could it be potentially gene editing that can help adjust biological aging and not only increase lifespan, but also health span? I think those concepts are really exciting.

Dr. Mercedes Carnethon:

I completely agree. There's a lot of richness in this paper and I think our readership is going to really enjoy digging in. Part of the richness is the use of three different cohorts and the use of multiple measures of epigenetic age. And I think you provided a really nice description of the unique information that each of these markers of epigenetic age provide. One thing I note are differences in the strength of association across the different measures of epigenetic age, which I think makes sense, because you said they characterize different aspects of the phenomenon, but I also see what looks like some variability across the cohorts with Framingham in particular seeming to stand out. And that being the only cohort that is 100% one race. It's white. Versus both the cardiovascular health study and the Eric study, which have more diverse study populations. I'm wondering what your hypothesis is about the differential strength of association that it seems Framingham is demonstrating and what you think is possibly the source of those differences.

Dr. Jason Roberts:

Yeah. I think those are great questions for all of genetics. The question is, does it apply to all races? For example, polygenic risk scores. It seems like when a polygenic risk scores develop for one race, it may not perfectly translate over to other races. So how relevant is that for epigenetic age acceleration. In this study, I think it's difficult to make definitive conclusions about it. We needed the three cohorts to have adequate statistical power in terms of being able to determine a differential effect of race. I think it would really be primarily hypothesis generating. We weren't really powered to look at the different races. So it's difficult for me to comment.

Dr. Jason Roberts:

I think ultimately and I want to believe anyways, that epigenetic age acceleration is relevant to all races, but in terms of, was it race that drove the differential impacts that we saw to some extent in terms of the magnitude of the hazard ratios, it's difficult to know in terms of tests for interaction and were these actually truly statistically different. We weren't adequately powered to address that hypothesis. So it's difficult for me to comment in a definitive matter I'd say. And sorry to cop out on…

Dr. Mercedes Carnethon:

No, not at all. I mean, I think there are a lot of things where there is no firm answer and that was just one of my hypotheses when I saw what was going on differently across the cohorts. I think that's a perfectly reasonable answer that sets us on a course for thinking about how we set up future studies. So I wanted to turn to you Vlad for the closing frame around this. As the editor, how do you hope that our readership will use these findings?

Dr. Vlad Zaha:

That is an excellent question. I was going to follow on this excellent unpacking of the core messages of the manuscript by Jason here to get his perspective as an electrophysiologist into what these type of work may represent for the everyday life of an electrophysiologist in the connecting with the patients and how would this type of approach influence, and maybe now, maybe later when our treatment for atrial fibrillation.

Dr. Jason Roberts:

Yeah. So that's a great question. I think, as I alluded to some extent before, as far as reinforcing healthy lifestyle, I think this provides more evidence in that respect. So we know that things like excessive alcohol consumption, being excessively obese, poor diets, not engaging in enough exercise, all of those things seem to accelerate your epigenetic age. And those are all things that we think or feel that are important with atrial fibrillation in terms of driving the path of physiology and people progressing. So I think this gives more data to us to reinforce the patients that in addition to the treatments that we're offering in terms of catheter ablation and antiarrhythmic drugs, the concern is that the substrate can continue you to progress. And that's likely driven by to some extent these modifiable risk factors. So keeping all of these under best control as possible, and hence trying to slow your biological aging as much as possible.

Dr. Jason Roberts:

I think that this will provide us more motivation to push these messages to our patients. A lot of patients can sometimes be like, "Let's just get on with a catheter ablation and I want to get on with my life…" but it really I think, provides more data to suggest that modifying these very important risk factors that can lead to accelerated biological agents, is very important. And in terms of the future as mentioned, so chronological aging, as people get older, people view it as, "Well, there's nothing I can do, and I'm just going to get gradually more and more unhealthy." I think, and this is somewhat futuristic, but to what extent can we slow biological aging? Can we potentially reverse it in the future? There's certainly lots of very compelling and interesting animal work and people are starting to delve into this in a big way.

Dr. Jason Roberts:

And not only to increase lifespan, will we some day live until we're 200. Who knows? But the concept of prolonging your health span as well. So the number of healthy years that you have before your body starts to gradually give way, I guess to some extent. Hopefully in the future will have therapies that will help keep us healthy. And if we do that increased health span, I think this data suggests that atrial fibrillation will be one thing that benefits from this. So hopefully in the future, maybe in terms of curbing the AFib pandemic, being able to address biological aging will help push things in the right direction.

Dr. Mercedes Carnethon:

Well, thank you so much Jason. And thank you so much Vlad for your thoughtful questions. I really like that the final bottom line leans towards my area as an epidemiologist, which is maintaining and promoting healthy lifestyles as a way to hopefully help prevent some of the difficulties of atrial fibrillation and its long-term outcomes. Really pleased to have you on this episode of Circulation on the Run, Jason, and thank you again Vlad, and I hope everyone enjoys this episode of the journal and has an opportunity to really dig into this piece. This is Mercedes Carnethon from Northwestern University Feinberg School of Medicine, saying thanks for listening today.

Dr. Greg Hundley:

Circulation December 7, 2021 Issue

7 december 2021 | 23 min

Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start?

Dr. Greg Hundley:

Very good.

Dr. Carolyn Lam:

Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find in this subgroup of patients?

Dr. Carolyn Lam:

So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery.

Dr. Greg Hundley:

Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go.

Dr. Greg Hundley:

All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery.

Dr. Greg Hundley:

So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection.

Dr. Carolyn Lam:

Wow, fascinating. So what did today's paper find?

Dr. Greg Hundley:

Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper?

Dr. Carolyn Lam:

Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right?

Dr. Greg Hundley:

Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn.

Dr. Carolyn Lam:

Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs.

Dr. Carolyn Lam:

The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation.

Dr. Carolyn Lam:

But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit.

Dr. Greg Hundley:

Okay. Carolyn, what a beautiful summary here. So what's the take home message here?

Dr. Carolyn Lam:

So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases.

Dr. Carolyn Lam:

Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study?

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Mercedes Carnethon:

Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization.

Dr. Mercedes Carnethon:

And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you.

Professor Gregory Lip:

Hello there.

Dr. Connie Hess:

Thank you for having me.

Dr. Mercedes Carnethon:

Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study?

Dr. Connie Hess:

Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about.

Dr. Connie Hess:

And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI.

Dr. Connie Hess:

And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death.

Dr. Connie Hess:

And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out.

Dr. Connie Hess:

And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction.

Dr. Connie Hess:

Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication.

Dr. Mercedes Carnethon:

All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind?

Professor Gregory Lip:

Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes.

Professor Gregory Lip:

So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding.

Professor Gregory Lip:

We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well.

Dr. Mercedes Carnethon:

Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study?

Dr. Connie Hess:

Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt.

Dr. Connie Hess:

I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic.

Dr. Connie Hess:

A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it.

Dr. Connie Hess:

I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy.

Dr. Mercedes Carnethon:

I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal.

Dr. Mercedes Carnethon:

This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation November 30, 2021 Issue

29 november 2021 | 22 min

Please join first author Cecilia Bahit and Associate Editor Graeme Hankey as they discuss the article "Predictors of Development of Atrial Fibrillation in Patients With Embolic Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to analyze the RE-SPECT ESUS trial. What does that pertain to? Well, you're going to have to wait and find out, but it relates to atrial fibrillation and embolic stroke. But before we get to that, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I sure would. Greg, we know that Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease or diabetes. The question is: What are the effects of Icosapent Ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes from the REDUCE-IT trial?

Dr. Greg Hundley:

Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What did it encompass there?

Dr. Carolyn Lam:

The REDUCE-IT trial was a multicenter double-blind, placebo-controlled trial that randomized statin treated patients with elevated triglycerides, who had cardiovascular disease or diabetes, and one additional risk factor, two treatment with icosapent ethyl at 4g daily versus placebo. After a median follow up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina.

Dr. Greg Hundley:

Ah, great summary of the original paper, but now this is sort of a follow-up paper. What did this paper research?

Dr. Carolyn Lam:

Well first, remember they focused on renal function and the median baseline GFR was 75 ml/min with a range of 17 to 123 mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent reduction in both primary and secondary composite endpoints across the baseline GFR categories. Patients with the GFR >60 treated with Icosapent Ethyl had the largest absolute, but similar relative risk reduction for the primary composite endpoint. And while patients with GFR >60 treated with Icosapent Ethyl had the highest numerical rates of atrial fibrillation of flutter and serious bleeding. The hazard ratios for atrial fibrillation flutter and serious bleeding were similar across GFR categories. In summary Icosapent Ethyl reduced cardiovascular events among patients with elevated triglycerides in a well-controlled LDL on statin therapy across a wide range of baseline renal function.

Dr. Greg Hundley:

Oh, Carolyn. Beautiful presentation. That presentation was so good that I know you are ready for a quiz. We haven't had Carolyn's quiz in a week, so we've got to get right back to that.

Dr. Carolyn Lam:

No, we don't (laughs).

Dr. Greg Hundley:

Can you describe the primary sequelae of Hutchinson-Gilford progeria syndrome?

Dr. Carolyn Lam:

Oh wow. Okay. So this is the syndrome where there's premature aging, there's a lot of vascular stiffening, calcification. I'm going to guess some sort of atherosclerotic consequence (laughs).

Dr. Greg Hundley:

Very nicely done Carolyn. Oh my goodness. I need to get you to take my ABIM recertification-

Dr. Carolyn Lam:

(laughing)

Dr. Greg Hundley:

Beautifully done. So Carolyn, this paper comes to us from Dr. Vicente Andrés from Centro Nacional De Investigaciones Cardiovasculares Carlos III, and Hutchinson-Gilford progeria syndrome is a rare disorder characterized, just like you said, Carolyn by premature aging and death, mainly due to myocardial infarction, stroke or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Carolyn, these patients look healthy at birth and symptoms typically emerge in the first or second year of life. In assessing the reversibility of progerin induced damage, and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies.

Dr. Carolyn Lam:

Wow, you've really, really piqued my interest. So what did these investigators do and what did they find?

Dr. Greg Hundley:

Oh Carolyn, very clever design. So the authors use CRISPR-Cas9 technology to generate mice engineers to ubiquitously express progerin while lacking lain A and allowing progestin suppression in lain A restoration in a time and cell type specific manner upon CRE recombinase activation. They characterize the phenotype of these engineered mice and cross them with CRE transgenic lines to assess the effects of suppressing progestin and restoring lain A ubiquitously at different disease stages, as well as specifically in vascular smooth muscle cells and cardiomyocytes. So Carolyn, what did they find? Well, number one, like Hutchinson-Milford progenia syndrome patients, their engineered mice appeared healthy at birth, and progressively developed Hutchinson-Milford progenia syndrome symptoms, including failure to thrive, Lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electric cardiographic anomalies and early death. Their median lifespan was 15 months versus 26 months in the wild types.

Dr. Greg Hundley:

Second, ubiquitous progestin suppression in lain A restoration significantly extended lifespan, when induced in six month old, mildly symptomatic mice, and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon the early intervention. And then finally, Carolyn remarkably major vascular alterations were prevented and lifespan normalized in engineered Hutchinson-Milford progenia syndrome mice when progestin suppression and lain A restoration were restricted to: just Vascular smooth muscle cells and Cardiomyocytes.

Dr. Carolyn Lam:

Wow, just fascinating, but, okay. What is the clinical take home message?

Dr. Greg Hundley:

Right, Carolyn. So these authors findings suggest that it is never too late to treat Hutchinson-Milford progenia syndrome, although the benefit is much more pronounced when progestin is targeted early in mice with mild symptoms. Also, restricting its suppression to Vascular smooth muscle cells in Cardiomyocytes is sufficient to prevent Vascular disease and normalize lifespan in mice, and therefore these data suggest that strategies to treat Hutchinson-Milford progenia syndrome through gene therapy or RNA therapy should consider targeting Vascular smooth muscle cells and Cardiomyocytes.

Dr. Carolyn Lam:

Oh wow. Very, very cool. Well, my next paper is a basic science paper that's significant for both its methods and its results.

Dr. Greg Hundley:

Oh wow, Carolyn, I can't wait. So tell us about this novel methodology.

Dr. Carolyn Lam:

Well, this paper is from Dr. Chang from Westlake University in Hangzhou, China, and colleagues who use a gene editing approach to efficiently institute Exon Skipping without introducing DNA double-strand breaks. So harnessing a fusion of a nuclease defective Case protein, and a cytidine deaminase, which is, we're going to abbreviate it as Targeted AID-induced mutagenesis (TAM) or base editor three (BE3), their approach precisely edited conserved guanines at splice sites, thus abrogating Exon recognition resulting in a programmable skipping of the targeted Exons. Isn't that neat?

Dr. Greg Hundley:

Yeah, it really is sophisticated Carolyn, wow. So what did they do using these methods?

Dr. Carolyn Lam:

A novel mirroring model of Duchenne muscular dystrophy was generated, which recapitulated many cardiac defects observed in the human form of the disease, including dilated cardiomyopathy, reduced left ventricular function and extensive cardiac fibrosis. Using this model, they examined the feasibility of using a cytidine base editor to install Exon Skipping and rescue the dystrophic cardiomyopathy in vivo. A single dose administration of an Adenovirus 9EtAm, instituted over 50% targeted Exon Skipping in the Chengdu muscular dystrophy transcripts and restored up to 90% dystrophin in the heart. And as a result, early ventricular remodeling was prevented and cardiac and skeletal muscle function were improved, leading to an increased lifespan of the mice. Despite gradual decline of the Adenovirus vector and base editor expression, the dystrophin restoration and pathophysiological rescue of muscular dystrophy lasted for at least a year. And so this technique really has the potential to be applied to monogenic human diseases, to modulate Exon Skipping or inclusion. Isn't that cool?

Dr. Greg Hundley:

Absolutely, Carolyn. Beautifully explained.

Dr. Carolyn Lam:

Well, let me end by sharing what else is in today's issue. There's a Perspective piece by Dr. Alexander on “Chest Pain Redux: Updated and Patient Centered.” There is an In Depth paper by Dr. Kroemer on NAD plus metabolism in cardiac health, aging and disease. And there's a Research Letter by Dr. Shepherd on sudden death in female athletes, with insights from a large regional registry in the United Kingdom.

Dr. Greg Hundley:

Very good, Carolyn. What a great issue. Now, how about we get to that feature discussion?

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Greg Hundley:

Welcome listeners to our feature discussion today on this November 30th. And we have with us Dr. Cecilia Bahit from Rosario, Argentina and our own associate editor, Dr. Graeme Hankey from Perth, Australia to talk to us about a paper pertaining to Atrial Fibrillation. Welcome to you both, and Cecilia, we'll start with you. Could you describe for us a little bit of the background information that went into formulating your study, and then what hypothesis did you want to address?

Dr. Cecilia Bahit:

Thank you for the invitation. So we all know that embolic stroke of undetermined source, which is called ESUS isn't just a subset of cryptogenic stroke, and is associated with stroke recurrence about 3-6% per year. And on the other hand, we know that continuous cardiac monitoring in this patient population shows that atrial fibrillation can be detected between 10% at six months or 30% at three years. So the underlying atrial fibrillation may be a mechanism for the recurrent thromboembolic stroke in this patient population. So we know that prior studies have identified some predictors of atrial fibrillation in these patients. And if we are able to identify which patients could benefit from cardiac monitoring and have a higher yield to detect atrial fibrillation, we could do a better job at treating them. So, that was our idea behind the paper. So using the RE-SPECT ESUS trial, which was a trial that included patient with ESUS stroke and were randomized to the bigger trend versus Aspirin, we look at predictors of atrial fibrillation unassociated regarding stroke.

Dr. Greg Hundley:

Very nice. And so, now was this a sub-study here and maybe define for us a little bit, your study design and specific study population.

Dr. Cecilia Bahit:

So this was a secondary analysis of a randomized clinical trial that as mentioned it was not a sub-study, it was a secondary analysis. We thought all along to do it because of the interest of the clinical question. We look at the total patient population was 5,390 patients. And we looked at those patients who developed atrial fibrillation during the 19 months of follow-up. And it was 7.5%, 403 patients developed atrial fibrillation.

Dr. Greg Hundley:

Very good. And what were your results?

Dr. Cecilia Bahit:

So, as I mentioned, we saw that 7.5% of our patient population developed atrial fibrillation during the follow-up. And we know those patients were older, were like, have higher morbidities, and we assessed, we did an one variable analysis and then a multi-variable analysis, trying to identify predictors for atrial fibrillation. And for our model, we identified different predictors, older age, hypertension, lack of diabetes, and higher body mass index, were independent predictors of atrial fibrillation. So the patients who have atrial fibrillation have a higher recurrence of stroke, it was 7.2 versus four, compared to those that did not have atrial fibrillation.

Dr. Cecilia Bahit:

So I think there's an important part, that 20% of the patient population of the overall trial, this is a little more than a thousand patients, had NT-prob measure at baseline. And when we included this biomarker into the model, only older age and NT-prob were independent predictors of atrial fibrillation. In addition, even though this was not the objective of this analysis, we look at the treatment effect of the bigger trend. And even though we saw that there was a statistical benefit of the bigger trend versus Aspirin in the higher group of these in our score, the overall treatment effect was not there. So we couldn't assess the fact that the bigger trend was better compared to Aspirin in patient with atrial fibrillation, but of course the numbers were very small.

Dr. Greg Hundley:

Very good. Thank you so much for that wonderful description. And Graeae, now we'll turn to you as associate editor for us at Circulation, and also the editorialist on this particular paper. What caught your attention about this particular study and the results from the many papers that really come across your desk.

Dr. Graeme Hankey:

Thank you, Greg. And congratulations to Cecilia and her RE-SPECT ESUS colleagues. I mean, this is a landmark study, the RE-SPECT ESUS study, and just to go back, embolic stroke of undetermined source is really common. About one in four ischemic strokes, we don't know the cause of, and it's one of the major subtypes of cryptogenic stroke is an embolic ischemic stroke in which the source could have come from the heart or the aortic arch or the carotids. And we're not really sure. And we think that some of these patients have occult atrial fibrillation, but we can't pick it up at the time. So one way is to try and monitor them with prolonged ECG monitoring. And another way is to actually treat them with anticoagulation because we know that, that's more effective in people with cardio embolic stroke. And so RE-SPECT ESUS and NAVIGATE ESUS used the latter strategy and said, let's see if treating people with ESUS with anticoagulation is more effective than antiplatelet therapy.

Dr. Graeme Hankey:

And both studies were not significant in terms of showing that Dabigatran or Parovarian for NAVIGATE ESUS was more effective than antiplatelet therapy. So we're left now with this default that all patients with ESUS just get Aspirin, but we have a hunch that some of them actually have cardiogenic embolism and are being undertreated with Aspirin and need anticoagulation. So it's a heterogeneous entity, but we're treating it homogeneously with a sort of weak antiplatelet. So we want to try and find out who's going to get AF or who's already got it that is occult. And this study is a really great and prospective study with 5,000 patients as Cecilia said, who of whom 7% did develop AF just through annual ECG reporting and just with symptom reporting. And that's probably an under report. You know, if they'd had monitoring, they probably would've found about 20 or 30% would've developed AF during that time of 19 months follow up.

Dr. Graeme Hankey:

And it's the first study to really then show that not just the AF people had a higher stroke rate, but in that group who they predicted to be at high risk of AF with older age and the NT-prob, that the high risk group had a significant reduction with Dabigatran versus Aspirin in that high risk group. It's just, when you look for hetero homogeneity or heterogeneity across the risk groups, it wasn't quite significant. And that might be because it's not significant or it might be that study was underpowered to look at those three, across those three risk subgroups. And also it might be a bit confounded because of it, the patients weren't randomized according to their risk status for AF, they were just randomized, whether they had ESUS, so it's further excited us that there might be a subgroup who needs anticoagulation. And that's why the ARCADIA trial is ongoing now, looking at where the people with ESUS who have high risk of AF benefit from a apixaban versus aspirin.

Dr. Greg Hundley:

Very nice. And so, with these results that we have here, maybe come back to Cecilia, what do you think would be the next series of studies that needs to be performed in this area of research?

Dr. Cecilia Bahit:

Well, there's one side that's ongoing as Dr. Hankie mentioned, but I think we should be able to identify which patients have a higher risk of atrial fibrillation and those patients who use cardiac monitoring for long term to identify atrial fibrillation and to treat properly. So I think that would be key in this area.

Dr. Greg Hundley:

Very nice. And Graeae, what are your thoughts?

Dr. Graeme Hankey:

Yes. Well, one way is to have our ESUS patients have prolonged ECG monitoring by implantable loop recorders, for example, and then those who develop AF randomizing them to anticoagulation versus antiplatelet therapy. Although if they declare themselves with AF they're usually just go straight onto anticoagulation therapy. So the burning question is, in these people with ESUS who haven't declared themselves as AF, but have predictors of AF like those shown in RESPECT ESUS, like older age, high blood pressure, high BMI ,prob, and perhaps echo features, like left atrial size or ECG features like lots of premature atrial contractions or P wave of abnormalities.

Dr. Graeme Hankey:

Are these, the subgroups or even LV dysfunction, are these subgroups who need to be more specifically targeted in a randomized trial rather than the whole group of ESUS. And also with longer follow up. NAVIGATE ESUS stopped after 11 months. The bigger RESPECT ESUS stopped after a median follow up of 16 months and the curves were diverging. Maybe with five years follow up, a lot of these people would've developed AF and would've benefited from longer term anticoagulation, but the trials were stopped early, because there wasn't a signal of benefit and there was an early risk of bleeding with anticoagulation.

Dr. Greg Hundley:

Very good. Well listeners, this has been a really interesting study and we want to thank Cecilia and Graeme for sharing results of the RESPECT ESUS study, highlighting that, in patients with embolic stroke of undetermined source, atrial fibrillation occurs and is a possible source of this stroke, and then also older age, and elevation of NT-prob can be associated with development of atrial fibrillation, subsequent to that stroke event.

Dr. Greg Hundley:

Well listeners, we want to wish you a great week. And on behalf of Carolyn and myself, look forward to catching you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Circulation November 23, 2021 Issue

22 november 2021 | 25 min

Please join first author Yuan Lu and Guest Editor Jan Staessen as they discuss the article "National Trends and Disparities in Hospitalization for Acute Hypertension Among Medicare Beneficiaries (1999-2019)."

Dr. Carolyn Lam:

Welcome to Circulation on the Run: your weekly podcast, summary and backstage pass to the journal and it's editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, and director of Pauley Heart Center at VCU health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature discussion is about the national trends and disparities and hospitalizations for hypertensive emergencies among Medicare beneficiaries. Isn't that interesting? We're going to just dig deep into this issue, but not before we discuss the other papers in today's issue. I'm going to let you go first today while I get a coffee and listen.

Dr. Greg Hundley:

Oh, thanks so much, Carolyn. My first paper comes to us from the world of preclinical science and it's from professor Christoff Maack from University Clinic Wursburg. Carolyn, I don't have a quiz for you, so I'm going to give a little break this week, but this particular paper is about Barth syndrome. Barth syndrome is caused by mutations of the gene encoding taffazin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Now beyond the first months of life, Barth syndrome cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, one of your favorites, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced Barth syndrome cardiomyopathy to mitochondrial formation of reactive oxygen species. Since mitochondrial function and reactive oxygen species formation are regulated by excitation contraction coupling, these authors wanted to use integrated analysis of mechano-energetic coupling to delineate the pathomechanisms of Barth syndrome cardiomyopathy.

Dr. Carolyn Lam:

Oh, I love the way you explained that so clearly, Greg. Thanks. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. Well, first defective mitochondrial calcium uptake prevented Krebs cycle activation during beta adrenergic stimulation, abolishing NADH regeneration for ATP production and lowering antioxidative NADPH. Second, Carolyn, mitochondrial calcium deficiency provided the substrate for ventricular arrhythmias and contributed to blunted inotropic reserve during beta adrenergic stimulation. And finally, these changes occurred without any increase of reactive oxygen species formation in or omission from mitochondria. So Carolyn what's the take home here? Well, first beyond the first months of life, when systolic dysfunction dominates, Barth syndrome cardiomyopathy is reminiscent of heart failure with preserved rather than reduced ejection fraction presenting with progressive diastolic and moderate systolic dysfunction without relevant left ventricular dilation. Next, defective mitochondrial calcium uptake contributes to inability of Barth syndrome patients to increase stroke volume during exertion and their vulnerability to ventricular arrhythmias. Lastly, treatment with cardiac glycosides, which could favor mechano-energetic uncoupling should be discouraged in patients with Barth syndrome and left ventricular ejection fractions greater than 40%.

Dr. Carolyn Lam:

Oh, how interesting. I need to chew over that one a bit more. Wow, thanks. But you know, I've got a paper too. It's also talking about energetic basis in the presence of heart failure with preserved ejection fraction, but this time looking at transient pulmonary congestion during exercise, which is recognized as an emerging and important determinant of reduced exercise capacity in HFpEF. These authors, led by Dr. Lewis from University of Oxford center for clinical magnetic resonance research sought to determine if an abnormal cardiac energetic state underpins this process of transient problem congestion in HFpEF.

Dr. Carolyn Lam:

To investigate this, they designed and conducted a basket trial covering the physiological spectrum of HFpEF severity. They non-invasively assess cardiac energetics in this cohort using phosphorous magnetic resonance spectroscopy and combined real time free breathing volumetric assessment of whole heart mechanics, as well as a novel pulmonary proton density, magnetic resonance imaging sequence to detect lung congestion, both at rest and during submaximal exercise. Now, Greg, I know you had a look at this paper and magnetic resonance imaging, and spectroscopy is your expertise. So no quiz here, but could you maybe just share a little bit about how novel this approach is that they took?

Dr. Greg Hundley:

You bet. Carolyn, thanks so much for the intro on that and so beautifully described. What's novel here is they were able to combine imaging in real time, so the heart contracting and relaxing, and then simultaneously obtain the metabolic information by bringing in the spectroscopy component. So really just splashing, as they might say in Oxford, just wonderful presentation, and I cannot wait to hear what they found.

Dr. Carolyn Lam:

Well, they recruited patients across the spectrum of diastolic dysfunction and HFpEF, meaning they had controls. They had nine patients with type two diabetes, 14 patients with HFpEF and nine patients with severe diastolic dysfunction due to cardiac amyloidosis. What they found was that a gradient of myocardial energetic deficit existed across the spectrum of HFpEF. Even at low workload, the energetic deficit was related to a markedly abnormal exercise response in all four cardiac chambers, which was associated with detectable pulmonary congestion. The findings really support an energetic basis for transient pulmonary congestion in HFpEF with the implication that manipulating myocardial energy metabolism may be a promising strategy to improve cardiac function and reduce pulmonary congestion in HFpEF. This is discussed in a beautiful editorial by Drs. Jennifer Hole, Christopher Nguyen and Greg Lewis.

Dr. Greg Hundley:

Great presentation, Carolyn, and obviously love that MRI/MRS combo. Carolyn, these investigators in this next paper led by Dr. Sara Ranjbarvaziri from Stanford University School of Medicine performed a comprehensive multi-omics profile of the molecular. So transcripts metabolites, complex lipids and ultra structural and functional components of hypertrophic cardiomyopathy energetics using myocardial samples from 27 hypertrophic cardiomyopathy patients and 13 controls really is the donor heart.

Dr. Carolyn Lam:

Wow, it's really all about energetics today, isn't it? So what did they see, Greg?

Dr. Greg Hundley:

Right, Carolyn. So hypertrophic cardiomyopathy hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic arrangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced crystal density coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, the hypertrophic cardiomyopathy hearts failed to up-regulate mitophagic clearance.

Dr. Greg Hundley:

So Carolyn, in summary, the findings of this study suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with hypertrophic cardiomyopathy, and these results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing myocardial injury.

Dr. Carolyn Lam:

Wow, what an interesting issue of our journal. There's even more. There's an exchange of letters between Drs. Naeije and Claessen about determinants of exercise capacity in chronic thromboembolic pulmonary hypertension. There's a "Pathways to Discovery" paper: a beautiful interview with Dr. Heinrich Taegtmeyer entitled,"A foot soldier in cardiac metabolism."

Dr. Greg Hundley:

Right, Carolyn, and I've got a research letter from Professor Marston entitled "The cardiovascular benefit of lowering LDL cholesterol to below 40 milligrams per deciliter." Well, what a great issue, very metabolic, and how about we get onto that feature discussion?

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Greg Hundley:

Welcome listeners to our feature discussion today. We have a paper that is going to address some issues pertaining to high blood pressure, or hypertension. With us, we have Dr. Yuan Lu from Yale University in New Haven, Connecticut. We also have a guest editor to help us review this paper, Dr. Jan Staessen from University Louvain in Belgium. Welcome to you both and Yuan, will start with you. Could you describe for us some of the background that went into formulating your hypothesis and then state for us the hypothesis that you wanted to address with this research?

Dr. Yuan Lu:

Sure. Thank you, Greg. We conducted this study because we see that recent data show hypertension control in the US population has not improved in the last decades, and there are widening disparities. Also last year, the surgeon general issued a call to action to make hypertension control a national priority. So, we wanted to better understand whether the country has made any progress in preventing hospitalization for acute hypertension. That is including hypertension emergency, hypertension urgency, and hypertension crisis, which also refers to acute blood pressure elevation that is often associated with target organ damage and requires urgent intervention. We have the data from the Center for Medicare/Medicaid, which allow us to look at the trends of hospitalization for acute hypertension over the last 20 years and we hypothesize we may also see some reverse progress in hospitalization rate for acute hypertension, and there may differences by population subgroups like age, sex, race, and dual eligible status.

Dr. Greg Hundley:

Very nice. So you've described for us a little bit about perhaps the study population, but maybe clarify a little further: What was the study population and then what was your study design?

Dr. Yuan Lu:

Yeah, sure. The study population includes all Medicare fee-for-service beneficiaries 65 years and older enrolled in the fee-for-service plan for at least one month from January 1999 to December 2019 using the Medicare denominator files. We also study population subgroups by age, sex, race and ethnicity and dual eligible status. Specifically the racial and ethnic subgroups include Asian, blacks, Hispanics, North American native, white, and others. Dual eligible refers to beneficiary eligible for both Medicare and Medicaid. This study design is a serial cross sectional analysis of these Medicare beneficiaries between 1999 and 2019 over the last 20 years.

Dr. Greg Hundley:

Excellent. Yuan, what did you find?

Dr. Yuan Lu:

We actually have three major findings. First, we found that in Medicare beneficiaries 65 years and older, hospitalization rate for acute hypertension increased more than double in the last 20 years. Second, we found that there are widening disparities. When we look at all the population subgroups, we found black adults having the highest hospitalization rate in 2019 across age, sex, race, and dual eligible subgroup. And finally, when we look at the outcome among people hospitalized, we found that during the same period, the rate of 30 day and 90 day mortality and readmission among hospitalized beneficiaries improved and decreased significantly. So this is the main findings, and we can also talk about implications of that later.

Dr. Greg Hundley:

Very nice. And did you find any differences between men and women?

Dr. Yuan Lu:

Yes. We also looked at the difference between men and women, and we found that actually the hospitalization rate is higher among females compared to men. So more hospitalizations for acute hypertension among women than men.

Dr. Greg Hundley:

Given this relatively large Medicare/Medicaid database and cross-sectional design, were you able to investigate any relationships between these hospitalizations and perhaps social determinants of health?

Dr. Yuan Lu:

For this one, we haven't looked into that detail. This is just showing the overall picture, like how the hospitalization rate changed over time in the overall population and by different population subgroups. What you mentioned is an important issue and should definitely be a future study to look at whether social determine have moderated the relationship between the hospitalization.

Speaker 3:

Excellent. Well, listeners, now we're going to turn to our guest editor and you'll hear us talk a little bit sometimes about associate editors. We have a team that will review many papers, but when we receive a paper that might contain an associate editor or an associate editors institution, we actually at Circulation turn to someone completely outside of the realm of the associate editors and the editor in chief. These are called guest editors. With us today, we have Dr. Jan Staessen from Belgium who served as the guest editor. He's been working in this task for several years. Jan, often you are referred papers from the American Heart Association. What attracted you to this particular paper and how do you put Yuan's results in the context with other studies that have focused on high blood pressure research?

Dr. Jan Staessen:

Well, I've almost 40 years of research in clinical medicine and in population science, and some of my work has been done in Sub-Saharan Africa. So when I read the summary of the paper, I was immediately struck by the bad results, so to speak, for black people. This triggered my attention and I really thought this message must be made public on a much larger scale because there is a lot of possibility for prevention. Hypertension is a chronic disease, and if you wait until you have an emergency or until you have target organ damage, you have gone in too late. So really this paper cries for better prevention in the US. And I was really also amazed when I compared this US data with what happens in our country. We don't see any, almost no hospitalizations for acute hypertension or for hypertensive emergencies. So there is quite a difference.

Dr. Jan Staessen:

Going further on that, I was wondering whether there should not be more research on access to primary care in the US because people go to the emergency room, but that's not a place where you treat or manage hypertension. It should be managed in primary care with making people aware of the problem. It's still the silent killer, the main cause of cardiovascular disease, 8 million deaths each year. So this really triggered my attention and I really wanted this paper to be published.

Dr. Greg Hundley:

Very nice. Jan, I heard you mention the word awareness. How have you observed perhaps differences in healthcare delivery in Belgium that might heighten awareness? You mentioned primary care, but are there any other mechanisms in place that heighten awareness or the importance?

Dr. Jan Staessen:

I think people in Belgium, the general public, knows that hypertension is a dangerous condition. That it should be well treated. We have a very well built primary care network, so every person can go to a primary care physician. Part of the normal examination in the office of a primary care physician is a blood pressure measurement. That's almost routine in Belgium. And then of course not all patients are treated to go. Certainly keeping in mind the new US guidelines that aim for lower targets, now recently confirmed in the Chinese study, you have to sprint three cells. And then the recent Chinese study that have been published to the New England. So these are issues to be considered. I also have colleagues working in Texas close to the Mexican border at the university place there, and she's telling me how primary care is default in that area.

Dr. Jan Staessen:

I think this is perhaps part of the social divide in the US. This might have to be addressed. It's not only a problem in the US, it's also a problem in other countries. There is always a social divide and those who have less money, less income. These are the people who fell out in the beginning and then they don't see primary care physicians.

Dr. Jan Staessen:

Belgium, for instance, all medicines are almost free. Because hypertension is a chronic condition prevention should not only start at age 65. Hypertension prevention should really start at a young age, middle age, whenever this diagnosis of high blood pressure diagnosis is confirmed. Use blood pressure monitoring, which is not so popular in the US, but you can also use home blood pressure monitoring. Then you have to start first telling your patients how to improve their lifestyle. When that is not sufficient, you have to start anti hypertensive drug treatment. We have a wide array of anti hypertensive drugs that can be easily combined. If you find the right combination, then you go to combination tablets because fewer tablets means better patient adherence.

Dr. Greg Hundley:

Yuan we will turn back to you. In the last minutes here, could you describe some of your thoughts regarding what you think is the next research study that needs to be performed in this sphere of hypertension investigation?

Dr. Yuan Lu:

Sure. Greg, in order to answer your question, let me step back a little bit, just to talk about the implication of the main message from this paper, and then we can tie it to the next following study. We found that the marked increase in hospitalization rate for acute hypertension actually represented many more people suffering a potential catastrophic event that should be preventable. I truly agree with what Dr. Staessen said, hypertension should be mostly treated in outpatient setting rather than in the hospital. We also find the lack of progress in reducing racial disparity in hospitalization. These findings highlight needs for new approaches to address both the medical and non-medical factors, including the social determinants in health, system racism that can contribute to this disparity. When we look at the outcome, we found the outcome for mortality and remission improved over time.

Dr. Yuan Lu:

This means progress has been made in improving outcomes once people are hospitalized for an acute illness. The issue is more about prevention of hospitalization. Based on this implication, I think in a future study we need better evidence to understand how we can do a better job in the prevention of acute hypertension admissions. For example, we need the study to understand who is at risk for acute hypertensive admissions, and how can this event be preempted. If we could better understand who these people are, phenotype this patient better and predict their risk of hospitalization for acute hypertension, we may do a better job in preventing this event from happening.

Dr. Greg Hundley:

Very nice. And Jan, do you have anything to add?

Dr. Jan Staessen:

Yes. I think every effort should go to prevention in most countries. I looked at the statistics, and more than 90% of the healthcare budget is spent in treating established disease, often irreversible disease like MI or chronic kidney dysfunction. I think then you come in too late. So of the healthcare budget in my mind, much more should go to the preventive issues and probably rolling out an effective primary care because that's the place where hypertension has to be diagnosed and hypertension treatment has to be started.

Dr. Greg Hundley:

Excellent. Well, listeners, we've heard a wonderful discussion today regarding some of the issues pertaining to hypertension and abrupt admission to emergency rooms for conditions pertaining to hypertension, really getting almost out of control. We want to thank Dr. Yuan Lu from Yale New Haven and also our guest editor, Dr. Jan Staessen from Louvain in Belgium. On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions express by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit aha journals.org.

Circulation November 16, 2021 Issue

15 november 2021 | 32 min

Please join authors Babken Asatryan and Anwar Chahal, and Associate Editor Ntobeko Ntusi as they discuss the Primer article "Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health at Richmond, Virginia. Well, Carolyn this week, our feature discussion, we're not going to go with one of our original articles, but we are going to feature a primer and a primer is a state of the art review article. The topic is going to be on arrhythmogenic cardiomyopathy and we'll be looking at the role of inflammation and the immune response in arrhythmogenic cardiomyopathy. But before we get to that feature, how about we grab a cup of coffee and talk about some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I would, because guess what? I'm going to be talking about prescription opioids. We know these are a major contributor to the ongoing epidemic of persistent opioid use. What do you think is the incidence after cardiac implantable electronic device procedures? Greg, let's start with a Greg Hundley quiz. I'll give you multiple choice, how about that? Do you think it is 1%, 10%, 25%. 50%?

Dr. Greg Hundley:

All right, Carolyn, I'm going to guess here. I'm going to go 10%.

Dr. Carolyn Lam:

Smart. Well, guess what? Today's paper actually gives us insight into that question, it's from Dr. Frankel from the hospital of the university of Pennsylvania and his colleagues, and these authors performed a retrospective cohort study using data from a national Administrative Claims Database from 2004 to 2018 of patients undergoing cardiac implantable electronic device procedures. Adult patients were included if they were opioid naive during the 180 day period before the procedure and did not undergo another procedure with anesthesia in the following 180 days.

Dr. Carolyn Lam:

Persistent opioid use, which is what we're interested in, was defined by filling an additional opioid prescription more than 30 days following the procedure. So, here's your answer. Of the more than 143,000 patients meeting these inclusion criteria, 11%, so you were right Greg, 11% filled an opioid prescription within 14 days of surgery. Among these patients, persistent opioid use occurred in 12.4% of patients, 30 to 180 days after surgery. The likelihood for developing persistent opioid use was increased for patients who had a history of drug abuse, pre-operative muscle relaxant or benzodiazepine use or opioid use in the prior five years. Also, patients who have prescribed more than 135 milligrams of oral morphine equivalence had a significantly increased risk of persistent opioid use.

Dr. Carolyn Lam:

Now, this is important because all physicians who perform cardiac implantable electronic device procedures and care for these patients should be aware of the risk of persistent opioid use. This is discussing in editorial by Dr. Kandil from UT Southwestern.

Dr. Greg Hundley:

Very interesting Carolyn, so connecting sometimes the prescription use of opioids after cardiac implantable electronic devices. Great presentation. Well, my first paper comes to us from the world of preclinical science and it's from our prior editor in chief Dr. Joseph Loscalzo from Brigham and Women's Hospital and the Harvard Medical School. So Carolyn, interferon gamma, producing CD4 positive and CD8 positive T-lymphocytes, have been identified as the predominant pathological cell subsets in human atherosclerotic plaques.

Dr. Greg Hundley:

While the immunological consequences of these cells have been extensively evaluated, their interferon gamma mediated metabolic effects on endothelial cells remains unknown. So Carolyn, the purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine interferon gamma on human coronary artery endothelial cells.

Dr. Carolyn Lam:

Interesting. So what did Dr. Loscalzo and colleagues find?

Dr. Greg Hundley:

Right, Carolyn. So, the authors found that interferon gamma impairs endothelial glucose metabolism via altered tryptophan metabolism while depleting NAD plus, which results in a metabolic shift toward increased fatty acid oxidation, and therefore, Carolyn, this work suggests a novel mechanistic basis for pathologic T-lymphocyte endothelial interactions in atherosclerosis, mediated by interferon gamma, linking endothelial glucose, tryptophan, and fatty acid metabolism with NADH and ATP generation and their adverse endothelial functional consequences.

Dr. Carolyn Lam:

Oh, very nice, Greg. Thank you. The next paper describes a comprehensive characterization of cardiomyopathy caused by filament C truncating variance.

Dr. Greg Hundley:

Whoa. Okay, Carolyn. Now what is filamin-C?

Dr. Carolyn Lam:

I thought you may ask and I wasn't going to quiz you, see Greg? The filamin-C gene can cause a striated muscle protein that crosslinks actin and anchors cell membrane proteins to the cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the co-corresponding authors of today's paper Drs. Mestroni and Taylor from University of Colorado, Denver Anschutz Medical Campus, analyzed longitudinal clinical data from an international multicenter cohort of 85 carriers of this filamin-C truncating variants. And this is what they found.

Dr. Carolyn Lam:

First, the cardiomyopathy associated with filimin-C truncating variants appeared to be a disease with heterogeneous phenotypic presentation, ranging from typical dilated cardiomyopathy to arrhythmogenic, right ventricular cardiomyopathy, and with frequently overlapping forms.

Dr. Carolyn Lam:

Number two, left ventricular ejection fraction was associated with the risk of death, either all cause or non-arrhythmic, heart transplantation, or LVAD, but not with the risk of sudden cardiac death or major ventricular arrhythmias, highlighting the need for alternative strategies of stratification of the arrhythmic risk in these patients with the filimin-C truncating variant cardiomyopathy.

Dr. Carolyn Lam:

And number three, this cardiomyopathy was associated with a high risk of ventricular arrhythmias with frequencies of life-threatening ventricular arrhythmias, not significantly different from things like Lamin and desmoplakin cardiomyopathy.

Dr. Greg Hundley:

Well, Carolyn, just fantastic. My next paper comes to us from Professor Lena Claesson-Welsh from Uppsala University and Carolyn, palmdelphin belongs to the family of paralemmin proteins implicated in cytoskeletal regulation and single nuclide polymorphisms in the palmdelphin locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis, and predict the severity of the disease.

Dr. Carolyn Lam:

Wow, interesting. Palmdelphin, great. So tell us, what did they find and what are the clinical implications please?

Dr. Greg Hundley:

Right, Carolyn, great question. So first, calcific aortic valves stenosis patients with the single nucleotide polymorphism RS754 3130 express reduce palmdelphin levels in valve endothelial cells, which shows hallmarks of palmdelphin deficiency, such as loss of cytoplasmic RanGAP1, altered nuclear morphology and nuclear rest of P53 of P21. Carolyn, second, gene-regulatory changes affecting actin reorganization, are detected in seemingly healthy regions of calcifying bowels, in agreement with disturbed actin-dependent processes, being an early event, instigating the calcific process. And so Carolyn, the take home message is that palmdelphin is prominently expressed in endothelial cells and the presence of the palmdelphin single nucleotide polymorphism correlated both with a Barrett endothelium and calcific aortic valve stenosis suggesting that endothelial cell dysfunction is essential in development of calcific aortic valve disease.

Dr. Carolyn Lam:

Oh, wow, wow. Thank you for translating that into the clinical implication. Thanks Greg. Let's maybe discuss what else is in today's issue. There's a prospective piece by Dr. Kirchof entitled “In Patients With Recently Diagnosed Atrial Fibrillation, Think Anticoagulation And Rhythm Control.” There's an exchange of letters between Drs. Liao and Hakala regarding the article Cardiovascular Risk Factor Trajectory Since Childhood And Cognitive Performance In Midlife, The Cardiovascular Risk In Young Finns, study.

Dr. Greg Hundley:

And Carolyn, I've got a research letter from Professor Ramin entitled “Association Between Sarcomeric Variants In Hypertrophic Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel Oxygen-Sensitive CMR Approach.” Well, how about now we get onto that primer feature discussion relating to arrhythmogenic cardiomyopathy?

Dr. Carolyn Lam:

Yay. All right, let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we are now onto our feature discussion and this week we've got a different aspect to the feature discussions. We're going to work through a review article and what we call as a primer. It's one of our state-of-the-art family of publications, where we take a topic and perform a review on a new evolutionary concept that might be occurring in a particular field. This week, we are going to discuss arrhythmogenic cardiomyopathy and we have with us two of the authors of this primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr. Anwar Chahal from Lancaster, Pennsylvania. And of course, as always, we invite one of our associate editors and we have with us this week Ntobeko Ntusi from South Africa. Welcome gentlemen and Babken, let's start with you. Can you give us just a little bit of review regarding arrhythmogenic cardiomyopathy? We hear that term as opposed to arrhythmogenic right ventricular cardiomyopathy, and then maybe also, what are the underlying fundamental histopathologic and pathophysiologic findings associated with this disease?

Dr. Babken Asatryan:

Thank you, Greg. It's really an absolute pressure being here and thank you for your invitation again. So arrhythmogenic cardiomyopathic is genetically-determined heart disease and the common cause of sudden cardiac death in individuals younger than 40 years of age, it's characterized pathologically by fibrosis and/or fibro fatty infiltration of the myocardium. This infiltration provides a substrate for electrical and stability and leads to ventricular arrhythmias ranging from isolated premature ventricular contractions to sustain ventricular tachycardia and ventricular fibrillation. Live ventricular arrhythmias are cardio manifestations of the orthogenic cardiomyopathy, and they typically occur at early stages of the disease, preceding pathological and functional abnormalities. We call that a concealed stage of the disease.

Dr. Babken Asatryan:

The typical form for arrhythmogenic cardiomyopathy, which has been previously termed as arrhythmogenic right ventricular cardiomyopathy, primarily affects the right ventricle and has been recognized for decades. Following implementation of postmortem autopsy, increased use of contrast, enhanced cardiac MRI, and improved understanding of the genotype phenotype correlations, more recently cases with more pronounced left ventricular involvement have been discovered as well as cases with biventricular involvement of the disease.

Dr. Babken Asatryan:

Nowadays, we believe that around 60% of cases have also left ventricular involvement, even if they're diagnosed based on the 2010 task force criteria for arrhythmogenic cardiomyopathy. Causative variants in desmosomal genes are identified in about 60% of patients with typical arrhythmogenic right ventricular cardiomyopathy.

Dr. Babken Asatryan:

Recently, there have been studies reporting non-desmosomal gene variants in patients with arrhythmogenic right ventricular cardiomyopathy, as well as in those left ventricular and biventricular forms of the disease. But the left ventricular form is quite new to us, so we are learning a lot every day about this disease.

Dr. Babken Asatryan:

The pathogenesis of this condition appears to be quite complex. We know that these pathogenic variant in desmosomal genes can initiate several pathways and these could be gene dependent. What we do know, that these eventually lead to fibrosis and fibro fatty infiltration of the myocardium, which is the hallmark feature of arrhythmogenic cardiomyopathy.

Dr. Greg Hundley:

And patients present generally when, in terms of lifespan?

Dr. Babken Asatryan:

So, patients present in between 30 to 40 years of age, there's a typical presentation for arrhythmogenic cardiomyopathies but young presentations are also common nowadays, particularly. So, programs in families, they usually present 30 to 40 years of age. But in families, we do discover patients who have typical arrhythmogenic right ventricular cardiomyopathy or left and right ventricular involvement were younger at age, but they still need the criteria.

Dr. Greg Hundley:

And then when we diagnose this condition, do we also need to think about, at least clinically, looking for other affected individuals within a family?

Dr. Babken Asatryan:

Absolutely. So most of the arrhythmogenic biventricular cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy cases are autosomal dominant diseases. So, this means if an individual carries a pathogenic variant in one of the genes responsible for the condition, the likelihood that the first degree family members will carry the same variant is about 50%. The disease however, presents with reduced penetrance and variable expressivity. Some of the family members may have just arrhythmias and others may develop arrhythmias and structural heart disease. And some of the individuals who carry pathogen occurrence in desmosomal are the genes responsible for the condition may not show phenotype at all. So, that makes the decision-making in families quite challenging.

Dr. Greg Hundley:

Very nice. Well, thank you so much Babken and now, we're going to turn to one of your co-authors, Anwar and Anwar, in this primer, you start to present a new sort of theme, that inflammation actually may play a role in this disease, at least in terms of adverse events. Can you describe a little bit what your team was thinking here and what took you in this direction and what are some of the research that you've revered here that supports this new line of thinking?

Dr. Anwar Chahal:

Thanks, Greg and Ntobeko, for first, the kind invitation to come on this podcast. I must add that I normally listen to the podcast and very much enjoy it, so it's a great honor and privilege for us.

Dr. Anwar Chahal:

Let me contextualize it, I think it's important to think about what are problems are when we evaluate cases, whether that's the program or the family members, and try to determine what's actually going on. There's been a number of changes over the last 15 years that really evolve around a better understanding and the availability of multimodality imaging, which has altered the way we evaluate these cases. If you look at the 2010 taskforce criteria, for example, they talk about volumetric changes and injection fractions by echo or MRI, and even ventriculogram synapse on fluoroscopy, which I don't think many people do anymore, but they don't mention gadolinium enhancement, and there is an updated version that will come out and talk about that, and the advantages of MRI and even contrast-enhanced CT, and now 18F-FDG, CT PET imaging.

Dr. Anwar Chahal:

So, the patient journey and the problem that we face is that actually some people present with very unusual features, chest pain, troponin rise, undergo coronary angiography, normal coronary arteries, or unobstructed coronary arteries. We put them through MRI scanners and we see a little bit of gadolinium enhancement. We follow them over the next five years or so, and it develops into taskforce criteria, positive ARVC. So, that's the sort of clinical angle where we've started to see this.

Dr. Anwar Chahal:

As we put people through scanners, we see the hearts lights up on PET scanners, pretty reproducibly and reliably, that tells us that there's some inflammation there. We look back into the literature and actually very, very early work that was done, autopsy-based, some of it endomyocardial biopsy-based describing lymphocytic infiltrates. Usually that's dry, as you say, or sterile, but there have been reports of even viral pathogens.

Dr. Anwar Chahal:

That's where it stirred this debate up for us about whether there's this signal that we're seeing there, what is it? What's actually going on? It raises a question, we recognize the other mechanisms, the fiber fatty replacement, the apoptotic pathways, that contribute to that. But there's such variable expressivity with this disease. It's a difficult disease to pin down and it raises a question. What are these other effect modifiers? Is there something else that we do not recognize? And that's really what's driven this.

Dr. Anwar Chahal:

Our group of co-authors are leaders in the field. Some of them are colleagues in veterinary medicine, Dr. Anna Geltser, and we work together on boxer dog patients. So, she is a practicing vet and a scientist, and has lots of boxer dogs with arrhythmogenic cardiomyopathy. We've been looking at how we could utilize that as a model to test some of the findings that we have in humans and pioneering work really by Bob Hamilton in Toronto, in this paper where they described anti-DSG2 antibodies, which were found not only in humans, whatever the underlying genotype, but also in boxer dogs with arrhythmogenic cardiomyopathy. And that's been followed up with work from Europe, describing anti-heart antibodies, anti-intercalated disk antibodies.

Dr. Anwar Chahal:

It doesn't really matter what the genotype is, but we're seeing these antibodies there and we're seeing these positive scans indicating inflammation. So the big question is, is this inflammation of primary insult or is it secondary? Is it that the heart in somebody with a genetic cardiomyopathy is predisposed, maybe the remodeling is affected. Bob Hamilton thinks this is probably the best explanation to explain why, whatever the genotype, that these antibodies were positive, that actually that myocardium becomes exposed. The epitope of DSG is now exposed to the immune system, which mounts an antibody response, and hence you see the rise in these antibodies, but it's possible it could it be primary as well. With COVID, and this is a bit of a stretch, so just bear with me there, with COVID we've been recognizing that there's myocardial injury.

Dr. Anwar Chahal:

There's not as much myocarditis as we expected, but there's been, with virus SARS-CoV-2, we know regular human coronavirus is a recognized cause of viral myocarditis. So, the question really arose are we going to see a lot more of this myocarditis? In our lab discussion, it was, "Well, do you think we're going to see something similar in that we've seen with arrhythmogenic cardiomyopathy, these genetically predisposed individuals are more likely to get invaded? Now, we haven't really seen that with COVID and I won't delve too much into it, but going back to the classical viral infections that we see with myocarditis, here's a really, really interesting biological link. Most of them invade through the desmosome, so with SARS-CoV-2, we see the ACE2 receptors as the way the virus really invades. But with these regular coxsackie virus, for example, parvovirus, a lot of them invade through the desmosome, and that's where we thought, here's a link.

Dr. Greg Hundley:

Very nice. Ntobeko, you see a lot of papers come across your desk. What attracted you to this group of investigators and this particular review article?

Dr. Ntobeko Ntusi:

Thank you very much, Greg. I want to start by congratulating Babken, and Anwar for a really fantastic submission, which as an associate editor, was an absolute pleasure to handle. There really are six things that stood out for me about this article. The first one really relates to the question that you ask Babken, which relates to the nomenclature and people have traditionally thought of this is a disease of the right ventricle. I think it's now timely to consider a clear change in nomenclature, that recognizes not only right ventricular involvement, but also left ventricular involvement. And the common finding of biventricular disease in patients with ACM.

Dr. Ntobeko Ntusi:

The second really important contribution for me from this primer was that we've always thought of arrhythmogenic cardiomyopathies as a genetic disorder with abnormalities in the genes, encoding components of the desmosome. Many groups recently, including our own group that described novel mutations for arrhythmogenic cardiomyopathy in adhering to poultry and other genes outside of the desmosome are showing that the genetic underpinnings are much wider. But the key contribution here is really the consideration of the centrality of inflammation to the pathogenesis of this disease. Anwar has spoken to some length about that, so I won't rehash those comments, but for me, what is key for future work in this area is really to clarify whether the inflammation, as in with many other forms of cardiovascular disease, is merely an epiphenomenon, or whether it plays a critical role in the causal pathway for the phenotypes that we see.

Dr. Ntobeko Ntusi:

The next important feature for me was the review of the literature and evidence in the association with myocarditis. So, we've seen lots of case reports and small case series showing young people presenting with myocarditis and meeting either the Dallas criteria histologically, or the Lake Louise criteria on imaging, and then subsequent genetic testing confirming the diagnosis of an arrhythmogenic cardiomyopathy. I thought for the first time with quite a compelling review of the link between these two.

Dr. Ntobeko Ntusi:

The fourth important contribution relates really to the contribution of imaging modalities, both in diagnostics, but critically in risk stratification for this clinical entity. And for me, the importance of cardiovascular magnetic resonance, either with planimetric mapping or late gadolinium enhancement to really add to our ability to predict future events.

Dr. Ntobeko Ntusi:

Then there's been quite a number of publications in the last five years that have clarified our understanding of the at risk patient with arrhythmogenic cardiomyopathy who's likely to suffer a sudden cardiac death event. This tends to be somebody who was young, who was male, who has a history of documented non-sustained ventricular tachycardia or a history of syncope and on ECG, quite extensive T wave inversion. So again, this is nicely reviewed, and we think about those as candidates who'll benefit from implantation of an ICD.

Dr. Ntobeko Ntusi:

Then I thought for me, the last really nice contribution from this piece was the review of advancing our understanding of the hot phase. So in all forms of heart muscle disease, we speak of the presentation of patients with the chest pain syndrome, with a troponin leak, but unobstructed coronaries. On further investigation, we don't really find any other evidence of an inflammatory event. We call this a hot phase. And in some case reports in small case series, endomyocardial biopsy has revealed the association of these, whether in TCM, HCM, or arrhythmogenic cardiomyopathy with lymphocytic infiltration. I thought this was all very nicely reviewed.

Dr. Ntobeko Ntusi:

So, the question that really left me with having read this review, was whether in the future, we may actually need to consider targeting inflammatory pathways as a therapeutic target in this heart muscle disorder. Thanks Greg.

Dr. Greg Hundley:

Yes. Thanks so much in Ntobeko. You've really led us to the next question that I'm going to ask both Babken and Anwar, you've discussed where do you feel this field is moving and what is the next study or series of studies we need to perform. Babken, first you, and then Anwar. Babken, what do you think is the next study to be performed in this space?

Dr. Babken Asatryan:

I so much agree with Ntobeko, that perhaps understanding better what can be targeted in these patients, in order to prevent development of phenotype or least to prevent cardiac events, is perhaps the most important next step. In our first figure, we have summarized this potential mechanisms, involving inflammation leading to with arrhythmogenic cardiomyopathy in these patients. We have also highlighted the potential mechanisms that perhaps in the future can be targeted. This could include both targeting the inflammatory cytokines, as well as the primary agents that cause the myocardial inflammation in patients, depending on the results that we will receive over the next years and perhaps animal models should be the next step to better understand how similar arrhythmogenic cardiomyopathy phenotype, where inflammatory contributors to the phenotype are important. And then we can understand whether this can be the same in humans as well.

Dr. Greg Hundley:

Very nice. And Anwar, do you have anything to add?

Dr. Anwar Chahal:

Yes. So, agree with that. I guess I would add what are we doing to try to help decipher this? So some of the work that we're doing, I mentioned earlier with the boxer dog patients, who have arrhythmogenic cardiomyopathy. So some of the aspects that we're actually looking at is taking swab cells to see if we can phenotype as a alternative tender myocardial biopsy. And one of the co-authors, Angeliki Asimaki, really pioneered that as a alternative tool because the desmosis are ubiquitous and this may help us phenotype patients better. But also, we want to look at using that as a tool in the pheno copies of arrhythmogenic cardiomyopathy. So we would advocate, re-phenotyping people as well as possible and trying to use some of these techniques.

Dr. Anwar Chahal:

The next thing we're really looking at is antibody based tools, either working with collaborators, who've already described these antibodies such as anti-DSG2, anti-heart antibody, and anti-skeletal disc to see if we can develop those and perhaps identify others in both human and ox models. And that will then hopefully open the way for us to develop therapeutics that may be able to target those and address that, and maybe use these antibodies as markers to see disease progression, or halting of disease.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Babken Asatran from Bern, Switzerland, Anwar Chalal from Lancaster, Pennsylvania, and our own associate editor, Ntobeko Ntusi from South Africa, really helping us see this new scientific consideration regarding the potential role of inflammation in causal pathways of adverse manifestations of arrhythmogenic cardiomyopathy. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Circulation November 9, 2021 Issue

8 november 2021 | 22 min

Please join author Maria Nunes and Associate Editor Ntobeko Ntusi as they discuss the article “Incidence and Predictors of Progression to Chaga Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.”

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this feature this week, we're going to talk about Chagas disease and we have some really important long-term, really for the first time, observational data and a cohort that's been followed in Brazil. And it's just a wonderful discussion from a team that's been working very hard in this area over an extended period of time. But before we get to that, how about we grab a cup of coffee and get started on some of the other articles in this issue? Would you like to go first?

Dr. Carolyn Lam:

I would. And with your coffee, I would like to tell you about non-combustible nicotine or tobacco products. Fancy a smoke with your coffee? Well, you know that those are novel forms of nicotine consumption composed of things like nicotine vaping products that vaporize the nicotine-containing fluids and heated tobacco products that really heat the tobacco products without combustion. Now, these have recently gained popularity because they're portrayed as being safer modes of smoking compared with the traditional combustible cigarettes. However, their associations with subsequent cardiovascular disease risks are still unclear. So Greg, here's today's quiz. Gosh, I miss our quizzes. What do you think? Are they safer or are they not?

Dr. Greg Hundley:

Oh, Carolyn, you're catching me on this and I never know which way to go, but I'm going to guess not. How about you tell us?

Dr. Carolyn Lam:

Well, the paper will tell us, and this is from co-corresponding authors Dr. Lee from Seoul National University Bundang Hospital and Dr. Park from Seoul National University College of Medicine and their colleagues. And they basically studied more than 5,000,000 adult men who underwent health screening examinations during both a first and second phase of health screening periods from the Korean National Health Insurance Service Database spanning 2014 to 2018. Initial combustible cigarette smokers who subsequently quit that cigarette smoking and converted to a non-combustible nicotine or tobacco product use was associated with a lower incident cardiovascular disease risk compared to those who continue the combustible cigarette use. However, compared with combustible cigarette quitting without using these non-combustible substitutes, those who ceased smoking but continued with the non-combustible products was associated with a higher cardiovascular disease risk. So the take home message is although the non-combustible nicotine or tobacco products may be associated with a lower cardiovascular disease risk compared with continued combustible cigarette smoking, those who quit without using these substitutes may benefit the most in reducing the risk of developing future cardiovascular disease events. And this is discussed in a wonderful editorial by Dr. Auer, Diethelm and Berthet.

Dr. Greg Hundley:

Very nice, Carolyn. Great presentation and really new information in this space. Well, my paper comes from the world of preclinical science and it involves long noncoding RNAs. And Carolyn, they are important regulators of biological processes involved in vascular tissue homeostasis and cardiovascular disease development. And so, the current study, led by Professor Lars Maegdefessel from Karolinska Institute, assessed the functional contribution of the long noncoding RNAs myocardial infarction associated transcripts and their relationship to atherosclerosis and carotid artery disease.

Dr. Carolyn Lam:

Hmm, interesting. They are the rage, these lncRNAs. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So long noncoding RNAs possess key regulatory functions directly interacting and mediating expression and functionality of proteins, other RNAs, as well as DNA. Next, the long noncoding RNA myocardial infarction associated transcript plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high risk patients with vulnerable plaques. And so, Carolyn, the take home therapeutic targeting of the long noncoding RNA myocardial infarction associated transcript, using antisense oligonucleotides, well that offers novel treatment options for patients with advanced atherosclerosis in the carotid arteries that are at risk of stroke.

Dr. Carolyn Lam:

Oh, very interesting. So from the preclinical world back to the clinical world with an important clinical trial. Now, we know that percutaneous closure of the left atrial appendage is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amplatzer Amulet Left Atrial Appendage Occluder IDE trial, called the Amulet IDE trial, was designed to evaluate the safety and effectiveness of the dual seal mechanism of the Amulet left atrial appendage occluder compared with the WATCHMAN device. And here, 1,878 patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned to undergo percutaneous implantation of a left atrial appendage occluder with the Amulet occluder or a WATCHMAN device. And the primary end points included safety, which was a composite of procedure-related complications all cause death or major bleeding at 12 months, and effectiveness, which was a composite of ischemic stroke or systemic embolism at 18 months. They also looked at the rate of left atrial appendage occlusion at 45 days. And this paper is from Dr. Lakkireddy and colleagues from Kansas City Heart Rhythm Institute.

Dr. Greg Hundley:

Well Carolyn, these devices, they are really being heavily tested in patients with atrial fibrillation. So what did they find?

Dr. Carolyn Lam:

The Amulet occluder was non-inferior with respect to safety and effectiveness compared to the WATCHMAN device, and superior with respect to left atrial appendage occlusion; however, procedure-related complications were higher with the Amulet occluder, largely related, perhaps, to more frequent pericardial effusion and device embolization. And the authors noted that the procedure-related complications decreased with operator experience; however, I think all of this still needs to be further investigated. Well, those were really nice original papers, but let's also discuss what else there is in today's issue. There is an exchange of letters between Drs. Mueller and Allen regarding the article “Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite U.S. Cohort.” There's a perspective piece by Dr. Olson, “Toward CRISPR Therapies for Cardiomyopathies.”

Dr. Greg Hundley:

And Carolyn, I've got a research letter from Professor Layland entitled “Colchicine in Patients with Acute Coronary Syndromes: Two Year Follow Up of the Australian COPS Randomized Clinical Trial.” Well, what a great set of papers that we've discussed. Now, let's get on to that feature discussion and learn a little bit more about the longitudinal history and progression of cardiovascular disease and patients with Chagas disease.

Dr. Carolyn Lam:

Yay. Let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we are here for our feature discussion today and a very exciting one we have, pertaining to Chagas disease. And we have with us today Dr. Maria Nunes from Belo Horizonte, Brazil, and also one of our Associate Editors, Dr. Ntobeko Ntusi from Cape Town, South Africa. Welcome to you both. And Maria, we'll start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Maria Nunes:

Yes, thank you for these opportunities. My main hypothesis is that Chagas disease is the major cause of dilated cardiomyopathy in endemic areas. So we selected patients without cardiomyopathy at baseline to see if the Trypanosoma cruzi seropositivity is a predictor of further developing of cardiomyopathy.

Dr. Greg Hundley:

Very nice. And so tell us, how did you construct this study? What was your design? And then also, maybe describe for us how you selected the participants for this study.

Dr. Maria Nunes:

We selected the participants from two blood donor centers. One in Sao Paulo and one in Montes Claros, which is north of Minas Gerais State. We select blood donors because it's the way that we have Chagas disease’s screening tests. And in asymptomatic patients, usually at the hospital, patients comes to us with heart failure or a kind of symptoms related to Chagas disease. Our main goals in this study is to select healthy participants based on the screen test of Trypanosoma cruzi. So the population was blood donors selected from two centers.

Dr. Greg Hundley:

Very good. And then again, your study design. So did you follow these two groups of individuals longitudinally over time, and for how long?

Dr. Maria Nunes:

Yes, we have different visits of this study with the patients initially was selected at first in 1996 and 2002. At this time, they don't have cardiovascular exams. And our study actually is starting 2008 to 2010, and we select all these patients with all comprehensive cardiovascular evaluation with the clinical examination, echocardiogram and electrocardiogram, and then just the baseline for our patient population. And we follow them 10 years on average until 2018, 2019.

Dr. Greg Hundley:

Very nice. So it sounded like from individuals in two regions of Brazil, identified those through screening of the blood, and I guess these were blood donors, and then performed a series of cardiovascular exams 2008 to 2010 and followed them for the next 10 years. And you're going to tell us about the results that occurred 2018 to 2019. And so what were those results?

Dr. Maria Nunes:

We found that Trypanosoma cruzi seropositive is a risk factor for developing cardiomyopathy. Nowadays, this is still a risk factor, seropositive without cardiomyopathy at baseline has two times higher risk of developing cardiomyopathy compared to the seronegative controls. And we have also detected that the parasite load or the level of parasite in the blood expressed by antibodies against Trypanosoma cruzi is an important risk factor for disease progression. That means some patients have Chagas disease, but the level of antibodies is not too high. These patients go well. And other hand, the patients with high level antibodies means the parasite load may be higher too. This is the high risk of disease progression to cardiomyopathy or of dying too.

Dr. Greg Hundley:

Very nice. And were there any subgroups of patients where you found these relationships to be particularly more striking? So for example, the elderly, or was there a discrepancy based on sex, men versus women?

Dr. Maria Nunes:

Yes, other studies has already shown that the male gender is a risk factors in Chagas disease. Usually they progress more, they have more severe clinical presentation, usually die at the age between 30 and 50 years old, the most productive years of the life. That's why Chagas is so important here in Brazil and Argentina, in Latin America countries because people die at early ages.

Dr. Greg Hundley:

And your results confirmed what was previously known in that regard.

Dr. Maria Nunez:

Yes, patients with developing cardiomyopathy with heart failure has a high mortality rate. And then even patients with cardiomyopathy detected by exams like based on ECG or echo, they asymptomatic, but they progress more for dying or to develop cardiomyopathy compared to seronegative with similar risk effects for cardiovascular disease, such as hypertension, diabetes, smoking.

Dr. Greg Hundley:

Very good. Well Ntobeko, you see many papers come across your desk as an Associate Editor for Circulation, and what attracted you to this paper and the results that Maria has described?

Dr. Ntobeko Ntusi:

Thank you, Greg. I was attracted to this paper because it's an important natural history study of Chagas disease. But secondly, it's also one of the largest contemporaneous cohorts of Chagas disease which provides important insights and advances in our knowledge with regard to this clinical entity. And for me, there were three things that stood out. The first one was an important description of the outcomes of Chagas cardiomyopathy. The second was the contemporaneous description of the epidemiology in a well-characterized cohort. And the third and novel contribution was the description of the determinants of disease progression. So I thought overall, the really important contribution to the field.

Dr. Greg Hundley:

Very good. And for those that might not live in the endemic area, but might occasionally encounter someone with Chagas disease, what results from this paper can we use to help manage patients in this situation?

Dr. Ntobeko Ntusi:

Thanks, Greg. So this was a study which had a number of really positives. Firstly, it's a large study, it was non acute [inaudible 00:16:42] design and it used PCR for diagnosis. And unlike many other studies, also ascertained antibody levels and had very good clinical characterization, which included electrocardiographic, echocardiographic assessment, including serum assessment of proBNP and CK-MB. And all really important take home messages are for me. The first one is understanding that the relationship of your antibody levels and baseline LV function to mortality. In other words, are finding that in those with existing LV structural abnormalities, or higher levels of antibody titers, mortality was higher. The second important contribution is a description of the incidence of Trypanosoma cruzi, and this was highest as one would expect in the seropositive donors and much lower in seronegative donors. The third important contribution relates to our improved understanding of the determinants of disease progression, which were related to the Trypanosoma cruzi antibody levels.

In other words, the higher your antibody titers, the quicker you progressed to manifest the cardiomyopathic phenotype. And then lastly, the predictors of mortality, which were related to your PCR being positive, as well as your antibody titers. Important is this contribution is there are a number of important caveats. The first is that the study is limited by the huge amount of loss to follow up, which as you can imagine, adds a number of biases to our conclusions. The second is that the observations may of course be confounded by comorbidity in particular because these patients are older and had higher comorbidity. The third is that we assume that the PCR positivity and antibody titers actually correlate with parasite pattern, but in fact, we know that is not always the case. And then lastly, for people who read this paper from non-endemic parts of the world, the result may not be clearly generalizable to those parts of the world.

Dr. Greg Hundley:

Very nice. Well, we've had a great discussion, listeners. From Maria and Ntobeko sort of presenting the paper and then what are some of the take home messages. So now I'd like to go back to both of them and Maria, first you and then Ntobeko. Maria, what do you think is the next study to really be performed in this sphere of research?

Dr. Maria Nunes:

We may should stratify patients with Chagas disease. Those who have high antibodies titers should refer to a kind of treatment or benznidazole treatment. We should intervene in this subgroup.

Dr. Greg Hundley:

Very good. And Ntobeko, anything to add?

Dr. Ntobeko Ntusi:

Yes, Greg, I think that there are two important next steps. The first one is that I think we need other large designed prospective studies that will validate the observations by Dr. Nunes and colleagues. And then the second key step for me would be the design of randomized controlled trials to test therapeutic agents with antitrypanosomal activity to demonstrate their ability to retard or completely block disease progression, which would be a nice way to complete the story.

Dr. Greg Hundley:

Very nice. Well listeners, we've had a great discussion today and we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from South Africa for bringing these really informative results pertaining to Chagas disease, and highlighting the natural history and showing an association between these high titer values and poor cardiovascular outcomes.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation November 2, 2021 Issue

1 november 2021 | 21 min

Please join author Ole Fröbert and Associate Editor Dharam Kumbhani as they discuss the article "Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU health in Richmond, Virginia. Well, listeners, this week we've got a really hot feature topic pertaining to flu vaccines, which are coming in the US, North America, South America, coming up soon, and their relationship to myocardial infarction. But before we get to that feature discussion, let's grab a cup of coffee and jump in to some of the other articles in this issue. Oh, wait a minute. Our first article, we've got a co-author here. Carolyn, something about the VICTORIA trial, which you were a part of. Can you tell us a little bit about this?

Dr. Carolyn Lam:

I would love to, and first of all, I'm doing this on behalf of a big team, and I want to really, really call up first Dr. Paul Armstrong who's the senior author from University of Alberta. But let me tell you first about the VICTORIA study. VICTORIA evaluated vericiguat, a soluble guanylate cyclase stimulator, compared to placebo, in patients with heart failure with reduced ejection fraction with a recent worsening heart failure event and the primary result was actually a significant reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization with vericiguat compared to placebo.

Dr. Carolyn Lam:

Now, interestingly though, in VICTORIA, we found that anemia occurred more often in patients treated with vericiguat at a rate of about 7.6% compared to placebo, which was 5.7%. Now, although earlier studies of another soluble guanylate cyclase stimulator like riociguat was found to be associated with anemia. The etiology really remains unknown. In the current paper, we explored the relationship between markers of anemia and vericiguat versus placebo in VICTORIA. We further explored the changes in hemoglobin and hematocrit over the course of the trial and their relationships with the primary composite outcome.

Dr. Greg Hundley:

Carolyn, this is such an important new study heart failure therapy for those with reduced ejection fraction, and again, an important topic related to anemia. What did they find?

Dr. Carolyn Lam:

Thanks, Greg. First, approximately a third of patients in VICTORIA had anemia at randomization, and this is using the standard sex-based definitions. With a lower hemoglobin indeed predicting a higher risk for cardiovascular death, heart failure hospitalization, all-cause mortality. As I had already mentioned, we found more anemia with vericiguat than with placebo. The interesting thing though is after 16 weeks, no further decline in hemoglobin occurred over the remaining and over 96 weeks of follow up, and the ratio of hemoglobin to hematocrit remained constant. Now, overall, the adverse event of anemia occurred in 7.1% of the patients.

Dr. Carolyn Lam:

Importantly, the lower hemoglobin was not related to the beneficial effect of vericiguat over placebo on the primary outcome. Now, I know all of that may be more descriptive and reassuring than really understanding the mechanism by which it occurred. Further mechanistic studies are certainly warranted to better understand the basis of the anemia development, and it's of principle importance because as you said, vericiguat I think it's going to be an important new medication that we can consider in high-risk patients with recent worsening heart failure with reduced ejection fraction.

Dr. Greg Hundley:

Thanks so much, Carolyn, especially the perspective of being an author on this particular study. Well, Carolyn, my next study is going to come to us from Dr. Zhao Wang from University of Texas Southwestern Medical Center, and it's really about the integrated stress response, and that's an evolutionary conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery perfusion is the most effective means to mitigate cardiac damage resulting from myocardial infarction. However, that can cause, as we know, additional reperfusion injury. This study aim to investigate the role of the integrated stress response in myocardial ischemia reperfusion injury.

Dr. Carolyn Lam:

Oh, very interesting. What were the results?

Dr. Greg Hundley:

Right, Carolyn. The authors found that the integrated stress response is activated by ischemia reperfusion injury in the heart, and the perk branch of the integrated stress response protects the heart from ischemia reperfusion injury through inhibition of protein synthesis. Also, Carolyn, mitochondrial complex proteins are selectively suppressed and oxidative stress is reduced by the integrated stress response. Carolyn, the takeaway is that this integrated stress response is cardioprotective against cardiac ischemia reperfusion injury. Perhaps pharmacological stimulation of the integrated stress response at reperfusion, well, that may reduce heart damage and improve cardiac outcomes after ischemia reperfusion injury.

Dr. Carolyn Lam:

Cool. Thanks, Greg. Well, I've got one more paper, and this deals with coronary microcircuitry dysfunction and acute rejection after heart transplantation. Co-corresponding authors, Doctors Lee and Choi from Heart Vascular Stroke Institute in Samsung Medical Center sought to evaluate the prognostic implications of coronary microcircuitry dysfunction assessed by the index of microcircuitry resistance or IMR for the risk of acute cellular rejection after heart transplantation. They did this by prospectively enrolling 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment one month after transplantation.

Dr. Greg Hundley:

Very interesting, Carolyn. What did they find here?

Dr. Carolyn Lam:

IMR measured early after heart transplantation was significantly associated with the risk of acute cellular rejection, and an IMR above or at 15 was highly predictive for the recurrence of acute cellular rejection during two years of follow up following heart transplantation. Adding IMR to the prediction model with clinical variables significantly increase discriminant and reclassification ability for the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, the implications are that early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation, and this is discussed in an editorial by Doctors Fearon and Valentine from Stanford University.

Dr. Greg Hundley:

Very nice, Carolyn.

Dr. Carolyn Lam:

Great. Greg, before we go to the exciting feature discussion, let's round it up by just a quick tour of what else there is in today's issue. There is an exchange of letters between Doctors Pappone Leor on atrial fibrillation as a cardiomyopathy, global rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr. Tsai on grouped beating following acute inferior myocardial infarction, and a research letter by Dr. Salem on electrocardiographic manifestations of immune checkpoint inhibitor myocarditis.

Dr. Greg Hundley:

Great, Carolyn. Well, I can't wait to get to this next feature discussion and learn a little bit more about the relationship between flu vaccines and future myocardial infarction.

Dr. Carolyn Lam:

Today's feature discussion was a really hot topic at the ESC 2021, and in fact, a simultaneous publication. It is about influenza vaccination after myocardial infarction, a very important topic and a very novel paper. We are so pleased to have the first and corresponding author, Dr. Ole Fröbert from Orebro University in Sweden to discuss this paper, as well as our associate editor, Dr. Dharam Kumbhani, from UT Southwestern. Welcome, gentlemen. Only if I could start with asking you to describe the rationale for why you did this study, and then perhaps quickly summarize the results.

Dr. Ole Fröbert:

Yeah, thank you so much, Carolyn. The background of the study was that during influenza epidemics, more people die from cardiovascular causes, and out in the literature, there are numerous observational studies suggesting a protective effect from influenza vaccination on cardiovascular events. There are also three smaller single-center randomized trials supporting these registered findings. Currently influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention guidelines, but uptake is low and vaccination timing is unclarified. Our aim was to determine whether influenza vaccination improves clinical outcomes in patients with a recent myocardial infarction or with high risk corona artery disease.

Dr. Ole Fröbert:

The study was international, multi-centers investigator initiated, double-blind randomized control trial, and we enrolled patients at 30 centers across eight countries in both the Northern and the Southern Hemisphere, Sweden, Denmark, Norway, Latvia, Scotland, Czech Republic, Bangladesh and Australia. We enrolled patients between October 2016 and March 2020. We had quite broad inclusion criteria. We included hospitalized patients with STEMI or non-STEMI, or high-risk stable patients over 75 years of age undergoing an angio or PCI. We excluded patients already vaccinated or intending to be vaccinated during the current season. We also included, of course, patients if they had allergy to X or influenza vaccine, if they had infection or if they were immunosuppressed or previously randomized in the trial.

Dr. Ole Fröbert:

Over these four years of inclusion, we enrolled a total of 2,571 participants. The primary outcome was a composite of all-cause death, MI and stent thrombosis. This outcome occurred in 67 participants assigned influenza vaccine and 91 assigned placebo corresponding to a reduction of the primary endpoint of 28% with a P value of 0.04. Also, rates of all-cause death and of cardiovascular death were reduced and both with a hazard ratio of 0.59 corresponding to a reduction of 41% in all-cause death and cardiovascular death. Based on these results, we think that this trial and what we know from previous smaller trials should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment after an MI.

Dr. Carolyn Lam:

Heartfelt congratulations, Ole. What an elegant intervention in a very frankly challenging situation that the trial obviously carried on through COVID as well, multinational. May I just double check? Was it investigator-led? Because-

Dr. Ole Fröbert:

Yes, this was-

Dr. Carolyn Lam:

That's amazing.

Dr. Ole Fröbert:

... an idea that just popped up, and then yeah, we did it, but it was seven years of work.

Dr. Carolyn Lam:

Wow. Hard work as I can just imagine. First, heartfelt congratulations. Very impactful results. Dharam, could I invite you to put those results in context and why we single this out?

Dr. Dharam Kumbhani:

Yeah. No, thank you, Carolyn. Ole, I want to amplify or recapitulate the amazement and wonder that Carolyn just articulated. I think this is a huge endeavor. It's a very important topic. It's "a fairly simple intervention." It's vaccination, and you've just really shown that even in the acute setting, that A, this is as feasible, B, it is safe, and three, it is effective. I think it's potentially ... Given the magnitude of influenza in the world, I think this has tremendous public health ramifications. I really want to congratulate you and your investigators for pursuing this important question and then just executing this, I'm sure despite multiple challenges over a long period of time.

Dr. Ole Fröbert:

Thank you very much.

Dr. Dharam Kumbhani:

Yeah, no. I guess you already alluded to the fact that this may influence guidelines. As you mentioned, it's a 1B. Maybe get your thoughts, I suppose this may move the needle towards becoming perhaps a little stronger on the recommendation front, both in the US and the European guidelines?

Dr. Ole Fröbert:

Yeah. I think what has been the challenge until now is that many places, of course, you commend patients to take a flu jab when treatment is over in the hospital. But then the responsibility is diffused. Who should take care of that? Is that up to the patient or the primary care physician? Who is in charge? One important finding of this study is, as you said, it's safe. There were no differences, adverse events between the two groups. It's safe and it could be given early. I think a take-home factor from the study is that it should be given at the hospital and it's a responsibility of the cardiologist.

Dr. Dharam Kumbhani:

Yeah, I really like that. Actually, I'm sure this would resonate across the board in the cardiology community. We've taken ownership for starting from statin and now SGLT-2 inhibitors, which kind of ... All of these medications have come from non-cardiology realms, so to say. But now we prescribe those medications. We know they have clear cardiovascular benefits. I suppose you could make a case to say we, the cardiology community, has to adopt this. The implementation gap that exists for a lot of these therapies, that also comes to us and for us to move that forward. It's thought provoking. I certainly felt very strongly after your study. I don't know how you feel about that. We should really be the ones driving this and help with more widespread immunization in these patients.

Dr. Ole Fröbert:

I think because not just this study, but also the previous studies and what we know from observational findings is that this is safe and it works. What we also saw in our study, and it has been indicated in previous meta analysis, is that the maximum effect is seen in the acute setting. It's the acute coronary syndrome patients, the patients we had in our study, that benefit the most. That's also a case for actually doing this in the hospital and not postponing it.

Dr. Carolyn Lam:

Wow. That's amazing. Ole, I do have one question. Just for clarification. You were careful to say that you did this during influenza seasons, right? Coming from my part of the world in Singapore where we don't really have influenza seasons, don't have any seasons, frankly, what would you think? What would you advise?

Dr. Ole Fröbert:

There is influenza seasons in all parts of the world, I'm sorry.

Dr. Carolyn Lam:

True.

Dr. Ole Fröbert:

For example, we had Bangladesh on board in our study. It's in the Northern Hemisphere, but influenza-wise, it's in the Southern, and their season is between May and September. But it's not as clearly defined as the Northern Hemisphere season. It's almost always in two waves during that season. One practical challenge with influenza vaccine is that it's produced for the seasons. It's difficult to say, "Yeah, we can just do it all year round," and also we didn't test that. I, of course, feel we should give it all year round, but it's not available, the vaccine. Perhaps it should be tested, but it is probably difficult to find funding for such a study.

Dr. Carolyn Lam:

Very fair, and thanks for the correction. It's true though. Singapore's on the Equator, so we don't have maybe weather seasons. But yeah, we do get vaccinated for both North and South. It's quite fascinating. But nonetheless, could I now switch topics a little bit and just over the next couple of minutes just ask you, could you please perhaps share with the audience what it was like to work with Circulation, to do this simultaneous publication? You see, our associate editor, Dharam Kumbhani, really leads this effort to get simultaneous a fast-track publication from major conferences, and it means a lot to us that investigators like you chose us. Could you share a bit?

Dr. Ole Fröbert:

Yeah, thank you very much. Overall, it was a pleasure. Of course, we were ... With every study of this size, you are under stress, you get the results late, and there's a conference coming up, and you would like your paper to come out at the same time across to maximize impact and attention. What I really like with working with Circulation was turnaround time was ultra fast, really extremely fast. Of course, we had a lot of questions to our study, but these were ... Some of them of course were quite difficult, but they were fair. In a way, they were also helpful in a way that made it easier to address the questions in a more, you could say, collaborative way. It was very smooth. No hiccups.

Dr. Carolyn Lam:

Thank you. Dharam, any final responses to that?

Dr. Dharam Kumbhani:

No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure to work with you on this. I think we all recognize that this was an important study and wanted to make sure that we were able to accomplish the goal of simultaneous publication. Thank you for working with us on that. I just want to put a pitch in, I think this, for Joe, Dr. Hill and the rest of the editorial team, having a robust simultaneous publication program has been very, very important. We are very committed to working with investigators and authors on this. We are really blessed with our team on the backside that works seamlessly with us nights, weekends, just to get these things done. I just want to end with that to say this is very important for us, and we look forward to the opportunity to work with Ole and others on future papers as well.

Dr. Carolyn Lam:

I love that. Thank you both for being on this podcast today. Today I want to especially call out David Rivera, a wonderful managing editor who really, really is part of leading this entire group that supports us, but also even this very podcast. You've been listening to Circulation on the Run. Thank you, from both Greg and I, for joining us today, and don't forget to tune in again next week. Thank you.

Dr. Greg Hundley:

Circulation October 26, 2021 Issue

25 oktober 2021 | 27 min

Please join author Jonathan Newman and Associate Editor Sandeep Das as they discuss the article "Outcomes of Participants With Diabetes in the ISCHEMIA Trials."

Dr. Carolyn Lam:

Welcome to circulation on the run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts; I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, this week's feature, a couple of weeks ago, we had that feature forum on the ischemia trial. Now we're going to explore some of the outcomes in patients with diabetes, from the ischemia trial in the feature discussion today. But, before we get to that, let's grab a cup of coffee and start in on some of the other articles in this issue. So, how about if I go first, this time? This particular paper, Carolyn, we're going to start on one of your topics. I know you're a fan of diet related interventions. So high intake of added sugar is linked to weight gain and cardio-metabolic risk. And in 2018, the U S National Salt and Sugar Reduction Initiative proposed government supported voluntary national sugar reduction targets.

Dr. Greg Hundley:

This intervention's potential health and equity impacts and cost effectiveness are unclear. And so Carolyn, these authors, led by Dr. Renata Micha from Tufts University, incorporated a validated micro-simulation model - CVD Predict coded in C++, and used it to estimate incremental changes in type two diabetes, cardiovascular disease, quality adjusted life years, cost and cost effectiveness of this national policy. The model was run at the individual level and the model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across three cycles spanning from 2011 to 2016, added sugar related diseases from meta-analysis and policy costs and health-related costs from established sources and a simulated nationally representative us population was created and followed until age 100 years or death with 2019 as the year of intervention start and findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives.

Dr. Carolyn Lam:

Ooooh, You so got my attention, Greg, a very important topic and so, what did they find?

Dr. Greg Hundley:

Right, Carolyn. So achieving the NSRI sugar reduction targets could prevent 2.48 million cardiovascular death related events, 0.5 million cardiovascular disease deaths, and three quarters of a million diabetes cases, gain 6.7 million quality adjusted life years, and save $160.8 billion in net cost from a societal perspective over a lifetime. The policy became cost-effective, defined as less than $150,000 for quality adjusted life years at six years and highly cost-effective at seven years with a cost savings noted at nine years. And therefore, Carolyn, implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains, and cost savings.

Dr. Carolyn Lam:

Wow, thanks Greg. So, moving from a very publicly health focused paper to this paper that really focuses on hypoplastic left heart syndrome with very, very scientifically significant findings. Now, first, we know hypoplastic left heart syndrome is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis is unknown, but hemodynamic disturbances are assumed to play a prominent role. Authors led by Doctors Moretti and Laugwitz from Technical University of Munich in Germany, as well as Dr. Gruber from Yale University School of Medicine, and their colleagues combined whole exome sequencing of parent offspring, trios, transcriptome profiling of cardiomyocytes from ventricular biopsies and immuno-pluripotent stem cell derived cardiac progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as well as single cell gene expression analysis to decode the cellular and molecular principles of hypoplastic left heart syndrome phenotypes.

Dr. Greg Hundley:

Wow, Carolyn, there is a lot of data, very complex preclinical science here. So what did they find?

Dr. Carolyn Lam:

Indeed, Greg. As I said, scientifically incredible and rigorous, and they found that initial aberrations in the cell cycle unfolded protein response, autophagy hub led to disrupted cardiac progenator lineage commitment, consequently, impaired maturation of ventricular cardiomyocytes limited their ability to respond to growth cues. Resulting in premature cell cycle exit and increase apoptosis under biomechanical stress in 3D heart structures. Together, these studies provide evidence that the hypoplastic left heart syndrome pathogenesis is not exclusively of hemodynamic origin, and they revealed novel potential nodes for rational design of therapeutic intervention.

Dr. Greg Hundley:

Wow, Carolyn, we really need research in this topic and this is great preclinical science that we're getting here in our journal. Congratulations to the authors and what a great presentation of that by you. Well, Carolyn and my next paper there remain major uncertainties regarding disease activity within the Retain Native Aortic Valve, as well as bioprosthetic valve durability, following transcatheter aortic valve implantation. And these authors led by Doctor Jacek Kwiecinski, from the Institute of Cardiology, aimed in a multi-center cross-sectional observational cohort study to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement or SAVR.

Dr. Carolyn Lam:

Oh, very interesting. And what were the results?

Dr. Greg Hundley:

An interesting comparison, Carolyn. So in patients with TAVI, native aortic valves demonstrated 18 F sodium fluoride uptake around the outside of the bioprosthesis that showed a modest correlation with the time from TAVI. Next, 18 sodium fluoride uptake in the bias prosthetic leaflets was comparable between SAVR and TAVI groups. Next, the frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echo cardiography 6 and 8% respectively, CT, 15 and 14% respectively, and with PET scanning. Next, baseline 18 F sodium fluoride uptake was associated with subsequent change in peak aortic velocity for both TAVI and SAVR. And on multi-variable analysis, the 18 F sodium fluoride uptake was the only predictor of peak velocity progression. And so Carolyn, therefore, in patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease and across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable midterm durability.

Dr. Carolyn Lam:

Very nice, important stuff.

Dr. Carolyn Lam:

Well, thanks, Greg. Let's tell everyone about the other papers in today's issue. There's an exchange of letters between Doctors Baillon and Blaha regarding the article very high coronary artery, calcium and association with cardiovascular disease events, non-cardiovascular outcomes and mortality from MESA. There's an ECG challenge from Dr. Bell Belhassen on a left bundle branch block, tachycardia following transcatheter aortic valve replacement. And On My Mind paper by Dr. Neeland on cardiovascular outcomes trials for weight loss interventions, another tool for cardiovascular prevention, another Research Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono therapy in heart failure, patients with atrial fibrillation and stable coronary artery disease. So insights from the AFIRE trial, and finally, a Research Letter from Dr. Kumoro three-dimensional visualization of hypoxia induced, pulmonary vascular remodeling in mice.

Dr. Greg Hundley:

Great, Carolyn, and I've got an in-depth piece from Professor Jia Sani entitled breadth of life, heart disease, linked to developmental hypoxia.

Dr. Greg Hundley:

Well, Carolyn, how about we get onto that feature discussion and learn more about results from the ischemia trial?

Dr. Carolyn Lam:

Let's go Greg.

Dr. Carolyn Lam:

Well, we all know how important diabetes is as a risk factor for atherosclerotic coronary disease. And we know it's a very common comorbidity among patients with chronic coronary disease, but the question is do patients with diabetes and chronic coronary disease on top of guideline directed medical therapy and lifestyle interventions, of course, do they derive incremental benefit from an invasive management strategy of their coronary disease? Well, we are going to try to answer that question today in our feature discussion. Thank you so much for joining us today. The first author and corresponding author of today's feature paper, which tells us about results from the ischemia trials. And that's Dr. Jonathan Newman from New York university Grossman School of Medicine. We also have associate editor Sandeep Das from UT Southwestern. So welcome both of you. And if I could please start with Jonathan reminding us, perhaps, what were the ischemia trials and then what you tried to answer and do in today's paper,

Dr. Jonathan Newman:

Of course, Carolyn, and thank you so much for having me and for the discussion with Sandeep. It's a pleasure to be here. So sure has a little bit of background, as you indicated, the ischemia trials basically enrolled and for the purposes of this discussion and this analysis, I'm referring to both the main ischemia trial and the ischemia chronic kidney disease trials. So ischemia CKD under the umbrella of the ischemia trials. Ischemia stands for the international study of comparative health effectiveness with medical and invasive approaches. And the purpose of the trial was to test to see whether a routine invasive approach on a background of intensive guideline directed medical therapy for high risk patients with chronic coronary disease and at least moderate ischemia and obstructive coronary disease documented on a blinded CCTA or computed coronary tomography angiography prior to randomization was associated with benefits for a cardiovascular composite. And we looked in this analysis at whether or not there was appreciable heterogeneity of treatment effect or a difference in treatment effect for patients compared without diabetes in the ischemia trials, in ischemia and ischemia CKD.

Dr. Carolyn Lam:

Great, thanks for lining that up so nicely. So what,

Dr. Jonathan Newman:

So the results of our analysis really highlighted a couple of things that I think you touched upon initially, the first thing that I would highlight is that diabetes was very common in this high risk cohort with chronic coronary disease, over 40% of participants in the ischemia trials, 43% with obstructive coronary disease and moderate to severe, you may have had diabetes. Perhaps not surprisingly patients with diabetes had higher rates of death or MI than those without diabetes. And the rates were highest among those patients that required insulin, had insulin treated diabetes, but using really robust methods to assess for heterogeneity using a Bassen assessment of heterogeneity of treatment effect accounting for violation of proportional hazards. The fact that there was an upfront hazard and a late benefit, we really saw no difference in death or MI, between the invasive or conservative strategies for patients with, or without diabetes over about three years of follow-up.

Dr. Jonathan Newman:

And the results importantly were consistent for ischemia and ischemia CKD and provided the rationale for us when we started by looking to see if the distribution of risk and characteristics allowed the trials to be combined. The study really confirms this higher risk of death or a MI for chronic coronary disease patients who have diabetes extends these findings for those patients with moderate or severe ischemia. And I think really notably also adds information about chronic coronary disease patients with diabetes and CKD. That's sort of the overall findings. And I'm happy to talk in more detail about that.

Dr. Carolyn Lam:

I love the way you explain that Jonathan and especially, going into detail on what was so different about the paper and the really important statistical methods that made these findings robust, very important and impactful findings. If I could ask Sandeep to share your thoughts.

Dr. Sandeep Das:

Thanks, Carolyn. You know, I am just a big fan of everything that's come out of the ischemia group. One of the things that I really most enjoy as a consumer of the literature is when well done studies give me results that are unexpected. And I know it's become fashionable now to say that everybody knew that all along that this is what going to be the result. But honestly, I think we all sort of are many of us thought that there's going to be a subgroup somewhere that's really going to benefit from an invasive approach in terms of preventing heart outcomes. I think the key here that really jumped out at me was that this is identifying what we typically think of is a very high risk subgroup. You know, patients with diabetes patients with multi-vessel coronary disease patients with insulin dependent diabetes.

Dr. Sandeep Das:

And we did see the association with mortality across the increased disease severity and the increased severity of diabetes as expected. But really we didn't see a signal that revascularization, routinely revascularizing patients, even the higher risk patients led to clinically relevant heart outcome benefits. So I thought that that was a really interesting top line finding and really that's kind of. I mean, it would have been interesting if it was the other way too, but it was, it really was kind of the hook that got me into the paper.

Dr. Sandeep Das:

I actually have a question for Jonathan, one of the things that I think we spend a lot of time as an editorial group thinking about and talking about, and we bounce back and forth with the authors a few times was the idea that relatively few of these patients with multi-vessel CAD ended up having CABG. So, you would typically think of diabetes multi-vessel CAD as being a pretty strong signal for patients that may benefit in terms of mortality from having bypass surgery. And here it was a relatively small group about a third, or maybe even less than a third. And I realized up front, they excluded the left main and the patients that had angina had a CTA, et cetera. But what I'd be curious as to your thoughts about, the benefits of bypass surgery and diabetes, which have been established in other trials.

Dr. Jonathan Newman:

It's a great question. And I think we really appreciated the questions from you and from the editors to try and get at some of the nuance with this issue. As you indicated in the ischemia and ischemia CKD trials overall, and the patients in the invasive treatment arm, it was about 25% or so 26% and 15% were revascularized with CABG. Part of the issue here is that it gets a little tricky with the use of CCTA of pre randomization CTA to define coronary artery severity, which was not required in the CKD population due to impaired renal function. But what we can say is among the patients with diabetes and multi-vessel coronary disease, 29% were revascularized surgically in their combined analysis, which is comparable to the 30% in Bery 2d that were revascularized via bypass surgery, as we've discussed. And as you know, the decision for surgical versus percutaneous revascularization in ischemia, as in Barry 2d was non-randomized though we might want to, we really tried to be very, very cautious in terms of comparing revascularization strategies on outcomes for patients with diabetes and multi-vessel CAD, which has you suggested.

Dr. Jonathan Newman:

And as we pointed out, the proportion with multi-vessel CAD was more common amongst in patients with diabetes compared with those patients without diabetes. The other thing I would sort of say in the framework of, the revascularization and strategies for revascularization, comparing, let's say ischemia to Barry 2d or to freedom. Basically we have very little data about revascularization approaches for those patients with creatinine with impaired renal function and, patients with the crediting greater than two were excluded from Barry 2d. So while we had about 15% or so that had severe CKD. So in the GFR, less than 30 are on dialysis. And we know that's an extremely high risk group of patients with diabetes and chronic coronary disease. And we don't have great evidence on which strategy for revascularization if at all provides additional benefit. So I think it's a really a tough question to answer, and we tried to be as judicious as possible in our comments about revascularization approaches, given the nature of the trial design.

Dr. Carolyn Lam:

Gee, thanks so much, Jonathan, for explaining that. So, well, I actually have a related question now, referring to the medical therapy. Can I, sort of ask you about the fact that, these days that the rage is all about GLP one receptor agonist, for example, that are known to reduce the risk of atherosclerotic cardiovascular disease and diabetes. So these ischemic trials, I assume, did not have a high usage of these medications. And what do you think would be the impact, if anything, I suppose even more for guideline directed medical therapy. Huh?

Dr. Jonathan Newman:

Yeah. So it's a great question, Carolyn. As you know, in strategy trials and clinical trials in general, that take a while it's always a real challenge to keep the trial contemporary with current clinical practice, whether it's revascularization strategies or changes in medical therapy. And as you indicated, the real revolution and glucose lowering therapies with profound cardiovascular benefit for patients with diabetes, we worked hard to try and stay up to date and encourage sites around the world with the use of best SGLT2 inhibitors and GLP ones. The rates were very, very low and we don't actually given the fact that the ischemia trials were conducted a real multinational and is really an international trial is over 330 sites worldwide. So we really had to balance the data that we could get from sites with the reality of collecting and running this trial across the whole world.

Dr. Jonathan Newman:

So we don't actually know. We know insulin use or non-use or oral medication use or non-use or no medication use or non-use, but not much more than that. From what, as, you know, unfortunately, even after now, six going on seven years of impressive data for the benefit of these agents, uptake remains low for patients with diabetes, whether it's with coronary disease or heart failure. And there was certainly the case with the trial, which started back in 2015, or sorry, before 2015, even before the results of EMPA-REG. So the rates of those agents were low. I would expect as you indicated that if we did have greater use of these beneficial therapies. Medical therapy may have performed even better and potentially given an added boost potentially for our high risk, even higher risk subgroups that we'd looked at that were available in these trials.

Dr. Carolyn Lam:

Oh, thanks again. I wish we could go on forever, but we've got just a little bit of time left. So I'd like to ask you both for your quick take home messages for the audience. Could I start with Sandeep and then Jonathan?

Dr. Sandeep Das:

Yeah. You know, I think a key take home from this is that, although it may be naively intuitive that a very aggressive invasive strategy would be superior, especially in high risk patients. You know, the data are very, very convincing that it's not. And so therefore I think in an absolute minimum, you have plenty of time and ability to think about these patients carefully, to select who, if anybody would be a great candidate for revascularization, more aggressive therapy and more invasive therapy, but the most patients will do well with conservative management.

Dr. Sandeep Das:

And I think that that's the, that's a real key take home here. And I think that the points that Jonathan raised about, you know, poor uptake of GLP one RAs and SGLT 2 inhibitors in the community as they're so far are key, right? So we have great medicines that we just under used, and that to me is the other sort of clarion call here is that if in the context of a nice trial, that you can see similar result for invasive conservative approaches, then lets, let's get our medical therapy where it needs to be to provide our patients the best outcomes we can

Speaker 3:

Love it, Jonathan.

Dr. Jonathan Newman:

Yeah. So I'm really glad that Sandeep brought up the issue of medical therapy in the trial. And maybe I can take a minute to sort of frame what San kind of build off of what Sandeep just said, you know, we, in the context of this clinical trial, you know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the co-chair and I, we worked very hard with optimizing medical therapy across the trials, for all participants. So really getting patients on the maximum tolerated doses of high-intensity statins, lowering patient's LDL as aggressively as possible evolving our systolic blood pressure targets. And it was extremely challenging. And at the end of the day, we see that patients with diabetes were more likely than those without to get to our LDL goal. We used a threshold problematic concept that that still may be to some extent, but they were less likely to achieve their systolic blood pressure goals.

Dr. Jonathan Newman:

And I think Sandeep was exactly right. We have a way to go with implementing existing therapies, existing medical therapy. There may be a benefit for as demonstrated in Dr. S. for patients that remain highly symptomatic to derive symptom benefit with revascularization. The other context I would sort of add with the medical therapy issue is that despite really aggressive medical therapy, and we really did as much as we could, patients with diabetes still had, a 40, 50% greater risk of death or MI than those without diabetes. So there's still this idea of kind of residual risk. And these were patients with diabetes that were very well managed from a medical and glycemic control perspective. So we still have a lot of work to do. And I think understanding ways we can benefit our patients is really that challenge.

Speaker 3:

Thanks so much, Jonathan, and thank you Sandeep for joining us today.

Speaker 3:

And thank you audience for listening from Greg and I. This has been "Circulation On The Run", please tune in again. Next week.

Dr. Greg Hundley:

Circulation October 19, 2021 Issue

18 oktober 2021 | 27 min

Please join author Khurram Nasir and Associate Editor Sandeep Das as they discuss the article "Social Vulnerability and Premature Cardiovascular Mortality Among US Counties, 2014-2018."

Dr. Carolyn Lam:

Welcome to Circulation on the Run your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm really excited about today's feature discussion. It's really meaningful on so many levels. It discusses social vulnerability. In other words, social determinants of health and its association with premature cardiovascular mortality among US counties. Now, even as an ex-US person I learned a lot, so everyone is going to want to listen in. But now let's start with going through some exciting papers in today's issue, shall we?

Dr. Greg Hundley:

You bet Carolyn. So, I'm going to grab a cup of coffee and we'll get started with the first article. And really gets into the world of cardiovascular risk and prostate cancer management.

Dr. Greg Hundley:

So, Carolyn in the light of improved prostate cancer survivorship, and the competing risk of cardiovascular disease, there's an ongoing need for rigorous cardio oncology clinical trials. As you probably know, androgen deprivation therapy is a cornerstone of prostate cancer therapy. Through different pituitary gonadotropin releasing hormone receptor mediated mechanisms both GnRH agonists, as well as antagonists, either indirectly or directly inhibit luteinizing hormone secretion, consequently inhibiting testosterone production. These GnRH agonists are the most commonly prescribed form of androgen deprivation therapy with only 3 to 4% of patients receiving a GnRH antagonist.

Dr. Greg Hundley:

So, Carolyn the relative cardiovascular safety of gonadotropin releasing hormone antagonists compared with gonadotropin releasing hormone agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains somewhat controversial. And therefore these authors led by Dr. Renato Lopes from both Brazil, as well as the Duke University Medical Center in Durham, conducted an international multicenter, prospective randomized open label trial, and men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomized one to receive gonadotropin releasing hormone, antagonist degarelix or the gonadotropin releasing hormone, agonist leuprolide for 12 months and the primary outcome was time to first educate major adverse cardiovascular event that combined the endpoints of composite death MI and stroke over these 12 months.

Dr. Carolyn Lam:

Nice Greg, and what did they find?

Dr. Greg Hundley:

Right Carolyn, due to slower than projected enrollment and fewer than projected primary outcome events enrollment was stopped before the 900 plan participants were accrued from May 3rd, 2016 to April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were really balanced between the two study groups. Now Mace occurred in 5.5% of the patients assigned to degarelix and 4.1% assigned to leuprolide and so in summary, Carolyn, this pronounced study is the first international randomized clinical trial to prospectively compare the cardiovascular safety of a gonadotropin releasing hormone antagonist as well as agonist in patients with prostate cancer. And the study was terminated prematurely due to smaller than planned number of participants and events. And so no difference in mace at one year was noted between the two groups and this pronounced study really provides a model for interdisciplinary collaboration between urologists, oncologists and cardiologist with a sheer goal of evaluating the impact of cancer therapies on cardiovascular outcomes.

Dr. Carolyn Lam:

That's so cool, Greg. I heard the presentation of these results at the ESC by Dr. Renato Lopes and it's a really cool and important study, but a paper I want to present is an analysis from Emperor preserved on inpatient and outpatient heart failure events.

Dr. Greg Hundley:

Great. Carolyn, so remind us, what did the Emperor preserved trial show?

Dr. Carolyn Lam:

Emperor preserved showed that in patients with heart failure and preserved ejection fraction empagliflozin reduce the primary endpoint of cardiovascular death or hospitalization for heart failure, primarily related to a lower risk of hospitalizations for heart failure. Greg you're smiling, because you can see me beaming because we finally have a robustly positive outcomes trial in have pep in this trial. Nonetheless in the current analysis, Dr. Milton Packer from Baylor Heart and Vascular Institute and others used prospectively collected information on inpatient and outpatient events, reflecting worsening heart failure, and pre specified their analysis in individual and composite end points.

Dr. Greg Hundley:

I've been in suspense here. What did they find?

Dr. Carolyn Lam:

Empagliflozin reduced the risk of severe hospitalizations as reflected by admissions requiring the use of ionotropic or vasopressor drugs and the need for intensive care. Empagliflozin also reduce the risk of outpatient worsening heart failure events, including the need for urgent care visits, diuretic, intensification, and unfavorable changes in functional class. So, basically benefit across the spectrum. Furthermore, because there's controversy about the effect across the spectrum of ejection fraction. The benefit on total heart failure hospitalizations was found to be similar in patients with an ejection fraction of above 40, but less than 50% and between 50 to 60%, although it was attenuated at the higher ejection fractions and we'll hear a lot of discussions about this.

Dr. Greg Hundley:

Wow, Carolyn. Just more information that keeps coming out about SGLT-2 inhibition. My next paper comes from the world of preclinical science and angiogenesis is a dynamic process, involves expansion of a preexisting vascular network that can incur in a number of physiologic and pathologic settings. But despite its importance, the origin of the new angiogenesis vasculature is really poorly defined in particular, the primary subtype of endothelial cells, whether they be capillary, Venus or arterial that might be driving, this process really remains undefined. These authors led by Dr. Michael Simmons at Yale University school of medicine, fate mapped endothelial cells using genetic markers specific to arterial, Venus and capillary cells.

Dr. Carolyn Lam:

What did they find Greg?

Dr. Greg Hundley:

This team study results found that Venus endothelial cells were the primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterial, venous malformation, and pathologic angiogenesis. And these observations highlight the central role of the Venus endothelium in normal development and disease pathogenesis.

Dr. Carolyn Lam:

Wow. That's really interesting. I don't think I've ever really paid attention to that bit. Venus endothelium. Thank you for that. Now what else is in today's issue? Well, there's an exchange of letters between Doctors Zhang and Liao regarding the article anti hypertrophic memory after regression of exercise induced physiologic, myocardial hypertrophy is mediated by the long noncoding RNA M heart 779, then ECG Challenge by Dr. Ahmed on challenges of interpreting smart watch and implantable loop recorder, tracings. There's cardiology news by Tracy Hampton and Highlights from the Circulation Family of journals by Sara O'Brien. These regular articles are just really worth a read. You learn so much from just these short lovely summaries. There's On My Mind paper by Dr. Meyer on a targeted treatment opportunity for taking advantage of diastolic tone. And there's also a Research Letter by Dr. Brozovich on a rat model of heart failure with preserved ejection fraction changes in contractile proteins, regulating calcium cycling and vascular reactivity.

Dr. Greg Hundley:

These journal issues, there's so much information. I'm in a close out with an in depth piece from professor entitled antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. I really look forward to your feature discussion on the social vulnerability and premature cardiovascular mortality in US countries.

Dr. Carolyn Lam:

Thanks Greg. It's good.

Dr. Carolyn Lam:

Today's feature discussion focuses on an extremely important topic of social vulnerability and premature cardiovascular mortality. So pleased to have the corresponding author of the feature paper, Dr. Khurram Nasir from Houston Methodist and Dr. Alana Morris, who is the editorialist for this paper. And she's joining us from Emory University in Atlanta, Georgia. So thank you both of you for joining and Alana if you don't mind, I'm going to borrow some of the words from your really-excellent editorial to bring us into the discussion. You very nicely brought up that early race and ethnic disparities and a death toll from COVID 19 really, laid the foundation for us having Frank conversations about vulnerable populations and has really brought to light social determinant of health and social economic inequality as risk factors. Now that's, COVID 19. And frankly, if we put everything in a global view of what kills most of us, it's still cardiovascular disease, which is why this paper is just so important, but current recognizing I'm not from the US, lots of our audience are not from the US. Could you please walk us through what your paper looked at and what it means?

Dr. Khurram Nasir:

Sure. Klan, thank you so much for having us today and what a wonderful editorial by Dr. Morris on this. As you pointed out about the COVID challenges, we were all touched by the significant disparities, really in a one of the lifetime crisis, such as COVID. But the reality is that even in times of calm the benefits, for example, cardiovascular disease prevention access have not been shared equally among vulnerable groups. So I'm a preventive cardiologist, and it gives me immense pride that despite being the number one cause of morbidity mortality for so long as a cardiology community, we have made significant strides over the last three decades, cutting into our losses. And if you look at the trends it's appeared and I'm very hopeful that we'll soon be losing the number one killer tag in US. At the same time we are seeing that those cuts are being lost, especially in the young individuals.

Dr. Khurram Nasir:

And at one point while we celebrate these decline. But the thing that bothers many of us that unfortunately these gains have not been equal, especially for our more vulnerable patients. And apart from the well documented, I think racial disparities that we all know and are becoming more aware. I think health disparities also form across various fourth lines and I believe the deepest and more persistent divides is around income. And you can even go a step further in US, unfortunately for our international group is unfortunate fact that in US, your zip code may hold more sway than your genetic code. And an example was made famous in St. Louis, Missouri Del marble award, which is known as the Delmer divide, a title that was made famous by a four minute BBC documentary that showed, that a sharp dividing line between the poor predominantly African American neighborhoods in the north and more affluent, largely white neighborhood in the south with health falling across this divide.

Dr. Khurram Nasir:

And in our practice, we see this phenomenon clearly in our own backyard. So, inspired by this sterling. We wanted to determine that a mirror geographical measure, where we can get insights of conditions where people live, learn, work, play, grow, and age, and commonly now known as the social determinants of health. Can that explain some of these rising risks, especially in the premature cardiovascular disease. So to design this study, we reached out to the CDC social vulnerable, the index that has been created that ranks communities and zip codes based on 15 factors across food domains, socioeconomic status, household composition of disability, that in includes single parents, elderly or children, minority status and language and housing type and transportation, all of them are put together and for each census. And then eventually at the county level, you can classify what their social vulnerability is. And as you know, this was really developed in to identify places where in times of disaster and emergencies, you can focus a little bit more, but we thought about how do we connect this to, for example, our data on mortality from CDC wonder.

Dr. Khurram Nasir:

And once we did that, we found very interesting patterns that across the scale social vulnerability, there is a risk dose dependent fashion and the age adjusted mortality rates for premature cardiovascular disease, which we define as less than 65, went from the least vulnerable and became the worst across the most vulnerable. At the same time, we also found this double jeopardy issues where this association was varied by race, gender, and ruler. And what we found that specifically Non-Hispanic lack individuals were more likely for certain types of cardiovascular, premature, such as stroke and heart failure, mortality, as compared to the rest, even if you were from the least vulnerable to the most women also unfortunately had a twofold higher risk of CBD mortality. And what is becoming clearly this whole ruler urban that a two to five fold risk of CBD mortality was seen among the least vulnerable. So this is in just the motive of our study, what we did and what we found.

Dr. Carolyn Lam:

That is so wonderful. Thank you for setting the context and then just to reiterate, so this was all within the US. Alana, could you maybe help frame how important these findings are for us?

Dr. Alana Morris:

Yes. I think that this analysis is so important, particularly within the context of some of the things that we see happening politically in our country and our landscape right now. And I think we tried to touch on some of those issues in the editorial. Again, I think that the COVID 19 pandemic, if you want to put that against this landscape has really brought into the forefront of our minds, this issue of disparities. Of course, there are many of us who have been thinking about researching and writing about disparities for a long time, but the issue of disparities really, came into the public mindset with the COVID 19 pandemic. The question now is how do we address these as we go forward? And what we're seeing politically is this question of how do we address inequalities that have been present for really since the beginning of time and maybe are widening and perhaps threaten many of the advances that we've made in terms of cardiovascular disease, morbidity, and mortality.

Dr. Alana Morris:

I think we have to think about in the US, universal healthcare coverage, because we have to be able to prevent disease and treat disease. And as current addressed, there are neighborhood zip codes where people not only don't have access to healthcare, but they don't even have access to the ability to promote health. They don't have access to things like parks, where they can exercise. They don't have access to healthy foods or grocery stores and in a country like the United States where there's so much wealth, you need to think about the fact that certain individuals, don't have the ability to access a grocery store, to access healthy food. It's just really striking and mind boggling that we have this, the difference in rural versus urban locations where some of our US residents, unfortunately don't have access to primary care clinicians, certainly not specialty clinicians is really very mind boggling. And we've seen this play out with the pandemic, but hopefully once we get past the COVID 19 pandemic, we still have to come back to a place where again, we're taking care of not only preventives or services to prevent the onset of cardiovascular disease, but certainly once people are diagnosed with cardiovascular disease, we want to get them access to specialty care. So we have to think as a community, how do we prevent disease, but also treat disease once disease is diagnosed within our country.

Dr. Carolyn Lam:

What you just said about the zip code being more powerful about, than the genetic code, that's like a quotable code. It's incredible. And for those of us coming outside of the US, we don't even realize how much that plays a role, even just within the US. But now let's get to exact point that Alana pointed out, which is what are the next steps. And could you maybe suggest Khurram, and Alana maybe come first, but what's the one thing you want to get out or the one next thing that should happen after this

Dr. Alanna Morris:

We put a figure in to the editorial that I think really gets to the heart of the matter, I think that those of us who are in healthcare or those of us who think about public health really would ask the question of, why in a country that has as much wealth as the United States, do we not have universal healthcare, most countries across the world that are in an economic position similar to the United States do have universal healthcare coverage for their residents. And you see much better statistics in terms of longevity for their residents as compared to what we have in the United States. And what you see when you look at the United States is that where there is the most vulnerable residents as per analysis identifies those states are the ones that actually don't have, Medicaid expansion.

Dr. Alanna Morris:

They don't have a safety net for their residents. And so there's really contrast and this disparity that just does not make sense. It does not make sense where there are residents in the United States, which need the most help and they just don't have it. They just are not able to get access to preventive services as well as diagnostic services. And it really just doesn't make sense what we're doing in the United States, in my humble opinion. And I think in the humble opinion of many of us who want to take care of patients, but just cannot, Kern and I both practice in states where this is an issue. And I think that's one big driver. But again, I think when we also think about the built environment in the US and how we think about promoting health and how we talk to patients, when we talk about individuals in the US, we try to give them advice about therapeutic lifestyle changes, how to exercise, how to eat healthy, to prevent disease. That's easier for certain individuals as compared to others, depending upon where you live, depending upon those five digits that make up your zip code. So if we really want our residents to be healthy, we have to create an environment that enables them to do that.

Dr. Carolyn Lam:

Wow, thank you very much. And as I let Khurram have the final words even about where you think mixed research should be. I just want to highlight that incredible figure from your editorial Alana. I mean, it is really started, there are three panels to it, everyone. The first one chose the social vulnerability index, the second, the premature cardiovascular disease mortality, and then the third, the status of Medicaid expansion. And you can see the colors are just vivid in, how it all makes sense and goes together. So pick up our journal and have a look, but then finally Khurram?

Dr. Khurram Nasir:

So, Alana, your figure was fantastic and so much add perspective to our findings. As you were saying, it took me back to 35 years back when, where we are before Medicare disparities, even in access to hospitals were dramatic. So where we practice in the south one third of the hospitals would not admit African Americans even for emergency. Now, this is where the policy comes in and suddenly in 1965 using the carrot of Medicare dollars, the federal government virtually ended the practice of racially segregating patients, doctors, and medical staffs, blood supplies so that is the direction that we need to go from the policy perspective and trying to affect the upstream determinants. Now moving forward, as I think more, and especially as a physician, I think while the census level measures are extremely useful to help refine these policy and focus programs in vulnerable areas.

Dr. Khurram Nasir:

I also think that there is a parallel need to start focusing on similar efforts at the individual level. The first thing is how do we even identify social determinants at this patient level? Are there three main categories, income, education, possibly healthcare, but I think that we need to broaden this. And in the past we have been challenged because we didn't have a set of consensus of the defined SDUH framework. But thankfully now in 2021, we have the healthy people, 2020. Actually for international community, the WHO there is a WHO framework of identifying SDOH at an individual level and in US a more comprehensive Kaiser family foundation. And not only that, we looked at superficially broadly, but we have to go deeper beyond these components of economic instability, education, housing, social context on healthcare beyond insurance, and even food.

Dr. Khurram Nasir:

For example, income and employment are predominant pillars of income stability, but it may not capture the full picture. For example, difficulty paying bills out of pocket cost and death related to medical care, same in education, where we captured the highest degree, but issues around health and digital literacy and language proficiency may be even more important. So not only we have to broaden the scope, but we have to go in depth. And thirdly, what I've realized from these kind of studies that we have to go a step further, that social disparities don't occur in silos. And we have to look at the aggregated information. And maybe it's time to potentially learn from advances in genetics, in what we have learned that manifestation of disease, especially cardio metabolic rather than being influenced by few major genes is manifested secondary to multiple interacting genes. So can we create similar to a poly genetic risk score, which is an aggregation of genetic smaller risk to a relevant something similar called poly social risk score.

Dr. Khurram Nasir:

Now, this is an area that our group has been extensively working. And over the last 12 months, we have tried to construct a comprehensive poly social risk score at an individual level based on almost about 50 sub components of the social determinants. And we have suddenly finding very interesting associations with premature CAD stroke. Almost one in two young individuals with stroke, have the worst poly social risk code at the individual level. I think so the next steps will be definitely validation of this tool, incorporation in practice, whether it's adoption and effective interventions can be tied. But the final thing, what I truly want to say is that I'm hopeful that these efforts, the census level at an individual level, at a societal level and the health system are waking up to the importance of social determinants that we can think outside the box and have strong community partnerships. Multi Pro strategies driven largely by social economic environmental factors. So we can all make a lead towards the mission of achieving social justice and equity that eventually cascades through the health system and beyond. So we had enough time to illuminate the issues and challenges. Now it's the time to act.

Dr. Carolyn Lam:

Thank you so much Kern for a beautiful paper. We are so proud to be publishing it in circulation. And thank you, Alana lovely, editor that we've said so many times. Thank you audience for joining us today. You've been listening to Circulation on the Run from Greg and I please tune in again. Next week,

Dr. Greg Hundley:

This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American heart association for more visit ahajournals.org.

Circulation October 12, 2021 Issue

11 oktober 2021 | 27 min

Please join author Milton Packer and Associate Editor Justin Ezekowitz as they discuss the Perspective "Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, it really is so great to be back with you chatting about the papers here in the Journal. Thank you for going solo and for just being the greatest partner on earth. Thank you for that. For everyone listening in, we are back with some gusto and especially with this feature discussion today. You are not going to want to miss it. We are talking to Dr. Milton Packer as well as Dr. Justin Ezekowitz. We are going to compare PARAGON and EMPEROR-Preserved trials in heart failure with preserved ejection fraction. A really interesting discussion you're not going to want to miss, but now let's start with some papers in today's issue. I'd like to start, please.

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

Greg, you know the optimal duration of antiplatelet therapy in patients with high bleeding risk with or without oral anticoagulation after coronary stenting? Well, that still remains a question. Today's paper is a pre-specified subgroup analysis of the MASTER DAPT trial and reports on the outcomes of patients with or without an oral anticoagulation indication in this study.

Dr. Greg Hundley:

Right, Carolyn. Remind us. What was the MASTER DAPT trial? What did it test?

Dr. Carolyn Lam:

Ah. MASTER DAPT investigated an abbreviated or one-month versus a non-abbreviated or three to 12-month dual antiplatelet therapy and a stopping of antiplatelet therapy at six months strategy after coronary stenting in an all-comer population at high bleeding risk.

Dr. Greg Hundley:

Carolyn, what did this subgroup analysis of outcomes in patients with and without oral anticoagulation show?

Dr. Carolyn Lam:

At 12 months of follow-up, ischemic and net risk did not differ with abbreviated versus non-abbreviated anti-platelet regimens in both subgroups, although significantly fewer clinically relevant bleeding events occurred in the group without an oral anticoagulation indication. Whereas only numerically fewer bleeding events occurred in the group with an oral anticoagulation indication that did not reach statistical significance. This subgroup analysis from the MASTER DAPT trial really adds additional evidence that dual antiplatelet therapy beyond one month in patients with or without an indication for oral anticoagulation really has no benefit and only increases bleeding risk.

Dr. Greg Hundley:

Oh, very important finding, Carolyn. Great research. Well, Carolyn, how the extracellular matrix microenvironment modulates the contractile phenotype of vascular smooth muscle cells and confers vascular homeostasis really remains elusive. Thus, these investigators led by Professor Wei Kong at Peking University applied protein-protein interaction network analysis to explore novel extracellular matrix proteins associated with the vascular smooth muscle cell phenotype.

Dr. Carolyn Lam:

Huh. Interesting. What did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. By combining an in-vitro and an in-vivo genetic mice vascular injury model, they identified nidogen-2, a basement membrane glycoprotein, as a key extracellular matrix protein for maintenance of vascular smooth muscle cell identity. Nidogen-2 exerted its protective function via direct interaction and modulation of Jagged1-Notch3 signaling.

Dr. Carolyn Lam:

Wow! Nidogen-2 and Jagged1-Notch3. I always learn so much. What are the clinical implications, Greg?

Dr. Greg Hundley:

Right, Carolyn. Perhaps targeting nidogen-2 to precisely modulate Jagged1-Notch3 signaling, well, that may provide novel therapeutic strategy for atherosclerosis and post-injury restenosis.

Dr. Carolyn Lam:

Very nice. Well, in the next paper, we discuss inflammation in heart failure. We know that inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Interesting, huh? Well, these authors, Dr. Wollert and colleagues from Hannover Medical School in Germany, identified an adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against persistent afterload stress-induced heart failure in mice. Monocytes and macrophages produced myeloid-derived growth factor in the pressure overloaded myocardium to augment SERCA2a expression in cardiomyocyte's calcium cycling and contractility. Myeloid-derived growth factor plasma concentrations were also found to be elevated in patients with aortic stenosis and to decline after aortic valve implantation indicating that pressure overload also triggers myeloid-derived growth factor release in humans.

Dr. Greg Hundley:

Carolyn, really informative preclinical science, but what are the clinical implications?

Dr. Carolyn Lam:

Ah. These observations molecularly defined a feature of the inflammatory response to hemodynamic overload that protects against heart failure development. Inflammation's beneficial trade therefore need to be considered when developing inflammation as a therapeutic target in heart failure. All of this is really discussed in a lovely editorial entitled Inflammation and Heart Failure: Friend or Foe? That's by Drs. Hajjar and Leopold.

Dr. Greg Hundley:

Great job, Carolyn. Well, my next paper focuses on resistant hypertension. Carolyn, although lifestyle modifications generally are effective in lowering blood pressure among patients with unmedicated hypertension or those treated with one to two antihypertensive agents, the value of exercise and diet for lowering blood pressure in patients with resistant hypertension is unknown. To address this, Professor James Blumenthal and co-authors at Duke University Medical Center enrolled 140 patients with resistant hypertension with an average age of 63 years, 48% women, 59% black, 31% diabetes, and 21% with chronic kidney disease and randomly assigned them to A, a four-month cardiac rehab center-based program of lifestyle modification. We're going to call that C-LIFE, consisting of dietary counseling, behavior and weight management, and exercise. Or number 2 or the B, a single counseling session providing standardized education and physician advice. We'll call that SEPA.

Dr. Greg Hundley:

The primary endpoint was clinic measured systolic blood pressure. Secondary endpoints included 24-hour ambulatory blood pressure and selective cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of baroreflex on heart rate; high-frequency heart rate variability to assess vagally-mediated modulation of heart rate; flow-mediated dilation to evaluate endothelial function; and pulse wave velocity to assess arterial stiffness; and then finally left ventricular mass to characterize left ventricular structure and remodeling.

Dr. Carolyn Lam:

Wow! That is a very, first of all, important clinical question. Then also, just very intricate methodology in assessing this. What did they find?

Dr. Greg Hundley:

Right, Carolyn. Between-group comparisons revealed that the reduction in clinic systolic blood pressure was greater in C-LIFE compared with SEPA. Next, 24-hour ambulatory systolic blood pressure also was reduced in C-LIFE with no change in SEPA. Then next, compared with SEPA, C-LIFE resulted in greater improvements in baroreflex sensitivity, high-frequency heart rate variability, and flow-mediated dilation. There was no between-group differences in pulse wave velocity or LV mass.

Dr. Greg Hundley:

Carolyn, diet and exercise can lower blood pressure in patients with resistant hypertension. When delivered in a cardiac rehabilitation setting, a four-month program of diet and exercise as adjunctive therapy, results in a significant reduction in clinic and ambulatory blood pressure, and improvement in selected cardiovascular disease biomarkers.

Dr. Carolyn Lam:

Wow! Really nice, Greg. Okay. Well, looks like we're all going to round up already with what else there is in today's issue. Let me start. There's an exchange of letters between Drs. Fang and Vinceti regarding the article Blood Pressure Effects on Sodium Reduction: Dose-Response Meta-analysis of Experimental Studies.

Dr. Greg Hundley:

Right, Carolyn. I've got a few things in the mail bag. First, Professor Anker has a Research Letter regarding the Kidney Function After Initiation and Discontinuation of Empagliflozin in Heart Failure Patients With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Dr. Gerstenfeld has an ECG challenge entitled Atrioventricular Block with Narrow and Wide QRS: The Pause That Refreshes. Then lastly, Dr. Donald Lloyd-Jones has an AHA update regarding the American Heart Association's focus on primordial prevention. Well, Carolyn, I can't wait to hear this fantastic feature discussion with you and Dr. Packer. How about we jump to that?

Dr. Carolyn Lam:

Great. Let's go, Greg.

Dr. Carolyn Lam:

Because side-by-side exam of PARAGON and EMPEROR is like side-by-side of...

Dr. Justin Ezekowitz:

You can compare our new and our old prime minister much like your paper did.

Dr. Milton Packer:

Yeah, yeah.

Dr. Justin Ezekowitz:

There are [crosstalk] and it could be viewed until they perform in the broader world how it goes. You don't quite know.

Dr. Milton Packer:

The only problem is you can't do a head-to-head comparison of the old prime minister and the new prime minister.

Dr. Justin Ezekowitz:

That is true except that the head-to-head comparison includes excellent care by both the new and the old. I think that comparison's going to be pretty equal. I think we can case-control that one.

Dr. Carolyn Lam:

I really liked that that was politically correct because we are recording. Everybody, welcome to the feature discussion. I am here with Dr. Milton Packer from Baylor and he really needs no introduction. We're discussing heart failure with preserved ejection fraction. As well as our associate editor, Dr. Justin Ezekowitz from University of Alberta. Hence, in case anybody's wondering, we were talking about the Canadian elections. Let's just launch straight into it, a side-by-side comparison of PARAGON and EMPEROR-Preserved. Dr. Packer... Milton, if I may, what in the world drove you to do this?

Dr. Milton Packer:

My God. Oh, my God. Yes.

Dr. Carolyn Lam:

Tell us about what drove you to do this and please, if you could just summarize the results.

Dr. Milton Packer:

Well, let me just say from the outset that this was a commentary, not an original research article.

Dr. Carolyn Lam:

Yes.

Dr. Milton Packer:

The commentary was motivated by two very straightforward observations. We had two large scale outcome trials of two different drugs in heart failure with a preserved ejection fraction. I was privileged to serve as you were, Carolyn, on the leadership committees of both trials. It's not as if we have involvement in only one trial. We have involvement in both trials and we are very proud of that involvement.

Dr. Milton Packer:

One trial came in with a effect size of about 13% on its primary endpoint with a borderline P-value. A second trial, EMPEROR-Preserved, came in with a 21% reduction and its primary endpoint with a really small and persuasive P-value. The two patient populations in the two trials were really amazingly similar. We wanted to understand why it was 21% in one trial and persuasively so and why it appeared to be smaller in the PARAGON trial with sacubitril/valsartan. We thought, well, maybe that difference was related to how endpoints were defined or maybe that difference was related to the influence of ejection fraction. The reason we got excited about that was that as almost everyone knows, PARAGON found an influence of ejection fraction on the effect of sacubitril/valsartan in patients with HFpEF. We found an influence of ejection fraction on the effect of empagliflozin in HFpEF in EMPEROR-Preserved. We wanted to understand whether that influence was similar in the two trials.

Dr. Milton Packer:

Just to make life simple, PARAGON had created certain cut points for ejection fraction. They had presented and previously published in Circulation endpoints based on those cut points of ejection fraction. All we did was we used their endpoints and their cut points, and we put the two trials side by side. We did not do a statistical comparison of the effect size. There're actually no P-values in the whole commentary. But what we wanted to see was: Was the shape of the ejection fraction influence relationship similar or different in the two trials? Well, very simple. In PARAGON, as has been reported, there was a linear relationship: as ejection fraction increased, the effect of sacubitril/valsartan got smaller. In EMPEROR-Preserved, there was also an attenuation at a highest ejection fraction, but the relationship wasn't linear. It was like a hockey stick. It was flat and then went up at an ejection fraction over 62.5, which was the cut point that PARAGON used.

Dr. Milton Packer:

When we compared patients between the low 40s and the low 60s, the effect size in empagliflozin appeared to be larger than the effect size of sacubitril/valsartan in that ejection fraction group using the same endpoints. In fact, for hospitalizations for heart failure, which is really what SGLT2 inhibitors do, it was twice as great with empagliflozin in EMPEROR-Preserved than with sacubitril/valsartan in PARAGON-HF. We thought this was really interesting. We put the pictures up side by side. We wrote a commentary and Circulation was so kind to accept it.

Dr. Carolyn Lam:

Oh, but Milton, you were very, honestly as always, very clever to have done this analysis. But if I could reiterate a few things for the audience, which is very important. First of all, as you rightly first pointed out, it's a perspective piece. It is not a head-on comparison with P-values. It could not be. Let's just also give the audience a bit of background in that PARAGON included patients with an ejection fraction of 45% and above. EMPEROR-Preserved was above 40. PARAGON looked at total heart failure hospitalizations and cardiovascular death as a primary outcome. EMPEROR looked at first cardiovascular death or heart failure hospitalization.

Dr. Carolyn Lam:

Let's just remember the designs were different. Of course in the comparison, PARAGON compared sacubitril/valsartan versus valsartan. I like the way you very carefully wrote in your study that it was more a study of neprilysin inhibition since it's sacubitril/valsartan against valsartan and it was empagliflozin versus placebo. We know that it's important to state that as a basis. Then really important to say to everybody out there, pick up our journal. You must look at this bigger. I myself have already cited it at least twice already, Milton, because people will just naturally ask that. "Are the results different because of ejection fraction or different endpoints?" What you did there in that beautiful figure is that you tried as best as you can to match it up in terms of ejection fraction bins and match it up in terms of hospitalizations. There. I just wanted to state those few things, but I'm really-

Dr. Milton Packer:

Oh, no. No. Carolyn, you're 100% right. That's why there are couple of things. I just want to underscore what you said because I think your points were spot on. First of all, we really lined up the endpoints and the ejection fraction. We tried our best to compare apples and apples. It would not have been a useful exercise for us to compare different endpoints and different ejection fraction subgroups. But I just want to make sure that everyone understands: I'm a big fan of sacubitril/valsartan and I'm a big fan of neprilysin inhibition. As you know, both PARADIGM-HF and PARAGON-HF weren't really tests of sacubitril/valsartan; they were tests of neprilysin inhibition. They were great tests at that. PARAGON in particular was a great test of that. We're comparing neprilysin inhibition and SGLT2 inhibition.

Dr. Milton Packer:

But here's my most important point: we do not want people to choose one over the other. That was not the intent. We think that there are data in patients with certain ejection fractions, let's say between 40 and 60, I'm just creating a range, where both interventions are appropriate. Now I understand there are cost considerations and I don't want to minimize that, but we are not suggesting that anyone prefer one drug over the other. All we wanted to do was we wanted to ask the question: Since the effect size in one trial seemed to be different than the effect size in the other trial, what were the ejection fraction subgroups that represented that difference? We found that the patients with ejection fractions greater than 60, 65% did not contribute to that difference. It was the patients with lower ejection fractions that contributed to the difference. I hope that's helpful.

Dr. Carolyn Lam:

Ah. That's wonderful. Justin, have you recovered from the talk about the Canadian elections?

Dr. Justin Ezekowitz:

Oh. I have indeed.

Dr. Carolyn Lam:

I'm on swinging.

Dr. Justin Ezekowitz:

I have indeed. Thanks for recognizing that Canada just had a major election we carried out in six weeks. But, Milton, I really enjoyed reading this. Maybe I can just ask you about two elements within this perspective piece, which is number 1, what's incredibly concordant is a lack of difference across cardiovascular death for both agents in both trials regardless of the trial differences and the potential differences in patient populations recruited; that's number 1. It's incredibly flat for cardiovascular death.

Dr. Justin Ezekowitz:

But number 2 is there is a danger in comparing trials even non-statistically. That's often a pitfall we get into, but we have to put some frame of reference on that. What is the one or two key things you think differ between PARAGON and EMPEROR-Preserved that you say, "You really need to look at these trials differently"? Those two questions came to mind when looking at this great figure that you produced.

Dr. Milton Packer:

Okay. The first question is so much easier and that is that these drugs don't reduce cardiovascular deaths. Full stop. It's really interesting because sacubitril/valsartan reduces cardiovascular death in people with ejection fractions of 40% or less, but not in patients with ejection fraction greater than that. The primary effect is heart failure hospitalizations. Empagliflozin didn't reduce cardiovascular death even in patients with the ejection fraction less than 40% or greater than 40%. What we're really, really talking about two drugs where the major effect is a reduction in heart failure hospitalizations. That comes out whether you do the analysis as time-to-first-event or total heart failure hospitalizations.

Dr. Milton Packer:

Of course, we're looking forward to the DELIVER trial with dapagliflozin. My own personal expectation is they're going to come out with a very striking effect on heart failure hospitalizations and not on cardiovascular deaths. Cardiovascular deaths in patients with HFpEF is really... It's a hard goal because only half of the deaths are cardiovascular. These patients have so many comorbidities that influence prognosis. The other thing, which is really important, is that heart failure hospitalizations only represented 18% of all hospitalizations in these patients; it's really small. I think of empagliflozin as being a treatment of the heart failure of HFpEF, not a treatment for HFpEF. I hope that makes sense. Justin, what was your second question?

Dr. Justin Ezekowitz:

Absolutely.

Dr. Milton Packer:

Oh, the differences between-

Dr. Justin Ezekowitz:

Yeah. Thank you, Milton.

Dr. Milton Packer:

Okay. There's always differences between two trials. As I said before, Carol and I were involved in both trials. They were done slightly at different times. They didn't overlap. Remember that the cut points in the two trials, one was 40%, one was 45%, really didn't matter to our analysis because we corrected for that in our ejection fraction subgroups. I was actually really much more impressed by the similarities than by the differences, but here's the catch. HFpEF is an incredibly heterogeneous disease. When we look at baseline characteristics, we're looking at means, medians, percentages. We're not picking up on any heterogeneity and there's a lot of heterogeneity. I actually think that HFrEF is a reasonably homogeneous disease. I think HFpEF is an incredibly diverse disease with a whole host of different disorders. What I'm amazed by is that we actually got an effect size that was greater than 20% in an all-comers HFpEF analysis.

Dr. Milton Packer:

But in all honesty, Justin, it wasn't really all-comers. We excluded people with BMIs over 45. There are a lot of patients who are obese and had BMIs greater than 45 who have HFpEF. By the way, especially in Texas. I didn't say that. We didn't enroll those patients. In all honesty, if I had to do it all over again, I would have. By the way, PARAGON didn't enroll them either.

Dr. Carolyn Lam:

Well, this is an incredible conversation. I know that we could just do a whole hour of chatting about what this implies for the higher ejection fraction, what this implies for how we should be treating heart failure. I don't even dare to ask for some last words maybe from both Justin and Milton, but recognizing that the time is short, anything else to add?

Dr. Milton Packer:

I think Justin should do last words.

Dr. Justin Ezekowitz:

Well, let me summarize by saying there is a hockey stick. We love hockey sticks in Canada. A simple and an excellent comparison. I think people should really look at that figure to understand it, but do not undertreat your patients with HFpEF and look at these with a grain of salt. Thanks for joining us, Milton. Thanks, Carolyn.

Dr. Milton Packer:

Thank you so much.

Dr. Carolyn Lam:

On behalf of Greg and I, you've been listening to Circulation on the Run. Thank you so much for joining us today and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.

Circulation October 5, 2021 Issue

4 oktober 2021 | 31 min

This week's episode features highlights from Circulation's 2021 Cardiovascular Surgery Themed Issue. Join Executive Editor James de Lemos along with Associate Editors Marc Ruel and Michael Fischbein as they discuss all of the articles found in this special issue.

Dr. James de Lemos:

Hi, my name is James de Lemos. I'm a cardiologist at University of Texas Southwestern Medical Center in Dallas, and the executive editor for Circulation. And I'm standing in for Carolyn and Greg today to host our annual cardiovascular surgery-themed issue podcast. And I'm delighted to be joined by Marc Ruel, professor and chairman of the Division of Cardiothoracic Surgery at the Ottawa Heart Institute, and the director of cardiac surgery content for Circulation, as well as Michael Fischbein, associate professor of cardiothoracic surgery at Stanford and the director of the thoracic and aortic programs there. Marc, thanks for all that you do for Circulation with cardiovascular surgery content and let me turn it over to you to introduce the issue.

Dr. Marc Ruel:

Well, James, thank you very much. We're very delighted to introduce this 2021 cardiovascular surgery-themed issue. We already feel that this is going to put together some of the very best science at the interface between cardiac surgery or cardiovascular surgery, I should say, because there's some peripheral vascular topics as well, cardiology, and as well, mechanistic research. I think you're going to find that this is really a very jam-packed issue that has a lot of important messaging that will change the field going forward.

Dr. Marc Ruel:

Also, this year, I want to highlight a couple of changes in the preparation of the issue. I want to first thank the tremendous contributions over the years to Circulation and to the entire field of cardiac surgery of Tim Gardner. Really, Tim, is an absolute giant. I think he's the only person known to me who was both president of the American Heart Association and of the ATS in the field of cardiac surgery.

Dr. Marc Ruel:

Tim has really paved the way for us to develop and enhance this issue over the years, and I think 2021 is a testament to his legacy, because I would argue it's our strongest issue ever. And I also want to introduce Mike Fischbein, James and everybody, who's associate professor at Stanford. Mike is a thoracic-aortic surgery expert, also runs a translational lab, so has a very dedicated, basic science and translational surgical science expertise. So we're very, very happy to welcome Mike to the themed issue of Circulation.

Dr. James de Lemos:

Well, thanks Marc. We'll do is follow the order of the issue so that our readers and listeners can really get a sense of the content and its various types that we're publishing this year. And the issue starts with a provocative frame of reference piece from Verma and colleagues discussing the surgical left atrial appendage occlusion. Marc, what were your thoughts on that piece?

Dr. Marc Ruel:

It's obviously a game changer in cardiac surgery. I was privileged to serve as a part of the BSMB for this trial, and we can now say we toyed with the decision as to stop the trial at the appropriate time. And that's always a very difficult BSMB decision, which, frankly, you want to get it right, and you don't want to err on either side. Anyways, LAAOS III was recently published and we have a fantastic editorial in Circulation from Subodh Verma, Deepak Bhatt, and Elaine Tseng saying, which essentially highlights the importance of the trial for practice of cardiac surgery.

Dr. Marc Ruel:

It probably is that no patient who comes to cardiac surgery with a history of atrial fibrillation should, based on those findings, not have their atrial appendage ablated. There's already very little caveat, the trial has not shown what was feared prior with regards to an increased incidence of heart failure or symptoms. And really, the surgery has been effective. The ablation of the left atrial appendage is very effective in diminishing the primary outcome or of stroke, ischemic stroke or cerebral hemorrhage.

Dr. Marc Ruel:

And essentially, this was, in most cases, a surgical ablation, so cut and sew. So we don't have all the information about either endovascular devices or even ablative devices at the time of surgery. But it was a very large trial, it was a publicly funded trial. It is really the authoritative information in the field that's available so far.

Dr. Marc Ruel:

Mike, what are your thoughts around this? Do you now come to any one of your patients needing a cardiac surgical cooperation with a history of atrial fibrillation and thinking that I now need to address the left atrial appendage? Is that what you get out of this paper as well?

Dr. Michael Fischbein:

Yeah. Thanks, Marc. I think that's an excellent question. Yeah, now, every patient after this trial, I talk to them ahead of time and offer them to have their appendage ligated in this setting if they have a history of atrial fibrillation. I don't think this adds much to our operation, it doesn't increase much the clamp time. And especially, although the trial was more surgically excising with some of the newer clips out there, it really doesn't add much time to the operation. So I think this is really an important paper that will change what we do as surgeons.

Dr. James de Lemos:

Can I just comment that I think the trial has indirect implications well beyond surgery, because the demonstration of combined benefit for oral anticoagulation with left atrial appendage occlusion really suggests that, even for patients not going for cardiac surgery, at some point in the future, we may be thinking about not and either/or between the devices and anticoagulation, but maybe both.

Dr. James de Lemos:

Mike, let me come back to you. There's a really fascinating paper by DeCarlo evaluating penetrating aortic ulcers that really change my thinking on this. Can you talk a little bit about this paper and your thoughts?

Dr. Michael Fischbein:

Thanks very much, James. I think this is really an important paper that's going to change what we do as surgeons. As you know, symptomatic penetrating aortic ulcers are grouped with dissections in tremula hematoma where we treat those patients immediately. None of us know what to do though with the asymptomatic aortic ulcer, which is actually more common. A lot of us are basing our reports on some observational studies. Many of these studies are mixed, symptomatic and asymptomatic. And so the treatment really varies, from watching them conservatively to treating them with open or endovascular approaches.

Dr. Michael Fischbein:

However, this paper by DeCarlo's really excellent. They followed 273 asymptomatic penetrating ulcer patients over time following their CT scans. And they really had two key important findings. One that these ulcers really didn't change much over time, and two, the risk of some complication occurring, whether that's rupture, symptoms or progression of disease was very low at 6.5% over 10 years. And so I think this is really going to be important, because we know that these asymptomatic penetrating ulcers, we can watch them conservatively. They do have to be still followed, but we don't have to go immediately to perform some surgical procedure.

Dr. James de Lemos:

Marc, any thoughts from you on this paper? Does this change what you guys will be doing in Ottawa?

Dr. Marc Ruel:

Absolutely. Yeah, I think this is, as Mike was saying, a very germane finding that's very helpful. I think the key word here, as Mike was alluding to, is really the word asymptomatic and how do you define that? Right? I mean, many of these findings are incidental findings. Someone comes in with a bit of shortness of breath or this or that, gets a PE protocol CT scan and then a penetrating aortic ulcer is found.

Dr. Marc Ruel:

So where do you draw the line between symptoms that may be a small left lateral effusion or a bit of shortness of breath. And it's also, I think that nuance will have to be determined going forward, what is truly asymptomatic versus a few symptoms that may be less specific and perhaps not relate to the penetrating aortic ulcer. But I think it's tremendously helpful in guiding practice going forward.

Dr. James de Lemos:

Fantastic. Thank you both. Mike, I want to come back to you on another really important paper from the vascular surgery standpoint, which is the paper from the Voyager investigators on the combination of rivaroxaban and aspirin for patients with surgical treatment of peripheral arterial disease.

Dr. Michael Fischbein:

Yeah, no, I think this is another or provocative paper. And as you know, peripheral arterial disease is a really highly-significant clinical problem. We say that affects 200 million people globally. And this includes patients with claudication, arrest pain, limb threat ischemia. And currently, the treatment for this is to either a open surgical or endovascular revascularization of the lower extremity. And the problem is while these patients, they have immediate symptomatic relief where you can save their limb, we say that one out of five will develop some sort of symptom or limb ischemia by three years.

Dr. Michael Fischbein:

And so the field is really looking for some sort of adjuvant therapy to help prevent these occurrences later on. And so the Voyager trial randomized over 6,000 patients who underwent surgery, whether it was open or endovascular, and then they randomized to either receiving rivaroxaban plus aspirin, versus aspirin and a placebo. And they showed that if you received riva, that those patients had a significant reduction in the instance of their primary endpoint, which included ischemia, limb loss or symptoms. And importantly, there was not an increase in major bleeding risk in these individuals.

Dr. James de Lemos:

So fascinating. I mean, this does this change practice and is this now the standard for surgically-treated peripheral arterial disease?

Dr. Michael Fischbein:

Yeah, I think there's still some questions that we have to answer. Yeah, I think definitely this, I think will be used after the bypass surgery, but some of the things in the trial that we would have to figure out is how applicable is this to everyone. In the trial, the open surgical arm had patients with less risks. Also, some patients received vein conduit versus a prosthetic conduit. And so, I think we'll have to look at some of the sub-analysis to see who we can apply this to.

Dr. James de Lemos:

Fantastic. Marc, any thoughts from your perspective on this one?

Dr. Marc Ruel:

Yeah. Mike provided a great summary. I think one other take-home message to me is that, really, these patients should be viewed as having panvascular disease, a little bit like our CABG patients. And essentially rivaroxaban or DOACs in general have a role, like in the COMPASS trial, in preventing other complications. So here, part of the composite endpoint was myocardial infarction, right? And we know that these peripheral vascular disease patients are very much at risk of it. So it may have an effect locally, but it really, probably, has most of its effect with regards to the panvascular disease that these patients present.

Dr. James de Lemos:

Excellent. And I'll just point out that just today, the FDA released news that they've granted an indication for this combination therapy for patients with peripheral arterial disease. Let me come back to Marc for a really interesting randomized controlled trial, from China, evaluating no-touch vein graft interventions for cardiac surgery. Marc, can you talk to us about this trial and your impressions on this?

Dr. Marc Ruel:

Absolutely. Thank you, James. So this is a trial from seven hospitals in China that randomized 2,600 patients between April, 2017 and June, 2019. And patients were randomized with the use of saphenous vein grafts between a no-touch technique and a conventional saphenous vein graft harvest technique. And I'll explain a little bit what this no-touch technique is. It actually consists of two things. You take the vein by a complete incision. Often, in fact, it's more invasive, and you take the actual saphenous vein with a surrounding layer of fat and connective tissue around it. And because of that, it's not easily amenable to endoscopic vein harvest or even using small incisions.

Dr. Marc Ruel:

The other component of no touch of vein harvesting is to really preserve the anterior layer by not using any syringe inflation and letting the conduit be rinsed, but flow naturally and not be distended at all. So the trial was positive, and the trial already showed a lesser incidence of saphenous vein graft closure at both three months and 12 months on CT scan. So to give you an example, the three months saphenous vein closure was 4.8% in the conventional harvest group, versus 2.8% in the no-touch group.

Dr. Marc Ruel:

Now what's interesting to here is twofold. There may be a couple of aspects in the benefits of the therapy, and one may relate, in fact, to the lack of pressure syringe dilatation. So it's hard to tease out, is it really the surrounding layer of fat or is it the fact that the syringe dilatation procedure is not being performed in the no-touch group? The second issue is the technique is definitely more invasive. The authors found in the trial more local complications, about 50 to a hundred percent increase in terms of a local numbness, exudation, et cetera, delayed wound healing. Because you have to make bigger incisions and you have to take more tissue around where the vein that you're harvesting.

Dr. Marc Ruel:

So it is a very intriguing trial. Obviously, graph patency is something that's tremendously important around the CABG operation. But unfortunately, it steers us towards a more invasive approach. In a nutshell, it is a positive trial, but it does require the surgery to be slightly more invasive, albeit, in most cases, with addressable issues with regards to delayed wound healing and exudation. But it would be ideal if we could combine the benefits of a no-touch technique with a less invasive approach to harvesting.

Dr. James de Lemos:

Mike, this is fascinating to me because you've got a procedure that probably improves the long-term outcomes of the operation, but is associated with a longer surgical time and more local complications. Mike, I'm wondering, what are your surgeon's going to do at Stanford? Are they going to adopt this or is this too difficult and associated with too much inconvenience for the patient to become something that's done routinely?

Dr. Michael Fischbein:

Brilliant, great question, James. Because I think, often, our patients, previous to endoscopic vein harvesting, they often complained more issues with their leg incisions than their actual sternotomy. And I always tell my patients now, though, one of the incredible things is that we can take their vein endoscopically. And now, we're talking about, while we do have improvement in graft patency for the vein, we're going to go backwards and maybe have some of these wound issues again. And I'd be curious what Marc thinks, though. We are trying to do more and more arterial grafts. And so, if we're just using one vein, is it worth accepting these higher wound complications?

Dr. Marc Ruel:

It's a great point, Mike, and perhaps exactly, as you say, perhaps an increased use of arterial grafts can be combined with lack of a pressure syringe dilatation of the vein after harvest, right? And there's already some data suggesting, as provided in the excellent editorial by Vidal, that this may be mechanistically important to enhance patency. So the study is very intriguing and still remains to completely unfold.

Dr. James de Lemos:

Excellent. Really important contribution to the surgical science. Marc, I want to come back to you with another important randomized control trial, this with a really novel therapeutic compound designed to address kidney injury after cardiac surgery. Marc, can you talk about the trial with the small interfering mRNA for renal protection?

Dr. Marc Ruel:

Absolutely. Thank you, James. This is an important trial, in my opinion. It's a Phase II study of a compound named, teprasiran, which is a interfering RNA, which modifies the p53 mediated cell death response in the renal tubal cells. So what does that do, essentially, is that the thought is that it may prevent acute renal injury after cardiac surgery. We know that's a tremendous problem. Most busy cardiosurgical ICUs would have at least between 15 to 25% of the patients requiring dialysis postop, depending on the level of risk acuity that your unit is presenting.

Dr. Marc Ruel:

And it's no different whether you're in Stanford or Ottawa or Germany, in my opinion. So we need solutions here. And this is a relatively simple compound, which is administered within four hours of completion of surgery. So for instance, if the surgery was performed on pump, it was given within four hours of completion of surgery. So, for instance, if the surgery was on-pump, it was given within four of hours completion of CPB, cardiopulmonary bypass. If it had been performed off-pump, it was within four hours of the last anastomosis.

Dr. Marc Ruel:

It's a two-minute infusion, 10 milligrams per kilo, and essentially in the trial, it was not associated with any safety concerns. And quite conversely, it was actually associated with the benefit, with regards to the development of early acute kidney injury, which was 50% prevalence in the patients who were treated with placebo, versus 37% in patients who received the compound, again, named teprasiran. So I think this is quite important. It has led to a Phase III which is currently ongoing, and I think this is a very instrumental finding in the field.

Dr. James de Lemos:

Fantastic. I mean really a testament to the progress in clinical science for cardiac surgery, that we've got these randomized controlled trials moving through a development phase that may be actionable in years to come. Let's finish the discussion of the original research articles, Mike, with a review of the Yang paper, really, which also, I think, is in Circulation's real sweet spot, where we're highlighting the very best of basic and translational science coming from Surgeon Laboratories. Can you talk about that paper for us?

Dr. Michael Fischbein:

Thanks very much, James. I think this is really an exciting paper. Qiong Yang's lab at University of Michigan, they're studying Loeys-Dietz syndrome. As you know, Loeys-Dietz syndrome is one of the connective tissue disorders. There's five subtypes, and these individuals form aortic root aneurysms. Importantly, it's specific to the aortic root that these aneurysms primarily develop. Although later on, you can see them in other locations, including intracranial and some of the branch vessels.

Dr. Michael Fischbein:

But these root aneurysms can dissect and this is life threatening. Currently, the only treatment strategy for these individuals is surgical, where you perform a prophylactic replacement of the aortic root. Unfortunately, there are no real medical therapies, primarily because we don't understand the mechanisms why these aneurysms form. So Dr. Yang's lab, they model this disease using a induced pluripotent stem cell model, where cells are differentiated into the different embryologic origins of the aorta.

Dr. Michael Fischbein:

The aortic group comes primarily from the second heart field. And so, when they studied these smooth muscle cells, they were able to show that there is lineage-specific smooth muscle cell defects, and they discovered some interesting pathways that might explain why aneurysms form specifically in the root in these in individuals. They also came up with some potential pharmacologic strategies to block some of these mechanisms.

Dr. Michael Fischbein:

And so, I think this is really exciting because this is using pluripotent stem cells more as a model to study disease states. And I could see the potential, also, for precision medicine, where you take an individual cells, make their iPSCs and study that individual's mechanisms, and perhaps come up with unique medical strategies for that individual.

Dr. James de Lemos:

So let's, Marc, finish, that's really all of the original research articles we covered. Really, an amazing spectrum of clinical translational and basic science that is a Testament, both to what you all have done to recruit content, but the tremendous growth in science and the surgical specialties. Marc, let's talk a little bit about the two terrific in-depth reviews that you picked for this issue and what their contributions are.

Dr. Marc Ruel:

Thank you again, James. We have two excellent reviews in this themed issue of Circulation. One is a frontiers piece about cardiac surgery in women in the current era, going over what are the gaps in care. And this is spearheaded by Leslie Cho, from the Cleveland Clinic, and it really goes over, very comprehensively, many of the issues around not only clinical trial enrollment of women, but specific issues pertaining to the care, and which goes back even to basic science of the sex and gender of animals being used in research for reasons that I said, that are very comprehensively, again, I want to emphasize highlighted by the authors.

Dr. Marc Ruel:

And I'll give you an example, for instance. In off-pump surgery, there are some discrepancies with regards to the use of off-pump versus on-pump surgery between males and females. And we off-pump surgeons know that there are really two very different ways from the surgery. Women, for instance, have a smaller heart which is easier to expose, for instance, for lateral and inferior territories. But in the same token, the coronary targets can be smaller. So there's really a number of discrepancies here, which can be anatomic, it can be sometimes due to the disease presentations.

Dr. Marc Ruel:

For instance, women have more tricuspid valve disease, and at a certain age start having an increased incidence of aortic problems versus males. And there's also some what I would call logistical issues with regards, for instance, to clinical trial recruitments from VA centers that typically have very, very few women being eligible for enrollment there. So these issues, again, are comprehensively addressed by Dr. Cho and her colleagues. And it's a very interesting read.

Dr. Marc Ruel:

The other piece you were referring to is a state-of-the-art paper around the use of transit time flow measurements during coronary bypass. And I think our cardiology colleagues and everyone in the cardiovascular field will be very interested to learn a bit more about this. Because essentially, when we perform bypass surgery, we don't have a validated easy way to ascertain whether the grafts that we just built are doing their job. And you may say, "Well, the surgeon's great at cutting and doing anastomosis," but as I like to tell my trainees, there's much more than suturing that might be happening.

Dr. Marc Ruel:

An anastomosis may have an unforeseen flap into it. There could be a small clot that's blocking something. There could be a kink or a twist in the graft that's not readily recognized. So I think it's very important to have a thorough assessment in everybody. I'm the last author of this piece, so I'm obviously somewhat partial to it. But I think it is important for the field to have quality checking of all grafts that are performed at something, especially something as invasive as bypass surgery. The patient should come out with functional grafts and that should be validated and objectively verified.

Dr. James de Lemos:

Fantastic. Marc, and we also have two research letters in this issue of Circulation. These are small pieces, but they pack a really powerful punch. Do you want to just briefly tell us about those two?

Dr. Marc Ruel:

Absolutely. Thank you, James. As a surgeon, I love research letters. I think they are a great venue. They're under a thousand words. Certain, sometimes we're busy, we don't want to always read a 5,000-word manuscript. And they're really, they are well-suited to what I would say are surgical follow-up studies. Once a technique has been described and you want to look at what are the late outcomes of this technique, I think they're an excellent format for that. And precisely, this corresponds to the two research letters that we have in the 2021-themed issue.

Dr. Marc Ruel:

One is a long-term, 10 year analysis of the SAVE RITA trial by Kim and Kim in South Korea. The SAVE RITA trial is a fairly famous trial in our specialty, which essentially, randomized patients to have a Y graft on the left internal thoracic artery, using either a saphenous vein conduit or the right internal thoracic itself. And essentially the early results were neutral. So the two groups were comparable, which is naturally neutral. I would say non-inferior for the saphenous vein graft.

Dr. Marc Ruel:

Now we have 10-year data in over 200 patients, equally randomized between receiving a saphenous vein graft versus the right internal thoracic artery. And the results are 10 years are equally excellent between the saphenous vein graft and the right internal thoracic artery. So this is quite non-intuitive to many. Essentially, what we're showing here is that a vein graft at 10 years has amazing patency. We're talking 90%-plus in those patients who received an angiogram. So I think there's a couple of messages to remember here.

Dr. Marc Ruel:

There may be a biologic role of connecting a saphenous vein graft onto the left internal thoracic artery with regards to nitric oxide dilution. Also, technically, the authors have readily acknowledged that the harvest the vein, again, back to this saphenous vein harvest issue, they harvest it from the lower leg. Therefore, the diameter of the vein is more suited to a Y graft. And, in fact, using a vein over right internal thoracic artery may have technical advantages, because the diameter is a little bit more facile to use with regards to complex composite grafting. So it may actually be something that, if you can maintain it with patency based on say, nitric oxide dilution, is a little bit easier to maneuver and build at the time of surgery.

Dr. James de Lemos:

Marc, can I ask a question here? Does this change your practice with regard to how often you're using Y graphs, in general, and the vein on artery Y? Because, Mike, outsiders experiences that these graphs aren't used and do these data suggest that we should be using why Y graphs, in general, and this particular type of Y more often in surgery?

Dr. Marc Ruel:

Absolutely. I think these data suggest precisely that. Whether the adoption will follow is another story. There's not a lot of groups, much to your point, that are using this configuration, but it's used commonly as a bailout strategy. Let's say, one of the arteries has been injured or is not available, or you have a porcelain aorta, I think based on these important data, you can now know that you can, if well-constructed, use a saphenous vein graft as a Y graft onto the LITA with relative impunity. In fact, excellent results, if done in the way that Kim and Kim are reporting.

Dr. Marc Ruel:

Our second research letter is actually a follow-up of hybrid palliation for hypoplastic left heart syndrome. This comes from the UK, where a number of centers had used several years ago the concept of a hybrid palliation in patients who were mostly high risk for hypoplastic left heart. So here, again, much to the research letter format, we have a follow-up series with regards to following all these children who had received either a initial Norwood approach or a hybrid approach progressing to a Norwood stage two. And essentially, the overall survival, which is about, between two thirds to 75% of children at three, four years, is no different between an initial Norwood stage one approach versus hybrid palliation.

Dr. Marc Ruel:

So I think this is obviously very intriguing data. It's used to be that a hybrid palliation would only be used in very high-risk cases. I think this would provide credence to using it in a more liberal fashion. There's still the possible caveat that the centers that use hybrid palliation have a little bit of a "expertise bias," if you will, because they have both modalities being available. But I think this is a very important and very intriguing data for this extremely challenging condition.

Dr. James de Lemos:

Well, thank you. And I'd like to thank both you, Marc, and Mike for just tremendous insight. I think for somebody that doesn't live in the cardiac surgery world, having the privilege, not just to hear you explain these terrific studies, but also provide your insights in pearls about cardiac surgery and vascular surgery care in 2021 has been invaluable. And I think our listeners will feel the same way. I'd like to turn it over to you, Marc, as our leader in cardiovascular surgery to close us out today from a wonderful podcast.

Dr. Marc Ruel:

Well, thank you very much, James. Again, I want to reiterate, I think this is really a tremendous issue. It's our best ever. And I want to thank you, James and Joe Hill, as well, our Editor-in-Chief, for your support of surgery within Circulation. I also want to thank Sarah, Molly, Nick, and Augie, really, for their in their indefatigable support of our issue. I want to, again, extend our gratitude to Tim Gardner and to Mike for their tremendous help with this issue. I think this is, again, very important. Do send your best work, and I'm speaking to our readership community and all surgeons to Circulation.

Dr. Marc Ruel:

Circulation is our premier journal and surgery's tremendously important. And the interface together is a strong one, because Circulation realizes that surgery provides, and I'm a bit biased when I say this, but I think it is true. It provides the most robust and durable treatment for advanced heart disease, so it is very important to be featured prominently in Circulation. And I think this is what our current leadership and staff at Circulation are supporting, and I'm tremendously thankful on behalf of all surgeons.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation September 28, 2021 Issue

27 september 2021 | 30 min

This week's episode features a panel discussion. Please join author Harmony Reynolds, editorialist David Newby, and Associate Editors Nicholas Mills and Sandeep Das as they discuss the articles "Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study, "Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity," and editorial "Forget ischemia, it's all about the plaque."

Dr. Greg Hundley:

Welcome listeners to this week's, September 28th, issue of Circulation on the Run. And I'm Dr. Greg Hundley, Director of the Poly Heart Center at VCU Health in Richmond, Virginia, and associate editor at Circulation. And this week, listeners, we have an outstanding feature discussion. It's actually forum where we're going to discuss from Dr. Reynolds two papers pertaining to the ischemia trial. One looking really at the functional importance of stress testing, the other looking at the anatomical importance of cardiac CT scanning. We're going to have two of the associate editors along with Dr. Reynolds, each that handled the two papers and also a guest editorialist that will help put the entire paper together. Well, before we get to that, we're going to start and review some of the other papers in this issue. And let's grab a cup of coffee and get started.

Dr. Greg Hundley:

The first comes to us from Dr. Maliheh Nazari-Jahantigh from Ludwig Maximilian University in Munich, Germany, and it pertains to atherosclerotic plaque rupture. So the necrotic core of an atherosclerotic plaque is partly formed by ineffective efferocytosis, which increases the risk of an atherosclerotic plaque rupture. And in cell biology, efferocytosis comes from the Latin word effero, which means to take to the grave or to bury. And it's really the process by which apoptotic cells are removed by phagocytic cells. And so therefore, it can be regarded as the burying of "dead cells." Now MicroRNAs contribute to necrotic core formation by regulating efferocytosis as well as macrophage apoptosis. We also know that atherosclerotic plaque rupture occurs at an increased frequency in the early morning, indicating that diurnal changes occur in plaque vulnerability. Now all those circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear.

Dr. Greg Hundley:

And so these authors investigated this phenomenon. And what they found, interestingly, their results suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mer 21 expression in macrophages that is not matched by efferocytosis, and thereby increasing the size of the necrotic core of these plaques. So clinically, the implications are that a macrophage death clock controlled by mer 21 may enhance lesion growth and susceptibility to plaque rupture indicating that the molecular clock can have detrimental effects under pathologic conditions. And additionally, the molecular clock in lesional macrophages may contribute to the circadian pattern of myocardial infarction, which could be a target for preventive measures to limit the mismatch between apoptosis and efferocytosis and thus reduce plaque vulnerability in the early morning.

Dr. Greg Hundley:

Well, our second paper comes to us also from the world of preclinical science, and it's from Professor Thomas Braun from the Max Planck Institute for heart and lung research. And this particular paper pertains to pulmonary hypertension. And as we know, pulmonary hypertension and chronic obstructive pulmonary disease, or COPD, originate from a complex interplay of environmental factors in genetic predispositions and little is known about developmental abnormalities or epigenetic dysregulation that might predisposed individuals to develop pulmonary hypertension or COPD in adults. So these authors screen a cohort of human pulmonary hypertension in COPD patients for changes of histone modifications by immunofluorescent staining. And also, they developed knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types.

Dr. Greg Hundley:

Now molecular, cellular and biochemical techniques were applied to analyze the function of SUV420H1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Well, what did they find? So the investigators found that loss of SUV420H1 in cardiopulmonary progenitor cells caused a COPD-like pulmonary hypertension phenotype in mice, including formation of perivascular tertiary lymphoid tissue, and goblet cell hyperplasia, hyperproliferation of smooth muscle cells and myofibroblast, impaired alveolarization and maturation of defects of the microvasculature leading to massive ripe ventricular dilation and premature death.

Dr. Greg Hundley:

Now mechanistically SUV420H1 bound directly to the five prime upstream in regulatory element of Superoxide Dismutase 3 gene to repress its expression and increased levels of the extracellular Superoxide Dismutase 3 enzyme in SUV420H1 mutants increased hydrogen peroxide concentration causing vascular defects and impairing alveolarization. So what can we take away, listeners, from this clinically? Well, the author's findings reveal a pivotal role of histone modifier SUV420H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. And now these results suggest that this study will facilitate the understanding of pathogenic events causing pulmonary hypertension in COPD and aid the development of epigenetic drugs for treatment of other cardiopulmonary diseases.

Dr. Greg Hundley:

Well, listeners, what else is in, we call it, the mail bag, but some of the other articles in the issue? Well, doctors Varricchi and Wang exchanged letters regarding the prior article, the role of IgE FcεRI in pathological cardiac remodeling and dysfunction. And our own Sara O'Brien highlights articles from our circulation family of journals. Professor Ross has a Research Letter regarding the effects of walnut consumption for two years on lipoprotein subclasses among healthy elders findings from the WAHA randomized controlled trial. And then finally, Dr. Maurer has a really nice On My Mind piece that raises concerns pertaining to the use of cardiac scintigraphy and screening for transthyretin cardiac amyloidosis. And now listeners, we're going to turn to that forum discussion where we have an author, our associate editors and an editorialist discussing two really important papers from the ischemia trial.

Dr. Greg Hundley:

Well, listeners, we are very excited today to discuss in sort of the forum feature, two papers pertaining to the ischemia trial. And with us this day, we have Dr. Harmony Reynolds from New York University Grossman School of Medicine in New York city; two of our associate editors, Dr. Nick Mills from university of Edinburgh in Scotland; and Dr. Sandeep Das from UT Southwestern; and then also an editorialist, Dr. David Newby, who's also University of Edinburgh in Scotland. Welcome to everyone.

Dr. Greg Hundley:

Harmony, we're going to start with you. And in the first paper, the natural history of ischemia and no obstructive coronary artery disease, can you describe for us a little bit of the context of what shaped this question for you, what hypothesis did you want to test? And then describe for us a little bit your study population and your study design.

Dr. Harmony Reynolds:

Sure. Thanks so much for having me here to discuss these papers. I'm really appreciative of the attention from circulation, and I'm excited for this discussion today. So in this first natural history paper, we were looking at ischemia with non-obstructive corona arteries, INOCA, the kind of thing that used to be called cardiac syndrome X. And we know this is an extremely common problem. It's defined by having signs or symptoms of ischemia and no 50% or greater lesion on coronary imaging. And we also know from prior invasive studies that the mechanisms of this are overwhelmingly microvascular coronary disease and provokable coronary spasm. Some patients prove to be normal and invasive testing, but most will have some objective abnormality.

Dr. Harmony Reynolds:

We know this problem is associated with a higher risk of cardiovascular events and with high costs, but what we didn't know was whether the symptoms and ischemia on stress testing are tracking together in these patients. So if we're trying to treat these patients, should we be doing serial stress testing and targeting the medical therapy to ischemia abrogation or should we just be making their symptoms go away? And would this provide any long range insights for us into when we can figure out the symptom are truly ischemic in nature?

Dr. Harmony Reynolds:

So we decided to use the ischemia trial, and we had a fantastic platform for that in ischemia because, as you know, patients were screened in part for randomization using coronary CT angiography. And even though these patients had moderate or severe ischemia, some had no obstructive coronary disease on that CT coronary angiogram. And those are the patients that we enrolled in CIAO-ISCHEMIA. They had an assessment of angina at baseline, and they had to be symptomatic at some point. They didn't have to be symptomatic at the moment. They were enrolled in CIAO, but they had their stress test generally to evaluate ischemic symptoms. And they had their stress echocardiogram read by a core lab. Importantly, that core lab did not know the result of that CT scan. So they read them like all the other ischemia stress echoes. And then these patients had an angina and ischemia assessment with a repeat stress echo at one year.

Dr. Greg Hundley:

And what did you find?

Dr. Harmony Reynolds:

There were a number of interesting findings from this study. The first thing was that the severity of ischemia in the CIAO patients with INOCA was very similar to the ischemia patients who had obstructive coronary disease. So that tells us that the INOCA problem can happen with quite a lot of ischemia, and that had not been as well delineated before. Another finding expected, but we did find that is that there were many more women in the INOCA group, two thirds of our child population was female. And in ischemia, overall, it was closer to a quarter. We found that the symptoms and the ischemia were quite changeable. So at one year, the stress echocardiogram was normal in half of the child participant and only 23% still had moderate or severe ischemia. Angina had improved in 43%, and it worsened in 14%. There was an awful lot of change over one year, but the change in angina and the change in ischemia did not track together. And that was a bit of a surprise to me.

Dr. Greg Hundley:

Very nice. Well, Nick, I know serving it as an associate editor, you see many papers come across your desk. What attracted you to pushing this paper forward for publication?

Dr. Nicholas Mills:

Thanks, Greg, and congratulations. Harmony, we love the papers you've been sending from ischemia trial, which genuinely is changing clinical practice all over the world. And it's been great to see the secondary analysis and follow-up papers. So this paper attracted me because it addresses an area where I still don't fully understand in clinical practice, what recommendations to make for my patients and what tests to arrange. As you say, INOCA is more common in women. I think these patients have largely been understudied over many decades, and there remains a lot of uncertainty. I liked it because you had a core lab, blinded core lab analysis with systematic follow up and it was a really well-done study. It reassured me in many ways because it told me that actually a lot of these patients, their symptoms get better, sort of irrespective of what we do. The treatments didn't seem to track within improvements of symptom, nor did the severity of ischemia, and that I think provides a lot of reassurance to our patients who are in this situation.

Dr. Nicholas Mills:

Of course, there is a group there who continue to have moderate to severe ischemia a year later. And I think this trial helps us understand maybe how we should study this group more, understand the heterogeneity that you've observed in this population in order to really try and resolve that and resolve their ongoing symptoms. But for the majority, four in five patients, they're going to do well and they're going to get better over time. And I think that's an important message from this study.

Dr. Greg Hundley:

Thank you so much, Nick. Well, Harmony, we're going to come back to you. You have a second paper, the outcomes in the ischemia trial really based on coronary artery disease and ischemia severity. Can you describe for us, again, working us back through, what were some of the constructs that you really wanted to address here? What was your hypothesis? And again, how did this study population maybe differ a little bit in this second paper?

Dr. Harmony Reynolds:

Thanks so much. So this paper tracked outcomes based on the severity of ischemia and the severity of coronary artery disease on the CT coronary angiogram now in randomized patients in the ischemia trial. So all of these had obstructive coronary disease and they were selected for randomization. And the premise of the ischemia trial was partly that we would be able to select patients who might benefit from revascularization and from an invasive strategy really based on how much ischemia they had on the stress test. Moderate or severe ischemia was required for randomization and for entry into the trial, but a core lab read those stress tests independently and independently assessed ischemia. And in some cases, when the site thought there was moderate or severe ischemia, the core lab did not agree. And the core lab independently decided whether it was moderate or severe. So we wanted to understand whether the ischemia severity at the time of trial entry influenced outcomes and influenced the outcomes by randomization treatment assignment.

Dr. Harmony Reynolds:

Similarly, about half of the patient had a CT that was interpretable for the number of vessels disease. And we wanted to understand in the context of all those prior stable ischemic heart disease trials, showing a lot of heterogeneity by the amount of coronary disease, whether in ischemia as well, there would be heterogeneity of the treatment effect based on how much coronary disease you started with. So the ischemia population, and this is almost the entire randomized cohort, but it's important to recognize for the CT analysis that only about three quarters of the patients had CT. They didn't get a CT, if your GFR was too low or if you had known coronary anatomy. And among those Cts, not every CT is perfectly interpretable for the number of vessels disease. These are sicker patients. These are not the super stable patients who have a low prevalence of disease. These were pretty sick, multi-vessel coronary disease patients, and they couldn't always hold their breast all that well. There was a lot of calcification in these.

Dr. Harmony Reynolds:

So for example, if there was motion artifact in the right coronary artery, we wouldn't be able to quantify the number of vessels disease. And that left us with a cohort of about half of our ischemia population, but that's still a giant cohort of several thousand patients. So that's how our study.

Dr. Greg Hundley:

Very good. And what did you find here?

Dr. Harmony Reynolds:

Here, we found that more severe ischemia was not associated with outcomes. Now that does go along with the COURAGE study in which after you adjust for clinical characteristics, ischemia was not associated with outcomes. But still it came as something of a surprise that even severe ischemia was not associated with a higher risk of outcomes than moderate or mild ischemia. We also found that in the coronary disease group, no matter how you measure the severity of coronary disease, the Duke prognostic index, the number of vessels disease, the segment involvement score, the segment stenosis score, all of these measures were very strongly associated with our outcomes, whether it was all cause mortality MI or our composite.

Dr. Harmony Reynolds:

When it came to treatment effect, we found that the ischemia severity were no relationship to treatment effect. There was no ischemia subgroup in which there appeared to be an advantage with an invasive strategy. But in the coronary disease group, and again taking into account the caveats of not everybody had a CT interpretable for the number of vessels disease, in those with the most severe coronary disease, that's the Duke 6 subgroup. And they had multi-vessel severe disease, either two vessel including the proximal LAD at 70% or three vessels with 70% stenosis. There was no benefit on mortality. But if we looked at the composite endpoint of cardiovascular death or MI, there appeared to be some advantage to the invasive strategy.

Dr. Greg Hundley:

Very good. Well, Sandeep, similar to Nick, working as an associate editor and meeting weekly, what attracted you to this particular paper? And why did you want to really see it come forward to be published?

Dr. Sandeep Das:

So first of all, I want to echo Nick's comments that these are great papers, and thanks very much for sending those our way and letting us have sort of first crack at them before they're released to the world. And I also want to comment on the side that Harmony and her team were just absolutely fantastic to work with in this process. From having been on the other side when you get 300 different comments from the editors and reviewers and you respond to them thoroughly and with grace, that's a feat in and of itself. So I want to shout out Harmony and her team for just being fantastic partners, because really we see ourselves as sort of the author's partners in kind of making the paper as good as it can be as the best it can be.

Dr. Sandeep Das:

So I'll admit upfront, I think it's kind of fashionable for people to say, well, I knew that this was going to show this, I knew this all from COURAGE, and this is not surprising to me. But I'll admit that I was surprised. And so this has been practice-changing for me, so this whole evolution post ischemia. And I really feel like a little bit of an existential crisis because I'm not sure I understand what ischemia means anymore. You ask me five years ago, I would've been very confident that I knew the answer to that. So you know what, really, as soon as this paper crossed our desk, I thought, wow, this is something we want to keep, this is something that's going to be really important to practice of cardiology. It's going to be really important to our readers. It's a great paper from a great group. This is something we want. So really it was never a question of, well, am I interested or am I not? I was interested from reading the abstract.

Dr. Sandeep Das:

So the question then became what are the real important questions that we need to sort of tease out and help elucidate for the clinician for the reader? And really for me, the question has always been, is there a subset of people where... So in my heart of hearts, I always kind of thought that burden of ischemia, if there was enough burden of ischemia, that it probably did help to revascularize that, right? I definitely practiced that way, right? There was some sort of number where I would start to say, that's a lot of ischemic myocardium and maybe we need to do something about that. Even though I know my intellectual brain says, no, there's no data that supports this, I really kind of thought it was true. And so Harmony and her team put another nail in that coffin here because it doesn't seem to be true, which to me was interesting and different and practice-changing.

Dr. Sandeep Das:

So the real questions here were sort of to tease out the interaction between anatomic severity, and we've all known that sort of anatomic burden of disease is proportional to adverse outcomes. That's not surprising. But the question then is, can we tease out a group where there may be benefit to revascularization? So there's a real interesting sort of interplay here between degree of ischemia and anatomic burden of disease. And is there a subset with enough of an anatomic burden of disease where you really may be interested in going after that to improve heart outcomes? So that's what I thought this was really fascinating paper.

Dr. Greg Hundley:

Very good. Well, David, we're going to turn to you next as the editorialist and asking you to sort of put the results of each of these two studies together. One, kind of highlighting for us how functional imaging might be useful to identify whether ischemia is present or not. And then the second study, really defining for us an association between anatomy and outcomes. So putting these all together, could you share your thoughts with us regarding these two papers?

Dr. David Newby:

Yes. Thank you. So I think that the CIAO-ISCHEMIA is very interesting, isn't it? And those clinicians were often challenged with symptoms versus our objective tests and trying to work out exactly what's going on, and it is. And such an important group as Harmony says, I can't agree more. We have a lot of morbidity here. As Nick said, I think the short term, a lot of the patients do seem to get better with just conservative management is good, but there's a core group that clearly are a problem. And as Harmony highlighted, you've got people with terrible regional wall-motion abnormalities on stress echo and yet no angina, others with no angina with no apparent difficulty on repeat testing. And then you've got a core group that has both, and it is fascinating to try and unpick that. And clearly, the symptoms are not correlating with our tests, and that's not the patient's fault.

Dr. David Newby:

And very often, no, no, you're wrong, can we say that to the patient? No, no, the patient is right and our tests are wrong, and we've got to work out how best to manage them. And I have a bit of analogy with Takotsubo cardiomyopathy as well, I think is at play here. I mean, here, you've got people with stable pain. We're not coming in as an acute emergency, but they're having regional wall motion abnormalities at times. They're getting a lot of symptoms. And we see similar things with Takotsubo, which is, I suppose, a much more flurry thing. I know that's something close to Harmony's his heart too. Excuse the pun. But this ischemia relationship, these regional wall motion abnormalities with chest pain, particularly in women, is something we really need to get our heads around and understand what's going on. It just reflects our ignorance, I think, of knowing exactly how to manage these patients.

Dr. David Newby:

And so for me, ischemia testing is about symptoms. It's about working out what's going on with the patient. It doesn't always give us the answer, but I certainly think that the role of ischemia testing is more about the symptoms.

Dr. David Newby:

And then when it comes to the second paper and outcomes with the ischemia trial, I absolutely was delighted to see those findings. I have to say place to what my prejudice is, I suppose, as someone that's been working with CT. And I suppose the slightly obvious thing is that the more disease you have, the more you will benefit from an intervention. And plaque and the burden of plaque is critical to that because how do you have a heart attack? Well, you have to have plaque, right? And it has to rupture. So the more plaque you have, the more likely you are. And I think that the analysis is again reinforcing what we've learned from some of the imaging trials with PROMIS and SCOT-HEART. Actually, the more plaque you have, the worse you are.

Dr. David Newby:

And yes, ischemia predicts risk, but ischemia predicts risk through its association with plaque burden, not through ischemia itself. And what I think we're seeing very nicely being played out in ischemia trial is the risk is definitely much stronger for CT than it is for imaging. And that's very clear, and that's exactly what PROMIS found exactly what SCOT-HEART found as well, and it's a rise robust finding. The interaction with the treatment effect that I find also fascinating and again plays to some of the bypass surgery trials that we've seen, bypass surgery tends to prevent spontaneous MIs and, even in some cases, mortality. And we're seeing trends in ischemia for mortality, can't over call them. I'd love to see what happens in 10 years. But I think in terms of the prevention of MIs, I'm putting all my money in one basket, which is the bypass surgery, 25% of course of patients revascularized that way. I don't believe that PCI is going to prevent the myocardial infarction. So I think all my money is in that box.

Dr. David Newby:

But it's absolutely fascinating data. It is all about the plaque if you're talking about prevention of clinical events downstream. And I think that's where the dichotomy is, scheme is about symptoms and understanding the patient's problems in terms of symptomatic improvement. If you want to improve their long term outcome, it's all about the plaque, understanding the burden of plaque and what you can do to hopefully prevent downstream event.

Dr. Greg Hundley:

Great. Thank you so much. And so listeners, we're going to ask each of our speakers today in really 20 or 30 seconds to go through and identify what do they think is the next study really to be performed in this space? So Harmony, we're going to start with you and then Nick, Sandeep and then finish up with David. Harmony?

Dr. Harmony Reynolds:

Thanks. Well, when it comes to INOCA, I would like to see more studies in the vein of CorMicA. So I'd like to see routine invasive testing to define the underlying pathophysiology problem and then targeted medical therapy interventions, and I'd like to see outcome trials. There's one outcome trial going on. It's a challenge because the event rate, though very important and higher than in the general population for sure, is low enough that these trials have to be quite large, and we look at ischemia with a relatively high event rate. And even so it's a stable population and that had to be large, this would have to be even larger. So we're going to need more mechanistic studies in order to lead to the treatment trials that will really influence practice.

Dr. Harmony Reynolds:

And in terms of the severity of coronary disease, this is a tough one. We felt like ischemia was a lift, and I'm not sure that there will be another huge stable ischemic heart disease trial. But sure, I'd love to see in people selected by CT for their advanced severity of coronary disease, whether an invasive management strategy makes a difference compared to medical therapy. I don't know that we'll see that one come to pass, but you never know.

Dr. Greg Hundley:

Nick?

Dr. Nicholas Mills:

Yeah. I agree. We need more mechanistic research, but I'd like to see more non-invasive methods to understand the mechanistic basis of this condition because CorMicA has caught an invasive protocol for a condition, which we know is benign and who most patients get better without any treatment. I would also like to see randomized blinded studies of treatment effects and because there are too many observational on blinded studies here. And I think the outcome has to be patient-focused and symptoms.

Dr. Greg Hundley:

Sandeep?

Dr. Sandeep Das:

Yeah. So everything that's been raised so far are fantastic comments and really on point. For me, I think if we can tease out the population that may benefit to get back to Dave's earlier comment that there's possibly not going to be a little humble here, there's possibly a population that has extensive, extensive CVD that could benefit from bypass surgery. And I think that that hasn't really been firmly demonstrated yet, although it's been suggested strongly. So that I think is an interesting study, and I hope that that gets done as a trial, but I can understand that it'd be a giant undertaking. And then the other thing I think is just algorithmic approaches that are driven by anatomical studies like SCOT-HEART and things like that, where we really try to make decisions based on the anatomical approach and pretend like the last 15 years never happened and that we kind are starting fresh with our best approach to how to treat these patients.

Dr. Greg Hundley:

And finally, David.

Dr. David Newby:

Yeah. I'm actually going to agree with everybody there, and I'm rooting for this trial actually because that's the one I want to do is look at advanced coronary disease on noninvasive imaging, irrespective of symptoms. And that's the big call actually if you've got no symptoms to put yourself through a bypass, because it's bypass, it's not standing. Bypass, we need. I'd also love to see some substudy coming out of ischemia. I think you're doing them. I hope you are looking at plaque burden and plaque characteristics because I think that's another level of complexity. We're so obsessed with stenosis, actually. And again, even anatomical and ischemia testing plays to that, it's not just about stenosis, stenotic arteries have big plaque burdens, et cetera. And it's not bypassing them, it's bypassing all the nonobstructive plaque and the obstructive plaque that has given you the benefit of revascularization with surgery. So I think you need to think about a really nice cool trial where we can do that trial even in the presence of nonobstructive disease, but big plaque burden, adverse plaque characteristics, and think about bypass.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Harmony Reynolds for bringing us these two really informative studies from the ischemia trial, and also our associate editors, Dr. Nick Mills and Dr. Sandeep Das for providing their perspective and our editorialist, Dr. David Newby, who really helped us organize our thoughts and put both of these two studies into great perspective highlighting in the first that functional testing can really help us identify the presence or absence of ischemia. And then our second study highlighting the association between CT coronary angiography and the identification of the anatomic severity of disease with cardiac outcomes.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speaker in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation September 21, 2021 Issue

20 september 2021 | 25 min

This week's episode features author Benjamin Levine and Guest Editor Walter Paulus as they discuss the article "One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage-B HFpEF."

Dr. Greg Hundley:

Well, welcome listeners. This is the September 21st podcast for Circulation on the Run. Sadly, I'm without Carolyn today, but I am your host today, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Greg Hundley:

Our feature discussion today is really interesting. It's from Dr. Ben Levine, and he's evaluating the utility of exercise training and actually trying to reverse abnormal left ventricular myocardial stiffness in individuals that have stage B, it's a very early heart failure and preserved ejection fraction. But before we get to that, let's grab a cup of coffee and we're going to work through some of the other articles in this issue.

Dr. Greg Hundley:

So the first one comes to us from Göran Bergström from University of Gothenburg in Sweden. He and his team used coronary computed tomography angiography or CCTA to determine the prevalence, severity and characteristics of coronary atherosclerosis and its association to coronary artery calcification scores in a general population of greater than 25,000 individuals all aged 50 to 64 years and without known coronary heart disease. It really comes to us from the Swedish CArdioPulmonary BioImage Study or SCAPIS. Well, Carolyn would ask me that is a really large study, and what did they find? Well, let's get to the results.

Dr. Greg Hundley:

So using CCTA to detect silent coronary atherosclerosis, the investigators showed that any coronary atherosclerosis was actually quite common, 42% of individuals and significant stenosis of greater than 50% was less common, only 5% of individuals. More severe forms were rarely found, only 1.9% in this very large, random sample of middle-aged individuals.

Dr. Greg Hundley:

Now disease onset was delayed by 10 years in women and a higher prevalence of coronary atherosclerosis was observed with higher age and accumulation of risk factors. Interestingly, CCTA detected atherosclerosis increased with an increasing coronary artery calcium score. All those with a high CAC score of greater than 400 had atherosclerosis and 45% had significant stenosis. 5.5% of those with no coronary artery calcification had atherosclerosis and 0.4% had significant stenosis. So although there was a strong association with high coronary artery calcium scores and significant stenosis, atherosclerosis was not excluded in those with zero coronary artery calcification especially in those with high baseline risk.

Dr. Greg Hundley:

Well, our second article comes to us from the world of preclinical science and it's from Dr. Nathan Palpant from the University of Queensland. So the article pertains to ischemia reperfusion injury, and it's one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. Now during cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6 to 6.5, and the resulting tissue acidosis exacerbates ischemia injury and significantly impacts cardiac function.

Dr. Greg Hundley:

So the authors today use genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a or ASIC1a, we'll call it from now, in cardiac ischemia reperfusion injury at the cellular and whole organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of ischemia reperfusion injury were used to test the efficacy of ASIC1a inhibitors as pre-imposed conditioning therapeutic agents.

Dr. Greg Hundley:

So what did the authors find in this study? Well, they demonstrated for the first time that acid-sensing ion channel 1a or that ASIC1a mediates cardiac ischemia reperfusion injury. The authors identify that ASIC1a inhibition is a novel therapeutic strategy for preventing acute injury response to myocardial ischemia reperfusion injury.

Dr. Greg Hundley:

So what are the clinical implications of this research? Well, first there are currently no drugs in clinical use that prevent acute injury response to myocardial ischemia, despite many promising candidates identified over decades of research, all of which ultimately failed in subsequent clinical trials. Second, the identification of new therapeutic targets for preventing the injury response to myocardial ischemia reperfusion injury would therefore have profound implications in cardiovascular medicine. Therefore, the results of this study reveal that ASIC1a inhibiting drugs, they're safe and they have potential applications in heart transplant and myocardial infarction with potential use in other clinical scenarios where myocardial ischemia reperfusion injury is a risk such as those that undergo cardiac surgery.

Dr. Greg Hundley:

Well, our next article comes from Robin Choudhury from the University of Oxford. Have you ever wondered why cardiovascular risk and diabetes remains elevated despite glucose-lowering therapies? Well, these authors hypothesized that trained immunity in response to elevated glucose accounts for diabetic hyperglycemic "memory", we'll call it, in relation to atherosclerosis. So accordingly, the author sought to determine if hyperglycemia-induced disease relevant changes in monocyte and macrophage function and whether these changes persisted after restoration of normal glucose, thereby implying fundamental reprogramming. So the team combined studies of cellular function, metabolomics, transcriptomics and epigenomics to define how hyperglycemia altered metabolism to modulate long-term activation through epigenetic modifications.

Dr. Greg Hundley:

Well, what did they find? First, hyperglycemia induced a trained immunity in bone marrow progenitor cells by inducing persistent epigenetic modifications. Second, hyperglycemia-induced trained immunity persisted after differentiation into those macrophages. Finally, hematopoetic stem cells transplanted from mice with diabetes to euglycemic mice promoted exaggerated atherosclerosis. So therefore, the findings of this study may explain the resistance of macrovascular complications of diabetes to conventional glucose-lowering treatments.

Dr. Greg Hundley:

Well, in the mailbag this week, there are some other articles. Professor Huang has a Research Letter entitled, “Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity.” Dr. De Caterina has an In Depth article on coronary artery anomalies. Finally, Professor Merid has a Perspective piece entitled, “Digital Redlining and Cardiovascular Innovation.”

Dr. Greg Hundley:

Well, listeners, what a great group of articles, and now we're going to turn to that feature discussion with Dr. Ben Levine.

Dr. Greg Hundley:

Welcome listeners to our feature discussion today and we're very fortunate. We have with us, Dr. Ben Levine from UT Southwestern in Dallas, Texas and also Dr. Walter Paulus from Amsterdam. Welcome gentlemen.

Dr. Greg Hundley:

Ben, we'd like to start with you. Could you describe for us a little bit of the background related to your study and what was the hypothesis that you wanted to test?

Professor Benjamin Levine:

Sure. Oh, nice to talk with you, Greg. As you know, our lab has been very interested in the effects of both aging and physical activity on cardiac mechanics. To cut a very long story short, what we know is that sedentary aging leads to stiffening of the heart. We also know that HFpEF, heart failure with preserved ejection fraction, is a disorder predominantly of the aged. I don't know about you, Walter, but I've never seen any lead masters athlete HFpEF.

Professor Benjamin Levine:

What we've shown is that if you regularly exercise over a lifetime that the heart can preserve its youthful compliance and flexibility. But if you wait until somebody is older, meaning over 65, 70, regardless of how hard or intense we train, the heart seems to lose its plasticity. It can't actually get that much better. But if we start in late middle age, it turns out that you can actually reverse some of the adverse effects of sedentary aging. So we said, "Okay, we know what the dose is, how much exercise you need to do. We know what the sweet spot in time. Now how do we find those people who are most likely to go on to develop HFpEF in whom getting them on a regular exercise program might help forestall this very challenging syndrome."

Professor Benjamin Levine:

So as part of an AHA-funded strategically focused research network and prevention, we identified a group of patients who had left ventricular hypertrophy, but evidence that they were on the wrong path. Their biomarkers were elevated. They have an elevated NT-BNP or a high sensitivity troponin. We did a right heart catheterization and we looked at their cardiac stiffness using a technique that we've done now for the past 25 years or so, and showed that indeed those patients' hearts are clearly stiffer than healthy, but otherwise sedentary middle-aged individuals.

Professor Benjamin Levine:

So our key question was what happens if we put them on a long sustained high intensity exercise program? Can we reverse the effects of sedentary aging superimposed with hypertension, left ventricle hypertrophy and elevated biomarkers?

Dr. Greg Hundley:

Really interesting, Ben. So describe your study design for us. How are you going to set up? It sounds like a very elaborate experimental setup here. Then also, maybe just define for us your study population. Did you have men and women or-

Professor Benjamin Levine:

Yeah, we started by going to the Dallas Heart Study. We're blessed here in Dallas by having this room access to our remarkable population where we know a lot about them. So we picked people in late middle age of all races, both sexes, and we reached out to the members of the Dallas Heart Study if they had left ventricular hypertrophy by echo or MRI and were of the right age range. We enriched that database by going to an EKG database and looking at the Ecolab database, trying to find people who did not have heart disease already. That was important. They couldn't have had a heart attack. They couldn't have had heart failure. They couldn't have had infiltrative disease. They had to be generally healthy except had left ventricular hypertrophy.

Professor Benjamin Levine:

We screened a lot of patients to get there, I have to acknowledge that, almost 4,000 of them or so to get the small number who were interested in doing a one-year exercise training program. But as we eventually got a good solid number that because we use such high resolution techniques, we were able to define the key outcome variable, which is cardiac stiffness.

Professor Benjamin Levine:

Briefly in our lab, we put a right heart catheter in to measure wedge pressure. We use 3D-echo to measure volume and then we use something called lower body negative pressure to unload the heart. It's almost like standing up progressively or tilting upright and then we give them a rapid saline infusion, 200 mls a minute. So a lot of saline, 15 and 30 mls/kg. We can get the left atrial pressure from about three or four up until about 18 to 20 and define the entire physiologic range of left ventricular filling. We look not just at the wedge pressure of course, but the transmural pressure.

Professor Benjamin Levine:

John Tyberg and his colleagues in Canada have shown clearly that the pericardial pressure is pretty close to right atrial pressure. So transmural pressure, which is the distending pressure of the heart, is left atrial minus right atrial pressure. We use that as the input into a pressure volume relationship.

Dr. Greg Hundley:

Very nice, and then what did you find?

Professor Benjamin Levine:

Well, what we found is after demonstrating that these patients with LVH and elevated biomarkers have increased stiffness, what we found quite remarkably actually was that we were able to reverse that by a year of training.

Professor Benjamin Levine:

Now when I say training, I mean, we do use the optimal approach to training that we've demonstrated in our lab. We didn't just pick one thing, get on a bike, do that for 30 minutes three times a week, right? These were sedentary people so we built them up slowly over about seven months. We added frequency, we added duration, we added intensity.

Professor Benjamin Levine:

I am enamored by the four by four in old Norwegian ski team workout, which is four minutes at 95% of max followed by three minutes of recovery repeated four times. We added interval training and long slow distance battle lasting about an hour on the weekends and a little bit of strength training, too.

Professor Benjamin Levine:

So what we consider the ideal prescription for life, four to five days a week, one long session, one high intensity session, two or three moderate intensity sessions and a little bit of strength. We did it for a year. It took a lot of effort. We had dedicated trainers. We gave them all heart rate monitors. Each person had a trainer to follow them.

Professor Benjamin Levine:

We did have a control group. We randomly assign them to a group that did stretching and yoga and mindfulness and a little bit of strength training, which makes people feel better. But we know from experience, it doesn't make them fitter and doesn't change their cardiac compliance.

Dr. Greg Hundley:

What happened with the treatment group?

Professor Benjamin Levine:

Oh, they got much more compliant. They got as compliant as if they had been training most of their lives. It was quite remarkable, actually, frankly, better than we expected it to be. We check the data multiple times by multiple people to make sure that this was a real finding. We really reversed much of the effects of the adverse effects of sedentary aging plus LVH. We hope that if that would be sustained over more than a year, years of long training study, there are very few training studies that go that long. But it's not a lifetime and at least we've set the stage for the concept that if this were to be sustained over a lifetime that we think it could forestall HFpEF.

Dr. Greg Hundley:

Very nice. Well, Walter, I know serving as a guest editor for us at Circulation and we're most appreciative for you doing that task. What struck you about this particular article and really enticed you to want to help us move it toward publication?

Professor Walter Paulus:

Well, I felt that the article was very visionary. Of course, as it comes from Ben, I didn't expect anything else. But what struck me were two points.

Professor Walter Paulus:

First of all, he looks at patients which we would label type B HFpEF. Most of our efforts have always been focusing on sick people, stage C HFpEF, stage D HFpEF. Now Ben was so clever to go to an early stage, and I believe that many of the so-called neutral outcomes in therapy for HFpEF are related to the fact that we actually address patients population who is quite far out on its natural history. So I think this was the first point to me. He, Ben, was addressing a population at the early stages of HFpEF.

Professor Walter Paulus:

The second point that struck me was that the variable he was looking at is in my opinion the key variable in HFpEF. It's the main reason I appreciated that this is the disease of myocardial compliance of left ventricle stiffness, and then very nicely addressed the stiffness of the heart as its primary outcome. This is something what we miss in all the pharmacological trials. I have always been curious when are we going to see the pharmacological trial whereby somebody is going to evaluate a compound in terms of its effects on left ventricular stiffness on myocardial compliance.

Professor Walter Paulus:

So these were for me two very salient features and very visionary in terms of treatment of a HFpEF population. Also, a couple of things that need to be clarified for me and I did. The patient's entry criteria were very demanding, has been also already said. I have the feeling that if you have LVH and then you will try NT-proBNP to be elevated and all your required troponins to be elevated, it's probably be very hard to get such a patient population and that may be then the only remark that could come up toward an extent in such a patient population still reflective of everyday health.

Dr. Greg Hundley:

Very good. Well, Ben, coming back to you, what's your next study?

Professor Benjamin Levine:

Well, we have a large program project grant, Greg, funded by the NIH, looking at the mechanisms of dyspnea and HFpEF. We're now just entered our third year. We're looking at a strategy to try to lower cardiac filling pressures acutely to see if that improves exercise tolerance and reduce dyspnea. We're looking at peripheral mechanisms of oxygen uptake and utilization and vascular control. We're looking at autonomic function, sympathetic nerve recordings, regulation of the sympathetic nervous system. We have a group focused on pulmonary mechanics, particularly on the effects of obesity.

Professor Benjamin Levine:

Our team with Tom Sarma is our recruitment core expert and one of the Circulation editors and is really the lifeblood of our study and leads our effort. We have Paul Fidel from UT Arlington who's leading our peripheral function studies, Qi Fu from UT Southwestern leading our autonomic group, and Tony Babb also from Southwestern in the pulmonary division leading our pulmonary mechanics.

Professor Benjamin Levine:

So we're entering this phase where we're trying to say, "Are there other components?" We know myocardial stiffness is a key factor, but what else in patients with the already manifest HFpEF is causing them to be so short of breath and can we change that?

Professor Benjamin Levine:

So that's what we're doing next, Greg. I think that if you ask what is the next step from this study, I think it has to be population-based and pushing the concept that exercise is medicine. When you find patients who have hypertension in general, and most of these had hypertension or diabetes, I mean, Walter has led this field and in emphasizing these comorbidities and what they do to the heart and the vasculature and the rest of the body, we have to catch people early. We can't wait until they have full-blown manifest HFpEF. We have to get them to include exercise as part of their personal hygiene.

Professor Benjamin Levine:

I know that that's a major effort from the American Heart Association. But I think that for the long-term health of our population and preventing this disease that is so difficult to treat when it's firmly established, we have to as cardiologists and as a healthcare system, we have to start by including incentives for reducing healthcare costs to get people to use exercise as part of their personal hygiene and daily life.

Dr. Greg Hundley:

Very nice. Walter, from your perspective, what do you see are the next studies that need to be performed in this sphere of research?

Professor Walter Paulus:

Well, I will be very curious to see how many patients would actually go on to develop HFpEF in their life. It should be as if Ben's hypothesis holds, then the control group probably would have an access development of HFpEF compared to his exercise training group. I think that would really extend to study from above, from a mechanical observation to a clinically, epidemiologically more relevant endpoint. So I think that to me would be the first question, how many patients will evolve to clinical HFpEF.

Professor Walter Paulus:

Second point I would be very intrigued in is, are there SIP groups in the patients who have a positive response to exercise? For instance, what happens with the different ejection fractions? Because we are very intrigued at present in HFpEF that at high ejection fractions nothing seems to work. Sacubitril was notable at high ejection fractions. Empagliflozin was also neutral to ejection fractions. What would happen with exercise? Do the patients who present with the 70% ejection fraction at the angio study, do they still have a positive response? This would be a game change because this would then be the only intervention that is able to cure the HFpEF with high ejection fraction. These are some future projects that come into my mind.

Professor Benjamin Levine:

Let me just add that we have studied and put patients with HFpEF on a yearlong exercise program with not as much effect as we would like. I think that's one of the things that pushed us to getting earlier into the course of HFpEF, as Walter said earlier.

Professor Benjamin Levine:

Ambarish Pandey and Jarett Berry, also from UT Southwestern, of course are very interested in this effect of fitness at different points in the lifespan, our fitness test, for example, measured in mid-life and what means for heart failure later. I think it's hard to do the kind of studies that we do and follow patients for 20 years to see if they're going to develop heart failure, and that's where I think being creative and looking at the studies that incorporate an assessment of fitness and that follow people over time will be very informative. I hope with me, Walter's hope and hypothesis that these patients are less likely to develop HFpEF. We've got to get in there early.

Dr. Greg Hundley:

Very good. Well, listeners, we want to thank Professor Benjamin Levine from UT Southwestern in Dallas and also Dr. Walter Paulus from Amsterdam for bringing us this really interesting study, indicating that in patients with LVH and elevated cardiac biomarkers, sort of the stage B HFpEF that one year of exercise training reduces left ventricular myocardial stiffness.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation September 14, 2021 Issue

14 september 2021 | 21 min

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Miriam Cortese-Krott and Associate Editor Charles Lowenstein as they discuss the article "Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-host I'm Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is one of those really, really landmark papers that really advance our understanding of Nitric oxide signaling. And it's about red blood cell and Endothelial eNOS, and how they independently regulate circulating nitric oxide, metabolites, and blood pressure. A real, real must, but let's go on and look at the other papers in this issue first. Greg, you want to go first?

Dr. Greg Hundley:

You bet, Carolyn. Better grab a cup of coffee. And my first paper is from professor Nathan Mewton from Hôpital Louis Pradel Hospices Civils de Lyon. Carolyn, these authors hypothesized that Colchicine a potent anti-inflammatory agent may reduce infarct size in left ventricular remodeling at the acute phase of STEMI. And so to address this hypothesis, they performed a double-blind multi-center trial and randomly assigned patients admitted for a first episode of STEMI referred for primary PTCA to receive oral Colchicine two-milligram loading dose followed by 0.5 milligrams twice a day, or matching placebo from admission to day five and the primary efficacy outcome was infarct size determined by cardiovascular magnetic resonance imaging at five days. And the relative left ventricular end-diastolic volume change at three months and infarct size at three months was also assessed by cardiac MRI. And these were secondary outcomes.

Dr. Carolyn Lam:

Nice. Okay. So what were the results?

Dr. Greg Hundley:

Right, Carolyn. So 192 patients were enrolled. 101 in the Colchicine group and 91 in the controls. And as a result of this trial, the oral administration of high dose Colchicine at the time of Reperfusion. And for five days thereafter did not reduce infarct size assessed by cardiac MRI. And so Carolyn, the clinical implications of these results suggest that other studies exploring the timing, pharma kinetics, and dose-response of Colchicine, as well as other anti-inflammatory agents are needed to identify an effective method to reduce infarct size and limit remodeling in this group of patients.

Dr. Carolyn Lam:

Wow, it's just such a rich field done with all this about Colchicine. Well, our next paper is a pre-specified sub-analysis of the randomized EAST-AFNET 4 Trial and the sub-analysis assess the effect of systematic early rhythm control therapy that is using Antiarrhythmic drugs or catheter ablation compared to usual care, which means allowing rhythm control therapy to improve symptoms in patients with heart failure. And this was defined in the sub-analysis as the presence of heart failure symptoms of New York Heart Association status two to three or a left ventricular ejection fraction of less than 50%.

Dr. Carolyn Lam:

Now, the authors led by Dr. Kirchhof at University Heart and Vascular Center UKE in Hamburg, Germany included 798 patients in this sub-analysis of whom 442 had HFpEF, 211 had heart failure with mid-range ejection fraction and 132 had HF-rEF over a median of 5.1 years of follow-up the composite primary outcome of cardiovascular death stroke or hospitalization for worsening heart failure, or for acute coronary syndrome occurred less often in patients randomized to early rhythm control therapy compared with patients randomized to usual care. And this was not altered by heart failure status with an interaction P-value of 0.6. Left ventricular function, symptoms, and quality of life improved equally in both treatment strategies.

Dr. Greg Hundley:

Wow, Carolyn, a lot of information here. So what can we take away from this?

Dr. Carolyn Lam:

Well, let's remember that this is a sub-analysis, albeit pre-specified of that randomized trial of the EAST-AFNET 4 Trial, but nonetheless, the data supports a treatment strategy of rhythm control therapy with Antiarrhythmic drugs or ablation within a year of diagnosing atrial fibrillation in patients with signs and symptoms of heart failure to reduce cardiovascular outcomes.

Dr. Greg Hundley:

Very nice, Carolyn. So, Carolyn, my next paper pertains to Alarmin Interleukin-1 Alpha, and it comes to us from Dr. Thimoteus Speer at Saarland University. So, Carolyn, Alarmin Interleukin-1 Alpha is expressed in a variety of cell types, promoting sterile systemic inflammation. And the aim of the present study was to examine the role of Alarmin Interleukin-1 Alpha in mediating inflammation in the setting of acute myocardial infarction and chronic kidney disease.

Dr. Carolyn Lam:

Wow, sterile inflammation. It's a really hot topic now. So what did these authors find?

Dr. Greg Hundley:

Right, Carolyn. So we're going to call Alarmin Interleukin-1 Alpha. Let's just call it IL-1 Alpha and so increased IL-1 Alpha surface expression on monocytes from patients with acute myocardial infarction in patients with chronic kidney disease was found to be associated with cardiovascular events. Next, IL-1 Alphas itself served as an adhesion molecule, mediating leukocyte-endothelial adhesion, and finally, abrogation of IL-1 alpha prevented inflammation after myocardial infarction and ameliorated chronic kidney disease in Vivo.

Dr. Carolyn Lam:

Wow. So what does this mean clinically?

Dr. Greg Hundley:

Right, Carolyn, so perhaps targeted therapeutic inhibition of IL-1 Alpha might represent a novel anti-inflammatory treatment strategy in patients with myocardial infarction and in patients with chronic kidney disease.

Dr. Carolyn Lam:

Amazing. Thanks, Greg. Well, in today's issue, there's also an exchange of letters between doctors Lother and Filippatos on Finerenone and risk of hyperkalemia in CKD and type two diabetes. There's an On My Mind paper by Dr. Sattler on the single-cell immunology and cardiovascular METs in, do we know yet what we don't know?

Dr. Greg Hundley:

And then Carolyn, from the mailbag, a Research Letter from Professor Wehrens entitled “Atrial Specific LK Beta One Knockdown Represents a Novel Mouse Model of Atrial Cardiomyopathy with Spontaneous Atrial Fibrillation.” Well, Carolyn, how about we turn our attention to those red blood cells and endothelial nitric oxide synthase.

Dr. Carolyn Lam:

Yeah. Can't wait.

Dr. Mercedes Carnethon:

Well, welcome to this episode of Circulation on the Run. Our podcasts, where we have an opportunity to speak with authors of important papers that are appearing in the journal of circulation. I'm pleased to introduce myself. My name is Mercedes Carnethon, professor and vice-chair of preventive medicine at the Northwestern University Feinberg School of Medicine. And I'm pleased today to invite our guest author, Miriam Cortese-Krott, who is the faculty of the University of Duesseldorf, and a guest professor at the Karolinska Institute in Stockholm. And we have with us as well the other associate editor who handled the piece for circulation, Dr. Charlie Lowenstein from Johns Hopkins University. So welcome to each of you this morning.

Miriam Cortese-krott:

Thank you.

Dr. Charles Lowenstein :

Thanks for having me.

Dr. Mercedes Carnethon:

Well, thank you. I'm really excited to jump right into this piece, Miriam, can you tell me a little bit about the rationale for carrying out the study, why you pursued it?

Professor Miriam Cortese-Krott:

The reason is because when I was working as a post-doc, I had to isolate an enzyme from red blood cells, which is a very, very difficult. And if you know, this enzyme is endothelial nitric oxide synthase, which produce nitric oxide, and actually, the red blood cell is full of the worst enemy of nitric oxide, which is hemoglobin. So actually, when I was talking about my project, everybody was asking, "Why are you doing that?" And I was actually able to isolate the enzyme and look at activity and be sure that the enzyme was fine, but the function of this enzyme was absolutely unknown.

Professor Miriam Cortese-Krott:

And the only way to study proteins in red blood cells is to make modification in the bone marrow of the mice. So in the Erythroid cells, because you can not, of course, if there are cells without nucleus you don't have any chance to modify them in culture, something like that. So the only way was to generate mice with modification specifically in the red blood cells. And I had the chance to create, to generate red cell-specific eNOS knockout mice. And of course, as a control endothelial-specific eNOS knockout mice by using the Cre-loxP technology. And with this technology, I could really understand what's happening to the physiology of the mouse if you remove this protein from the red blood cells. And so this was the whole idea.

Dr. Mercedes Carnethon:

Thank you so much. It was really exciting for me to read this piece. We are on opposite ends of the scientific inquiry spread as I'm an epidemiologist who does things at the population level, and you're identifying things at the basic science level. I thought the paper was extremely well-written and that encouraged people to dig in, even if you're unfamiliar, and in part that's because you provided such a great explanation of how your findings are used and how they're relevant to the process. Do you mind sharing a little bit about your findings and how you expect that they will be used by our scientific community?

Professor Miriam Cortese-Krott:

I think the main finding of this paper is that if you remove eNOS from the red blood cells if the mice are hypertensive, have hypertension, and this is completely something that you actually will not expect, as I told you that indeed red cells are full of the enemy of nitric oxide that remove it immediately. So you can ask yourself how it is possible. But I think the key finding here in this paper was that I also generated the opposite model. So I created the model a conditional eNOS Knockout model where you can decide in which tissue you want to have your enzyme. And of course, I applied for red blood cells. And what you see in this model is that you start from a global knockout mouse with hypertension, you reintroduce the eNOS just in the red blood cells, you have normal tension. So this means, this is the main finding. You have a switch in the red blood cells, which is the enzyme eNOS, which it's behaving in a completely different way clearly as compared to the vessel wall eNOS and still regulating blood pressure.

Dr. Mercedes Carnethon:

Well, thank you so much. I think this is the point at which I like to turn to the associate editor who handled the piece. Charlie, you and I don't get to talk as often given the diversity of work that we each pursue, but Charlie, tell me a little bit about what excited you about this piece?

Dr. Charles Lowenstein:

Thanks, Mercedes. So I love this piece. I thought Miriam, your article is so great. So a couple of thoughts. One is nitric oxide and nitric oxide synthase are so important in biology and medicine, nitric oxide regulates blood pressure. It regulates neurotransmission. It regulates inflammation. And this is true, not only in the lab, looking at cells in mice, but also in the human. So genetic variance in the endothelial nitric oxide synthase gene or NOS3 are associated with risks for diseases like coronary artery disease. So eNOS is just so important in biology and medicine. And now some ancient history. When I was a cardiology fellow, about a hundred years ago, I worked in the lab that first purified nitric oxide synthase proteins, and we cloned two of the nitric oxide synthase genes that was in the lab of Dr. Solomon Snyder at Johns Hopkins back in the 1700s.

Dr. Charles Lowenstein:

So when we cloned the nitric oxide synthase genes, when we and others did, we made a huge mistake. We chose the names for these isoforms from the tissue where they were first isolated. So we called the brain nitric oxide synthase nNOS, because it's a neurons, macrophages MCnos we called it MCnos and in endothelial cells, we called it the nitric oxide synthase eNOS or endothelial NOS. But in the last 20 years, lots of investigators have found these isoforms are in other cells, not just the original cells at discovery. And so Miriam's question is just so important, which cells make endothelial NOS also called NOS3. That's the history. Now what Miriam has discovered is just so important. I was so fascinated by her work because as she just said, she made two amazing discoveries. One, red blood cells make endothelial nitric oxide synthase.

Dr. Charles Lowenstein:

And that's been a controversy for a long time. Some people have said, "Yes." Some, "No." And Miriam made the definitive answer. Yes, red blood cells make eNOS, and secondly, she has discovered so much about the physiology of ENO coming from red blood cells, the nitric oxide that's made inside red blood cells regulates blood pressure. What a magical, interesting, and important finding. That's a little bit about the history. Nitric oxide and NOS are important in medicine. The people who originally cloned and purified the nitric oxide synthase isoforms named them after the tissue in which they discovered. And Miriam has made a major discovery that it's not only endothelial cells that make nitric oxide but also red blood cells.

Dr. Mercedes Carnethon:

Thank you so much for that summary. And I guess, I would have thought perhaps this was something of an Elixir of youth because if you've been working in this area for 200 plus years and Miriam, you started working on this as part of your dissertation work, you both have a lot of insight and background on where we've been and what the advances are. Miriam, can you tell me a little bit about how you'd like to see these findings used by the scientific community?

Professor Miriam Cortese-Krott:

I think I would like that the scientific community would use my mice first because I think, as Charles has said, it's not only red cells that express eNOS and it's not only endothelial cells. There are other cells producing eNOS and the function in the other cells is not known even in leukocytes, even when they have iNOS of course, but also have eNOS. So you can use my mice since it's a flux model. You can choose whatever you want, what cell you want, and then knock it in and knock it out. So this is one thing that I think the community could really do. I cannot do everything. So I'm happy to give my mice away.

Professor Miriam Cortese-Krott:

And the second thing is I would like too that in particular, the clinical community would see this link between Emathology and cardiovascular disease. This is something that was started, of course, there are studies looking at anemia and cardiovascular disease, but these studies have sometimes some issues I of course cannot speak as a basic scientist. I cannot speak about huge clinical trials, but I think this link exists and exists at the molecular level and it can be a target for pharmacological therapy. So I think this is what I would like to transport with this study to the clinical community and the basic science community.

Dr. Mercedes Carnethon:

Yeah. I think this is the point at which Charlie, I turn it to you because you really stand at the intersection of both of those communities. What questions do you have for Miriam going forward, as you think about spreading the word on this important work?

Dr. Charles Lowenstein:

So Miriam's discovery is just so important and she now has the tools to help answer really, really important questions. How is nitric oxide made in red blood cells? How is it stored in red blood cells? How is it transported throughout the body in red blood cells? What is the chemistry of nitric oxide, when it is stored, when it combines with oxygen when it forms nitrite and nitrate, how is it released from red blood cells? How is it targeted from a red blood cell to the vasculature? So there're these great basic science questions that Miriam and her colleagues are now poised to answer. So there's the science part of it. Then there's the medicine part of it because Miriam's mice and her great discovery have really huge implications for medicine. And so the question is, how can we use ENO? How can we deliver it? How can we target ENO to human tissues?

Dr. Charles Lowenstein:

How can we turn on erythrocyte, nitric oxide synthase? How can we turn it off? Because there are all these medical diseases where too much nitric oxide is bad, like in sepsis or inadequate amounts, don't protect the vasculature like atherosclerosis. Then there are all these other interesting questions. When we transfuse red blood cells, sometimes if you transfuse aged red blood cells, it's not good. You can harm people. Maybe we can load up or activate eNOS in stored red blood cells and then help deliver more ENO to patients who need red blood cells. So there are all these fascinating medical questions that we can look at based on Miriam's really important discovery.

Dr. Mercedes Carnethon:

Well, thank you so much. We're coming to the end of this wonderful and informative podcast. And I guess, I'd just ask Miriam, do you have anything else you'd like our listeners to know about your work and about the findings from this study?

Professor Miriam Cortese-Krott:

I would like people know that hard work help a lot, and that you have to believe in what you are doing and the quality of your science at the end would bring their true discoveries. So I think it's important specifically, for the young women in science that having this message too. So the science per se must be excellent and to proceed, you need a lot of work, but then the work goes to a good end.

Dr. Mercedes Carnethon:

Miriam, thank you so much for that inspirational note. The hard work that scientists need, the persistence across one's career and building from earlier discoveries, and bringing those forward through one's career are always critically important. And so I hope everyone has really enjoyed this episode and this opportunity to hear from Dr. Cortese-Krott. Miriam, you've done such wonderful work, and thank you as well, Charlie, for your insights about the intersection of this work with clinical care and basic science.

Professor Miriam Cortese-Krott:

Thank you.

Dr. Charles Lowenstein:

Thank you.

Dr. Mercedes Carnethon:

Thank you all very much for joining us today in this episode of Circulation on the Run.

Dr. Greg Hundley:

Circulation September 7, 2021 Issue

7 september 2021 | 29 min

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first?

Dr. Carolyn Lam:

All right. I got my coffee.

Dr. Greg Hundley:

So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown.

Dr. Carolyn Lam:

Wow. Okay. And what did the current paper do and find?

Dr. Greg Hundley:

Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke.

Dr. Carolyn Lam:

Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample.

Dr. Carolyn Lam:

However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm.

Dr. Greg Hundley:

Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear.

Dr. Carolyn Lam:

So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter.

Dr. Carolyn Lam:

And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use.

Dr. Greg Hundley:

Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1.

Dr. Greg Hundley:

Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations.

Dr. Carolyn Lam:

Oh, okay. And what did the authors find?

Dr. Greg Hundley:

Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling.

Dr Carolyn Lam:

Okay, Greg, that was super summarized but what are the clinical implications?

Dr. Greg Hundley:

Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias.

Dr. Carolyn Lam:

Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection.

Dr. Greg Hundley:

And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.”

Dr. Carolyn Lam:

Nice. Well, let's go on to our feature discussion. Can't wait.

Dr. Greg Hundley:

You bet.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it.

Dr. Mercedes Carnethon:

Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you?

Dr. Sung-Min Cho:

Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study.

Dr. Mercedes Carnethon:

Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you?

Dr. Sung-Min Cho:

Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3.

Dr. Mercedes Carnethon:

Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece.

Dr. Marc Ruel:

Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration.

Dr. Marc Ruel:

Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it?

Dr. Sung-Min Cho:

Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data.

Dr. Sung-Min Cho:

So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through.

Dr. Marc Ruel:

Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD.

Dr. Marc Ruel:

Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events.

Dr. Marc Ruel:

So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera.

Dr. Marc Ruel:

So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this?

Dr. Marc Ruel:

Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found.

Dr. Sung-Min Cho:

Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3.

Dr. Sung-Min Cho:

So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3.

Dr. Mercedes Carnethon:

Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more?

Sung-Min Cho:

Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market.

Sung-Min Cho:

So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah.

Dr. Marc Ruel:

Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team.

Dr. Marc Ruel:

If you still have a minute or two, I had a couple of more secondary questions?

Dr. Marc Ruel

In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this?

Dr. Sung-Min Cho:

Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript.

Dr. Sung-Min Cho:

And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke.

Dr. Sung-Min Cho:

There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications.

Dr. Marc Ruel:

Mercedes, if I'm so allowed, I do have one final comment and question.

Dr. Mercedes Carnethon:

Most definitely. This has been delightful, so yes.

Dr. Marc Ruel:

Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that.

Dr. Marc Ruel:

And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question.

Dr. Sung-Min Cho:

Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not.

Dr. Sung-Min Cho:

We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients.

Dr. Sung-Min Cho:

But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into.

Dr. Sung-Min Cho:

Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent.

Dr. Mercedes Carnethon:

Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it.

Dr. Mercedes Carnethon:

I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time.

Dr. Greg Hundley:

Circulation August 31, 2021 Issue

1 september 2021 | 27 min

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Kypros Nicolaides and Associate Editor Karol Watson as they discuss the article "Pravastatin versus Placebo in Pregnancies at High Risk of Term Preeclampsia."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley associate editor, director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

We have a really important feature discussion today. It's on pravastatin versus placebo in pregnancies at high risk of term preeclampsia. Very important condition. And I'm just so glad that we will be discussing this issue, coming right up. But first, I want to start on the other papers in this issue. And this first study, which is the first study to assess the effects of aerobic exercise training with and without caloric restriction on changes in the proximal aortic stiffness using cardiovascular magnetic resonance imaging. Now the corresponding author is Dr. Brinkley from the Sticht Center of Healthy Aging and Alzheimer's Prevention in Wake Forest School of Medicine. But guess what? Our very own Dr. Greg Huntley is a co-author. So whether you know it or not, Greg, we're going to do a mini feature, right now. So Dr. Huntley, could you please give us some background to your study, it's so cool?

Dr. Greg Hundley:

Oh, Carolyn, thank you so much. It's quite a privilege to be, actually being interviewed by you. So about the paper. Aortic stiffness is really a prominent manifestation, as we know, of vascular aging. And it's an independent predictor of cardiovascular events and mortality. And risk factors such as hypertension, diabetes, obesity, they can promote vascular changes that lead to accelerated vascular aging. Now, on the other hand, lifestyle factors such as healthy diet, regular physical activity, they may attenuate age related increases and aortic stiffness.

Dr. Greg Hundley:

And both cross-sectional and longitudinal studies indicate that exercise is associated with lower aortic stiffness. However, some data suggests exercise alone may not be sufficient to improve aortic stiffness in certain subpopulations of older adults. And so what Tina did, she worked in combination with all the co-authors and determined the effects of aerobic exercise training, with and without moderate to high caloric restriction on the structure and function of the proximal aorta in a 160 older, so 65 to 79 year old men and women with obesity that had a body mass index of 30 to 45 kilograms per meter square.

Dr. Carolyn Lam:

Wow. Okay, cool. But how do you assess this by MRI? Isn't that part of the novelty of the study, right?

Dr. Greg Hundley:

Right, Carolyn. So kind of two ways magnetic resonance imaging assesses aortic stiffness. First is to look at the distensibility. What is this distensibility? That's the change in the area of the aorta, relative to the distending pressure. And you can't measure that distending pressure noninvasively. So what we do is use a surrogate, your cuff pressure at your brachial artery. So that's one measure. Area change divided by basically the pulse pressure indexed for the resting area. And the second is pulse wave velocity. And for the listeners, remember pulse wave velocity, the faster the blood moves around through the aorta, the stiffer the artery is. And so we measured both aortic distensibility and pulse wave velocity.

Dr. Carolyn Lam:

I love it. You're such a good decentral educator. Okay. So what are the results real quick?

Dr. Greg Hundley:

Thanks Carolyn. So there were significant treatment effects for descending aortic distensibility and strain. And aortic arch pulse wave velocity with the aerobic exercise training plus the moderate caloric restriction group, having a 21% increase in distensibility, and an 8% decrease in pulse wave velocity. And none of the aortic stiffness measures changed significantly in the aerobic exercise training. Only, or in the aerobic exercise training plus very intensive caloric restriction.

Dr. Carolyn Lam:

So how do you put that all together? What does this mean for us clinically?

Dr. Greg Hundley:

Right, Carolyn. So I think the findings that Tina and everyone here in this group are showing, they suggest that exercise alone, that is in the absence of significant weight loss, has minimal effects on proximal aortic stiffness in older adults with obesity. Second, although obesity likely blunts the beneficial effects of regular aerobic exercise on aortic stiffness in older adults, these data support a growing number of studies indicating that intentional weight loss can be safe for older adults with obesity. And then finally, Carolyn, the addition of moderate caloric restriction appears to maximize improvement in aortic stiffness. Whereas higher intensity caloric restriction may not be necessary or even really advised. And that has important indications for weight loss recommendations to improve cardiovascular disease risk among older adults.

Dr. Carolyn Lam:

Oh, wow. Thanks Greg. And congratulations to you and your co-authors on this beautiful paper. Well, in the next paper, we switch to the preclinical world and I'm going to tell us about the WW domain containing E3 ubiquitin protein ligase 1. And I'm not going to be able to say that again. So I'll call it WWP1. We know that this is an important regulator of aging related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload induced cardiac remodeling and heart failure is yet to be determined. So this next paper looks at that with co-corresponding authors, Dr. Li and Ling from the State Key Laboratory of Space Meds and Fundamentals and Application, China Astronaut Research and Training Center in Haidian district in Beijing. Now the authors use WWP1 Knockout Mice, and adeno associated virus, serotype nine, carrying cardiac troponin T promoters driven by small hairpin RNA targeting WW1. And in these special mice, found that WW1 regulated cardiac hypertrophy induced pressure overload by stabilizing disheveled segment polarity proteins, or DVLs.

Dr. Greg Hundley:

Carolyn. So disheveled segment polarity proteins. So what are those?

Dr. Carolyn Lam:

Well, the DVLs, which include DVL one, two, and three are important cytoplasmic mediators, involved in canonical and non-canonical WNT signaling. And these are pivotal in cardiac remodeling. The authors demonstrated that WWP1 interacts with DVL2, and stabilizes it through an atypical ubiquitin type modification. And thus WWP1 has the potential as a therapeutic target for cardiac hypertrophy and heart failure.

Dr. Greg Hundley:

Excellent, Carolyn. Boy, what a fantastic summary. Well, my next paper comes from Dr. Zhao Wang from University of Texas Southwestern Medical Center. And Carolyn, as we know, metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. And the elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, it's role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully understood. And so these authors aim to dissect the role of cardiac pyruvate kinase muscle iso enzyme 1 in glucose metabolic regulation and cardiac response under pressure overload.

Dr. Carolyn Lam:

Oh. Wow. So what were the results?

Dr. Greg Hundley:

Right, Carolyn. So they found that pyruvate kinase muscle iso enzyme 1, so let's call that PKM1 expression, is reduced in failing human and mouse hearts. And importantly cardiomyocytes specific deletion of PKM1 exacerbated cardiac dysfunction and fibrosis in response to pressure overload. Now inducible over expression of PKM1 and cardiomyocytes protected the heart against TAC induced cardiomyopathy and heart failure. And at the mechanistic level PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration and ATP production under pressure overload. And furthermore deficiency of PKM1 caused a defect and cardiomyocytes growth and a decrease in pyruvate dehydrogenase complex activity at both the in vitro and in vivo levels. So, Carolyn, in summary, these findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.

Dr. Carolyn Lam:

Oh, nice, Greg. Well, let's go on to what else is in this issue? There's a Research Letter by Dr. Aguib on a new variant with a previously unrecognized mechanism of pathogenicity in hypertrophic cardiomyopathy.

Dr. Greg Hundley:

And, Carolyn, I've got three papers. First, there's an ECG Challenge from Professor Gunnaseelan [Rajendran], “Not All Waves Are Factual.” There's a nice On My Mind piece from one of our associate co-editors Torbjørn Omland entitled “Cardioprotective Therapy in Cardio-Oncology: Quo Vadis?” And finally, there's an In-Depth article from Dr. Brilakis entitled the “Saphenous Vein Graft failure From Pathophysiology to Prevention and Treatment Strategies.” Well, Carolyn, how about we head off to the feature discussion, and learn a little bit more about pravastatin versus placebo in pregnancies at high risk of term pre-eclampsia.

Dr. Carolyn Lam:

Let's go.

Dr. Mercedes Carnethon:

Well, welcome to Circulation On the Run. I'm pleased to be one of your hosts today. My name is Mercedes Carnethon. I'm an epidemiologist and professor at the Northwestern University's Feinberg School of Medicine, and one of the associate editors of the journal. I'm really excited to participate in the podcast today with our featured guests. We have a paper led by Dr. Nicolaides, Kypros Nicolaides, from the University of Exeter in the United Kingdom. And we have the associate editor, Dr. Karol Watson, who handled the piece for the journal.

Dr. Mercedes Carnethon:

So I'm really pleased to have each of you with me today and good morning.

Dr. Karol Watson:

Good morning. Thank you for having us.

Dr. Mercedes Carnethon:

Well, thank you. So why don't we jump right in? So the title of today's piece is pravastatin versus placebo in pregnancies at high risk of term preeclampsia. A really exciting read that I think provides important insights to us as well as emphasizes what we can learn from negative trials and negative studies. And so I'll jump right in and rather than me providing a summary, I'll turn it over to you. Kypros. Tell me a little bit about your inspiration for carrying out this work and why you pursued this topic.

Dr. Kypros Nicolaides:

Thank you. Well, preeclampsia is one of the major causes of death and handicap for the mother, and the fetus, and the baby. We have been trying for many decades to develop a method of identifying a high risk group of women that would develop preeclampsia. And we succeeded in doing so. And five years ago, we carried out a major trial at 12 weeks where we gave aspirin to the high risk group. And that study was very successful. We managed to reduce the rate of preterm pre-eclampsia by about 60%. And it was published in the New England Journal of Medicine.

Dr. Kypros Nicolaides:

However, screening at 12 weeks was not very effective in identifying women that deliver with pre-eclampsia term. And aspirin was not effective in preventing term preeclampsia and although preterm preeclampsia individually has more serious complications than term preeclampsia. Because three quarters of preeclampsia happen at term, the overall contribution of term preeclampsia is actually higher than that of preterm preeclampsia.

Dr. Kypros Nicolaides:

So that was the rationale, the background of having to do something to first identify the high risk group for term preeclampsia. And secondly, see whether we could do something to prevent it. So we, in this study involving about 30,000 women carried out in several hospitals in England, essentially, and Belgium, we screened at 35 to 56 weeks. We identified that 10% of the population at high risk. And then we randomized 1,120 women in trial with pravastatin 20 milligrams against placebo. Why pravastatin? Because a study from the United States by Constantine in a preliminary study, 10 women that were randomized to try the pravastatin or placebo starting from 12 weeks showed extremely promising results. So pravastatin studies are very commonly used for the treatment or prevention of hypertensive disease outside pregnancy preeclampsia and hypertensive disease are very closely related. So we felt that perhaps pravastatins given at this late stage would prevent the development of preeclampsia. Unfortunately, we found that that was not the case.

Dr. Mercedes Carnethon:

You know, your final point, there is one that we often lecture about and talk about with students. What do you do when you have a negative trial? I noticed that you said, unfortunately, you found that wasn't the case. But tell us about the value of the negative trial. I think part of the reason why this is so compelling and important is you may have ruled something out. So tell us a little bit about your findings. Did they surprise you? What do you make of them?

Dr. Kypros Nicolaides:

I can divide the findings into two, Mercedes. Firstly, the ability to screen in a multicenter study using our method, it was a method of validating our previous model. And we had found that we could identify 75% of the women that would develop term preeclampsia for a screen positive rate of about 10% and I think that that was very important. And I think that Karol Watson that was editing and dealing with the article identified that as being an important component of the article. And to me, that is very much so. We found, we have now a method of identifying a very high proportion of women that will develop term preeclampsia.

Dr. Kypros Nicolaides:

We failed. The drug, it was disappointing. But we have a background method with which we can identify the high risk group to try new methods of intervention that perhaps would be helpful. I think that I will have, in a sense, great success with aspirin in the first semester. And to a great extent, elimination of preterm preeclampsia forced us to move with optimism of preventing term preeclampsia. But perhaps giving pravastatin starting from 35, 36 weeks was perhaps too late. We should have perhaps started giving treatment before that. But we couldn't be because we did not have a good method of identifying the high risk group. So as far as I am concerned, we learned that pravastatin is unlikely to be beneficial, even if we try it every year, because we cannot identify the high risk group.

Dr. Karol Watson:

I'm so sorry for interrupting, but I just -

Dr. Kypros Nicolaides:

I'm glad you did.

Dr. Karol Watson:

This was such an important trial in so many respects. I think you under sell it a little bit. This was phenomenal to be able to identify this high risk group. As you say, just phenomenal. You know, 35,000 women screened, identifying this high risk group, and then to do a randomized trial of statin therapy in pregnancy. That is landmark. That was really very, very prescient, thoughtful, and really important to study. And I'm so grateful that you guys did.

Dr. Kypros Nicolaides:

Carol, thanks very much for your kind words and for accepting our paper for publication. Thank you.

Dr. Mercedes Carnethon:

You know, Kypros, this is really exciting. And I'm glad that you jumped in, Carol. You know, it stands out to me that part of why I will love having this as a potential paper to add to cases where we teach people, how to understand, how to carry out a study and how to respond when your primary hypothesis isn't born out. However, even if your primary hypothesis wasn't born out, you did learn something. And it sounds as though you learned a strategy to identify high risk individuals. And it is informing your next steps in your next study. Carol, you are obviously very involved. It was great to hear your feedback. What are your thoughts about what the lessons are for the practicing cardiologist?

Dr. Karol Watson:

Well, there are several that I took away from this. One is, I mean, I think building on your prior work with aspirin, that was landmark. As you know. And the first time we actually had a viable therapy for preventing preeclampsia. So we can prevent preeclampsia. That's the really important thing that we found out. And then there was a really good theoretic basis for thinking pravastatin might work. I mean, the rationale for this study was so solid and so important. I think the timing issue is, I think it's still an answered whether treating with pravastatin earlier might've helped. I don't know.

Dr. Karol Watson:

But again, we'd have to be able to identify people at risk, which is what your group is so good at doing. But I also think it was brave and very important that you guys decided to treat pregnant women with statin therapy. As you know, there was an FDA contra-indication to that until about a week ago when they removed, or a month ago when they removed it. So you guys had to say, we have the data, we know this seems to be safe, certainly in this time period, and we want to do this. And that was a really important thing to do. This is just such a rare and important trial. The randomized controlled trial of statin therapy in pregnancy. We just don't see that. You guys are groundbreaking

Dr. Kypros Nicolaides:

And, Carol, on that point for those that are still, I know that in the United States, people are planning new trials, starting from the first trimester. But as you said, they were stopped by the FDA. We provided further evidence of the potential safety of the drug. It was not published in the journal, but as part of the trial, we were collecting from some women cord blood. And it had shown that there were no adverse biochemical events. And also there were no significant differences in adverse events between the placebo and the pravastatin group. So in that respect, it is a good starting point to encourage those that want to do studies everywhere only in pregnancy.

Dr. Karol Watson:

So important, so important.

Dr. Mercedes Carnethon:

Thank you so much, Kypros. And I'm really excited that we're featuring this in Circulation On the Run because it means that we can get word out beyond our core audience of cardiologists. This is really an important piece as well for the obstetrician gynecology community to hear about given the steps that they will, how they'll consider using these data. Certainly, and you both touched on a really important point, which is that it isn't as common that we do intervention studies in vulnerable groups and protected groups. And pregnant women typically are. You enrolled 1,100 people into this trial. That is really impressive. Can you share with our audience a little bit, to the extent, a little bit about that process. How did you convince the team of the safety and were women enthusiastic and how did they respond? I look forward to using your responses to discuss with my trainees, how we go about carrying out this important work.

Dr. Kypros Nicolaides:

One of the issues about trials, Mercedes, is to have the background method of identifying a high risk group. In the United States, unfortunately, there is no method of routine screening in pregnancy during the first trimester. In very few cultures, if I take ultrasound scanning, for example, a few decades ago I was instrumental in introducing a 12 week scan. Because I have noticed that increased nuchal translucency is a marker of chromosomal abnormalities and so on. And that created a 12 week routine assessment in many countries of the world. It was at the back of that assessment that we introduced first trimester screening for preeclampsia. That led to the aspirin trial and the successful results of prevention. We have pioneered, in my hospital, the series of hospitals that I have under my influence, because they are run by ex research fellows of mine, a routine 36 weeks scan in pregnancy.

Dr. Kypros Nicolaides:

I call three scans in pregnancy important. One at 12 weeks, we find out whether the woman is truly pregnant or not, whether she carries one baby or not, whether the babies are generally all right. Whether we can screen at that point for chromosomal and other abnormalities, and now screening for preeclampsia. At 20 weeks scan, where we look for the fetal anatomy again, and then the development of the baby. In the third trimester scan, which I call it the delivery scan. At 36 weeks, we can tell whether the baby is developing normally or not. Whether the baby's in the right position cephalic or breach. And now whether the baby's too big or too small. And now whether you can identify they're high risk group for preeclampsia. So you need that background of routine screening of the whole population. And then of course we are quite experienced in recruiting women into our studies.

Dr. Kypros Nicolaides:

I deliberately call my center—although it is a routine, national health center institution—I call it an institute of research in fetal medicine. The ideology of the center is research. There are so many things that we do not know. And women have understood the value arriving in a research institute. They accept the ideology that if you participate in research, you will benefit or others will benefit or you will benefit your next pregnancy. So I think a successful recruitment into trials is the projection that you have a center that is actively being involved in research. And research is an integral part of providing a good clinical service. That's all I can say as a general point.

Dr. Mercedes Carnethon:

That is wonderful. You know, Kypros, I've really appreciated the time you spent with us. And I just want to end by calling on my colleague, Carol. Any final words or comments as we wrap up today?

Dr. Kypros Nicolaides:

I just thought from soup to nuts, beginning to end, this study was so informative and illustrative. We were able to, thanks to you and your group, Kypros, to understand that you can identify this high risk group. That you can treat pregnant women with statin therapy, with safety. And that you can get information out of a neutral study. And I just think all of those are so important and I am really looking forward to your next step. Because I think your group has just been groundbreaking in so many levels.

Dr. Mercedes Carnethon:

Well, thank you so much, Kypros, Carol. I think we've had a really exciting discussion this morning and our listeners from the cardiology community, to even the more broad research community, and the OB GYN community have learned a great deal from your work. So this is Mercedes Carnethon, one of the associate editors at Circulation and the happy host of the Circulation On the Run podcast. So thank you very much.

Dr. Karol Watson:

Thanks so much.

Dr. Kypros Nicolaides:

Thank you.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also wish everyone a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.

Circulation August 24, 2021 Issue

23 augusti 2021 | 25 min

This week's episode features special Guest Host Victoria Delgado, as she interviews author Qiang Zhang and Greg (who was the editorialist and handling editor) as they discuss the article "Towards Replacing Late Gadolinium Enhancement with Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohost. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. And Carolyn, this week's feature actually is a magnetic resonance imaging paper, which you know, of course, I'm very fond of. And these authors have come up with a new methodology to get information equivalent to a late gadolinium-enhanced exam without administering gadolinium. But before we get to that feature discussion, how about we start in with some of the other articles in this issue?

Dr. Carolyn Lam:

Yep.

Dr. Greg Hundley:

Well, how about if I go first? So Carolyn, the first paper I'm going to discuss is from Dr. Paul Welsh from the University of Glasgow, and it pertains to abdominal aortic aneurysms, which you know can occur in patients who are ineligible for routine ultrasound screening. A simple abdominal aortic aneurysm risk score was derived and compared to current guidelines used for ultrasound screening of abdominal aortic aneurysms.

Dr. Greg Hundley:

And so, this study comes to us from the UK Biobank, and they examined participants without previous, and let's just abbreviate this as AAA or AAA. So without previous AAA, we're split into a derivation cohort of 401,820 individuals, and a validation cohort of 83,000 individuals. An incident AAA was defined as a first hospital, inpatient diagnosis of AAA, death from AAA, or a AAA-related surgical procedure. And, of course, they used multivariable Cox models to develop the derivation cohort, and then apply that to the validation cohort.

Dr. Carolyn Lam:

Wow, Greg, that is a large number of people, the power of the UK Biobank, huh? So, what did they find?

Dr. Greg Hundley:

Right. So, Carolyn, components of the AAA risk score were age, stratified by smoking status, weight, stratified by smoking status, any hypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and then diabetes.

Dr. Greg Hundley:

So, Carolyn, in the validation cohort, over 10 years of follow-up, the C index, for the model for the USPSTF guidelines, was 0.705, whereas, the C index of the risk score as a continuous variable was 0.856. And in the validation cohort, the USPSTF model yielded a sensitivity of 63%, and a specificity of 71%.

Dr. Carolyn Lam:

Okay, Greg, but what's a take-home message?

Dr. Greg Hundley:

Right, Carolyn. So the take-home message is that in an asymptomatic general population, a risk score based on patient age, height, weight, and a medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. And also, these results highlight that further development and validation of risk scores to detect asymptomatic AAA are needed.

Dr. Carolyn Lam:

Wow, and that was a great summary with a lot more data in the article, huh? Let's refer the readers to it. But for my paper, it highlights the key role of histidine triad nucleotide-binding protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy.

Dr. Greg Hundley:

Wow. Carolyn, so tell me a little bit more about HINT 1.

Dr. Carolyn Lam:

I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton protein that belongs to the histidine triad super family. It was previously shown to play a role in diverse neuropsychiatric diseases. Loss of HINT 1 increased susceptibility to carcinogenesis in mice, suggesting, as well, a tumor suppressor role. So recently, HINT 1 has emerged as a tumor suppressor with multiple molecular mechanisms, involving regulation of apoptosis, gene transcription, and cell cycle control.

Dr. Carolyn Lam:

Now, with that as a background, today's paper from co-corresponding authors Drs. Ji, Xie and Han, from Nanjing Medical University, used animal models and cell models of hypertrophic growth, and found that HINT 1 deficiency aggravated overload-induced cardiac hypertrophy and fibrosis and deteriorated cardiac dysfunction in mice, whereas, cardiac-specific HINT 1 over-expression attenuated cardiac hypertrophy, and rescued cardiac dysfunction.

Dr. Carolyn Lam:

Furthermore, the more the authors uncovered Homeobox A5, or Hox A5, as a HINT 1 target gene, which contributed to hypertrophy through activating the TGF beta signal pathway. Combined, these findings demonstrate HINT 1 may be a prognostic biomarker, and this may establish a foundation for future investigation of its potential as a therapeutic target for cardiac hypertrophy and heart failure.

Greg Hundley:

Great, Carolyn. So, we get a hint for future cardiac hypertrophy.

Dr. Carolyn Lam:

Hahaha.

Dr. Greg Hundley:

Couldn't resist.

Dr. Carolyn Lam:

Bravo.

Dr. Greg Hundley:

Couldn't resist. So, Carolyn, my next paper comes to us from Dr. Mark Gladwin from the University of Pittsburgh. And, as you know, many patients with one of your faves, heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension. Now, increases in pulmonary vascular resistance, in patients with HFpEF portend a poor prognosis. This phenotype is referred to as combined pre- and post-capillary pulmonary hypertension.

Dr. Greg Hundley:

And therapeutic trials of exercise-induced pulmonary hypertension, and pre- and post-capillary pulmonary hypertension, have been disappointing, suggesting the need for strategies that target upstream mechanisms of the disease. And so, this work reports novel rat exercise-induced pulmonary hypertension models and mechanisms of pulmonary vascular dysfunction, centered around the transcriptional repression of the soluble guanylate cyclase enzyme in pulmonary artery smooth muscle cells.

Dr. Carolyn Lam:

Ooh, so much of this is of interest to me, from HFpEF to soluble guanylate cyclase. Ah, all right, so what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So, in the HFpEF and in the pre- and post-capillary pulmonary hypertension models, metabolic syndrome contributed to pulmonary vascular dysfunction and exercise-induced pulmonary hypertension through enhanced reactive oxygen species and MIR193B expression, which downregulates NFYA-dependent soluble guanylate cyclase beta-1 expression, and adenovirus mediated NFYA over-expression and SGLT-2 inhibition restored NFYA soluble guanylate cyclase beta-1 cyclic GMP signaling, and ameliorated exercise-induced pulmonary hypertension.

Dr. Greg Hundley:

So Carolyn, after all of that, these results uncover a molecular explanation for the unsolved clinical associations linking metabolic syndrome with exercise-induced pulmonary hypertension in patients with pre- and post-capillary pulmonary hypertension, as well as HFpEF.

Dr. Carolyn Lam:

Wow. That is super, Greg. Thanks. Now, other articles in today's issue include a research letter by Dr. Schunkert on identification of a functional PDE5A variant at the chromosome 4q27 coronary artery disease locus in an extended myocardial infarction family.

Dr. Carolyn Lam:

There is a policy front paper by Dr. Lackey on applying decision analysis to inform FDA's benefit risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke, based on the THEMIS trial. There's an exchange of letters between Drs. Olson and Reiffel regarding the article emulating randomized controlled trials with non-randomized real-world evidence studies, the first results of the RCT Duplicate Initiative.

Dr. Greg Hundley:

Great. Carolyn. Well, I've got two other papers. There's an ECG challenge from Professor Macherey entitled, Wide QRS complex bradycardia in a hemodynamically unstable young woman. And then, finally, one of our nice perspective pieces from Dr. Armstrong entitled, Extending the product label for ticagrelor: Looking under the FDA hood. Well, Carolyn, now we're going to learn a little bit more about that non-contrast method of MRI to get, maybe, the equivalent to late gadolinium enhancement in patients with hypertrophic cardiomyopathy.

Dr. Carolyn Lam:

And all by AI. Very, very cool. All right, let's go.

Dr. Victoria Delgado:

Hello, I'm Victoria Delgado, associate editor of Circulation, and working at the University Medical Center, and I have the privilege to welcome Dr. Zhang from the University of Oxford, division of cardiovascular medicine, and first author of the article published in Circulation, which presents a new technology that has the potential to change our clinical practice, and how do we assess myocardial tissue characteristics, particularly fibrosis with cardiac magnetic resonance.

Dr. Victoria Delgado:

With us, we have also Dr. Greg Hundley from VCU Pauley Heart Center, associate editor of Circulation, and host of Circulation on the Run and editorialist of this article. And Greg has handled this article in the review process and guided Dr. Zhang and coworkers to finally get a very impactful, in my opinion, and novel paper that has the potential to change clinical practice. He will help us to put in perspective the main message of this article. But first, Dr. Zhang, why don't you tell us briefly, what is this new technology for myocardial tissue characterization with cardiovascular magnetic resonance, and why did you develop it?

Dr. Qiang Zhang:

Well, first, I want to say thank you very much for the invitation. Well, as we know, CMR late-gadolinium enhancement, or LGE, has been the imaging gold standard for micro tissue catheterization. However, LGE requires the injection of a contrast agent, which prolongs the scan, increase the cost, and is cautioned in some patient groups. It is therefore desirable to develop a contrast-free technique to replace LGE. A native or pre-contrast CMR such as cine imaging, T1-mapping and the T2-mapping are alternative means for myocardial tissue characterization without the need for contrast.

Dr. Qiang Zhang:

And notably, T1-mapping can detect a wider range of pathology, but its clinical application is hindered by confounding factors and a lack of clear interpretation. So we thought that since MRI is inherently multimodal and multiparametric, with different modalities reflecting complimentary information about micro tissue, therefore can we use the ones of an AI method to combine the enhanced pre-contrast and modalities to produce a virtual LGE image without the need for contrast, and this leads to our concept of CMR virtual native enhancement.

Dr. Victoria Delgado:

Excellent. And in which population did you evaluate this technology? Why did you choose? So, can you tell us a little bit the characteristics of the population where you choose to assess the performance of this new technology?

Dr. Qiang Zhang:

Yes, so we validated this concept first on the hypertrophic cardiomyopathy patients using the image data from HCMR study, which is a larger multinational study. We trained the new network models on about 2,700 images, and then we tested independently on 124 patient materials.

Dr. Victoria Delgado:

And what were the results? Can you summarize them for us to understand what you found, how you evaluated the performance of this new technology compared to classical late gadolinium enhancement?

Dr. Qiang Zhang:

Yeah. So, we found that first, the VNE image had significantly better image quality than the traditional LGE, and the secondly, the VNE revealed characteristic HCM lesions in hypertrophic segment and added the anterior and the inferior right ventricular insertion point, and those VNE lesions were in high visual spatial agreement with the lesions detected by LGE. And thirdly, VNE correlated strongly with LGE in quantifying hyperintensity, micro lesions, but also more subtle intermediate-intensity lesions as often observed in the HCM patients.

Dr. Victoria Delgado:

Exciting. And now I would like to turn to Greg. You are a renowned expert on CMR. What did this article attract you? What were the main findings that you found interesting in this article?

Dr. Greg Hundley:

Yes. Thank you so much, Victoria. And just first, before I get started, I wanted to thank Zhang for sending us this work, and his entire team really spanning several institutions around the globe. Victoria, I want to thank you for leading this discussion. And Victoria, we work as a team looking at imaging, and what's very impressive is this caught multiple of us on the imaging team, but also the editorial board. So want to thank you Victoria. And then, finally, I want to thank Dr. Charlotte Manisty and Jennifer Jordan who helped with the editorial.

Dr. Greg Hundley:

So, just to take a little bit of a step back in the year 2000, Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern University, in Chicago, administered gadolinium contrast. It's an extra cellular agent and they were examining myocardial perfusion, and then they noticed if they took images 10 or so minutes after that administration, they appreciated this late enhancement of the myocardial tissue that was associated with two things, one myocardial injury, and then, also, scar formation.

Dr. Greg Hundley:

And for the last 21 years, that technique has been very valuable in assessing infarct size in those with ischemic cardiomyopathy, and then also recognizing extracellular fibrosis or forms of myocardial injury in a variety of non-ischemic cardiomyopathy processes. And one of those is hypertrophic cardiomyopathy. And so, Zhang and his group have been working on a technique that did not utilize gadolinium anymore. And they based this on, really, had two important features.

Dr. Greg Hundley:

One is, some examination of the T1 relaxation that's available when you acquire magnetic resonance images, and then also applying artificial intelligence to analysis of these images. Those two factors allowed this investigative team to produce images that are very similar to what we appreciate with gadolinium enhancement in patients with hypertrophic cardiomyopathy. And why is that significant? So administration of gadolinium, we think about two things, again, that are an issue with that.

Dr. Greg Hundley:

Well, one, we've got to give the contrast agent, and some patients are not well-suited. If you have renal dysfunction, you can develop nephrogenic systemic fibrosis, a scleroderma-like syndrome when the gadolinium is not cleared, and it's stays in your body a long time. The other thing we tend to worry about much more recently was accumulation of gadolinium in the brain stem. We don't know that that has an adverse effect, but we're certainly aware of it.

Dr. Greg Hundley:

And finally, I guess there is a third point. There are a few patients, one in 20 to 40,000 that have allergic reactions. So, for all those patients that really can't get gadolinium, this is another potential opportunity moving forward. The second point is time. So during an MRI scan time, or process, we administer the gadolinium. And remember what I said, we've got to wait about 10 minutes to then collect these images. Well, if you can have a technique where you don't have to administer gadolinium, you get the same administration and you don't have to wait that 10 minutes, we might be able to save a large amount of time. And you say, well, 10 minutes, what does that mean?

Dr. Greg Hundley:

But if you're doing many patients during the day, that really could equate to a big time-savings. So what attracted us to this article? A technical innovation that perhaps may obviate the need for the administration of gadolinium in many cases, and here in these patients with hypertrophic cardiomyopathy, I think the images were quite stunning in that they appreciated the extent of the fibrosis and scar in patients with hypertrophic cardiomyopathy to the same degree, and maybe even with higher image quality than we had in the gadolinium-enhanced comparitors.

Dr. Victoria Delgado:

Yeah. I agree with all those comments, indeed. For these 20 years, there have been other developments, in terms of assessing diffuse fibrosis with T1-mapping techniques after administration of gadolinium, but also before administration of gadolinium. And this technology Dr. Zhang and co-workers have shown actually reduces the time of acquisition because you only need 15 minutes to acquire the cine images and the T1 images. And the analysis is not very long in terms of post-processing, because it's also very short. As seen the paper was indicated.

Dr. Victoria Delgado:

And as you said, the administration of gadolinium enhancement is not free of potential risks. And in these patients, for example, we have hypertrophic cardiomyopathy that can undergo repetitive evaluations during follow-up. The use of this imaging technique can help to reduce the exposure to gadolinium enhancement.

Dr. Victoria Delgado:

Now, the question for you, Qiang, will be, what are the next steps for you and your team to further develop this technique, to further convince the community to implement this technique in clinical practice, and that can have an impact in our management of these patients with hypertrophic cardiomyopathy, or with other patients on whom we also evaluate the presence of myocardial fibrosis?

Dr. Qiang Zhang:

Thank you, Victoria. And thank you Greg, for the very insightful comments. So we think that the immediate future work would be to validate the VNE HCMR study clinical outcomes as a potential new contrast-free biomarker for HCM patients. And in the meantime, we are working on extending the method to other pathologies, particularly myocardial infarction, for viability assessment.

Dr. Qiang Zhang:

And we also think that the concept of AI virtual contrast agent maybe apply it to other post-contrast images, such as early gadolinium enhancement and extracellular volume refraction mapping, or even, maybe, first perfusion. And also in collaboration with MR vendors, we plan to implement VNE as inline sequence on the scanner to display lesions immediately after the pre-contrast cine and the T1-mapping acquisitions.

Dr. Victoria Delgado:

Very interesting. And Greg, another group of patients, for example, that I'm thinking of where this technology can be very helpful, and you have expertise on this, are patients undergoing treatment with chemotherapy, what we need to address, for example, or to evaluate the presence of cardiac toxicity. Would you see in this population the value of this technique, or how do you see the future of these technique in clinical practice?

Dr. Greg Hundley:

Yeah. Great questions, Victoria. I think probably five things and many of those Qiang has already just brought up. One, with the current study, it's going to be great to follow these patients over time and look at the outcomes. What did amount, presence, location of the findings with this new technique, how did they equate to outcomes in patients with hypertrophic cardiomyopathy? So we're going to anxiously await that.

Dr. Greg Hundley:

I think once we move out of the current study, thinking about other vendors, using this and acquiring images from General Electric and Phillips, and multiple vendors around the world and multiple field strengths, how do we going to understand the findings there? I think another particular issue will be different diseases as Qiang ha said, ischemic cardiomyopathy. Well, what about amyloid? Victoria, you've mentioned using the other possibility here is, can this technique help us produce something similar to extracellular volume fraction measures? And could that be used to identify interstitial disease processes?

Dr. Greg Hundley:

And, for example, as you mentioned, the fibrosis that's associated with the administration of certain chemotherapeutic agents or radiation therapy. I think another thing is, Qiang, can we go back and use retrospectively-collected data? Can your technique be modified so that many of the studies that have been performed in the past, large population studies, like Mesa or a Framingham or Jackson heart study, and could we use that to develop forecasting and algorithms moving forward?

Dr. Greg Hundley:

And then, lastly, I think as you mentioned, the artificial intelligence component of what you've described and how's that can compare when Victoria and I look at the images, and could we get into combining reads from one institution, reads from another, reads from another, tracking outcomes? And so, when a patient comes in and has a study performed, your artificial intelligence, not only does it read that study and highlights the increased signal in the myocardium, but then goes and looks at outcomes across multiple sites, and what would that mean for a given patient with a different condition? So, oh my goodness, the horizon is just so expansive here. The future is very bright. And just to congratulate you on, I really think this could be another landmark technical innovation, so fantastic work.

Dr. Victoria Delgado:

Indeed. Thank you very much, Greg, for all these insightful comments and these perspectives that we have in the future, particularly with the use of this technique in retrospective studies in large cities, that where we can develop these algorithms. And I would like also to thank Qiang for submitting your article to Circulation, for giving us the opportunity to present this new technology and make this article, like the landmark article, where there will be many other articles to follow. We hope that you also choose us.

Dr. Victoria Delgado:

But with this, I would like to thank both of you, Greg and Qiang, for the excellent discussion that we have had in this new technology, based on artificial intelligence, that can identify myocardial fibrosis without the use of gadolinium enhancement, that maybe by now will be obsolete in the future, and that can impact on how we do our clinical practice. Many thanks to all of you and happy to discuss in the future other articles.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also, wish everyone a great week. And we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation August 17, 2021 Issue

16 augusti 2021 | 22 min

This week's episode features author Philippe Gabriel Steg and editorialist Gregg Stone as they discuss the article "International Observational Analysis of Evolution and Outcomes of Chronic Stable Angina: The Multinational Observational CLARIFY Study."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Welcome to Circulation the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore here with my other co-host, a little bird that you can hear I think in the background and then my real co-host, Greg.

Dr. Greg Hundley:

Thanks so much, Carolyn. Yes, I'm Dr. Greg Hundley. I'm not the bird this week. Associate editor, director of the Pauley Heart Center in Richmond, Virginia. Carolyn, so this week, our feature discussion is really going to be on the importance of stable angina and what that means prognostically. But before we get to that, how about we grab a cup of coffee, talk to our other bird friends and then we jump in and talk about the other papers in the issue. Would you like to go first?

Dr. Carolyn Lam:

Love it, Greg. Thank you so much. This first paper, very important question. We know that while the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It's still unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. And so today's paper is really important from Dr. Mills from the University Center for Cardiovascular Science Royal Infirmary of Edinburgh in the University of Edinburgh and colleagues.

Dr. Carolyn Lam:

What they did was a secondary analysis of the high stakes trial of more than 46,000 consecutive patients with suspected acute coronary syndrome. They evaluated the performance of the 99th percentile rule in threshold and thresholds of 64 ng/L and five times the upper reference limit for the diagnosis of type 1 myocardial infarction. They found that troponin concentrations at presentation have a low, positive predictive value for type 1 myocardial infarction and a threshold of 50 times the upper reference limit is required to achieve a positive predictive value of more than 70%. A change in troponin on serial testing only marginally improved positive predictive value for type 1 myocardial infarction over the presenting troponin alone.

Dr. Greg Hundley:

Interesting, Carolyn. Very important data. What's our take home message here.

Dr. Carolyn Lam:

Well, troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction and should not be used in isolation to guide management decisions in patients with suspected ACS. Consideration of other important clinical factors may be more helpful than any particular rule in threshold to guide initial triage and management.

Dr. Greg Hundley:

Wow, Carolyn, so really great new data and more data on the utility of these troponin concentrations.

Dr. Greg Hundley:

Well, my next paper comes from the world of preclinical science and it's from Professor Vladimir Kalinichenko from Cincinnati Children's Hospital Medical Center. Carolyn, as we know, pulmonary hypertension is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a severe congenital disorder associated with mutations in the Foxf1 gene. Now, while the loss of alveolar microvasculature causes pulmonary hypertension in, and we're going to abbreviate this ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent pulmonary hypertension and right ventricular hypertrophy in these subjects.

Dr. Carolyn Lam:

Wow. Wow. Okay. Let's repeat that. ACDMPV stands for alveolar capillary dysplasia and misalignment of pulmonary veins. Really cool stuff. What did they find, Greg? This sounds like a first of its kind study.

Dr. Greg Hundley:

Right, Carolyn. Thanks. The Foxf1 wild type, S52 mice developed pulmonary hypertension and RV hypertrophy after birth. The severity of pulmonary hypertension in these mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Second, increased fibrotic remodeling was found in the human ACDMPV lungs. Third, the mouse endothelial cells carrying the S52F Fox1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that the Foxf1 wild type S52F endothelial cells have a propensity to differentiate into pulmonary myofibroblasts. And then finally, intravascular delivery of nanoparticles carrying Stat3 copy DNA protected the Foxf1 wild type S52F mice from RV hypertrophy and pulmonary hypertension, improved their survival and decreased that fibrotic lung remodeling. Carolyn, nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent pulmonary hypertension in alveolar capillary dysplasia with misalignment of pulmonary veins.

Dr. Carolyn Lam:

Wow, thank you, Greg. Such incredibly hopeful papers here. The next paper identified a key role of a particular amino acid in cardiac aging.

Dr. Greg Hundley:

Ah, Carolyn, so you didn't ask me the quiz but I guess it's implied here. Okay, I give up. Which amino acid is it?

Dr. Carolyn Lam:

Spot on, Greg. Well, the answer is phenylalanine. This is an essential amino acid whose levels are regulated by the tetrahydrobiopterin or BH4 dependent rate limiting enzyme, phenylalanine hydroxylase and whose expression is physiologically restricted to the liver and the kidney. Well, co-corresponding authors Dr. Czibik and Derumeaux from Paris, France, hypothesized that phenylalanine plays a causal role in promoting cardiac senescence and dysfunction based on prior evidence from human metabolomics that shed light on a link between amino acids, aging and heart failure, as well as data showing that plasma levels of phenylalanine increase with age and inversely correlate with leukocyte telomere length. In addition, increased serum phenylalanine levels are associated with heart failure. Here, the authors tested their hypothesis in a series of elegant mouse experiments and showed for the first time that a decline in hepatic phenylalanine catabolism was a causal contributor to a rise in systemic levels, leading to cardiac ectopic phenylalanine hydroxylase activity and resultant cardiac aging.

Dr. Carolyn Lam:

They demonstrated that phenylalanine administration induced a remarkable premature cardiac deterioration in young mice, closely mimicking that of aged mice and leading to cellular senescence in vitro. They identified hepatic phenylalanine catabolism to decline with age in a p21 dependent manner, while demonstrating that p21 deficiency prevented age related cardiac dysfunction. Administration of phenylalanine hydroxylase cofactor BH4 or dietary phenylalanine restriction, both abrogated the age related rise in the plasma levels and reversed age associated cardiac alterations. This study really identifies phenylalanine and its hydroxylase modulation as a potential therapeutic strategy to promote cardiac health and prevent age related cardiac impairment. Amazing, isn't it?

Dr. Greg Hundley:

Yeah, Carolyn. Really interesting about phenylalanine and while it may impact cardiovascular health and the aging process.

Dr. Greg Hundley:

Well, I know we've got some other articles in this issue, so how about I'll go and dip into the mailbag first? The first is from Professors Wong and Finn and they're exchanging letters regarding the prior publication entitled, Microthrombi as a Major Cause of Cardiac Injury in COVID-19 and it's a pathologic study. There's a nice Research Letter from Dr. Zhu entitled, “Catheter Based Adrenal Ablation Remits Primary Aldosteronism: A Randomized Medication Control Trial.” There's a Perspective piece from Dr. Stehlik entitled, “The Long and Winding Road to an Effective Left Ventricular Assist Device: The Demise of Medtronic's HVAD.” And then finally a report from Dr. Mehta and colleagues, really Carolyn, thinking about clinicians' wellbeing and addressing global needs for improvements in the healthcare field. And it's a Joint Opinion representing the American College of Cardiology, the American Heart Association, the European Society of Cardiology and the World Heart Federation. Really a nice report on really addressing physician stress in the workplace.

Dr. Carolyn Lam:

Nice. Well, there's also an ECG Challenge by Dr. Shi entitled, “An Acutely Breathless Patient with Inferior St-Segment Elevation: A Diagnostic Trap.” In Cardiology News, Bridget Kuehn describe studies detailing heart risks for firefighters. Wow, what an interesting issue, but let's go on now to the feature discussion shall we, Greg?

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Welcome listeners to our feature discussion. And today we have with us Dr. Gabriel Steg from Paris, France, Universite de Paris. And also Dr. Gregg Stone, an editorialist from Mount Sinai in New York. Welcome gentlemen. And Gabriel, we'll start with you first. Could you describe for us some of the background related to your study and what was the hypothesis that you wanted to test?

Dr. Gabriel Steg:

Thank you, Greg. As you know, there have been tremendous changes in cardiology over the past 25 years with the advent of effective anti-anginal therapy, with the advent of myocardial revascularization and the dramatic changes produced by widespread availability of percutaneous coronary intervention and finally the availability of evidence based secondary prevention therapies. And there has been really a sea change in the presentation and treatment, management and outcomes of patients with coronary artery disease. And when we started off, we asked ourselves, is angina pectoris really prognostic in patients with stable coronary artery disease? Is the symptom of angina really prognostic? That was the question we tried to address.

Dr. Greg Hundley:

And Gabriel, what was your study population and your study design?

Dr. Gabriel Steg:

It was a very simple descriptive design. We use a large international registry of patients with stable coronary artery disease called the CLARIFY registry, which enrolled almost 35,000 patients with stable coronary artery disease and followed them up for five years. Now, how was stable coronary artery disease defined? It was defined as any of the following conditions, a prior MI, more than three months before enrollment, a prior PCI or a CBG, angina pectoris was a demonstration of myocardial ischemia on noninvasive stress testing or finally the presence of a fixed stenosis of the coronary arteries on an angiogram. And you could get any of these criteria. Of course you could have more than one at the same time. And the design was to describe the anginal status at baseline and every year based on investigator reports, not a formal angina questionnaire, as there are several, including the Seattle angina questionnaire. We had a very simple assessment of angina and angina severity based on presence or absence and then Canadian class of angina.

Dr. Greg Hundley:

Did you follow these individuals too? Did they experience specific events?

Dr. Gabriel Steg:

Yes. We collected all the cardiovascular hospitalizations events, revascularizations. We followed the medications and we collected the biological results, although there was no core lab but we collected the results of the tests that were done. We essentially aimed was that registry to describe the population, their management and their outcomes over five years. And this is over 40 plus countries. And fortunately does not include any patient from the United States but has a substantial contribution from Canada and Mexico.

Dr. Greg Hundley:

Very nice. And so what did you find, Gabriel?

Dr. Gabriel Steg:

Well, the first observation is the prevalence of angina at baseline and it's 22%. We found that in a patient population selected for having stable coronary artery disease, approximately a fifth to a quarter will have anginal symptoms. I don't think that's a major surprise but what was a big surprise to us is that angina resolved very, very substantially, 40% of the patients who had angina at baseline had no longer angina by one year. And what was even more surprising is what caused the resolution of angina. And it was rarely changes in anginal medications, rarely revascularization. It was largely spontaneous. Almost 80% of the patients had spontaneous resolution of angina. And so, yes, it's been known that angina can regress but we did not expect that it would regress that often and that much spontaneously without intervention or need for increasing medications.

Dr. Gabriel Steg:

And the other aspect is then we looked at what happened for those patients who had angina resolution at one year and what were the subsequent outcomes? And we found they were indistinguishable from those who had no angina at baseline. And then we looked at those patients who had persistent angina at one year or occurrence of angina at one year, despite not having angina at baseline. And again, we found that having angina at one year was detrimental to the longterm prognosis. It's really good that you either not have angina or that your angina resolve. That's really important.

Dr. Greg Hundley:

Did you find any differences, Gabriel, between men and women?

Dr. Gabriel Steg:

No. We looked at a variety of subgroups. We looked by criteria for enrollment. We looked across geographic locales. We looked according to the presence or absence of diabetes and sex and other variables and there were really no major differences. The results were remarkably consistent.

Dr. Greg Hundley:

Very nice. Well listeners, one of the advantages of some of the publications that we pursue at Circulation is the ability to bring in an editorialist. And with us today, we have Dr. Gregg Stone from Mount Sinai in New York. And Gregg, we want to turn to you. How do we put the results of this study in perspective with other studies that have been involved in this sphere of research?

Dr. Gregg Stone:

Well, thank you, Greg. First off, I'd like to congratulate Gabriel and his colleagues for a tremendous study and thank you and Circulation for offering David Waters and I, the chance to provide our perspectives. I think this study raises a lot of important issues. Angina is kind of like the common cold to cardiologists. We're always dealing with it but it can be very difficult to diagnose. There's typical angina, atypical angina, anginal equivalent disease, non-anginal chest pain, et cetera. And we've learned in the last several years or decade that the etiology of angina can be very complex. It's not just epicardial coronary disease. There can be microvascular disease, macro or microvascular spasm and other causes. I think that we have to, when we're thinking of angina, we have to try to understand the mechanism and know whether or not it's really due to at least epicardial coronary artery disease, which is the type of disease that may respond to revascularization.

Dr. Gregg Stone:

In this regard, both David and I were struck with the fact that the CLARIFY even though a very large population, is a very mature population of patients with coronary disease, who I believe were diagnosed at least approximately seven years ago, most had undergone a prior revascularization therapy, about 50% ahead of myocardial infarct and the minority interestingly had inducible ischemia. We wondered is this real angina? Is this true angina that these patients are having? Because they've been effectively revascularized. In contrast, I was one of the co-principal investigators of the ISCHEMIA trial, which was a very different population because we took only with exercise induced moderate or severe ischemia. And while we excluded most patients with class three or four angina because we know those patients basically don't tolerate medical therapy without frequent crossovers. We found that in our trial, angina was more persistent and was substantially reduced by revascularization, by an interventional approach. Much more so than in the medical therapy arm. I think that it really does depend on the patient population and the likelihood of which the angina is due to true inducible ischemia that may respond to a revascularization approach.

Dr. Greg Hundley:

Very nice. And so Gabriel, want to turn back to you, what do you think is the next study that really needs to be performed in this space?

Dr. Gabriel Steg:

Well, I think it's really in line with Dr. Stone's comments. I think that what we need to do is to have a much more formal prospective assessment of a broader population of patients with angina using formalized questionnaire, such as the Seattle angina questionnaire, which allow a much better and thorough characterization of the presence, type and severity of symptoms and to look across the whole spectrum of patients with and without myocardial ischemia and look at the prognostic importance of the symptoms. I think that teasing out the relationship between the anginal symptoms, their severity, myocardial ischemia and outcomes is really critical to our interpretation of the series of recent trials, the last of which being ISCHEMIA, which have revolutionized our thinking regarding management of coronary artery disease. And we're still somewhat in the dark as to how to incorporate that information relative to the symptoms and outcomes of our patients. And I think we still have a lot of work to do in that respect.

Dr. Greg Hundley:

Very Good. And Gregg, do you have anything to add to that?

Dr. Gregg Stone:

Yeah. I would certainly echo Gabriel's comments. In addition, I think we have to think of angina as a collection of different diseases. And we have to do a better job at trying to understand the mechanisms underlying angina. First, we have to be able to determine whether it's really cardiac in origin versus non-cardiac. And then second, we have to understand again, whether it's coming from epicardial coronary disease, microvascular disease or other mechanisms. We've just been struck in even many of our simple stent studies, how often patients redevelop angina after treatment with no re-stenosis whatsoever, suggesting that many of them may have other etiologies of angina. I think these studies to me are very important because they really highlight, yes how much we've learned but how much more work there still is to do for us to be able to effectively diagnose and treat these patients.

Dr. Greg Hundley:

Well listeners, we want to thank both Dr. Gabriel Steg, the author of this paper and also Dr. Gregg Stone, who provided his editorial expertise, in bringing us information from these 32,000 plus individuals from the CLARIFY registry, of patients with stable coronary artery disease and helping us answer really two questions regarding the presence of angina. One, both that angina may resolve spontaneously and then second, persistent angina is associated with future cardiovascular events.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, I want to thank our speakers and then also wish everyone a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation August 10, 2021 Issue

9 augusti 2021 | 36 min

This week's episode features a panel discussion in regard to Covid-19. Please join authors Kathryn Larson, Christopher deFilippi, James de Lemos, and Biykem Bozkurt as they discuss their articles regarding temporary myocarditis and Covid-19 vaccination.

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Greg Hundley:

Carolyn, this week, oh my goodness. It's a forum, almost a triple or quadruple feature, and you know what we're going to be discussing? COVID-19 vaccinations and their relationship potentially to myocarditis. We're going to have our associate editors and our deputy editor involved, be really interesting. But before we get to that, how about we start in with the papers in the issue. Would you like to go first?

Dr. Carolyn Lam:

Absolutely. And my first paper is so interesting. It identified a novel underlying mechanism of graft arteriopathy, or otherwise known as coronary allograft vasculopathy, a devastating development of heart transplant in which arterial intimal thickening limits coronary blood flow and could lead to transplant failure.

Dr. Greg Hundley:

Oh wow, Carolyn. So, what did they find?

Dr. Carolyn Lam:

Well, this was Dr. Martin from Yale Cardiovascular Research Center and colleagues. What they did is they used both human coronary allograft vasculopathy and renal transplant samples as well as murine models, basically, and found that TET methylcytosine dioxygenase 2, or TET2, is a critical negative regulator of vascular smooth muscle cell apoptosis in graft arteriopathy and vascular injury. Enhancing smooth muscle TET2 activity with a high dose of ascorbic acid rescued donor vascular smooth muscle cells apoptosis and intimal thickening in murine transplant vasculopathy. Furthermore, TET2 expression and activity were repressed in arterial vascular smooth muscle cells in human and mouse graft arteriopathy compared to controls.

Dr. Carolyn Lam:

Interferon gamma signaling in vascular smooth muscle cells resulted in TET2 repression. Preventing donor vascular smooth muscle cell apoptosis with high dose ascorbic acid may therefore represent a safe and cost-effective therapeutic strategy for limiting graft arteriopathy in patients undergoing solid organ transplant. Neat, huh?

Dr. Greg Hundley:

You bet, Carolyn. Really an interesting article on limiting graft arteriopathy.

Dr. Greg Hundley:

Well, Carolyn, my next paper comes to us from Dr. Greg Stone and colleagues at the Cardiovascular Research Foundation. It involves the randomized COAPT trial. Remember that in the COAPT trial, there were 614 heart failure patients with 3+ or 4+ secondary mitral regurgitation and had trans-catheter mitral valve repair with the MitraClip, reduced mitral regurgitation, heart failure hospitalizations and mortality as well as improving quality of life compared with guideline directed medical therapy alone. So the authors here, Carolyn, sought to examine the prognostic relationship between mitral regurgitation reduction and outcomes in trans-catheter mitral valve repair versus guideline directed medical therapy alone.

Dr. Carolyn Lam:

Wow, okay. So, what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So, among patients with heart failure and severe, grade 3+ or 4+ secondary mitral regurgitation randomized to trans-catheter mitral valve repair with the MitraClip versus guideline directed medical therapy, the reduction of MR to 2+ was strongly associated with subsequent two year freedom from death and heart failure hospitalization and improved quality of life regardless of whether this reduction to 2+ MR was achieved by trans-catheter clip or guideline directed medical therapy alone. And the improvement in long term prognosis was similar after this mitral regurgitation reduction to grade 2+ compared with grade 0 or 1+ in both arms, although the mitral regurgitation reduction was a little more durable over time after the trans-catheter mitral clip.

Dr. Greg Hundley:

So Carolyn, the take-home message is that substantial benefits are realized even if mitral regurgitation is reduced to only 2+.

Dr. Carolyn Lam:

Nice, Greg. Thanks.

Dr. Carolyn Lam:

Now, this next paper, oh, close to my heart. We know that individuals of South Asian ancestry actually represent 23% of the global population, corresponding to 1.8 billion people, and that they have a substantially higher risk of atherosclerotic cardiovascular disease compared with most other ethnicities. However, what is the magnitude of that enhanced risk, the extent to which it is captured by existing risk estimators, and what are its potential mechanisms?

Dr. Carolyn Lam:

This was studied in this beautiful paper. Dr. Khera from Massachusetts General Hospital and colleagues used data from the large UK Biobank prospective cohort study to investigate the relationship between South Asian ancestry and incident atherosclerotic cardiovascular disease within the context of contemporary medical care. Their findings confirmed an approximate doubling of atherosclerotic cardiovascular disease risk among South Asian compared with European individuals that was not captured by the pooled cohort equations. The higher risk of atherosclerotic cardiovascular disease persisted despite adjustment for a broad range of potential clinical, anthropometric, and lifestyle mediators. Hypertension, diabetes, and central adiposity explain a greater proportion of risk of atherosclerotic cardiovascular disease in South Asian compared with European individuals.

Dr. Greg Hundley:

Wow, Carolyn. So, a lot of data here. How do we take all this and put it together clinically?

Dr. Carolyn Lam:

Well, the results confirm and extend the current guidelines that consider South Asian ancestry a risk-enhancing factor in assessing future risk for atherosclerotic cardiovascular disease. Residual risks that persisted after accounting for a range of potential mediators may relate to differences in social determinants of health, unmeasured risk factors and genetics and so on, that this warrants further investigation. Whether a targeted intervention can attenuate the outsized impact of diabetes or central adiposity among South Asian individuals also warrants further attention.

Dr. Carolyn Lam:

This is accompanied by a beautiful editorial entitled The South Asian Enigma: Solving a Puzzle of Global Importance, love that, from Drs. Kandula from Northwestern University Medical Center and Kanaya from University of California San Francisco.

Dr. Greg Hundley:

Very nice, Carolyn. I just want you to know, after being quizzed last week on phospholamban, I went and did a little bit of studying, okay? So I get to bring to you, Carolyn, this week, a paper on phospholamban. But I'm going to spare you from the quiz.

Dr. Greg Hundley:

All right.

Dr. Carolyn Lam:

Yay!

Dr. Greg Hundley:

This comes to us from Professor Fadi Akar from Yale University. Carolyn, arginine 14 deletion is the calcium regulatory protein phospholamban, so hPLN R14 deletion. It has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy, and mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling really remain unclear.

Dr. Carolyn Lam:

Interesting, Greg. So, what did they find?

Dr. Greg Hundley:

Right, Carolyn. Adverse electrophysiological remodeling was evident in the absence of significant structural hemodynamic changes, and the R14 deletion hearts exhibited increased arrhythmia susceptibility compared to their wild-type counterparts. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to beta-adrenergic stimulation. A steep repolarization gradient at the LV/RV interface provided the substrate for inter-ventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. And then once sustained, these circuits evolved into high frequency rotors, which in their majority were pinned to the right ventricle. Importantly, these rotors exhibited unique spatio-temporal dynamics that promoted their increased stability in the R14 deletion compared to the wild-type hearts.

Dr. Greg Hundley:

So Carolyn, in summary, this research found the crucial role of primary electrical remodeling caused by the hPLN R14 deletion mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of the PLN R14 deletion induced a cardiomyopathy.

Dr. Carolyn Lam:

Oh, and ties up very nicely about how we mentioned that this dilated cardiomyopathy is associated with lots of ventricular arrhythmias that we discussed last week. Really cool.

Dr. Carolyn Lam:

Well, let's do a little tour around what else there is in today's issue. Tracy Hampton presents from the literature discussing how excessive exercise may damage mitochondria and impair glucose control in a publication from Cell Metabolism. Data on an oral antisense oligonucleotide for PCSK9 inhibition was published in Science Translational Medicine.

Dr. Carolyn Lam:

And there's a paper on structuring clinical text with AI. How very interesting, published in Patterns. There's an On My Mind paper by Dr. Berger on summoning strength to question the placebo in reducing.

Dr. Greg Hundley:

Right, Carolyn. Also in the mail bag, there is a reply to the Quintao and Cazita from Professor Brunham entitled High-Density Lipoprotein Cholesteryl Ester Transfer Protein and Sepsis. And then finally, from Dr. Goldstein, an ECG challenge. Does this ischemia pattern look right?

Dr. Greg Hundley:

Well, Carolyn, this is going to be a really interesting feature forum discussion today on COVID-19 vaccinations and myocarditis. How about we get on to that discussion?

Dr. Carolyn Lam:

Yep. A really important issue now. Yup, let's go.

Dr. Greg Hundley:

Welcome, listeners. We have a very exciting, really series, of feature discussions. We're going to call it a forum, and focusing on COVID-19 vaccine associated myocarditis. We really have four manuscripts to discuss today. We have Dr. Kathryn Larson from the Mayo Clinic in Rochester. We have another author, Dr. Chris deFilippi from Inova Health, really in the Washington DC metro area. We have our executive editor, Dr. James deLemos from UT Southwestern in Dallas, Texas. And then also one of our senior associate editors, Dr. Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Welcome to everyone.

Dr. Greg Hundley:

Well, first, listeners, we're going to start with Dr. Larson. So, Kathryn, can you tell us a little bit about the background and the hypothesis that you were testing in your research project, and then a little bit about your study design and what were the results of your study?

Dr. Kathryn Larson:

Absolutely. Well, first off, thank you so much for having me, Greg. It's a pleasure to be here and in such good company. My study really grew out of a clinical interest in a number of patients that had presented to our institution and other institutions that we had been in discussion with of really young male patients with no significant past medical history who were coming in two to three days after receiving their COVID vaccines, most often the second dose, and presenting with laboratory and clinical findings consistent with myocarditis. I think in a lot of arteriosity and what the course of their illness may be and what the best course of treatment may be, that really drove our hypothesis to try and describe other cases that were coming up and that we had heard about from a lot of our colleagues around the country and around the world.

Dr. Kathryn Larson:

Our paper really grew out of a case series of eight patients, and they're from the United States and from Italy, and they're of eight patients who were diagnosed with laboratory and clinical and imaging findings consistent with myocarditis after receiving their COVID-19 vaccines. Our patients had received either the Pfizer BioNTech or the Moderna vaccines, the mRNA vaccines. Really, only two of our patients had previously been infected with COVID at all, and so most of these patients were coming in with really no relevant medical history. They were really young in age, between 21 and 56 years old, and basically all patients except for one developed their symptoms after receiving the second dose of the vaccine.

Dr. Kathryn Larson:

The timeline was generally about two to three days after that dose and was often accompanied by other symptoms which we have seen and heard about things like myalgias, subjective fevers, chills, and kind of a general malaise. They presented really with very typical features of myocarditis, chest pain, one of the patients had a more pleuritic type of chest pain, and had ECG changes, troponin elevations, elevated inflammatory markers, and most importantly cardiac MRI findings that were significant and really diagnostic of myocarditis.

Dr. Kathryn Larson:

There was a good amount of investigation into other potential causes and none other identified in any of those eight patients. All thankfully had a relatively unremarkable course clinically and all are currently doing very well. There was mild reductions in LV function, no clinically significant heart failure, and at last known contact, those patients really had recovery of LV function and are essentially back to baseline.

Dr. Greg Hundley:

Excellent. Well, listeners, we're going to move to another part of the country, and again, Dr. Chris deFilippi is in the Washington metro area. Chris, you also have a case series. Can you describe for us what you were looking at with your study, and then what were your study results?

Dr. Chris deFilippi:

Greg, first, thank you for having me here today. As a regular listener to Circulation on the Run, it's really a privilege to actually be able to participate and contribute to it. First, I would have to say was a little bit of serendipity. We recognized one case out of the ordinary with respect to suspected myocarditis in early March, and given our location around Washington DC, some of our faculty were former active military and serve in the reserves and one returned and said, "The military is beginning to find a small series of cases."

Dr. Chris deFilippi:

We've worked hard within our academically oriented independent health system to develop a research clinical trials network, and we called upon our cardiologists and cases started coming forward actually fairly rapidly, drawing upon five hospitals in our network. Combining our efforts with UT Southwestern, we identified seven individuals. They were all men or young adults in their 20s and 30s. Six out of seven had received the mRNA vaccines. Most of them had developed symptoms between three to seven days after their second vaccination.

Dr. Chris deFilippi:

Very similar to Kathryn's presentation, we did an extensive evaluation, of course including advanced imaging with MRI using the Lake Louise criteria, but also did a lot of serologic measurements. I think it was remarkable that troponin values using still a conventional assay ranged from mild elevations, 0.34 to as high as 44 milligrams per milliliter.

Dr. Chris deFilippi:

All patients fortunately had resolution of symptoms within several days and returned back to normal life and then all return follow-ups seemed to remain symptom-free. Again, we looked for multiple other etiologies including autoimmune disease, other respiratory infections, and these were all effectively negative.

Dr. Greg Hundley:

Very nice. Well now, listeners, we're going to head south, down to Dallas, Texas and bring in Dr. James deLemos. James, you also have a case report and did some extensive study, I believe, in your patient in terms of investigating perhaps mechanisms. Could you share with us your study and some of your findings?

Dr. James deLemos:

Yeah. Thanks, Greg. Ours was like Kathryn and Chris's experience, purely serendipitous. I was on service in late January at our university hospital and we had a case that came in three days after receiving the Moderna vaccine with what appeared to be clearly myocarditis in temporal association with the vaccine. At that time, we reported it to the CDC, but there was really not much, if anything, and so what we decided to do was pull together a translational team. We brought together clinical pathologists, immunologists, infectious disease experts, and a panel of folks to think about how we might get at a potential mechanism, obviously in a highly exploratory fashion because this was one case and at this point we really didn't know whether this was a true causal association or just circumstance.

Dr. James deLemos:

What we did was really a broad exploratory analysis, comparing our index case with a number of vaccinated controls, COVID infected controls, and normal controls. We did autoantibody panels, cytokine panels. We looked at flow cytometry for cell fractions, and really tried to see if there was a signature for our case that distinguished it from these other control groups.

Dr. James deLemos:

I think one important thing we didn't see was an exuberant or over exuberant response in terms of the spike antibody. That was also not seen in several other cases from Chris and Kathryn. The antibody response seemed to be in the normal range of what would be expected after the vaccine. We also didn't see broad spread inflammation in our case compared to controls. There were several cytokines that were upregulated, some of which have been reported in myocarditis, and there were some natural killer cell subsets that would seem to be upregulated, and then several autoantibodies as well that have been reported in myocarditis. But interestingly, none of the poor prognosis autoantibodies that had been reported, which may in part, we think, explain why these cases seem to be doing quite well.

Dr. James deLemos:

I'd emphasize it's one case, so we recognize this is purely exploratory and hopefully will set the stage for other people as they try to investigate this in more depth.

Dr. Greg Hundley:

Thank you, James. Well, Biykem, you've been spending a large segment of time, the last year, really year and a half, trying to put together for us at the American Heart Association what may be operative in these patients receiving these vaccines, and also really studying COVID-19. It sounds like what we're hearing amongst all three of these, young men, really a myocarditis that develops after the second vaccine. We have typically elevated troponins, there's MRI findings. You've put together a review. Maybe you could start to share with us what have you learned over this past year and a half?

Dr. Biykem Bozkurt:

Thank you, Greg. As my colleagues have alluded to, the characterization of the presentation is pretty concordant. What I did in the review was to review all the case reports and case series published to date, which summed up to 61 cases. Additionally, I looked at what has been reported by the Vaccine Adverse Event Reporting System by the CDC and their internal analyses, and also looked at the reports that came from Israel as well as the US military, which is a large cohort and population base reporting.

Dr. Biykem Bozkurt:

The messages for the clinicians, number one, the presentation in most of these reports have been pretty unified in the sense that most patients presented day two or day three after the second dose of mRNA vaccination. Secondly, most if not all had cardiac troponin elevation along with chest pain on presentation. The majority of the patients, more than 90, 95 in the case series, had EKG abnormality, usually with ST elevation. When we're to examine the echo findings, about two thirds or sometimes in the case series about 40% of abnormalities and only a small percentage had LV systolic dysfunction with EF less than 50.

Dr. Biykem Bozkurt:

When done as was the case in all the case series and case reports, cardiac MRI was always abnormal. They were very self-limited. Important concepts are, these were very self-limited cases. All of them recovered and were discharged and had resolution of their symptoms, biomarker findings as well as imaging findings.

Dr. Biykem Bozkurt:

Now, let's look at the benefits versus risk concept that was examined at the CDC level. The current reporting in the VAERS system, the Vaccine Adverse Event Reporting System, is about 12.6 cases per million doses of vaccination. This is after 300 million doses being given in the US and about 170 million individuals being vaccinated in the US. Of those, when compared to what we have been expecting in the population, there appears to be a temporal association that the CDC has confirmed. If we were to look at the risk versus benefits ratios, it's very clear that COVID-19 is a deadly disease. It results in mortality even amongst the younger population, somewhere at the order of 0.1 to 1% per 100,000 people being infected. So for 12 to 39 years old, where the myocarditis risk is felt to be higher, still we need to keep in mind, that risk is very low. 12 per million doses, compared to about 0.1 to 1 death for about 100,000 infections.

Dr. Biykem Bozkurt:

And of course, if we were to add the number of hospitalizations, ICU stays, cardiac involvement, which we know is seen in about 12 to 20% of hospitalized patients by cardiac troponin elevation, as well as multisystem inflammatory syndrome that is seen in young populations, the benefits significantly outweigh the risks. In terms of mechanisms which James has alluded to, the things that are coming as potential signals or hypothesized mechanisms include the following. There could be molecular mimicry between the spike protein and the self-antigens. Currently, that experimental data, antibodies against spike protein have been reported to cross react with human proteins including alpha myogen. Other mechanisms could be vaccine and it making a response triggering a pre-existing dysregulated immunopathological pathway in predisposed patients. But mind you, we don't right now have a pattern of who's predisposed to myocarditis. It doesn't look like comorbidities as we have seen with COVID-19 infection.

Dr. Biykem Bozkurt:

And in James' case, there was no predisposition to cardiomyopathy identified by a gene variant that are known to be associated, so those were negative in the case reports that James had mentioned. There was increased frequency of autoantibodies in that case report that James had published. Again, this may be in reaction to the inflammation or injury rather than being the cause. It may be the outcome, but still it raises a concern whether autoantibody formation is one of the mechanisms.

Dr. Biykem Bozkurt:

Male predisposition is a known risk for myocarditis. We've known this even before the vaccine related myocarditis cases. In the experimental as well as population based studies in the past, young males have a higher predisposition than females or older age, and it's thought to be due to the differences related to sex hormones, especially testosterone, being pro-inflammatory. But of course, in the passive vaccine adverse event reporting, we also do know that the chest pain presentation did not appear to be as different among males compared to females and the imaging and studies were done in less frequency in females, so there may be also a bias toward work-up in females which needs to be further examined.

Dr. Biykem Bozkurt:

The most important message we'd like to put out there is the benefits highly outweigh the risks, but there needs to be recognition that there is such a risk for clinicians, and definitely do an appropriate work-up for patients presenting with chest pain to the emergency room or to the clinical setting for an appropriate work-up to be carried out including EKG, cardiac troponin in all patients, followed by imaging, such as cardiac MRI and/or other imaging as necessary depending on the symptomatology, the age, as well as the findings on the troponin and EKG. And cardiology moment is essential for those ones who are diagnosed with myocarditis. The treatment strategies in the case reports range all the way from non-steroidal colchicine to IV steroids to intravenous immunoglobulin. Probably the way to approach these cases is if it's very self-limited with resolution of symptoms and biomarkers within two or three days, they may not need to resort to very intensive therapy, but if the case is with unrelenting symptoms, persistent biomarker abnormality, an imaging finding higher level of intense geo-treatment with intravenous steroids or IV immunoglobulin may be considered.

Dr. Biykem Bozkurt:

So far in the published reports, there have not been any bad outcomes such as death and/or requirement for mechanical circulatory support, but again, further research is needed.

Dr. Greg Hundley:

Very nice, Biykem. Well, listeners, we're going to go back through our authors and just really quickly, Kathryn, Chris, James, Biykem, what study, maybe in 15 seconds, do you think might need to be performed next in this sphere of research? And then second, what's the one point that you think we ought to emphasize as we close out going forward? So, both questions for each author. Kathryn, we'll start with you.

Dr. Kathryn Larson:

Okay, cool. I think I'll bring a little bit of an imaging bias as that's my personal interest. I'd really like to see a lot of the data that's already out there from these patients both at their baseline studies, and I'd really like to see their follow-up studies in terms of what happens to things like LV function and in terms of their MRI findings. I think that could be really helpful given the amount of weight that imaging has in the diagnosis of these patients.

Dr. Kathryn Larson:

I think the biggest take-away for me in a lot of these discussions that we were having is, these are very rare issues and incidents when patients are presenting with these, and I think the vast majority of the information we have at hand is that these are self limited, there's good recovery of any decline in LV function, and that I think overall the clinical course is favorable.

Dr. Greg Hundley:

Very nice. Chris?

Dr. Chris deFilippi:

First, I shouldn't be promoting my colleague's work, but I've got to say that Biykem's review was terrific. I know I did a lot of background reading in this case presentation. I've gone through that review a couple times and it's clearly, I think, helped my thinking on this topic. As Biykem mentions in that review, the recording of myocarditis can have a number of biases either under or over reporting, basically what's available in the public and what sort of people are thinking about. I think looking at it from a population health standpoint, the risk benefits are so favorable for the benefits of vaccination. We knew that even a month ago, we know that even more today. But I think it would be great to get an understanding, recognizing that there may be cases of unrecognized myocarditis, myocardial fibrosis, at a population level in what we would assume would generally be very healthy, young adult males, do we see more cardiac related hospitalizations over time? Do we see more sudden death? I think we should just affirm that, hopefully we can affirm that isn't the case and keep moving forward.

Dr. Chris deFilippi:

That being said, I'm still really a big advocate for vaccination and the benefits of vaccination combined with these very small risks.

Dr. Greg Hundley:

Very nice. James?

Dr. James deLemos:

I'd say really two avenues for research. I'd echo Kathryn's point that we need longer term follow-up data for patients that have this syndrome. To do that we're going to have to collaborate, because each of us individually see very few cases, because fortunately this is rare, and we're going to need registries that look at longer term follow-up of patients with vaccine associated myocarditis. And then really getting to Chris' point on the front end, I think that's what's needed are prospective studies measuring high sensitivity troponin and cardiac MRI in younger individuals who get vaccinated, so we study them not once they get the disease, but trying to determine whether there might be even less severe versions of myocardial injury that are occurring after the vaccine and try to understand why that's the case, because mRNA vaccines are here to stay. They're remarkable advances. And let's understand what this apparently self limited myocarditis is all about.

Dr. James deLemos:

The take-home message I'd echo is that this is important and all of us even had angst about recording and talking about this, because we don't want this ever to be misconstrued to suggest that these vaccines, which are absolutely remarkable, don't have a favorable risk benefit, even for our cardiac patients. These data in no way affect the safety and efficacy of the vaccine, even in people with underlying cardiac disease, who are some of the ones that have the greatest priority to get vaccinated.

Dr. Greg Hundley:

And finally, Biykem.

Dr. Biykem Bozkurt:

I think I echo all my colleagues' sentiments in the necessity for prospective and imaging and biomarker. The way to do that, as James alluded to, is we should right now develop a consortium for a registry, and we should have a bioregistry. I would urge us to not solely consider it for vaccine related entity, but also COVID-19. So I think we need to straddle the whole concept of COVID-19 itself, the infection plus the vaccinated individuals and follow them in a prospective manner with the known biomarkers, the cardiac biomarkers as well as imaging, but also the thing that is lacking right now is to characterize them with a specific immune cell populations as to what is rising, what kind of response we've seen, with the changes that we're seeing in males and others, and capture further mechanistics, perhaps signaling. Quite a few of this phenotyping is needed in these individuals as well as perhaps a genotyping characterization and maybe a tissue characterization.

Dr. Biykem Bozkurt:

I think the consortium will need to entail pathologies as well as immunopathology along with biomarkers and imaging. And of course, prospectively following these individuals. As was done in certain other vaccines in the past may give us a totally different signal and prevalence.

Dr. Biykem Bozkurt:

Take-home message, I fully agree. Being able to get a message of the risk is low compared to benefit. While we're calling for, the necessity for further research is a delicate balance of what the scientists have to straddle. Yes, the vaccine is very safe. It's been shown in numerous, several randomized clinical trials. Current data actually validates that because it's a few cases in millions of doses of the safest vaccine. But for those very few cases, for those very few cases we need to be on the alert and treat them appropriately and not miss those diagnoses.

Dr. Biykem Bozkurt:

One other message I'm going to share is the rapidly evolving conceptualization of myocarditis. The lymphocytic myocarditis concept that historically was the gold standard characterization of myocarditis with other viruses is, I think, rapidly changing now with the recognition of what we saw with COVID-19 itself, as well as now with the vaccine. It does not seem to be the classical characterization of myocarditis, so again, understanding of myocardial injury, cardiomyocyte injury is now a continuum beyond what we used to call the path to MI and injury, now straddling all the way to a concept of injury that is much different than the lymphocytic myocarditis we've seen with other viruses, which we need to embrace.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Kathryn Lawson, Dr. Chris deFilippi, Dr. James deLemos, Dr. Biykem Bozkurt, for this wonderful forum discussion on COVID-19 vaccine associated myocarditis.

Dr. Greg Hundley:

Well, thank you so much and on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021.

Dr. Greg Hundley:

The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAJournals.org.

Circulation August 3, 2021 Issue

2 augusti 2021 | 26 min

This week's episode features author Shih-Chuan Chou and editorialist Alexander Sandhu discuss the article "Impact of High-Deductible Health Plans on Emergency Department Patients With Nonspecific Chest Pain and Their Subsequent Care."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart center at VCU health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I am so excited about today's feature discussion that's going to be about high deductible health plans and their impact on emergency department patients with chest pain and their subsequent care. Now, I can tell you as coming from outside of US, I learned so much from this discussion so everybody's going to want to hear it. But before we go there, let's discuss the other papers in today's issue. Greg, do you have a paper?

Dr. Greg Hundley:

You bet. Thanks Carolyn. So my paper is going to really evaluate a very interesting question about the role of measuring lipoproteins and their subfractions in patients, not with coronary disease, but peripheral arterial disease. And it comes to us from Dr. Scott Damrauer from the University of Pennsylvania School of Medicine. So Carolyn lipoprotein related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, just like we said. Largely based on their role in progression of coronary artery disease, but the relative contributions of these lipoproteins to those with peripheral arterial disease really haven't been as well defined. So these authors leveraged a large scale genetic association data to investigate the effects of circulating lipoprotein related traits on peripheral arterial disease risk.

Dr. Carolyn Lam:

Interesting. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So ApoB was prioritized as the major lipoprotein fraction usually or almost causally responsible for both peripheral and coronary artery disease risk. Extra small VLDL particle concentration, we'll call that excess VLDLP was identified as the most likely subfraction associated with peripheral arterial disease risk while large LDL particle concentration was most likely the sub fraction associated with coronary artery disease risk. And genes associated with excess VLDLP and large LDL particle concentration included canonical ApoB pathway components although gene specific effects were quite variable. And then finally Carolyn, lipoprotein A was associated with increased risk of peripheral arterial disease, independent of Apo protein B. So therefore Carolyn, I think the take home message from this study is that ApoB lowering drug targets and ApoB containing lipoprotein subfractions had really diverse associations with atherosclerotic cardiovascular disease and distinct subfraction associated genes suggested that possible differences in the role of these lipoproteins really are involved in the pathogenesis of peripheral arterial as opposed to coronary arterial disease.

Dr. Carolyn Lam:

Wow. Thanks Greg. Hey, it struck me that we haven't had a quiz in a long time. Okay, but we're not going to do it now. Don't choke because this one's kind of tough. I don't think I could even answer it. What is phospholamban?

Dr. Greg Hundley:

Well, let me guess. I remember having this, I think. Let's just... Carolyn I do not know what phospholamban is.

Dr. Carolyn Lam:

Let me just tell us all. Phospholamban is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in phosphate lanvin is associated with dilated cardiomyopathy and a high prevalence of ventricular arrhythmias. But how this deletion causes dilated cardiomyopathy is still poorly understood. And there are no disease specific therapies. And hence today's paper, which comes from Dr. Karakikes and colleagues from Stanford university school of medicine. What they did is they employed human induced pluripotent stem cells and CRISPR Cas9 gene editing technologies to create an in vitro model of dilated cardiomyopathy associated with this phosphate lanvin 14 deletion mutation. Single cell RNA sequencing revealed the activation of an unfolded protein response pathway, which was also evident by significant up-regulation of marker genes in the hearts of patients with the deletion. Pharmacological and molecular modulation of this unfolded protein response pathways suggest a compensatory role in this type of dilated cardiomyopathy. Augmentation of the unfolded protein response by the small molecule BIP protein inducer X Millia rated contractile dysfunction.

Dr. Greg Hundley:

So Carolyn, tell me what are the clinical implications?

Dr. Carolyn Lam:

Well, these findings suggest a mechanistic link between proteostasis and the phospholamban 14 deletion induce pathophysiology that could be exploited to develop a therapeutic strategy for this kind of cardiomyopathy. The study also highlights how human induced pluripotent stem cells and cardiomyocyte modeling could be combined with small molecule testing as a paradigm for studying genotype, phenotype associations in heart disease.

Dr. Greg Hundley:

Very nice Carolyn. Well, my next paper comes to us also from the world of preclinical science. And it's from Dr. Philip Marsden from the University of Toronto. And Carolyn endothelial nitric oxide synthase or eNOS is an endothelial cell specific gene predominantly expressed in medium to large size arteries where endothelial cells experience athero-protective laminar flow with high shear stress. Now disturbed flow with lower average shear stress decreases eNOS transcription, which leads to the development of atherosclerosis especially at bifurcations and in the curvatures of arteries. So the prototypical arterial endothelial cell gene contains two distinct flow responsive SIS DNA elements in the promoter. The shear stress response element and the Kruppel-like factor or KLF element. Previous in vitro studies suggested there're positive regulatory functions on flow induce transcription of the endothelial genes, including eNOS. However, the in-vivo function of these SIS DNA elements remains unknown.

Dr. Carolyn Lam:

Wow. So what did these investigators do, Greg?

Dr. Greg Hundley:

Right. So Carolyn the authors report for the first time that the shear stress response element and the KLF elements are critical flow sensors necessary for a transcriptionally permissive hypo methylated eNOS promoter in endothelial cells under chronic shear stress in vivo. Moreover endothelial nitric oxide synthase expression is regulated by flow dependent epigenetic mechanisms, which offers novel mechanistic insight on eNOS gene regulation in atherogenesis.

Dr. Carolyn Lam:

Nice. Thanks Greg. Well, let's go through what else is in this week's issue. In a cardiovascular case series, Dr. Ribeiro discusses the Platypnea-Orthodeoxia Syndrome, a case of persistent hypoxemia in an elderly patient. In ECG challenge, Dr. Challenge shows a case of diffuse St. Segment elevation with idiopathic malignant ventricular arrhythmias. There's an exchange of letters between doctors Wang and Sattler regarding the article cross priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart. And there's an On My Mind article by Dr. Mullasari Sankardas on of occlusions, inclusions and exclusions time to reclassify infarctions. So interesting.

Dr. Greg Hundley:

Very nice, Carolyn. So I've got a couple of things in the mail bag. There is from Professor Kunfu a Research Letter entitled PTP MT-1 is required for embryonic cardio lipid biosynthesis to regulate mitochondrial morphogenesis and heart development. And then finally our own Bridget Kuhn has a cardiology news entitled vegan diets that are culturally aligned with traditional soul food gained popularity among black individuals. Well Carolyn, I can't wait to get to your feature discussion today.

Dr. Carolyn Lam:

Me too. Today's feature paper is about the impact of high deductible health plans on emergency department patients with non-specific chest pain and their subsequent care. I'm so pleased to have with us the first author Dr. Andrew Chou from Brigham and Women's hospital, as well as the editorialist Dr. Alexander Sandhu from Stanford university. Welcome gentlemen, please tell us about your current study.

Dr. Andrew Chou:

Yeah, so I think the reason we did this study was really obviously aware of the context, but also me working as an emergency decision. So anybody in the ED will now that, there's all kinds of versions of chest discomfort that comes through the ED and they always are worried about heart attack. And we do this testing kind of day in day out, it gets kind of inundated. So a lot of people have put thought into what we should do in the emergency room. We should get ECG, we should care cardiac enzymes when we're worried about it. But what really quite remains uncertain is really what to do afterwards. We get this patient, we test them, we didn't really find heart attacks, but there's a lot of uncertainty about what to do after. Do we do stress test, do we hospitalize them to get the stress test or other testing.

Dr. Andrew Chou:

As a result, there's a lot of variation in care. And I think partly because of that, they're kind of the shared decision making came out of that. As a part of the solution was to involve patient via, Hey, here are your risks. Let's talk about whether or not this would make sense for you to stay, get testing among other decisions. But what's always interesting to me is that even though we have this push towards having patients have kind of needing to make these decisions because of money, we don't really talk about costs and even their sort of sense of pride about, oh, we don't want to talk about costs. We just want to be the best medical treatment for you, but cost is such a reality for the patients. So, that's kind of the motivation behind getting this study done. So the way we wanted to test it was to set it up as closely as possible to run my trial but knowing that it's not really possible in the real world to do something like that.

Dr. Andrew Chou:

So we had to be pretty selective about who we include as a study population. So the first thing we did was we took essentially a large national insurer and their claims database. We look at only the people who enrolled in insurance products through their employer. So employers in the US can choose what type of plan they want to offer patients. And we only chose employers that offer only one type of insurance at a time within each year of a plan. So what we did is we chose people who had essentially two years of enrollment. And in the first year, they all have to have loaded up full plans.

Dr. Andrew Chou:

Meaning deductibles are less than $500. It's still a lot of money, but it's less compared to... The second year either they still have low deductible plan or the experimental group is going to be a group of people who employer only offer high deductible plan, which we define as having deductible greater than $1,000. So that sort of set up a control and experimental group with a similar baseline and then a different followup period of a year. And then we also did additional matching by employer characteristics and their own, the member characteristics to kind of make them as close as possible in terms of compabilities, age, as well as employer size, which we find to be a really big factor. Because large employers tend to have lower deductibles because they can risk care a lot better among their employees where a small employers like companies with five, 10 employees tend to have high deductible plans. So we use that population to compare essentially what happens after a certain company switch to kind of calculate the effect of the high deductible plan.

Dr. Carolyn Lam:

Great. Very novel design. But could you please tell us your results?

Dr. Andrew Chou:

Yeah, so we found is that once the employees from the companies that switch, there were less ED visits that ended up with a diagnosis of chest pain. This is important to bring in also the nuance here, which is that these are ED visits that effectively are not have been seen and test it. And they don't have a severe diagnosis like a heart attack or other significant cardiac issues that were found at least during the initial ED stay. And that decreased, which sort of makes the question whether or not these decreased visits or either where they just another chest visit without really other diagnoses or are they visits that actually have diagnosis. The other thing we found was also that there's a decrease in admissions from these ED visits actually. And majority of it, even though when we did our study, we actually were looking at admissions through the 30 days after these ED visits.

Dr. Andrew Chou:

But we found that the majority of difference is actually the admissions directly from these initial ED visits with time is just horrible. Two more things we found was that the amount of testing that was done after the ED visits, or not really consistently decreased because of high deductible, some tests really didn't have a difference and some more invasive and expensive tests did have some differences. But if you account for the decrease in the chest pain ED visits, then they're not really that notable. But the last finding, which perhaps is the most interesting of which is that there seems to be an increase in heart attack diagnosis and admissions after these visits for chest pain and our statistics for the entire study population actually wasn't significant. But we decided to look at the subgroup patients from poor communities who presumably have lower income and found that the same findings in this group was actually statistically consistent and so we felt comfortable reporting that. So I think that was probably the most interesting finding from our study.

Dr. Carolyn Lam:

Right. Thanks Andrew. Alex, I have to bring you in here. I really love the editorial love that you said to go or not to go as the title. But could you put these findings in context, please?

Dr. Alexander Sandhu:

Yes. Happy to and thank you for having me. I think studies like this study by Andrew and colleagues are incredibly important as we make health policy decisions that have large impacts on clinical decision-making for both patients and clinicians. It's important that we study them to understand how they impact patient decision-making clinical outcomes and costs, because obviously that can have important ramifications for future design at the end detecting unintended consequences. I think this study adds to a large body of work done by Andrew and his colleagues, really helping us to understand the implications of high deductible health plans on patient decision-making and subsequent outcomes. This is an incredibly important topic because of the proliferation of high deductible health plans over time and then potentially since the advent of the Affordable Care Act with fixed premiums leading to more and more cost sharing for patients. And it's really critical that we understand how that cost sharing impacts patients.

Dr. Alexander Sandhu:

And I think that chest pain is a wonderful test because chest pain can be something very serious. It's almost universal that when patients have acute onset chest pain, that a clinician asks them to go to the emergency department for further evaluation. However, we also have a large body of evidence that suggests that the large majority of chest pain episodes are not serious and don't end up needing additional treatment. So it's an area that I think both you could imagine decreased utilization once you applied cost sharing to patients. But what were you very much worried about the unintended consequences of people not going to the emergency department, if it's a serious condition. I think this was a well-designed quasi experimental analysis to look at the lower risk, but majority of episodes of chest pain where they're non-specific and not resulting in acute coronary syndrome and to try to demonstrate it that the high deductible health plans do lead to reductions in those episodes.

Dr. Alexander Sandhu:

I think as Andrew said, one of the most fascinating findings was this increase in acute MI's it was consistently significant amongst the low-income patients, but was not related to patients that were discharged because of potentially the effects of the high deductible and then came back in with acute MI's but were actually acute MI's during the initial admission. I was wondering if Andrew could maybe both explain that nuance a little bit more, which you get into the discussion of that paper, and then also walk us through maybe some thoughts that you and your study team had for causes for that potential finding.

Dr. Andrew Chou:

Yeah, absolutely. Thanks for raising that. So I think going into it initially, our hypothesis was really that, but when we first saw it, our initial thought was that, oh, maybe perhaps after they're discharged, they're supposed to get testing and patients or then follow up with their doctors. So they have increased poor outcomes. And so after that thought, that's when we did the kind of subgroup analysis looking at just patients who were discharged versus those who were admitted when they were diagnosed with chest pain at their initial ED visits. And exactly what we found is that the difference is really among people who were admitted initially, which is surprising to us. So I think what that signals to us is that our initial thought was not correct in the sense that this is not really a result of lack of followup or didn't intend to the testing that they were scheduled or didn't go see their doctor afterwards. But really like patients who are showing up in the ED already are more prone to perhaps having a heart attack.

Dr. Andrew Chou:

And so it really points to which is what you mentioned at your program, which we totally agree as well, that more upstream factors is affecting this. Could it be that they don't tend to take their medications as they should, or they didn't go to their doctors for checkups as they should, or they could have had earlier identification of heart problems if they have more perhaps milder symptoms beforehand until before the ED visits that could have presented certain things. So, that's hard to say. I do think that there is a... One of my mentors in this paper, Dr. Wareham, who has done a ton of work in the space of high deductible plan with kind of chronic disease management, they have definitely shown a lot of differences when patients have higher cost sharing. They'd certainly defer a lot of carriers, especially in diabetics have more complications and it might be a similar scenario here that which would make the most sense and fits the best with our findings here.

Dr. Carolyn Lam:

So that's a great question Alex and great insight Andrew. I think at this point, I need to ask you both. So what overall do you think is the clinical implication or there'd be any practical next step that you think should follow from this? Maybe I'll let Andrew start and then Alex finish?

Dr. Andrew Chou:

Sure. Thank you. I think there's kind of... I think two aspects to this one is really broader policy changes. I think if anything, it's quite uncertain whether or not the reduction in ED visits for chest pain is something detrimental. It's unsure whether or not the reduce admission is detrimental. But what is certain is that especially in lower income population certainly feels the higher out-of-pocket costs a lot more. And if there is an unintended consequence, it will certainly be magnified in this population. And in fact, I think a couple of past studies who having compared really high income versus low income population has found that really, high income patients tend to do okay and they're able to pick and choose appropriately of type of care they need. Whereas low-income patients tend to have really unanticipated changes. So, really trying to minimize the impact for low-income patients is going to be important policy direction.

Dr. Andrew Chou:

And there are a number of ways of doing it. I think there certainly is an increasing trend for companies to fund the health savings account, which is actually a tax deferred almost like investment accounts or certain fund to help them offset some of their healthcare out-of-pocket costs. But the other aspect of it, which I think is all a bit harder to push for is really for employers and insurance to just keeping their account patient's income when they're kind of pushing forward products for a high deductible plan. So low-income patients should just not have quite as big of a deductible as the high income earners do. But a different aspect it's really clinically for clinicians. It's tough because I think insurance put this forward because they want to influence patient decisions before they even see the clinician. But after they decide to come visit clinician, I think the clinician should be aware of the financial reality for the patient when making these decisions.

Dr. Andrew Chou:

But it's really hard for me to think about whether or not this is going to be a good thing for the patient or not. And one of the biggest concerns for really my colleagues in the department is really whether or not if we are really talking poor patients out of certain care by reviewing their financial reality with them and by through that are we essentially discriminating against other patients. So that's really a big unknown. I think that's definitely an area that we should definitely heavily invest in research because we're just pushing forward with price discussion for care to encourage price discussion at the clinic here without really knowing what's going to happen.

Dr. Carolyn Lam:

Yeah. Wow. Alex?

Dr. Alexander Sandhu:

Yeah, I definitely agree with Andrew. I think if we want to make decisions based on cost and we want patients to make those decisions and we as clinicians, obviously should be helping them. We need more transparency around costs, current deductible status, and that has to be available at the point of care so it actually can be integrated in decision-making. But I think that's likely not enough. I mean, even for clinicians, it's hard to determine how clinically necessary it is to get emergency evaluation before you see the patient when you get a phone call. So I think, if it's hard for clinicians with all of our years of experience, it's hard to understand how we can really expect that from our patients.

Dr. Alexander Sandhu:

I wholly agree with Andrew that I think a critical step is it's going to be important to reduce the risk of cost sharing for low-income patients with a number of potential interventions to do that, which I think are the real policy implications here. And then more generally, I think we should make sure that deductibles aren't discouraging utilization of high value cost effective intervention. There are currently safeguards in the Affordable Care Act about that. But I think we need to think about those closely and probably expand that so we don't see high deductible health plans leading to lower stat rates or worse diabetes prevention.

Dr. Carolyn Lam:

Wow. Words of wisdom. I just cannot thank you both enough for publishing such a beautiful paper, important findings, as well as just a very lovely editorial in Circulation. Thank you. Learned a lot. I'm sure the audience did too. Please remember you're listening to Circulation on the Run. Please tune in again next week with Greg and I.

Dr. Greg Hundley:

This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more visit ahajournals.org.

Circulation July 27, 2021 Issue

26 juli 2021 | 26 min

This week's episode features author Aaron Baggish and Associate Editor & Editorialist Satyam "Tom" Sarma as they discuss the article "SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts ... I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center from VCU health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, this feature discussion is just so relevant to our current times. It talks about SARS-CoV-2 cardiac involvement in young competitive athletes. Oh, one that I'm sure we're all dying to get to. Very important. But first, let's tell you what's in this week's issue. Greg, you want to go first?

Dr. Greg Hundley:

You bet, Carolyn. I'm going to grab a cup of coffee, and we're going to dive into the world of preclinical science. Our first paper comes to us from Professor Naftali Kaminski from Yale University. Carolyn, these investigators reprocessed human control single-cell RNA-sequencing, or scRNA sequence data from six datasets to provide a reference atlas of human lung endothelial cells to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium. Also, the signaling network between different lung cell types was studied.

Dr. Carolyn Lam:

Wow. Okay. So what did they find, Greg?

Dr. Greg Hundley:

Six lung single-cell RNA-sequencing datasets were reanalyzed and annotated to identify over 15,000 vascular endothelial cells from 73 individuals. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous endothelial cells, the co-authors found two previously indistinguishable populations. Pulmonary venous endothelial cells, called COL15A1neg localized to the lung parenchyma and systemic venous endothelial cells, COL1581positive localized to the airways and visceral pleura.

Dr. Greg Hundley:

Now, among capillary endothelium cells, the authors confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1, and TBXX2 and general capillary endothelial cells. The authors confirmed that all six endothelial cell types, including the systemic venous endothelial cells and aerocytes, are present in mice and identified endothelial marker genes conserved in both humans and mice.

Dr. Greg Hundley:

So Carolyn, I'm going to take a question I bet you're getting ready to ask. What are the clinical implications of this research? Well, mainly that understanding the lung endothelial diversity is crucially important to identify new therapeutic approaches for vascular diseases such as pulmonary hypertension.

Dr. Carolyn Lam:

Wow. That was interesting, Greg. Thank you. I've got another one from basic science world as well, and this one talks about the initial functional characterization of an exercise-induced cardiac physiological hypertrophy associated novel long non-coding RNA or LncRNA.

Dr. Greg Hundley:

Okay, Carolyn. Quick quiz. Can you remind us what these long-coding RNAs are?

Dr. Carolyn Lam:

Ha. Sure. So long non-coding RNAs or LncRNA refers to RNAs that are longer than 200 nucleotides and lack the potential to encode proteins, but have still been closely related to the occurrence and development of many diseases.

Dr. Carolyn Lam:

The current paper comes from co-corresponding authors, Dr. Li from the First Affiliated Hospital of Nanjing Medical University and Dr. Xiao from Shanghai University. They identified a LncRNA in the heart named cardiac physiological hypertrophy associated regulator, or CPhar. This was increased following exercise training and was necessary for exercise-induced cardiac growth. In neonatal mouse cardiomyocytes, over expression of this LncRNA induced an increase in these cardiomyocytes' size and expression of proliferation markers while inhibition of the LncRNA reduced these neonatal mouse cardiomyocytes' size and the expression of proliferative markers. Over expression of the LncRNA led to a reduction in oxygen glucose deprivation reperfusion-induced cardiomyocyte apoptosis, while LncRNA knockdown aggravated the apoptosis.

Dr. Carolyn Lam:

In vivo over expression of that LncRNA prevented myocardial ischemia reperfusion injury and improved cardiac function. So mechanistically though, the transcription factor, ATF7, acted as the functional downstream effector of this cardiac physiological hypertrophy associated regulator, the LncRNA.

Dr. Carolyn Lam:

Now Greg, following your example, I'm going to ask what are the clinical implications and tell you. So these results provide new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of this LncRNA known as cardiac physiological hypertrophy associated regulator in the heart. It also expanded our knowledge and understanding of the functions and fundamental mechanisms of LncRNAs in general.

Dr. Greg Hundley:

Wow, Carolyn. Beautifully described. Well, my next paper comes to us from the world of clinical science and really it's kind of something that's going to get into spending. It comes to us from Dr. Brandon Bellows from Columbia University.

Dr. Greg Hundley:

So Carolyn, spending on cardiovascular disease and cardiovascular risk factors, in total cardiovascular spending, accounts for a significant portion of overall US healthcare spending. The author's objective was to describe US adult cardiovascular spending patterns in 2016 and changes from 1996 to 2016, and look at the factors associated with these changes over time.

Dr. Carolyn Lam:

Wow. Okay. So were the authors are viewing time-dependent changes in cardiovascular spending. Is that it? What did they find?

Dr. Greg Hundley:

Absolutely Carolyn. So a bunch of data. Just kind of some interesting facts here. So let's work through them. Adult cardiovascular spending increased from 212 billion in 1996 to 320 billion in 2016, a period when the US population increased by over 52 million people and the median age increased from 33 to 36.9 years.

Dr. Greg Hundley:

Next, over this period, public insurance was responsible for the majority of cardiovascular spending at 54% followed by private insurance at 37% and out-of-pocket spending at 9%.

Dr. Greg Hundley:

Next, health services for ischemic heart disease at about 80 billion and hypertension, 71 billion, led to the most spending in 2016.

Dr. Greg Hundley:

Next, increased spending between 1996 and 2016 was primarily driven by treatment of hypertension, hyperlipidemia, and atrial fibrillation flutter on which spending rose by $42 billion, $18 billion and $16 billion respectively. Increasing service price and intensity alone were associated with 51% or 88 billion, and cardiovascular spending increased from 1996 through 2016. Whereas, changes in disease prevalence was associated with a 37% or $36 billion spending reduction over the same period after taking into account population growth and population aging.

Dr. Greg Hundley:

So in summary, Carolyn, US adult cardiovascular spending increased by about $100 billion from 1996 to 2016. Maybe policies tailored to control service price and intensity and preferentially reimburse higher quality care, perhaps that could help counteract future spending increases due to population aging and growth.

Dr. Carolyn Lam:

Oh, wow. Those are staggering numbers. Thanks Greg. Now let's go through what else is in this week's issue. There's an exchange of letters between doctors Mehmood and Houser regarding the article, Cardiac Remodeling During Pregnancy with Metabolic Syndrome: A Prologue of Pathological Remodeling. There's an ECG challenge by Dr. Real on an unusual call from the urology ward. There's also a Research Letter from Dr. Molkentin on cardiac cell therapy failing to rejuvenate the chronically scarred rodent heart. And finally a Special Report by Dr. Althouse on Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report from the American Heart Association.

Dr. Greg Hundley:

Great, Carolyn, and I've got a Perspective piece entitled, Intravenous Iron Therapy in Heart Failure with Reduced Ejection Fraction: Tackling the Deficiency. It's from Professor Ardehali.

Dr. Greg Hundley:

Well, Carolyn, how about we get on to that feature discussion and learn more about SARS-CoV-2 in young competitive athletes.

Dr. Carolyn Lam:

Ooh, let's go. In our current COVID-19 pandemic a huge question is, does cardiac involvement in athletes with COVID-19 preclude their further participation in sports? What is their involvement after they've recovered from COVID-19? Guess what? Today's feature discussion is really hitting the spot with this question. So pleased to have with us the corresponding author of the feature paper, Dr. Aaron Baggish from Massachusetts General Hospital, as well as Dr. Satyam Sarma also known as Tom Sarma, our dear Associate Editor from UT Southwestern, who is also an editorialist for today's paper. So welcome Aaron and Tom. Aaron, could you start us off by describing your study and what you found?

Dr. Aaron Baggish:

Sure. So just very briefly, some historical context. As everyone is quite aware, when we first started seeing COVID-19 in the hospital, there was a lot of concern about what the virus did to the hearts in people that were sick enough to be hospitalized. Those of us in the sports cardiology community were quite concerned that when young athletes that developed COVID-19 infection got sick and then returned to sport, that we'd be seeing the adverse events associated with cardiac involvement. So that was the impetus to start the ORCCA Registry, which was really an opportunity to try to capture the large-scale experience with collegiate athletes returning to sport after COVID-19 infection. Indeed, with roughly 19,000 student athletes across 42 universities, there were approximately 3,000 that developed COVID-19 infection and then went through some form of cardiac screening prior to return to play. The registry was really about telling that story of what we found and what we think the implications are.

Dr. Carolyn Lam:

Aaron, I mean, first of all, more than 19,000 athletes recruited in just ... What was it? September 1st to December 31, 2020? How did you accomplish this amazing registry so quickly? That's amazing.

Dr. Aaron Baggish:

I need to acknowledge the fact that this was an incredible team effort. I was joined and continue to be joined in this by my co-PIs, Dr. Jon Drezner and Kim Harmon, who are sports medicine physicians out of the Seattle area, and the combination of cardiology, expertise and sports medicine expertise really able to pull in many of the large universities and colleges around the country, including most of the Power Five schools to participate in this registry.

Dr. Aaron Baggish:

In short order, team physicians from all these schools understood the importance of this work and agreed to partner with us to work very hard to enroll their student athletes and to provide us with the information we needed.

Dr. Carolyn Lam:

Incredible. But with the foresight, congratulations, this in and of itself is amazing. Now, could you please tell us what you found?

Dr. Aaron Baggish:

Sure. So we found that indeed, as we expected, that these student athletes were undergoing a fair bit of cardiac testing prior to being allowed to return to sport, and that there was variability in terms of what type of testing they were getting. The majority of schools were following what at that point were the recommendations, which were do, what we call the cardiac triad testing, which includes an echocardiogram, a high-sensitivity troponin, and an ECG and to use that information to either clear athletes or send them through further clinically indicated tests. A small number of early adopters had decided to do mandatory cardiac MRIs. So within that, we were able to understand what the prevalence, if you will, of cardiac involvement in these COVID-19 student athletes looked like, and it varied as a function of what type of tests people were doing.

Dr. Carolyn Lam:

And? Give us a sneak peek.

Dr. Aaron Baggish:

As people would expect, the more sensitive tests you do, the more abnormalities you detect. So among the schools that were using a mandatory cardiac MRI approach, there was a 3% prevalence, if you will, of either definitive, probable or possible COVID-19 cardiac involvement. When schools were following the triad testing first followed by clinically indicated CMR that prevalence was much less. It was approximately 0.5 or 0.6%. So I would emphasize that on the whole, regardless of which test was being used, that the involvement was at a much lower rate than we expected based on what we saw early in the hospitalized patient experience. So I think it's a very good news story.

Dr. Carolyn Lam:

Indeed. That's exactly, I think the title almost of Tom's editorial. Tom, could I bring you in here, please? Could you give us the context of this and then tell us what as editors we thought of the paper when it kind of reached out doors at Circulation?

Dr. Satyam “Tom” Sarma:

Sure. No, this was, I actually remember almost exactly when I was asked to handle this paper from an editorial standpoint. Joe texted me, Joe, our editor-in-chief texted me ... I think, the night, actually it was a Friday night I think ... That we had a really important paper, would you be able to take care of it on an expedited basis? I said, "Of course." So took a look at it over the weekend, and it's one of those papers when you're reading it, you almost wish you had a time machine because you realize if we had known this information eight, nine, 10, 11 months ago, it would have totally changed how we handle the pandemic from an athlete and young person standpoint. So from that aspect, I thought this is obviously a very high impact paper.

Dr. Satyam “Tom” Sarma:

Which then led me to the second challenge is finding the right reviewers for this paper because obviously this is a very controversial topic. We wanted to make sure we had the best reviewers we can get. The challenge, unfortunately, was that a lot of my usual go-to reviewers were actually members of the ORCCA Registry. So there were some issues with conflict of interest there, and so from a reviewer standpoint, I looked to sort of leaders in the field who had done something similar. The first thing that came to mind was really how the field has handled ECG screenings for our young athletes. I think there's, again, a perspective there that I think is very similar to how do you handle patients or young athletes with COVID and then how do you emphasize shared decision making? So from that standpoint, I had a narrow list of experts in shared decision making in sports cardiology, and really leaned on them to help guide us through the process because this is a complex paper.

Dr. Satyam “Tom” Sarma:

I think their feedback was instrumental in really helping to kind of distill the message, to kind of phrase things in a way that allowed the message to be easily digested by both the lay media, but more importantly, by sports trainers and athletic directors around the country. From that standpoint we really work hard and again, really thank you to Aaron and Jonathan on this manuscript because they worked so hard with our reviewers. They were incredibly responsive to almost every review comment. From that standpoint, I think the end result was amazing to really see it in final format.

Dr. Carolyn Lam:

I love that behind-the-scenes look. Thank you so much, Tom. What is the strong clinical implication of this? If you have questions for Aaron, please go ahead.

Dr. Satyam “Tom” Sarma:

Sure. No, I think the biggest thing for us as editors and sort of from the public health impact was, as Aaron mentioned, some schools have unlimited resources to really throw as much money as they can at the problem or what they think is the best approach to the problem. Again, when you have unlimited resources, you can get the "best tests." I think, unfortunately not every school in this country, both from a collegiate or high school level, has a capacity and more importantly, around the world. That's a really important limiting factor.

Dr. Satyam “Tom” Sarma:

Is there a way to distill the algorithm in a way that's both safe for the athletes, but more importantly is feasible for most schools? For us, that was the most important public health message was really to get that out there. The second of course, was that thinking back to last summer, just how many COVID myocarditis papers we handled in Circulation. Looking back with the again, in the heat of the battle, things are always challenging, but just to sort of see how the pendulum shifted in such a 180 degree sort of manner. So that also I think was important to get out there as well.

Dr. Carolyn Lam:

Yeah. And exactly why this paper is so important. So thank you once again for publishing it with Circulation. Tom though ... Okay. I mean, not to underestimate the MRI findings and so on. I think you had a question for Aaron in relation to that?

Dr. Satyam “Tom” Sarma:

I do. One of the challenges, again, being on the myocardial side is that we're not always experts in the papers we're assigned, and it's obviously been an incredible learning process. For me, I was hoping to pick your brain a little bit about the MRIs and sort of how you think the field will evolve from a sports cardiology standpoint. Especially as scanners get more powerful, as scanners get more sensitive, the challenges I think the field's going to have is really detecting the tiniest fleck of an abnormality.

Dr. Satyam “Tom” Sarma:

I think the context here is really the recent paper out of the Big 10 where they MRI'd, I believe, everyone in that registry ... I want to say it was over 2,000 athletes. Just out of curiosity, how was that handled, again, amongst your co-authors in deciding how best to present the MRI data? I like how you use the probabilistic language of it's either definite, probable or possible. How do you see that sort of progressing in terms of is that something practical that can be used by sports trainers and sports medicine staff to help restratify your athletes or athletes?

Dr. Aaron Baggish:

Tom, there's so much packed into that question. Let me try to unpack it piece by piece. So first off in our registry, there were a few schools that were early adopters in mandatory CMR screening, and so we wanted to very much responsibly report that. Again, there was about a 3% prevalence of something being abnormal with the myocardium based on the scans. We also realized that not all abnormalities were created equal, and that's why we did come up with that definitive, possible, probable nomenclature to really capture the fact that there were a few people that looked like they had overt myocarditis. But the vast majority had non-specific findings that those of us as clinicians pre-COVID would not have considered myocarditis.

Dr. Aaron Baggish:

The issue with MRI is a complicated one. The way I like to think about this as, as you mentioned earlier, is to go back to the historical experience we had with ECG screening in which doing that before we understood how to use it as a screening tool caused more problems than it solved.

Dr. Aaron Baggish:

It was really back in the mid-2000s when the Italians published their first ECG screening paper that the Americans got interested in it. What we learned is that if you used ECG, and this applies to MR too, without having good normative data, without understanding the cost implications, without having the experts prepared to interpret the test and deal with the downstream findings, that you're just not ready for prime time.

Dr. Aaron Baggish:

While I think the use of MRI as a screening technique during COVID was done with the best of intentions, I think the Big 10 paper, which is a very important dataset in this discussion, highlighted why MRI is just simply not a useful screening tool right now. If you look across their schools, they had tremendously variable rates of cardiac involvement, which is not a function of pathobiology. This virus is not different in Virginia than it is in Tennessee than it is in Wisconsin. It's just simply that people are using the tool in different ways and coming up with different findings. What we're now seeing clinically is that all these MRIs are finding a lot of stuff that either we don't want to care about or we don't want to know, and we're stuck dealing with it. So a challenge ahead of us, for sure.

Dr. Satyam “Tom” Sarma:

No, I think that's a really important point, Aaron. I think looking back even from a clinical standpoint in those, didn't not necessarily look at athletes, I think what you bring up is really important. The cognitive bias. Find something abnormal. I do wonder if you could talk a little bit about ... One of the other concerns we had behind the scenes was if you know an athlete, if you're an MRI reader and you know an athlete or the scan in front of you says 19-year-old athlete with COVID, can you talk a little bit about the cognitive biases that kind of go into sort of assuming either the worst case scenario, especially with athletes, because again, these are young, robust, healthy people who may or may not be on TV or in a very public format. How do you handle that as a sports cardiology in general, just kind of overcoming the cognitive bias, both from a public policy standpoint, but also from a lay public standpoint?

Dr. Aaron Baggish:

Yeah. So I think bias is such an interesting word to me because bias has a negative connotation, but bias actually also has some positive attributes associated with it. Bias really pushes people to be, in this situation, to be conservative and to try to do what they think is best.

Dr. Aaron Baggish:

But what I think it boils down to is going back to a very simple tenet and that's understanding the pre-test probability of disease. So when we interpret imaging data or exercise testing data, it always goes back to the question of why did this person get the test done in the first hand and what is our pre-test probability of finding something wrong? I think what we've learned through the COVID pandemic is that just simply having COVID does not equate with a high pre-test probability of having myocarditis in this young population. That it's really the kids that present, and these are the rare few and far between, that present with clinical findings that any doctor would think of as being consistent with myocarditis, where the scan is really helpful. The vast majority of time it's just simply not that case.

Dr. Satyam “Tom” Sarma:

No, I agree. I think that's always the challenge as well, too clinically as well too, with the diagnostic creep of you get one test that's kind of abnormal and the next thing you know, you're doing a cardiac biopsy and trying to figure out how you got to where you got to.

Dr. Satyam “Tom” Sarma:

I wanted to circle back to Carolyn's comment. I guess obviously COVID kind of really was the dominant health story over the last 12 to 14 months. Has there been a similar rash, in other words, I'm thinking back to H5N1 or some other pandemics in the past, was there a similar concern historically from the sports cardiology community with those viral outbreaks?

Dr. Aaron Baggish:

No. Not to my knowledge, and that's simply because there wasn't as much of an experience with hospitalized patients in the US in those prior pandemics. Again, our concern in sports cardiology world really stemmed from a very different population than the one we deal with on a daily basis. I think we learned that, although we thought that was a well-intending way to approach it, that it turned out to be an overreaction.

Dr. Aaron Baggish:

Before we end, I want to return to Tom's comments about the process and just share with the listeners what a satisfying process this was as an author. Having been through the peer review process, many hundreds of times with different journals, I don't remember one that was as satisfying nor one that led to as high quality of paper based on the feedback we got from the reviewers. So very much appreciative.

Dr. Aaron Baggish:

I also want to acknowledge the American Heart Association that has become a long-term partner in this effort. As we move out of the pandemic, the ORCCA Registry will be pivoting to really capture what happens to young athletes that are diagnosed with genetic and congenital forms of heart disease. We're very appreciative that the AHA has agreed to partner with us on this.

Dr. Carolyn Lam:

Aw, my goodness. Thank you so much, Aaron and Tom, for this incredible discussion. I really want to end with, if I may Tom, citing your editorial. I love the way you ended it by saying, "As Nelson Mandela said, 'Sports has the power to change the world. It has the power to inspire. It has the power to unite people in a way that little else does.'" We got seriously scared with COVID-19, but this paper is just so important in providing some reassurance that there has not been a single case of cardiac complication to date, documented to be clearly related to COVID-19 in this population. It's a real testament to the hard work that you've put in. So thank you. Thank you very much for this paper. For all the effort. Thank you both for being here to discuss this.

Dr. Carolyn Lam:

Well, audience, you've been listening to Circulation on the Run. Thanks for joining us today, and don't forget to join us again next week.

Dr. Greg Hundley:

Circulation July 20, 2021 Issue

19 juli 2021 | 19 min

This week's episode features author Kieran Docherty and Associate Editor Torbjørn Omland as they discuss the article "The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts: I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate, editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got an exciting feature this week involving Neprilysin license inhibition and left ventricular remodeling in patients with asymptomatic left ventricular systolic function after they've sustained myocardial infarction. But before we get to that feature discussion, how about we grab a cup of coffee and jump in on some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I'd love to, and I want to talk about transcatheter aortic valve replacement, or TAVR, that we all know is really transforming our management of aortic stenosis. Despite rapid improvements, however, serious complications remain relatively common and are not well-described by single outcome measures. So the purpose of this paper was to determine if there was site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. And this is from Dr. Desai and colleagues from Hospital of University of Pennsylvania. So they performed a retrospective cohort study using data from the STS/ACC TVT registry to develop a novel-ranked competent performance measure that incorporates mortality and serious complications. Based on the associations with one-year risk adjusted mortality and health status, they identified for peri-procedural complications to include in the composite risk model, in addition to mortality. And ranked empirically, according to severity, these were: stroke, major life-threatening or disabling bleeding, stage three acute kidney injury, and moderate or severe perivalvular regurgitation.

Dr. Carolyn Lam:

Now, based on these ranked outcomes, they found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better-than-expected site performance was observed in 8% of sites, whereas performance as-expected was observed in 80%, and worse-than-expected performance was observed in 11% of sites.

Dr. Greg Hundley:

Carolyn, really interesting comprehensive data. So how do we put this all together? And what's the take-home message for us, clinically?

Dr. Carolyn Lam:

Well, there are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine the structural, process-related, and technical factors associated with high- and low-performing sites. And all this is discussed in a beautifully, beautiful accompanying editorial by Drs. Dharam Kumbhani and Eric Peterson.

Dr. Greg Hundley:

Oh, fantastic. You know, Carolyn, those editorials are so helpful in helping us put these new data in perspective. Well, my next paper comes to us from the world of preclinical science, and it's from Professor Vincent Christoffels from Amsterdam in UMC. So genetic variants of SCN10A, encoding the neural voltage-gated sodium channel NaV1.8 are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. And these investigators studied the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, and coding the major essential cardiac sodium channel NaV1.5.

Dr. Carolyn Lam:

Wow, great. So what did they find, Greg? Sounds like a first-of-its-kind study.

Dr. Greg Hundley:

Right, Carolyn. So genetic variants in and around SCN10A modulate enhancer function and expression of the cardiac-specific NCN10A short transcript, and the authors propose that non-encoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV .8 and cardiomyocytes that impacts NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.

Dr. Carolyn Lam:

Wow, that was a lot. So what are the implications, Greg? Could you simplify it for us?

Dr. Greg Hundley:

Yes. Right, Carolyn. So three things. First, the authors uncovered a novel alternative mechanism for how the SCN10A locus regulates cardiac conduction. Second, their data implicate that genetic variation-sensitive regulation of expression of NCN10A short modulates conductivity of the heart, and can predispose to arrhythmia in the human population. And then finally, Carolyn, in deciphering the underlying mechanism of the increased NaV1.5 mediated current density by NaV1.8 short, the authors believe their findings could ultimately lead to the development of novel therapeutic strategies for particular conduction disorder.

Dr. Carolyn Lam:

Thanks, Greg. Well, this next paper is really interesting. It's the first validation of the enhanced potency of human-induced pluripotent stem cells-derived cardiomyocytes over-expressing Cyclin D2, or CCND2, under the control of myosin heavy chain promoter, and differentiated into cardiomyocytes. Now, that was a mouthful, but so interesting, because Dr. Zhang and colleagues from University of Alabama in Birmingham used infarcted pig hearts, and transplanted these amazing cardiomyocytes, and found that they were associated with proliferation of recipient heart cardiomyocytes, epithelial cells, and smooth muscle cells, all, at least partly, by paracrine activity.

Dr. Greg Hundley:

Well, Carolyn. Really an involved clinical design. So, what are the clinical implications of all this research?

Dr. Carolyn Lam:

Well, first, I think the paper validated a novel therapeutic strategy aimed at upregulating proliferation of recipient cardiac cells using human-induced pluripotent stem cells-derived cell or cell products. Furthermore, targeting the myocyte cell cycle regulators, such as Cyclin D2, holds a strategic potential for re-muscularization of an infarcted region.

Dr. Greg Hundley:

Very good, Carolyn. Well, how about we see what else is in this issue? So I'll start first. There's a Research Letter by Professor Marston, entitled 'Combining High-Sensitivity Troponin with the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'. Next, there's an ECG challenge from Dr. Feliciano, entitled 'An Ominous EKG'. And then finally, there's a very nice exchange of letters from Drs. Lang and Sattar regarding a prior publication: volume status is the key in heart failure.

Dr. Carolyn Lam:

And finally, a very important perspective piece by Dr. Catapano on omega-3 for cardiovascular disease: where do we stand after reduce it in strength? Wow, that was great, Greg. But let's move on now to our feature discussion.

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Well, listeners, we are on to our feature discussion today, on this July 20 issue. And we're very excited to have with us Dr. Kieran Docherty from University of Glasgow in Glasgow, Scotland, and our own associate editor, Dr. Torbjørn Omland from University of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's start with you. Could you describe some of the background related to your study, and what was the hypothesis that you wanted to address?

Dr. Kieran Docherty:

Well, firstly, thank you very much for the invitation to discuss our trial today on the podcast. The background of our trial was that we are all aware that the development of left ventricular systolic dysfunction following acute myocardial infarction places patients at a subsequent increased risk of the development of heart failure, and the process of progressive dilatation of the left ventricle and a reduction in stroke volume, known as adverse left ventricular remodeling, is the process which underlies this elevated risk of heart failure. And many of the treatments that have been shown to be beneficial following myocardial infarction, such as [inaudible 00:09:24] , and angiotensin receptor blockers and beta blockers, the benefit of these medications, in part, is due to their ability to attenuate this process of adverse remodeling. Now, our hypothesis was that it would be possible to further attenuate, prevent, or delay the process of adverse remodeling in patients at risk of heart failure following myocardial infarction, by the addition of a Neprilysin inhibitor to current standard of care.

Dr. Kieran Docherty:

Now, as we all know, a Neprilysin inhibitor in the form of sacubitril valsartan when combined with an angiotensin receptor blocker, has been shown to improve outcomes in patients with symptomatic heart failure, with reduced ejection fraction in the PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous levels of natriuretic peptides, amongst a range of other substrates for Neprilysin, including adrenomedullan, GLP-1, and bradykinin. And our hypothesis was that adding in a Neprilysin inhibitor, thereby increasing endogenous levels of these peptides with potentially beneficial effects, such as reducing fibrosis, reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have an additive beneficial effect on left ventricular remodeling in these high-risk patients with left ventricular systolic dysfunction following myocardial infarction.

Dr. Greg Hundley:

Very nice hypothesis. So, how did you set up, Kieran, your study design, and what study population, how many patients and whatnot, did you include in your study?

Dr. Kieran Docherty:

Well, the first consideration when designing the study was broadly, what group of patients should we involve? And the main limitation was the indication for the use of sacubitril valsartan in patients with symptomatic heart failure, so we did not feel that we could include these patients. Therefore, our study population included patients who had asymptomatic left ventricular systolic dysfunction following previous myocardial infarction. And specifically, we wanted patients who were at least three months following my cardiac infarction. And the reason for that was to try and exclude patients who had transient systolic dysfunction or left ventricular stunning. And we performed a screening transthoracic echo at this time point. And if patients had an ejection fraction of 40% or less on echo, and if they were tolerant of a minimum dose of an ACE inhibitor, 2.5 milligrams of ramipril BD or equivalent, and they were taking a beta blocker, unless contraindicated or not tolerated, then they were suitable for randomization.

Dr. Greg Hundley:

Very good. And what did you find?

Dr. Kieran Docherty:

So we find that in comparison with the ARB Valsartan, sacubitril valsartan did not have any beneficial effects on cardiac MRI-based measures of left ventricular remodeling. And the primary end point of our study was left ventricular end systolic volume index. There was also no improvements in biomarkers of myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high sensitivity to Troponin I.

Dr. Greg Hundley:

Very nice. And any pertinent issues relevant to, perhaps, some subgroups, regardless of age or perhaps gender?

Dr. Kieran Docherty:

So in a post-hoc analysis, we performed an analysis of the primary endpoint in patients who were below or at or above the median NT-proBNP level, which is 238 p-grams per mil. And we found, very interestingly, the suggestion of a benefit, in terms of left ventricular remodeling with a reduction and systolic volume index in patients who had higher levels of NT-proBNP compared to those who had lower levels.

Dr. Greg Hundley:

Very good. Well, listeners, let's turn now to our associate editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers come across your desk. What attracted you to this manuscript? And then how do you put the results of this study in the context with other studies that have been published, particularly recently, in patients with heart failure that have received sacubitril valsartan?

Dr. Torbjørn Omland:

So, Greg, there were many aspects of this trial that made it very attractive for circulation. I think the hypothesis was very interesting, and also it is a very well-conducted study using the reference methods for assessing left ventricular function, using that for assessing the primary endpoint. And they also have a broad array of secondary end points that also sort of provide insight in potential pathways or mechanisms that can explain the effect sacubitril Valsartan. So, that's also a very sort of hot topic within the cardiology research currently, and we know that the ACC, actually a much larger study, PARADISE-MI, was presented. And we knew that this study was also very interesting, because we knew when we received this manuscript, that another, bigger trial that's sort of related would be presented at the ACC at the late-breaking clinical trial sessions there the PARADISE-MI study. But this sort of provided insight that nicely complimented the results of that study.

Dr. Torbjørn Omland:

And I think as Kieran alluded to, we already have the very impressive results from PARADIGM-HF is showing a very substantial benefit in patients with chronic heart failure and reduced ejection fraction. And then we have sort of the borderline results from the Paragon trial, in those with preserved ejection fraction, where it actually was a gradient from those with mildly elevated, where there seemed to be a beneficial effect to those with more normal EF, where there was no effect. So, this study sort of provided new information, very relevant to the whole field, I think.

Dr. Greg Hundley:

Very nice. Well, gentlemen, I want to turn back to you and ask each of you, first Kieran, and then Torbjørn. Kieran, what do you think is the next study that needs to be performed in, really, this sphere of research?

Dr. Kieran Docherty:

As Torbjørn has already alluded to, PARADISE-MI kind of... It fills the gap across the spectrum of heart failure. So in patients who are at high risk of heart failure immediately following myocardial infarction, that that group of patients were studied in PARADISE-MI. And there is an echocardiographic sub-study of PARADISE-MI, which we await the results for. And I think that will be very interesting, because our patient population was distinct from the group studied in PARADISE-MI, namely the fact that the median time from MI was 3.6 years. So, these patients were not in the throes of the neural humoral activation at the time of acute myocardial infarction and prior to the development of established my cardio scar and fibrosis. And so, it may be that the addition of a Neprilysin inhibitor to patients immediately following myocardial infarction may have some benefits, in terms of attenuating or preventing ventricular dilatation reduction and injection fraction that is observed. So I think we await the echocardiographic results of PARADISE-MI with great interest.

Dr. Greg Hundley:

Very good. And Torbjørn , do you have anything to add?

Dr. Kieran Docherty:

Yes. I found observations that actually, in terminal proBNP measurements, could potentially identify a higher-risk group that actually could benefit from the intervention. It was very interesting. So I think we always speak about precision medicine and cardiology, and I think this is sort of one avenue that we should pursue and see whether we use biomarkers like NT-proBNP to identify those patients who will benefit most from interventions like sacubitril Valsartan

Dr. Greg Hundley:

Excellent. Well, listeners, we've heard a really interesting discussion today. Another study investigating Neprilysin inhibition in combination with angiotensin receptor blockers, and basically highlighting that in patients with asymptomatic left ventricular dysfunction following several years after myocardial infarction, that treatment with sacubitril Valsartan did not have a significant reverse remodeling effect just compared with valsartan alone. Well, on behalf of Carolyn and myself, we want to thank Dr. Kieran Docherty and his submission here to circulation, and also our own associate editor, Dr. Torbjørn Omland.

Dr. Greg Hundley:

And for all of you, we wish you a great week, and we hope to catch you next week on The Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Circulation July 13, 2021 Issue

12 juli 2021 | 28 min

This week is a Double Feature Circulation on the Run. Please join author Patrick Serruys, editorialist Shamir Mehta, and Associate Editor Emmanouil Brilakis as they discuss their article "Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study" and editorial "Achieving complete revascularization for multi-vessel coronary artery disease." Then, please join author G. Michael Felker, and Associate Editor Mark Link as they discuss the Research Letter "Implantable-Cardioverter-Defibrillator Eligibility after Initiation of Sacubitril/valsartan in Chronic Heart Failure: Insights from PROVE-HF."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

So guess what, Greg, we have another double feature this week. First, we need to talk about completeness of revascularization in patients with three-vessel disease or left main coronary artery disease. Always a question, and this time we've got insights from the SYNTAX Extended Survival Study. And then, the next feature talks about implantable cardioverter defibrillator eligibility after initiation of sacubitril/valsartan in heart failure, and these are insights from PROVE-HF. But before we get to that, I suggest, as I pick up my coffee, could you tell us what some of the papers you've spotted?

Dr. Greg Hundley:

Thanks so much, Carolyn. Sure. So I'm going to start from the world of preclinical science, and the paper comes to us from Dr. Vadim Fedorov from The Ohio State University Wexner Medical Center. Carolyn, up to 50% of the adult human sinoatrial node is composed of dense connective tissue, and cardiac diseases, including heart failure might further increase fibrosis within the sinoatrial node pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atrium. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inheritantly fibrotic sinoatrial node environment.

Dr. Carolyn Lam:

That's true. So what did these authors do?

Dr. Greg Hundley:

Right, Carolyn. So these authors found that increased sinoatrial node-specific fibrosis, with presence of myofibroblasts and CILP-1, and periostin-positive interstitial fibrosis only in heart failure versus non-heart failure human hearts. And comprehensive proteo-transcriptomic profiles of sinoatrial node fibroblasts identified up-regulation of genes and proteins promoting stiffer sinoatrial node extracellular matrix in heart failure hearts.

Dr. Greg Hundley:

And next, fibroblast specific profiles generated by the team's proteo-transcriptomic analyses of the human sinoatrial node provided a comprehensive framework for future studies to investigate the role of sinoatrial node-specific fibrosis in cardiac rhythm regulation and arrhythmias. So really very interesting preclinical science, Carolyn.

Dr. Carolyn Lam:

Yeah. Makes me think of arrhythmias and heart failure very differently, too. Thanks Greg. Well, for my next paper, we know that dietary high salt is bad for us. It's associated with mortality and morbidity. Serum sodium can accumulate at sites of inflammation and affect the function of both innate and adaptive immune cells. But how do changes in extracellular sodium actually affect mononuclear phagocytes?

Dr. Greg Hundley:

Ah. Carolyn, this is really an interesting question, but how would you even set this up or go about investigating this?

Dr. Carolyn Lam:

Ah, good question, Greg, and these investigators are really smart. So first, let me tell you about the co-corresponding authors, Dr. Kempa from Berlin Institute of Medical Systems Biology at Max Delbrück Center for Molecular Medicine in the Helmholtz Association, and Dr. Müller from the Experimental and Clinical Research Center in Berlin, Germany. Now, guess what they did? They used sea horse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays to characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under high salt, in vitro.

Dr. Carolyn Lam:

And what they found was a disturbance of mitochondrial respiration as the initial step by which high salt mechanistically influenced immune cell function. While these functional changes may help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory cardiovascular disease. A further potential implication is that mitochondrial functional analysis in monocytes and other immune cells upon a high-salt challenge, could serve as a test for salt sensitivity of immune cells in future.

Dr. Greg Hundley:

Oh wow, Carolyn. We don't often think about salt sensitivity in immune cells. Really informative research. Well, my next paper comes to us from the world of clinical science, and it's from Professor Derek Chew, from the school of medicine, at Flinders University, the Department of Cardiovascular Medicine at Flinders Medical Center.

Dr. Greg Hundley:

Carolyn, this paper reports results from a multicenter prospective, patient-level, randomized comparison of care informed by unmasked zero to one-hour, high-sensitivity troponin-T protocol, reported as less than five nanograms per liter versus standard-practice, masked high-sensitivity, cardiac troponin T-testing, reported at a value of less than 29 nanograms per liter, assessed at zero to three hours, and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. And the primary endpoint was timed to all-cause death or myocardial infarction.

Dr. Carolyn Lam:

Interesting experiment there. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So, while the use of the zero to one-hour, high-sensitivity, cardiac troponin T-protocol expedited discharge of patients presenting to the emergency department, with a low-event rate at 30 days, an increase in death or myocardial infarction was observed at one year in those with unmasked, high-sensitivity, cardiac troponin T-concentrations. Next, among those with intermediate cardiac troponin concentrations, where care was informed by zero to one-hour unmasked, high-sensitivity, cardiac troponin T-protocols, increases in revascularization and reductions in noninvasive cardiac investigation were observed.

Dr. Greg Hundley:

So these changes in practice that result from the use of rapid-discharge protocols, may be potentially associated with an increase in all-cause death or MI, by 12 months among those low-level troponin elevations. So in summary, Carolyn, this research found that unmasked, high-sensitivity, cardiac troponin T-reporting, deployed within a zero to one hour protocol, did not reduce ischemic events over a 12-month followup, and changes in practice associated with the implementation of this protocol may be associated with an increase in death in MI among those with newly-identified troponin elevations.

Dr. Carolyn Lam:

Wow, that's very, very interesting and clinically important. Thanks, Greg. Well, let's do a little bit of a tour around what else is available in this week's issue, shall we? I want to talk about a Special Report that I was so privileged to contribute to and was led by Dr. Gemma Figtree. And it's a Call to Action for new global approaches to cardiovascular disease drug solutions. There's also a Research Letter by Dr. Solomon on the prognostic value of natriuretic peptides and cardiac troponins in COVID-19.

Dr. Greg Hundley:

Great, Carolyn. So I'm going to tell you about an exchange of letters between Professors Correia and Chaitman regarding a prior published article, entitled “Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.” Also, there's a very nice Case Series from Professor Shapira entitled, “In the Heart of the Ancient Silk Road: Fever of Unknown Origin, Right Ventricular Mass, and Systemic Vasculitis. And then, finally, Dr. de Boer has a very nice On My Mind piece From Studying Heart Disease and Cancer Simultaneously to Reverse Cardio Oncology.

Dr. Carolyn Lam:

So interesting. Well, let's get onto our double feature, Greg.

Dr. Greg Hundley:

Absolutely. Well, listeners, we are here for our first feature discussion today and we have with us really, an very interesting panel. First, Dr. Patrick Serruys from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster University in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute. Welcome gentlemen. Patrick, we're going to start with you. Could you describe for us the hypothesis that you wanted to test.

Dr. Patrick Serruys:

Yeah. The hypothesis was that if the surgeon and the interventional cardiologist doesn't achieve a complete revascularization, there will be a penalty. The penalty is we look at the all-cause mortality because that's really a unbiased assessment.

Dr. Greg Hundley:

And then, tell us the design of your study for us.

Dr. Patrick Serruys:

So SYNTAXES, which is the extension of the SYNTAX study up to 10 years, had 1,800 patient, and then basically, we took a threshold of eight. If you have a residual SYNTAX for more than eight, you have an incomplete revascularization. We stratify for less than four, four to eight, and above eight. And clearly, the group above eight has a bad outcome, not only with PCI, but also with surgery. The score is a little bit more difficult to establish in surgery, because you don't have an angiography immediately after the procedure.

Dr. Patrick Serruys:

And then as I said, if you do a complete revascularization by PCI, and that's basically a residual SYNTAX score of zero, then you have an outcome which is comparable to the surgical outcome. What is interesting, if you have above eight, you have to think twice and maybe refer that patient to surgery. It's difficult to anticipate, but of course, bifurcation, total chronic occlusion, small vessel, is the three major reason to have a residual SYNTAX score.

Dr. Greg Hundley:

Very good. So Shamir, could you help us put these results in context with other studies that have been performed in this sphere of research?

Dr. Shamir Mehta:

Yeah, sure. I would be happy to. So the SYNTAX study was unique in that they were able to look at the degree of revascularization, and the key finding that PCI was comparable to CABG surgery in terms of outcomes, when complete revascularization was able to be achieved, is a very intriguing finding. In cases where PCI was not able to achieve complete revascularization, it was clear superiority of CABG surgery. And so the question is in this study, this comparison, which is a non-randomized comparison, whether or not there's any type of external validity for these findings.

Dr. Shamir Mehta:

And, in fact there is. It's a timely publication, because recently we had the 4,000-patient multinational COMPLETE trial, which looked at the issue of complete revascularization versus incomplete revascularization in patients with STEMI, and found that complete revascularization with multi-vessel PCI, in appropriately-chosen patients, reduced hard clinical outcomes, including the composite of cardiac mortality and/or current myocardial infarction. And it reduces it quite substantially, by about 26%, and it's a highly-significant benefit.

Dr. Shamir Mehta:

I think the caveats to this finding are important, though. Because in the COMPLETE trial, patients were not eligible for recruitment, unless the interventional cardiologists felt that all of the lesions were amenable to PCI. So complete revascularization had to be achieved in the trial. And in fact, over 90% of patients in the trial were able to achieve complete revascularization. So that's absolutely key, and that brings up the importance of having a heart team in evaluating these patients.

Dr. Shamir Mehta:

The second point is that the SYNTAX score, Patrick had referred to was relatively low in the trial, it was only 4.6. Meaning that the lesions that were attempted were relatively straightforward, meaning that there was a high probability of achieving complete revascularization. So again, I think we're starting to see from the randomized trials and from the observational studies, the types of patients that may be suitable for PCI versus suitable for CABG surgery.

Dr. Greg Hundley:

Very nice. Well, Manos, Shamir, what an outstanding description in helping us put this paper in context with other research in this space. Manos, I know you see a number of papers come across your desk. Also, for you, what attracted you to this particular study?

Dr. Emmanouil (Manos) Brilakis:

Yeah, thank you, Greg. And again, congratulations to Patrick for a phenomenal study. I think the main strength of this analysis is the clinical relevance. I think everyone is still debating this question, is complete revascularization the goal in every patient? And all of the data, as mentioned already, have several limitations. Nevertheless, they move us a little bit closer to understanding better on whom complete revascularization should be used.

Dr. Emmanouil (Manos) Brilakis:

So the clinical relevance is one key. I think this paper does set the stage well for a randomized trial. End of the day, we are still not hundred percent sure if COMPLETE is the best for everyone, because COMPLETE counts as a risk, and the risk is going to be higher in those patients who have more complex anatomy. But that study will give us the definitive answer about which is the best way to go for each individual base.

Dr. Greg Hundley:

Very nice, Manos. So that's a great segue. So I'll turn to both Shamir and Patrick, and ask them also, as well, what do you think is the next study to be performed in this particular space? Shamir, you first and then we'll finish with Patrick.

Dr. Shamir Mehta:

Well, I think the concept of complete revascularization has now essentially been proven in multiple trials. And don't forget, if you go back several decades, really the first proof was in the context of CABG surgery. So really, this should be the goal in patients with multi-vessel disease. The next large randomized trial that is going to be starting very soon is the COMPLETE 2 trial where we are actually looking at the lesions physiologically to see whether or not we need to revascularize lesions that are physiologically significant versus anatomically severe.

Dr. Shamir Mehta:

This is an important question because what it does is it has the potential to reduce the number of lesions that we perform PCI in, by about 50%. We are also looking at plaque composition in that trial with optical coherence tomography. A very, very large number of patients will be receiving that. So that will be trying to target PCI to the actual pathophysiology of the disease, by targeting unstable plaques to perform PCI on. I think this is the whole next era of coronary intervention, where we are now beginning to target our therapies to the actual pathophysiology of the disease, which is a very, very exciting idea.

Dr. Greg Hundley:

And Patrick, do you have anything to add?

Dr. Patrick Serruys:

Yeah. I think, that obviously, you have to convert the anatomical SYNTAX Score in a functional SYNTAX Score. You could do that with the pressure wire and hyperemia of diastolic resting gradient. You can also do that by QFR or FFR CT. So we are going in that direction since a few years. The second point is that we have been working on machine learning that, at some point, the segmentation of the coronary segment, the assessment of the narrowing is done. And then, the next step that we are doing right now to is to convert that to the multi-slice CT scan.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Patrick Serruys, from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster university in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute, really bringing to us this paper that, in patients with complex coronary artery disease, incomplete revascularization can be common after PCI. And the degree of incompleteness can be associated with 10-year mortality. And therefore, if it's unlikely that complete or nearly complete revascularization can be achieved with PCI in patient with three-vessel disease, maybe we should be considering coronary artery bypass grafting.

Dr. Greg Hundley:

Well, again, let's get on now to that second feature discussion. Well, listeners, we are now here for our second feature discussion today, and we have with us Dr. Michael Felker from Duke University, and our own associate editor, Dr. Mark Link, from UT Southwestern. Welcome, gentlemen. And Mike, we'll start with you. Tell us a little bit about the background pertaining to your study and what hypothesis did you want to address?

Dr. G. Michael Felker:

Great. Thanks, Greg. So I think everybody's very familiar with the concept of favorable ventricular remodeling in patients with heart failure, that we know is something that happens when we treat our patients with guideline-directed medical therapy, like beta blockers, ACE inhibitors, MRAs. Interestingly, with the introduction of sacubitril/valsartan and the landmark PARADIGM trial, we had a drug where we had clearly a major outcome benefit, but we actually had very little understanding about whether that was mediated by remodeling.

Dr. G. Michael Felker:

And those questions led us to design the PROVE trial, which was a single-arm trial of 794 patients, looking at whether or not patients with heart failure and reduced ejection fraction who met the FDA label for sacubitril/valsartan, the initiation of that therapy will be associated with favorable changes in ventricular structure and function, as well as favorable changes in natriuretic peptide. The current paper's really trying to put those results in a clinical context around some of the things that we make clinical decisions about, in taking care of heart failure patients in this case, whether and when patients qualify for a primary prevention ICD.

Dr. Greg Hundley:

Fantastic, Mike. And so you've told us a little bit about the study design, and did you have exactly the same number of patients, or what was the study population for this sort of substudy, if you will?

Dr. G. Michael Felker:

Yeah. So in PROVE, we enrolled people who had chronic heart failure in the EF, less than 40%, because that's the FDA label for sacubitril/valsartan. In this analysis, because we were interested in patients who qualified for ICD therapy, we limited our analysis to those who an EF plus or equal to 35%. Because, as you all know, the guideline for primary prevention ICD is people who have a EF less or equal to 35% after at least three months of optimized heart failure therapy.

Dr. G. Michael Felker:

And so, one of our questions was in some patients start on sacubitril/valsartan, what happens to their ventricle and how many patients might favorably remodel? This is, obviously, a question that comes up a lot clinically as more and more we're switching people from ACE inhibitors, or ARBs, to sacubitril/valsartan in line with the recommendation that's 1A from the AHA guidelines.

Dr. Greg Hundley:

Fantastic. ell, we're all listeners waiting to hear your results, Mike. This is very exciting. So what did you find?

Dr. G. Michael Felker:

I think our results were quite interesting. I mean, for one thing, the patients that were enrolled PROVE were incredibly well-treated at baseline, and they had had heart failure for quite some time, and a average median time of over six years. So this is not patients who are just recently diagnosed. A lot of these are people that you might think, clinically, we're unlikely to go on and have much favorable ventricular modeling, but that's not what we found. We actually found that after the initiation of sacubitril/valsartan, after six months, on average, we had a five point increase in injection faction.

Dr. G. Michael Felker:

And by 12 months, on average, that was almost 10 points. So quite a bit of favorable remodeling, even in these patients you might think were less likely to do that. And we put that in the context of ICD decision-making. By six months, 32% of the patients who would initially have been eligible based on the guidelines for primary prevention ICD, no longer met those criteria because their EF had risen to greater than 35, and by 12 months, it was up to 62% of those patients. So as we're thinking about decision-making around ICDs, I think these data have some pretty obvious direct clinical relevance to decisions we now make in the care of our patients.

Dr. Greg Hundley:

Really interesting. So Mark, I know you get several papers coming across your desk, and as associate editor, boy, I think I can see why this paper was attractive to you. Tell us a little bit, how do we put these results from this study into the context of how we decide whether a patient should receive an ICD?

Dr. Mark Link:

Yeah. The current guidelines are to wait three months after guideline-directed medical therapy, and then repeat the ECHO and see if they still qualify. I think what this study shows us is that patients can continue to improve after three months, and that improvement is somewhat continuous, actually. Because at six months, the improvement in EF was five percent, and at 12 months, it was 10%. So I think that's what this shows, the context is, if you have a patient who has a low EF and they are improving, but still haven't quite made it to 35, let's say when they went from 25 to 30 in three months, I'd probably hold off and wait another three months and repeat the ECHO again.

Dr. Greg Hundley:

Excellent. Well, Mike, Mark, I'm going to ask you question. And we'll start with you Mike, and then go to Mark. What study would you perform next in this space? Mike, you first.

Dr. G. Michael Felker:

So, I think it's important to recognize some of the limitations of any study you do, including this one. So this was not a randomized trial. PROVE was a single-arm trial, there wasn't a control group. And the question about the ICD per se was not pre-specified. It was really a post-hoc analysis. So as is often the case, I think these are intriguing and highly-suggestive results, but I think there's clearly an opportunity to confirm them in perspective studies designed to answer this specific question.

Dr. G. Michael Felker:

So you could imagine a trial where patients who are starting on sacubitril/valsartan who don't have ICDs, get randomized to waiting three months or waiting six months, or 12 months or whatever the interval would be. So I think these are intriguing, and that there definitely opportunities to develop confirmatory results.

Dr. Greg Hundley:

Excellent. Mark, do you have anything to add to that?

Dr. Mark Link:

I think the big thing we would really like to know are predictors, predictors of response and predictors of non-response. And that would take a larger trial perspective, and that would be very, very valuable. Because if you could have a predictor of a non-responder, they would get an ICD earlier, and predictors of responders, you might wait a while.

Dr. Greg Hundley:

Very nice. Well, listeners, we get rate studies here in circulation, and you'll find this one as a research letter, highlighting that in the substudy of the PROVE heart failure study, that in patients with an EF less than or equal to 35%, the introduction of sacubitril/valsartan improved EF to greater than 35%, at 62% of subjects at 12 months. Really an interesting finding, and perhaps further randomized clinical trials as suggested by both Mike and Mark here, are maybe warranted in the future.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to A, thank Dr. Mike Felker and also our associate editor, Mark Link, and wish you, as listeners, a great week, and we will catch you next week On the Run.

Dr. Greg Hundley:

Circulation July 6, 2021 Issue

6 juli 2021 | 24 min

This week's show features a panel discussion between authors Adrian Wells and Hyeon Chang Kim as they discuss their articles "Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation PATHWAY—A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy" and "Associations of Ideal Cardiovascular Health and Its Change During Young Adulthood With Premature Cardiovascular Events: A Nationwide Cohort Study."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, also your co-host. And Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, we're starting off the month with double features, and these are just so interesting. The first paper talks about psychological interventions for depression and anxiety in cardiac rehabilitation. And the next talks about ideal cardiovascular health and its change during young adulthood and how that relates to premature cardiovascular events. Cool, huh?

Dr. Greg Hundley:

Absolutely. Well, Carolyn. How about we grab a cup of coffee and start discussing some of the other articles in the issue? And I could go first. Carolyn, the first article that I've got is from Mrs. Elizabeth Jordan from Ohio State University Wexner Medical Center. And it really pertains to cardiomyopathies. And remember, Carolyn, classically, we categorize hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathy. And each has a signature genetic theme. Hypertrophic cardiomyopathy and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins. But in contrast, there are over 250 genes spanning more than 10 gene ontologies that have been implicated in dilated cardiomyopathy. And therefore, it really represents a very complex and diverse genetic architecture. So to clarify this, a systematic curation of evidence to establish the relationship of genes with dilated cardiomyopathy was conducted by an international panel with clinical and scientific expertise in dilated cardiomyopathy genetics. And they evaluated evidence supporting monogenic relationships of genes with idiopathic dilated cardiomyopathy.

Dr. Carolyn Lam:

Oh, wow. That sounds like a lot of work. And what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So in the curation of 51 genes, 19 had high evidence. 12 are definitive strong, and seven moderate. And notably, these 19 genes only explain the minority of cases, leaving the remainder of dilated cardiomyopathy genetic architecture really incompletely addressed. And clinical genetic testing panels include most high evidence genes. However also, the panel noted that genes lacking robust evidence are very commonly observed clinically.

Dr. Greg Hundley:

So Carolyn, the take home message from this international panel is that while dilated cardiomyopathy genetic testing panels include an average of about 60 genes, when curating published evidence for dilated cardiomyopathy, only 19 have really emerged as high levels of evidence. And then in this study, 51 genes were evaluated. And the 19 genes appraised as high evidence were recommended to be routinely used in the genetic evaluation of dilated cardiomyopathy. And one more point. Rare variants from genes without moderate, strong, or definitive evidence should not be used in clinical practice to predict dilated cardiomyopathy risk most importantly when also you're screening at risk family members.

Dr. Carolyn Lam:

Wow. Very nice. Stunning numbers. Well, my paper is identifying a novel therapeutic target in pulmonary arterial hypertension. Do you want to know what that is?

Dr. Greg Hundley:

Ah, yes, Carolyn. Very interesting. So what is it?

Dr. Carolyn Lam:

It's switch-independent 3A. Which is an epigenetic modifier, which is drastically down-regulated in pulmonary arterial hypertension patients and rodent models of pulmonary arterial hypertension. And strongly associated with decreased bone morphogenic protein receptor type two, or BMPR2 expression. So this switch-independent 3A overexpression up-regulated BMPR2 expression by modulating critical epigenetic pathways and decreasing a specific transcription factor binding to the BMPR2 promoter in pulmonary vascular smooth muscle cells. Furthermore, aerosolized lung-targeted gene transfer of adeno-associated virus zero type one and containing switch-independent 3A reversed and prevented pulmonary arterial hypertension phenotype in preclinical animal models. So this beautiful study, from Dr. Hadri from Icahn School of Medicine at Mount Sinai in New York and colleagues, really suggests that switch-independent 3A can be a clinically relevant molecule for the treatment of pulmonary arterial hypertension.

Dr. Greg Hundley:

Wow, Carolyn. Really nice. Very intricate science for the study of pulmonary hypertension. Well, my next paper actually comes to us from Dr. Joe Hill and colleagues at UT Southwestern Medical Center. And Carolyn, as we know, cardiac hypertrophy is an independent risk factor for heart failure. Of course, the leading cause of morbidity and mortality globally. And the calcineurin NFAT, or nuclear factor of activated T-cells pathway, and the MAP kinase ERK, or extra cellular signal regulated kinase pathway, contributes to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. However, Carolyn, how these pathways interact really remains unclear. And so Dr. Hill and colleagues engineered a cardiomyocyte-specific ETS2, a member of the E26 transformation specific sequence or ETS domain family knockout mouse, and investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth.

Dr. Carolyn Lam:

Wow. Okay. So what were the results, Greg?

Dr. Greg Hundley:

Right, Carolyn. Three main findings. First, ETS2 is activated by ERK1/2, or extracellular signal-regulated kinase 1/2, in both hypertrophied murine hearts and in human dilated cardiomyopathy. Second, ETS2 is required for both pressure overload, and calcineurin induced cardiac hypertrophy responses involving signaling cascades distinct from, but interdependent with ERK1/2 signaling. And third, this group discovered that ETS2 synergizes with NFAT to transactivate RCAN1-4, an established downstream target of NFAT, or nuclear factor of activated T-cells. And they identified an MIR-223 as a novel transcriptional target of NFAT ETS2 in cardiomyocytes.

Dr. Carolyn Lam:

Wow. Wow. That sounds like a lot of detailed work. Could you tell us what the clinical implications are, Greg?

Dr. Greg Hundley:

You bet, Carolyn. So in aggregate, these findings unveil a previously unrecognized molecular interaction between two conical hypertrophic signaling pathways, MAP kinase-driven hypertrophy, and calcineurin driven hypertrophy. And therefore, as pathological cardiac hypertrophy is an established risk factor for heart failure development, this unveiling of novel signaling mechanisms really is of potential clinical relevance.

Dr. Carolyn Lam:

Thanks, Greg. Well, let's round up with what else there is in this week's issue. There's a Frontiers paper by Dr. Chris Granger. And it's a big call to action to the cardiology community, to incorporate SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular and kidney disease risk reduction. There's a Joint Opinion piece from the American Heart Association, World Heart Federation, American College of Cardiology, and European Society of Cardiology on, “The Tobacco Endgame: Eradicating a Worsening Epidemic,” by Dr. Elkind.

Dr. Greg Hundley:

Oh great, Carolyn. Well, I've got an On My Mind piece from Professor Bhatt. And it's entitled, “Does SGLT1 inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes Mellitus?” And next, Dr. Viskin has an ECG Challenge entitled, “Long QT Syndrome and Torsade de Pointes Ultimately Treated With Quinidine, The Concept of Pseudo Torsade de Pointes.” And then finally, there's a Letter to the Editor by Dr. Lu regarding the article, “Association of Body Mass Index and Age with Morbidity and Mortality in Patients Hospitalized with COVID-19, Results from the American Heart Association COVID-19 Cardiovascular Disease Registry.” Well, Carolyn, I can't wait to get on to this double feature.

Dr. Carolyn Lam:

Me too. Let's go.

Dr. Greg Hundley:

Welcome, listeners, to our feature discussion today. And again, we're going to create today a forum, because we have two very interesting papers to present during this timeframe. Our first is going to come to us from Dr. Adrian Wells from University of Manchester. And our second paper will come to us from Dr. Hyeon Chang Kim from Yonsei University. I want to welcome you both, gentlemen. And Adrian, I would like to start with you. Tell us a little bit about the background related to your study. And then what was the hypothesis that you wanted to address?

Dr. Adrian Wells:

Okay, well thank you for inviting me to take part in this podcast. Following cardiac events, around one in three individuals will develop significant anxiety and depression symptoms. And we know that anxiety and depression can have an impact on prognosis, quality of life, future outcomes. Psychological treatment isn't routinely offered in cardiac rehabilitation for anxiety and depression, despite the fact that we identified that many of our patients felt that they would benefit from a psychological intervention to address these issues. And they felt that their needs were not really being met. So our primary question was, can we improve psychological outcomes in patients with cardiovascular disease?

Dr. Greg Hundley:

Very nice. And Adrian, what was your study population? And also, what was your study design?

Dr. Adrian Wells:

So we selected patients who entered cardiac rehabilitation in the UK. So these are patients with acute coronary syndrome, revascularization, stable heart failure, heart transplantation, and so on. And so, a wide group of individuals. We recruited 332 patients, all of whom had had anxiety and depression scores of eight or more. So these were people showing mild to severe levels of psychological distress. We conducted a two arm single blind randomized controlled trial, with 332 patients who were randomly allocated to one of these two conditions. And we assessed anxiety and depression symptoms before treatment at four months and at 12 months.

Dr. Greg Hundley:

Describe a little bit some of the specifics of your intervention. And then what did you find?

Dr. Adrian Wells:

We use relatively recent new treatment called metacognitive therapy. And this was delivered in a group format over six sessions. And we trained cardiac rehabilitation staff, nurse consultants, physiotherapists, in the delivery of this intervention. Metacognitive therapy works on helping patients discover unhelpful patterns of thinking, such as worrying and ruminating ,and excessive threat monitoring. And to reduce those patterns of thinking that contribute to anxiety, depression, and poor adaptation following stressful life experiences.

Dr. Greg Hundley:

And what did you find?

Dr. Adrian Wells:

Well, what we found was that the addition of metacognitive therapy to treatment to usual cardiac rehabilitation, significantly improved outcomes at four months and 12 months. What was striking about this was that our effect sizes were modest and moderate to large. They seem to be larger than those obtained in other studies or psychological treatments. And of note, the treatment seemed to impact well on both anxiety and depression symptoms. Whereas other types of intervention evaluated in the past have tended to treat the depression, but not so much the anxiety.

Dr. Greg Hundley:

Very good. So it sounds like a group-based intervention. And I'm assuming maybe participants interacted not only with your staff, but with one another. How would you put your results really in the context with other research that's going on in this space?

Dr. Adrian Wells:

Well, there have been a number of studies in the past that have looked at individual and group-based treatments, and patient preference for different types of intervention. I think this is the first study to use a clear manualized intervention that's based on the psychological theory of mechanisms that contribute to the maintenance of psychological problems. Obviously, this tended to use more prescriptive interventions like anxiety management, stress management, taking techniques from a range of different sources. So I think there's a difference of conceptual basis to this kind of intervention. And it's something that is highly manualized and structured, and in fact can be delivered by a range of different healthcare professionals.

Dr. Greg Hundley:

Very nice. And also during cardiovascular rehab. Correct?

Dr. Adrian Wells:

Absolutely, yeah. During cardiac rehab. One interesting finding... And we were a little concerned that this might adversely affect attendance at cardiac rehab. But we found that the treatment was well tolerated, and it didn't have any negative impact on attendance at these other sessions.

Dr. Greg Hundley:

Excellent. Well, congratulations on this new finding. Well, listeners, we're next going to turn to Dr. Hyeon Chang Kim from Yonsei University in Korea. And Yong-Chan, could you describe for us also the background related to your study, and the hypothesis that your research wanted to test?

Dr. Hyeon Chang Kim:

Thank you for inviting me to this wonderful discussion. South Korea is among the countries with the lowest cardiovascular mortality in the world. And the rate is even decreasing. However, cardiovascular risk factor is worsening. Especially in younger generation in Korea. So these young people may not have a very high cardiovascular risk, but I wanted to know the potential impact of worsening cardiovascular risk profile in this younger Korean generation. And furthermore, I wanted to know how much we can lead youth cardiovascular risk by improving their cardiovascular health profile.

Dr. Greg Hundley:

Very nice. And so tell us about your study design and what was the study population, related to your study?

Dr. Hyeon Chang Kim:

My study is basically based on the national health checkup program and national health insurance claim database. In Korea, adults over the age of 20 and employed workers of all ages are required to take general health checkup every two years. The participation rate is between 70 and 80%. So we identified three and a half million adults, age 20 to 39 years, who complete the health checkup. And cardiovascular health scores was calculated as the number of ideal cardiovascular health component, which include non-smoking, moderate physical activity three times a week, body mass index below 2030, normal blood pressure, normal cholesterol and normal fasting glucose. So the score can range from zero to six. And higher score meaning better cardiovascular health. Our outcomes were myocardial infarction, stroke, heart failure, and cardiovascular deaths in about 16 years. In addition, we also evaluate the risk of cardiovascular disease. According to two year change in how the vascular health score using repeated health checkup data.

Dr. Greg Hundley:

Very nice. So evaluating a set of behavioral patterns and risk factors in younger individuals, and then predicting what their longer term adverse cardiovascular outcomes would be. So what did you find?

Dr. Hyeon Chang Kim:

So even in this relatively low risk population, better cardiovascular health score was associated with significantly lower cardiovascular risk. About 20% reduction per one point higher score. And more importantly, people with improving cardiovascular score over two years showed leading toward cardiovascular risk. Even if their baseline cardiovascular health score was very low.

Dr. Greg Hundley:

Really unique findings. Tell us about the impact of your results relative to other studies published in this space. And was this also.... This was unique, because it's an Asian population,

Dr. Hyeon Chang Kim:

Asian population. And we are among the very low risk population. And even in this low risk population, cardiovascular health score was... Fear can be a good predictor of cardiovascular risk. And compared to many Western countries, we have very low cardiovascular risk. And our population was younger than most other studies. So we can provide some evidence that even in the higher risk population, they can do much better, based on our study. Another important thing, we can check the impact of a changing cardiovascular score, even in the younger generation.

Dr. Greg Hundley:

Very good. And just as a frame of reference for our listeners. Give us some characteristics, if you wouldn't mind, on what really constitutes practically a low risk score, versus what would constitute a high risk score

Dr. Hyeon Chang Kim:

In this younger Korean population, their cigarette smoking, and their obesity, and physical inactivity are the most common causes of worsening cardiovascular profile. And the behavioral risk factor also can attack the blood glucose and cholesterol blood pressure. So in this younger generation, they're keeping the good behavior. Past behavior is very important and it's beneficial in the very long-term.

Dr. Greg Hundley:

Very nice, well listeners. We're going to turn to our experts here. Two very interesting studies. And ask them both, what do they think is the next study that needs to be performed in their respective areas of research? So Yong-Chan, we'll start with you. Since we just discussed your paper. What do you think is the next study to be performed really in this sphere of research.

Dr. Hyeon Chang Kim:

Korea is a relatively low cardiovascular risk, has a very small size, and no racial diversity. But even in this country, disparity and inequality in cardiovascular health is becoming an important issue. So I want to identify subcultural relatively poor cardiovascular health among younger population. And also I want to find ways to improve their cardiovascular score. The conventional approaches, such as education and mass campaign, are less effective oppose this younger adults have a poor socioeconomic status. So, we may need to develop newer target-specific strategies to improve their cardiovascular health.

Dr. Greg Hundley:

Good. And Dr. Wells, our agent will turn next to you. What do you see is the next area of investigation or research study that needs to be performed in your sphere of interests?

Dr. Adrian Wells:

Well, I think the next step is to look at rollout of this intervention. Is that feasible, and how acceptable is this to cardiac services? In fact, the National Institute of Health Research have just awarded us some funding to examine feasibility and barriers to implementation in the healthcare system. In addition to that, we're beginning to examine the effects of metacognitive therapy with other health conditions, such as cancer in children and adolescents.

Dr. Greg Hundley:

Nice. Well listeners, we have had just a wonderful discussion today from both Dr. Adrian Wells from University of Manchester. Who brought to us combining a group-mediated, psychological stress-reducing, anxiety-reducing, intervention to the cardiac rehab sphere. And how impactful that was in reducing both anxiety, and overall depressive symptoms. And then also exciting research from Dr. Hyeon Chang Kim from South Korea. Identifying for us that in Asian population, as well as what we know in other races, those individuals in their twenties to thirties with favorable lifestyle habits, have reduced cardiovascular risk much later in life.

Dr. Greg Hundley:

Well, on behalf of both Carolyn and myself, we want to wish you a great week. And we'll catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.

Circulation on the Run: Come Meet the Team

28 juni 2021 | 30 min

This week, we have a special podcast: the interviewers become the guests! Join Digital Strategies Editor Amit Khera as he interviews Carolyn Lam, Greg Hundley, and Managing Editor David "Augie" Rivera as they provide a behind-the-scenes look at how Circulation on the Run comes to you each and every week. Come meet your favorite podcast hosts!

Dr. Amit Khera:

Hi, this is Amit Khera. I'm digital strategies editor for Circulation, and boy, do I have a treat today? I get to step in for Carolyn Lam and Greg Hundley, but wait, I actually get to interview Carolyn Lam and Greg Hundley today. So we have a very special Circulation on the run. Well, the interviewer becomes the interviewee. These two you get to hear every week and hear this amazing back and forth and deep insight into Science and Circulation. But, who are these folks behind the Circulation on the Run podcast? And boy, what interesting life stories they have and how they work through this. And wait, we also have a third joining us today, and that is Augie Rivera, who is the managing editor of Circulation. So we get to see the mastermind behind how all this runs. Well, Carolyn, Greg, Augie, welcome you three.

Dr. Carolyn Lam:

Thanks, Amit. Feels weird.

Dr. Amit Khera:

Good. Then mission accomplished this week. Well, first let me start with you, Carolyn. I know you and I started this long ago, with help from so many folks. People hear you every week and I'm sure many people know you quite well. I will say you have one of the most interesting backgrounds, incredible scientific and personal accomplishments, professional accomplishments. So we're very fortunate to have you as leading this podcast in the beginning, but a lot of people may not know your background story about sort of your training and your day job, because you do have a day job outside of podcasting. So tell us a little bit about yourself, about how you got here in life.

Dr. Carolyn Lam:

Oh my gosh. Amit, I'm humbled by your question. My goodness. I feel just very lucky to be part of the Circulation editors. And I humbly did my med school in Singapore, and did cardiology here, and traveled and lived overseas for the first time. Guess where, in Rochester, Minnesota. Tropical Singapore island to refrigerator state. Other than that, it was absolutely the most pivotal moment of my life. Met my first female mentor and Dr. Margaret Redfield. Really, really just came into my own and got involved in population-based research. And then hopped on over to Boston where actually I was working at the Framingham Heart Study. So continuing sort of the epidemiologic work, but then I think another mentor I really have to call out too is Dr. Scott Solomon, who kind of took me under his wing a little bit and showed me a little bit of the world of clinical trials. And boy, all I can say is I haven't looked back. And so here I am.

Dr. Amit Khera:

I think you took a detour in the Netherlands too. Am I right to say that?

Dr. Carolyn Lam:

Oh yes, but that was quite a late detour in life. I was really, really fortunate meet Dr. Adrian Voris who supervised my own PhD. That was a really interesting thing because I come from a family of a pediatrician in my mom, and a scientist, a biologist really, specialized in fish, in my father. And I'm saying this because my father told me never ever follow his footsteps and do a PhD. Make sure I follow my mom's footsteps and be a clinician, and go into private practice.

Dr. Amit Khera:

Well, it looks like you followed both of their footsteps, maybe the best of both, so they're very proud of you for that. We recently had the privilege of having you give us grand rounds and get to hear your impressive work in clinical trials. And I have to say, the work you're doing in half half and really with some great clinical trial and cohort data involving Asian populations was quite inspiring and impressive. How did you sort of get things going? You've traveled around and moved back and how did you start getting your career going and the momentum you've had so far, incredible success?

Dr. Carolyn Lam:

Oh goodness. Thanks for letting me share. Amit, honestly, I don't know. And I can only look back and be on my knees and be grateful for being at the right place at the right time. I think it's a combination of taking what I had learned in Olmsted County and Framingham. Coming back to Singapore and realizing that there was a need for similar epidemiologic studies. I firmly believe if I didn't do it, someone else would. I'm not that brilliant. I just get things done. And so that's what I did. I started that. And one thing led to another. It's having really friends as well. And so I really, really want to say big thanks to my mentors who have become my friends and colleagues. And to people listening. This is really, really from the heart. You don't plan these things. You just go the next step that you see, and you go with all your heart. And you make sure that you've got your eyes open to see the next opportunity, and have the energy to seize that one when it comes by as well. I think that's how it all happened.

Dr. Amit Khera:

Well, that is a good pivot because one of the next opportunities that came up in Circulation on the Run after you'd done it for a while, was to bring in this gentleman, Greg Hundley. And so we're so glad that you two partnered. Now, Greg, you and I have a little bit of a shared background. You were at UT Southwestern for a period of time, where I am currently. Well, tell us your story, Greg. Tell us a little bit about your background and training and where you are currently.

Dr. Greg Hundley:

Sure. Thanks so much, Amit. Again, I think like Carolyn, we really feel this is an incredible opportunity. The journal is a wonderful blend of collecting impactful science, both clinically and pre-clinically. And trying to bring that to the forefront. It's just been a fantastic opportunity to participate on the editorial side, but then after that, share with the rest of the world, the findings that we really develop each week. And it is truly a team effort. All the way from identifying impactful science, discussing it, preparing it, and then sharing it. And so I think like Carolyn, I just feel very privileged to have this opportunity. Now, my path, listening to Carolyn, and for listeners, you kind of move with it a little bit, and follow along seeking, I don't know, new opportunities, but also being very humble. And as they approach you, and doing kind of the best that you can in the situation.

Dr. Greg Hundley:

So my career path started at what was Medical College of Virginia, but is now VCU in Richmond, Virginia, and medical school there. And then, at Southwestern, did my internship, residency, and cardiology fellowship. And I would say, probably my first strong mentors was really a mentor team. There was expertise there. Jim Willerson had brought Ron P Shock and Craig Malloy on the magnetic resonance imaging side. So for those that are listening, I'm more of an imager in cardiovascular medicine. But also a key fundamental pivotal figure or figures were David Hillis, and Rick Lang in the cath lab. And at the time, magnetic resonance imaging, we were trying to figure out, well, could this noninvasive methodology help us understand problems related to cardiovascular disease that came along maybe before, or we needed to go to an interventional situation, or how they would relate to an interventional situation.

Dr. Greg Hundley:

And then was briefly a faculty member at Southwestern, and then recruited back to the East Coast to Wake Forest. Another really pivotal figure for me was Dr. Bill Little at Wake Forest. Now, he's passed away, but bill had again, that great insight and excellence in science, and performing research and investigations, but also clinical expertise and emphasize the world... We haven't talked a lot about this, but education. How we take the information that we gather and educate others. Began working with the American Heart Association, with the American College of Cardiology in that realm. Then after 22 or three years, another opportunity came up actually to return back to VCU, and be the director of the heart center. And so now have that position here in Richmond, Virginia. Again, very excited to be working here with Circulation on the Run.

Dr. Amit Khera:

Well, I hear some amazing themes from both of you about mentoring and people along the way. It's a great story obviously for our younger listeners that are thinking about life and careers and opportunity sort of finding where life takes you. I think those are great themes for both of you. Now, we won't have as much time for this story, but Greg, you and I spoke recently. You told me this most amazing story of how you were going to be an interventional cardiologist, walked over to drop off something. A patient had an MRI machine and saw this MRI and fell in love.

Dr. Amit Khera:

I'll paraphrase about staying up all night, drinking soda and coding zeros and ones since that's the technology back then, but what an amazing story. We'll have to do that for our next podcast. All right. I'm going to bring in Augie Rivera. Now, he is the managing editor of Circulation. Meaning he really keeps everything going, and is the engine and brains behind the operation. And one of the many things he does, is the podcast. And we'll talk more about the logistics of that. But Augie, people never get to hear your voice. So tell us a little bit about how you got into this medical publishing and circulation in the pacific, sort of your background.

David “Augie” Rivera:

Well, thanks, Amit. Also thanks to Carolyn and Greg for inviting me as well to participate. This is going to be shocking and maybe scary, but I only have a couple of years of scientific journal publishing experience, and that's with the Circulation family. My background for my entire career has been in educational school publishing, specifically in mathematics. And mainly grade K to 12 mathematics. So making the jump over to scientific publishing seemed a bit daunting, but after like 20 plus years, I was looking to do something else. And I was grateful that I saw something on LinkedIn. I interviewed for the position and I was very fortunate the American Heart Association that ended up hiring me. In a sense I always say, "Taking a chance on the long shot." And so that's what brought me here. So a lot of this has been very, very new to me, but at the same time, all the Circulation editors have been so helpful, as well as my staff that I work with. They've been so beneficial to me in learning the side effects. So, that's a little bit about me.

Dr. Amit Khera:

We're very glad that the DHA found you, Augie, and you've been obviously this incredible resource for us. I'm glad you brought up the staff because there's so many people on Circulation that make it run and we're very grateful for all their efforts, including those who help us put on this podcast. Well, I want to dig into the podcast. Carolyn, we haven't told the story in a long, long time. I think you told it on the very first podcast, but Circulation on the Run. For those that missed in earlier days, remind us how you came up with that name.

Dr. Carolyn Lam:

Okay, very quickly. I'm a runner, and I know a lot of us are. It's just on one of my runs that I realized, "My goodness, wouldn't it be great to be able to just feed my mind at the time?" I was on a treadmill actually, and I was trying to read, and it occurred to me, "It is impossible. I'm getting a serious headache to try to read while you're trying to run." And so I thought, "Wow, wouldn't it be great if somebody just read that to me, so I could just read the journal while I was running?" Yeah, you can join the dots. So that was exactly the idea. That, "No, I'll do that for someone. I'll give them the nuts and bolts of that issue."

Dr. Carolyn Lam:

At least the main papers. The way it's grown since then, it's frankly thanks to Greg. I need to make a plug here. Greg has admitted that he's humble. And in fact, that's why I need to drag this out of him. I did not realize until I interviewed him on one of the podcasts, that he is totally gifted at interviewing. And then he tells me just, by the way, in the usual Greg way, he has a history and thick experience in this. He had done the interviews like... Greg, you have to tell me, but he had done several of these. He had a show, he had ideas. He used to do it. And I was like, "Why are you hiding all this? You got to come do this with me." But he hides it. So Greg, now you have to fess up.

Dr. Greg Hundley:

Oh gosh. And now Carolyn, she's too kind. So Carolyn, listeners as you can tell, just has a very warm, inviting personality. And she so couples that with just brilliance and interest in science. I mean, I can't take credit for the things, but she's also open to listening. And I think one of the really exciting things, this sort of team of three with Augie and Carolyn, we have great discussions behind the scenes on how we can bring the information in the journal to you as listeners, in a way that is inviting, engaging, and educational. It's really being part of a team, that has that common goal in mind and in thought. Carolyn and Augie, I just treasure the opportunities that we get to work together every several weeks and putting together the most exciting science that our journal really brings forth. So it's a team effort for the listeners. And just to maybe anticipate the next question, how do we do that?

Dr. Greg Hundley:

We do get the joy of reading the journal every week, and we spend some time each of us, on our weekends and late at nights reading thoroughly the journal. And Carolyn and I kind of divide up the articles. Both of us taking and becoming enthralled with areas of expertise that we may have. Again, we've talked about Carolyn in heart failure expertise and maybe me a little bit more on the imaging side and cardio oncology and the like. And then in any way we divide up the articles, we read them thoroughly, and then we produce a script. So one of the fun parts of this is working with Augie. We're producers as well as editors, as well as the spokespersons.

Dr. Greg Hundley:

So it's kind of all done in one shop and put together, and interactive, if you will. And then we are able to record that in sessions with Augie, coordinating them, and involving some of our authors, editorial experts. And then other experts that we gather from around the world that are also involved in the science. And the goal is to create discussions in addition to presenting the information that's in the journal, but to create meaningful, thoughtful discussions regarding this impactful science, so that we can actually take it in as practitioners or other researchers and scientists in the field quickly. And that's sort of the general concept.

Dr. Amit Khera:

You jumped right in there, Greg. And that's exactly what we want to dive into, which is sort of the behind the scenes, the mechanics about the why. Now, you two have an incredible chemistry. I will say since you two have been doing this together, it's really been a joy listening to you two. Carolyn, just maybe the dovetail on what Greg just talked about, about sort of the chemistry. That back and forth that you two do, the preparation behind that. Tell us a little bit about how that works out.

Dr. Greg Hundley:

Oh, absolutely. I've been dying to share. You should hear the bloopers. It's hilarious. So after a while, we just totally like... We have the fun doing this. And we realize it's very serious science that we're talking about. We're so solidly proud of circulation, but it's okay to have fun. It's okay by the way, to mispronounce some of these basic science words and to call Joe Hill, which I've done by the way, literally called him to ask him how to pronounce certain things. And you know what? And have fun at the same time. And so Greg starts these quizzes. Now, that is all Greg, okay. This Carolyn quizzes and... So after a while, we started to try to hide little quizzes inside our script with the answers given just in case. But it sometimes catches us unaware, and it's just really hilarious.

Dr. Greg Hundley:

And once or twice, I think Greg and I have tried to quiz Augie as well. But Augie never allows us to do that. So it's really great when we're having fun. And that is exactly what I'm so grateful for Greg to showing me that. He's the one who had the experience with the back and forth and gave us the idea. He's the one who push to say, "Look beyond the original articles, I really like as a listener, to have an overview of every single article." That was Greg. He's the one who initiated the sort of forum type discussions and double bill discussions, because he got feedback and acted on it, that people really, really enjoy listening to the authors too. And finally, we're really trying to make it even more useful for the audience based on feedback by seeing if we can get CME accreditation, seeing if we can be more responsive. I just want to let people know, even if we don't manage to achieve it, that we're listening, and we're trying, and we're constantly trying to improve. And that's what I really, really thank both Greg and Augie for.

Dr. Amit Khera:

Thanks for that. Listen, I want to just pick up on many things that you just said. First, I think what people may not appreciate is how much work goes into this. You read all of the articles and prepare with the featured articles. You create a script, and you have fun doing it, which is the most important thing. You record and have to coordinate. Takes a lot of time. I've seen this too, then people don't realize afterwards, you listen to the entire thing and edited again. This is impressive. And it shows, because it's a fantastic product. I want to talk a little bit about some of the deeper features. So you two obviously summarized in the beginning, the original research and we talked a little bit about the back and forth. I want to talk about the featured articles and the interviews of these different folks. Tell me a little bit about that and how that goes. What do you enjoy about the interview part of that. Greg, you want to start?

Dr. Greg Hundley:

Well, I thoroughly enjoy what we call the feature discussions, where we bring together the authors of the paper, editorial experts that... With Circulation, there's a team of associate editors that process the papers. And actually, when you as a listener submit an article, we review these in a discussion format. And one of the associate editors is leading that through a discussion group. And so we bring in that expert. And then oftentimes, we have an editorialist, or an expert from the world, and bringing together a discussion and focusing on the content, not only in that article, but how that article pertains to the world's literature, and then where we really want to go next with research.

Dr. Greg Hundley:

And I think that's sort of our objective, is to bring a living discussion for us as listeners, with authors, the active researchers, with the editorial team and the experts. Why of all the papers you get did this impactful science really come to the forefront for you? And then from the editorialists, how do we take this information and put it in the context of the world's research that's going on in cardiovascular medicine? So those are sort of the main insights and as listeners, just as Carolyn said, we really enjoy receiving feedback from you, and how we can perfect that further. One of the things we've started thinking about is, if we have a basic paper and a clinical paper on the same topic, is really having even a broader discussion, a forum discussion, where we talk about several papers at one time and really embrace a topic. And I love what Carolyn said about providing not only continuing medical education credits, but for those in the United States or maybe North America in particular, maintenance of certification credit, and something we're actively looking at, trying to work through right now.

Dr. Amit Khera:

Thank you for that. And Carolyn, do an add to the features and the interviewing these folks and some of the... what it is that's most interesting to you in doing that process and what you've learned.

Dr. Carolyn Lam:

Yeah. I certainly want to add, but probably in an angle you would not expect. And here, I really, really want to point out the tremendous work of coordinating this, that Augie takes care of. It is incredible. When we have an editor in Europe, a author in California, a me in Singapore, himself in another part of the US. I do not know how Augie does it. And not only does he do it super well, it's always with a smile. Augie, you truly are amazing. Your positivity has honestly kept me going many times, when I just came on the recording half dead. Kudos to you, truly.

Dr. Amit Khera:

Thank you, Carolyn, because I wanted to bring in Augie back again now. Augie, it must be amazing for you. I mean, first, the logistics. Maybe you can tell us about coordinating people from all over the world, different time zones, every single week and obviously people that are quite busy and show what a hard thing to do. And then maybe seeing the process. Boy, from seeing these papers come through our meeting, to the selection, to coordinating, to seeing the final product at the end, it must be a pretty satisfying process for you. Tell us a little bit about the mechanics and what this is from your vantage point.

David “Augie” Rivera:

Well, indeed, it is very interesting. It's something that I did a little bit of production back in college when I did college radio, way back in the day, but I never do. I would end up doing this again, but I think as far as the logistics are concerned, I'm not by myself in this at all. I mean, a big shout out to Sarah O'Brien who trained me when I took on this job because she was covering Circulation on the Run while there was a search for a managing editor. So she was the one who taught me all the tricks of the trade, on how to make some of this happen. But also it's the two assistants for Carolyn and Greg, Afshaan and Angela, who I contact and I go, "Please let me know what their availability is, when, and what can we fit here? And what can we fit there? And can we try to move a meeting?"

David “Augie” Rivera:

In fact, I get to tell Greg that we were successful in moving a meeting for tomorrow, and we have another one scheduled. So we made it work. So really Afshaan and Angela really help out with those logistics as well. We also have to thank you Ishara and her team over at Learner's Digest. They're the masters who put together all of our raw audio files, and cut them all together, to make the final product of the podcast. And not only does her team do that flawlessly, but it also coordinates with having those reviewed and approved by the editors as well. So there is no way that we would ever be able to get any of our podcasts out and delivered without their awesome help and support. So a big shout out to Ishara and team. And most importantly, and the viewers can't see this, but also to the authors and associate editors, editorialists.

Augie Rivera:

First of all, we're grateful that they've sent and submitted their articles to circulation for peer review, and then eventual publication, but their flexibility, because I know that they are very busy during their time too, and trying to make things work. I have had an author say, "Oh yeah, 12:30 in the morning, past midnight? Oh totally. I can totally do that. No problem." Or an associate editor who says, "Yeah, I can probably do that for 5:00 AM in the morning." So the flexibility of the authors, the editorialists and the associate editors is also what makes the logistics and everything work out. So it's not me, but it's completely a team effort. And it's also thanks to Carolyn and Greg for finding those pockets of time while they're doing their day job, to also take the time to be prepped and interview our authors and editorialists. So on that end, like I said, it's not me, it's a team of all of us that put this together.

Dr. Amit Khera:

Well, I appreciate everyone's humility, including yours, Augie. And you are right, there's a broader team and I appreciate you calling them out, but we certainly acknowledge you're at the center of that, and appreciate all your work to make this come to fruition. Well, we're winding down. I have maybe one last question for you two, Carolyn and Greg. Tell us about the future of Circulation on the Run. Where do we go from here? What's the future of this specifically? Or maybe podcasting and Circulation in general.

Dr. Carolyn Lam:

Well, what I can say is, it is continuously going to improve. You've heard us commit to that. We will and promise to try to make it as short and snappy as we can. So for those of you listening, who kind of don't get to the end, please hang in there with us. We're continuously getting better.

Dr. Greg Hundley:

Yeah. I would just want to echo that. If listeners have suggestions and there's a pathway to gather that information from you, we are all ears. We're listeners, and we would love to shape and mold this further based on your suggestions, because really, your suggestions have shaped a lot of where we are today.

Dr. Carolyn Lam:

And Amit, if I could, because the podcast is only one cog in the whole wheel of what you do as overall strategy for us, digital strategy. Could I ask you to give us that last word? I have to be the interviewer again.

Dr. Amit Khera:

You can't get it out of your system. This one is not about me. I'll give two seconds on my role specifically, but I have a neat role. We purposefully chose the term, digital strategies, because we appreciate there's so many different things behind getting medical literature out there, including website, working with traditional media, social media, podcast, and whatever else comes in the future.

Dr. Amit Khera:

So I'm very lucky because I get to work with you all plus a ton of other folks to really bring this material to life. And the coolest part is, you all are so easy to work with and so creative, and have done so many amazing things with this podcast. And it's been real privilege just to watch this grow and develop. What I love that you both said, and I hope the listeners heard this, that have hung on with this, you're appreciated for feedback and you always have been. Have made tweaks along the way to make this better and better. And so if anybody has any, feel free to email any one of us, and we welcome that feedback to make this even better. Listen, I want to say what a treat this has been to interview the interviewers. Amazing, and certainly did not disappoint learning about your backgrounds and a little bit more about all of you, and about what makes Circulation on the Run come to life.

Dr. Amit Khera:

So that's it. There's another rap. I'm Amit Khera, stepping in and interviewing Carolyn Lam and Greg Hundley, who will join you again next week. Thank you.

Dr. Greg Hundley:

Circulation June 22/29, 2021 Issue

21 juni 2021 | 29 min

First join author Marc Dweck and Associate Editor Victoria Delgado as they discuss the article "Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial." Then, join authors Torbjørn Omland and Geeta Gulati as they discuss the article "Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol."

Dr. Carolyn Lam:

Welcome to Circulation On The Run. Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Hooray, it's another double feature week! And guess what, these two papers are two randomized control trials. One looking at progression of aortic stenosis and the other, looking at a prevention of cardiac dysfunction following adjuvant breast cancer therapies.

Dr. Carolyn Lam:

So, very interesting two papers coming right up. But Greg, why don't you start by highlighting some of your favorite papers from today's issue.

Dr. Greg Hundley:

You bet Carolyn.

Dr. Greg Hundley:

So my first study was conducted by Dr. Gabriela Trifan and colleagues from University of Illinois who performed a meta analysis of major studies that compare the efficacy and safety of dual anti-platelet therapy versus monotherapy for secondary prevention of recurrent stroke or transient ischemic attack in those previously experiencing minor non cardioembolic stroke. And their primary outcomes were stroke and the composite of stroke, TIA, acute coronary syndrome and death of all cause. And the safety outcome was major hemorrhage.

Dr. Carolyn Lam:

Oh, okay. Very important study. What did they find?

Dr. Greg Hundley:

Right Carolyn. So the analysis included 27,358 patients. And compared with monotherapy, dual anti-platelet therapy reduced the risk of recurrent stroke and the composite outcome, but increased the risk of major bleeding. And in subgroup analysis at less than or equal to 30 days, dual anti-platelet therapy increased the risk of hemorrhage relative to monotherapy. In sensitivity analyses, the risk for hemorrhage with less than or equal to 30 days of dual anti-platelet therapy, after excluding the combination of aspirin plus Ticagrelor, was comparable to monotherapy. However, the risk of stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remained decreased compared to monotherapy.

Dr. Greg Hundley:

And so Carolyn, the take-home message from this paper is that dual anti-platelet therapy decreases the risk of recurrent stroke and composite events compared with monotherapy. But, dual anti-platelet therapy increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus Ticagrelor.

Dr. Carolyn Lam:

Ah, thanks for that last take home message. Thank you.

Dr. Carolyn Lam:

Well, the paper I'm going to tell you about is the first to examine the role of epicardial fat derived extracellular vesicles in the pathogenesis of atrial fibrillation. And this comes from Dr. Leor from Sheba Medical Center, Tel Aviv University in Israel and his colleagues who collected epicardial fat specimens from patients with and without atrial fibrillation during elective heart surgery.

Dr. Carolyn Lam:

Epicardial fat samples were grown as organ cultures and the culture medium was collected every two days. And the authors then isolated and purify these epicardial fat extracellular vesicles from the culture medium.

Dr. Carolyn Lam:

They found that epicardial fat extracellular vesicles of patients with atrial fibrillation had unique pro-inflammatory, profibrotic and proarrhythmic properties. Epicardial fat extracellular vesicles could in fact induce cellular, molecular and electrophysiological remodeling that could result in atrial fibrosis, myopathy and the development of atrial fibrillation.

Dr. Greg Hundley:

Wow Carolyn, so what are the clinical implications of epicardial fat extracellular vesicles?

Dr. Carolyn Lam:

Hmm, good question. Well, understanding their role in the pathogenesis of atrial fibrillation may for one lead to the discovery of new diagnostic markers or new targets for the prevention and treatment of atrial fibrillation. And that combined pro-inflammatory profibrotic and proarrhythmic effects of these epicardial fat and extracellular vesicles may in fact be relevant to the pathogenesis of other cardiovascular diseases associated with obesity and abnormal adipose tissue deposition.

Dr. Greg Hundley:

Very nice Carolyn.

Dr. Greg Hundley:

My next paper comes again to us from the world of preclinical science and these authors led by Dr. Masanori Aikawa from Harvard Medical School applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. They use global proteomics and high dimensional clustering on multiple vein graft tissues to identify potential pathogenic mechanisms. And experiments were conducted in both in vivo mouse models and in vitro human macrophages.

Dr. Carolyn Lam:

Oh wow. So what did they find?

Dr. Greg Hundley:

So Carolyn, peroxisomes proliferator activated receptors or PPAR alpha agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development.

Dr. Greg Hundley:

Now, metabolomics, lipidomics, functional metabolic assays and single cell analysis of cultured human macrophages revealed that PPAR alpha modulates macrophage glycolosis, citrate metabolism, mitochondrial membrane sphingolipid metabolism and heterogeneity.

Dr. Carolyn Lam:

Okay. So what is the take home message Greg?

Dr. Greg Hundley:

Right Carolyn, thought you would ask me that.

Dr. Greg Hundley:

So PPAR alpha activation suppresses the development of vein graft and arterial venous fistula lesions. And PPAR alpha reduces macrophage activation by influencing macrophage heterogeneity, mitochondrial integrity, and the metabolome. So Carolyn, given that peripheral arterial disease and chronic kidney disease prevalences are increasing, warranting needs for more vein grafts and arterial venous fistulas, this target discovery platform is applicable to investigating therapies for these diseases.

Dr. Greg Hundley:

And a really nice accompanying editorial is provided by doctors Reilly and Bornfeldt.

Dr. Greg Hundley:

Well Carolyn, how about we turn to look at what is in the mailbag this week?

Dr. Carolyn Lam:

Well let me tell you about it Greg. We've got a cardiovascular case series by Dr. Borlaug on things are not always as they seem, multimodality exercise assessment and evaluation of dyspnea. In cardiology news by Kuhn there's a discussion of Evinecumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag. A perspective piece by Dr. Watkins on time to think differently about sarcomere negative hypertrophic cardiomyopathy. And finally a research letter by Dr. Ahn on reduction in Kawasaki disease after non-pharmaceutical interventions in the COVID-19 era, a nationwide observational study in Korea.

Dr. Carolyn Lam:

Wow. That wraps it up for the summaries. Let's go on to the feature discussions shall we, Greg?

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

We are about to talk about the extended follow-up results of the PRADA trial. Oh, so interesting. So happy to have with us today, doctors Geeta Gulati and Dr. Torbjørn Omland, both from the Akershus University hospital in Norway, and you would probably recognize that Dr. Torbjørn Omland is also one of our associate editors, but both here are the co-corresponding authors of this beautiful paper.

Dr. Carolyn Lam:

Thank you so much for coming here today. Torbjørn, maybe you could start with what is the PRADA trial? Why did you decide to do an extended follow-up?

Dr. Torbjørn Omland:

Yeah so PRADA was a two times two factorial randomized double blind clinical trial that sought to evaluate the effects of intervention with receptor blocker Candesartan. And a beta blocker Metoprolol in patients with early breast cancer who received anthracycline therapy as part of their chemotherapy. And then we wanted to assess the effect of this sort of preventative therapy, left ventricular function and injury.

Dr. Torbjørn Omland:

So we reported the primary results of the trial a few years ago and showed that intervention with Candesartan most associated with a significant elevation of the reduction in left ventricular ejection fraction that these patients may experience, and also that treatment with the beta blocker Metoprolol was associated with an intimation of the increase in cardio proponents suggesting a beneficial effect on myocardial injury. However, whether these results were or these effects were sustained after termination of the study drugs was unknown. And that was what we really wanted to address with extended follow-up study.

Dr. Carolyn Lam:

Yeah, makes a lot of sense, especially because these injuries I suppose could still continue. And just to be very clear, the medications though were only taken during the adjuvant chemotherapy and therefore could be a variable duration from what I understand. Right? Great.

Dr. Carolyn Lam:

So Geeta then, could you tell us what did the extended analysis show?

Dr. Geeta Gulati:

The extended follow-up was interesting and it was something we really wanted to figure out because there are not many studies who have been done on the extended follow-up and you're not giving these study medications afterwards.

Dr. Geeta Gulati:

So very interestingly we saw that the decline in the ejection fraction was still there in the whole group. But this time there was no difference in the group who received Candesartan do those who didn't. And we show that there was a different in the primary results, but now in the extended follow-up there was no difference. And then also in the Metoprolol group that had previously shown that there was lesser rise in the troponins. Again, there was no difference in the groups now on the extended follow-up.

Dr. Geeta Gulati:

So this is very interesting because this shows that there is a small, modest decline in a left ventricular ejection fraction during and after the breast cancer therapy. But what does this really mean? It's a small decline and it's within the normal range and the cardioprotection is not working. So, are we perhaps looking at the wrong group? Perhaps we should look at patients who have the higher cardiovascular risk factors. Perhaps even we should look at more novel heart failure or cardiac drugs that may have a stronger effect on the ejection fraction.

Dr. Carolyn Lam:

Right. So Geeta though, can we unpack that a little bit? You see, the patients were not on the medication anymore at the time of follow-up. So you're saying that even though they were given adjuvant chemotherapy and covered with the drug, that even not having any more chemotherapy, their ejection fraction still fell. And if I'm not wrong, this was an MRI analysis. And so it was only by an ejection fraction of two percent on mean fall, right? How do we think about that clinically?

Dr. Geeta Gulati:

And that's the important question, isn't it? Because a decline in the ejection fraction of less than two percent within the normal range, what does it really mean? Well initially we thought that if there was a different in those who had cardioprotective medication compared to those that didn't, it may prevent development of further decline in the cardiac function and then heart failure in the future. But now, there is really no difference between the groups. So perhaps the clinical implication of giving cardio protection to all cancer patients is not really that useful. Perhaps they should look at those who are at higher risk because they would have a greater fall in ejection fraction and then more cardioprotective effect of these drugs.

Dr. Carolyn Lam:

Yeah, totally. And perhaps the metrics that we're used to seeing in the past with greater falls of ejection fraction, maybe it just doesn't apply currently or perhaps with the specific chemotherapeutic regimens perhaps that you're using now. Because with a very small fall, and I believe you only had one heart failure event, right? If I'm not wrong in this extended follow-up. So, just to let the audience know, it was very small fall, little number of events. It's hard to really tease apart what that clinically means. Now, could I ask though, does it mean we need actually a more sensitive marker? Because there was some interesting stuff about global longitudinal strain. Could you-

Dr. Geeta Gulati:

I would throw that question back to Torbjørn I think.

Dr. Torbjørn Omland:

Yes. So that's a very interesting question Carolyn. So we did observe what seemed to be a beneficial, but a sort of minor effect on global longitudinal strain. So we know that that is the more sensitive index of systolic function than left ventricular ejection fraction, that was the pre defined primary outcome. So that's raises of course questions whether a future trial should more focus on these more sensitive indices of cardiac function.

Dr. Carolyn Lam:

Yeah. Geeta, could I then really put it back to you? And the tough question I always get, how do we apply these results clinically then? I mean, you see these patients right? Now what? Do you give or do you don't give? And which one do you give? And how do you identify high risk patients? I don't know.

Dr. Geeta Gulati:

Again, I think all the patients are unique aren't they? So that's where we have to start. So in my clinic, if I have a high risk patient with hypertension, diabetes, hypercholesterolemia, yeah perhaps they even have had a cardiovascular disease before something like this. Then I will take more care of these patients and be more careful with the echo measurements I'm doing and if I find that they have a decline in their cardiac function, I may be more eager to start them on cardioprotective medication.

Dr. Geeta Gulati:

But then in R-Regen we follow all the HER two positive breast cancers with echo. If I don't have echoparamaties that clearly tells me that they have a decline in the cardiac function, then I may wait to start cardio protection because none of the studies has really so far show that all patients should have these cardioprotective medication or prevention.

Dr. Carolyn Lam:

Nice. Thank you. That was a tough one to get at. And I suppose Torbjørn I have to give you another tough one then. Because how to address the remaining unanswered questions, right? Because one of them on my mind too, is how to identify the high risk, do biomarkers play a role? And then the other is if we then start the preventive therapies like ERBs and beta blockers, should we actually continue it forever? And so on. But anyway Torbjørn please, please, what does the future hold?

Dr. Torbjørn Omland:

I think it's worthy of a recap or underscoring that these are really good news for many breast cancer patients that actually the risk of an important decline in ventricular function is lower than we thought. So that may be because of several things. I think in general, those whose used these cardiotoxic drugs are lower. And we also, I think that there's increased collaboration between oncologists and cardiologists. Also meaning that we are better to pick up the high-risk patients at an early stage.

Dr. Torbjørn Omland:

But of course, it's very important questions that you asked regarding how to identify the high risk patients. And I think that's where really future research should focus. So there we know that traditional risk factors are important. We are looking into whether biomarkers can be used, if there's more sensitive imaging in this can be used. But so far we haven't really succeeded in getting the risk model that really identifies it on the patient level. So that's work that remains to be done.

Dr. Torbjørn Omland:

And then we are also looking for new types of intervention, good exercise, good other drugs. We are doing now a PRADA two study where we look at the effects of Sacubitril Valsartan in this setting. And those are also very exciting, I think, and we look very much forward to present that in the future.

Dr. Carolyn Lam:

Oh wow thank you so much Torbjørn and Geeta. The PRADA two trial. I've got to ask you, why do you then call it the Chanel trial? But I think I'll save that for another day. So thank you. Thank you once again, this is fabulous and congratulations to you both.

Dr. Torbjørn Omland:

Thank you.

Dr. Geeta Gulati:

Thank you.

Dr. Greg Hundley:

Well listeners, welcome to our second feature discussion today. And we have with us Dr. Marc Dweck from University of Edinburgh in Scotland and our own associate editor, Victoria Delgado from Leiden in the Netherlands. Welcome to both of you.

Dr. Greg Hundley:

Marc, we're going to get started with you. Could you tell us a little bit about the background for your study and what was the hypothesis that you wanted to test?

Dr. Marc Dweck:

Thanks very much Greg for the invitation. So I guess aortic stenosis is perhaps the last major cardiovascular condition where we don't have a medical therapy. We're unable to treat these patients. We're unable to prevent progression. We're only left with a valve replacement. And so we, like a lot of groups around the world, want to develop a treatment for aortic stenosis. Our group did the first SALTIRE trial, where we looked at statins seeing if we could slow aortic stenosis progression. And that, like similar trials, was neutral. No effect on the valve progression.

Dr. Marc Dweck:

And so actually I've spent the last 10 years looking at some of the factors associated with aortic stenosis progression in particular. The answers that we've had from those trials have kind of come back telling us that really it's a process of calcification. If you look at what triggers progressive valve narrowness is this calcific process, that seems to be a self perpetuating disease.

Dr. Marc Dweck:

So the question is, how do you target this calcification process? How can you interrupt it? And how can you do that without compromising bone health in these elderly patients? So in trying to come up with a solution to that we thought about using osteopetrosis agents, which we hypothesized would maintain both bone health and reduce vascular calcification on the basis of observational data and also animal data suggesting that. And that was really where we came from in the design of the SALTIRE two trial.

Dr. Marc Dweck:

And doing a big trial with clinical endpoints wasn't felt to be feasible and instead we decided to look at imaging end points and see whether we could slow disease progression using these agents.

Dr. Greg Hundley:

Very nice Marc. And so you're really leading us into, tell us a little bit more about your study population and your study design.

Dr. Marc Dweck:

Yeah so we wanted to take patients from our outpatient clinic with mild, moderate and even early severe disease, asymptomatic patients crucially, patients that aren't scheduled for aortic valve replacement and see the effects of these drugs on disease progression.

Dr. Marc Dweck:

So we did a randomized control trial. There was three arms. Patients were randomized to Alendronate, Denosumab, these are the two osteopetrosis agents, or placebo. We then did a series of baseline imaging tests. So the primary end point was based on CT calcium scoring. So they had a baseline CT calcium score. They also had a baseline echocardiogram and they had a baseline fluoride PET scan. So this measures calcification activity in the valve. And then we essentially repeated those tests after a period of time on the drugs, or on placebo. We repeated the calcium score and the echo after two years and repeated the PET scan after one year.

Dr. Greg Hundley:

Very nice, and so before you tell us your results, a little bit, how many patients? And maybe their average age and the rough distribution of men versus women.

Dr. Marc Dweck:

Yeah so study recruited roughly 50 patients in each arm. The average age was 72 and there was 21% females in the study. So, like a lot of studies in aortic stenosis, a low female prevalence. Despite our best efforts, that's something we need to attend to in the future, but otherwise, a representative age group and patients with this disease.

Dr. Greg Hundley:

And what did you find?

Dr. Marc Dweck:

Well we found that the drugs didn't have an effect on any of these imaging assessments. So, there was no effect on the progression for CT calcium score at two years, no effects on any of the echocardiographic assessments of hemodynamic severity, and no effect on calcification activity as measured with the fluoride.

Dr. Marc Dweck:

So a very consistent result using multiple different imaging modalities, which I think gives us confidence that there isn't at least a dramatic effect of these drugs on disease activity or disease progression, in aortic stenosis.

Dr. Greg Hundley:

Very good. Well listeners, we're now going to turn to one of our associate editors, Dr. Victoria Delgado, and she is really a valvular heart disease expert member of our team.

Dr. Greg Hundley:

Victoria, I know you see a lot of papers that kind of come across your desk. What attracted you to this manuscript? And then how do you put the results in the context of other research that's going on to halt the progression of aortic stenosis.

Dr. Victoria Delgado:

Thank you Greg. So first the first thing that attracted my attention for this article is the question. We know that we don't have any medical therapy for halting the progression of aortic stenosis. And even if the previous studies have been negative or neutral, still there is the interest of trying to find a less invasive therapy for these patients, or even prevent that they arrive to surgical or transcatheter aortic valve replacement.

Dr. Victoria Delgado:

And the second is that these are very strong analysis because it's a randomized clinical trial and using as end points imaging. So that trial also in a way answers the question of which imaging technique we need to use in order to see the effects of specific therapies. Previous studies have used mainly echocardiography, but that only gave us information on the modynamic effects of the aortic stenosis. While in this study, we have the combination of CT and a combination of a PET that he give us also information on how the calcification is happening. So that makes the study very comprehensive and give us more insights into this pathophysiology, to this pathology particularly.

Dr. Greg Hundley:

Very nice. So it sounds like looking at aortic stenosis from multiple different angles, whether it be echocardiography or perhaps imaging processes that look at the progression of calcification.

Dr. Greg Hundley:

Well, Marc, I want to come back to you. What do you think is the next, sounds like you've been working in this area for an extended period of time. What do you see as the next research study that you and your group may undertake in this area?

Dr. Marc Dweck:

I Think we've got the study design about right. I think if in the future studies we want to do, I think we would adopt a similar design using these imaging end points.

Dr. Marc Dweck:

I have to say I'm very influenced by the recovery trial that has been conducted in the UK with COVID. I mean, here's a disease where we wanted to get a treatment as quickly as we can. And in doing that, developing a platform type trial where you potentially test multiple different promising agents simultaneously across multiple centers across the world or the UK, I think that would be the quickest way to developing a treatment. And so I'm encouraged that there are five or six very good targets where we could, for a new therapy in aortic stenosis. And I think a platform type design where we engage multiple groups using imaging as that initial end point. And then, the drugs that appear to have an effect on these imaging end points we can start to recruit more patients at those sites, into those centers, looking for clinical end points.

Dr. Marc Dweck:

I think that kind of discussion is happening around the world now between groups that are interested because we want to crack this problem quickly. We don't want to wait and do these different studies sequentially. We want to try and do them simultaneously. And I'm excited about that. I think if we do that, we've got a real shot at developing a treatment over the next five to 10 years say.

Dr. Greg Hundley:

Fantastic.

Dr. Greg Hundley:

And Victoria, I know you have interest in this particular area. Do you have anything you'd like to add?

Dr. Victoria Delgado:

Yeah. I think that those studies that Mark said are really welcome and I hope that they are positive. And give us a little bit of more to treat these patients. My main fear is that these patients are not as frequent, for example, as heart failure patients. Where we have several therapies where we have possibility to enroll patients in trials for new drugs, that we know that probably are going to be effective. But for valvular heart disease it has been always the end point to reach surgery or to reach an aortic valve replacement or indication of the mitral valve and mitral valve repair. So in early phase of the disease, my main concern is that maybe the patient is not going to be well-trained to understand what are the consequences. I want to always wait until maybe when is needed for the surgical or transcatheter procedure.

Dr. Victoria Delgado:

But I think that increasing the awareness of the prevalence of valvular heart disease and the consequences may help people to understand, to put more attention for an early diagnosis and develop new drugs that can help, like in this case, aortic stenosis one of the most frequent valvular heart disease, to prevent the proliferation and to prevent the replacement of the valve.

Dr. Greg Hundley:

Very nice. Well listeners, this has been a wonderful discussion and we greatly appreciate the input that we've been able to gather today from Dr. Marc Dweck from Edinburgh in Scotland and our own associate editor, Dr. Victoria Delgado. Bringing this information from a randomized trial, evaluating osteoporosis drugs, and really indicating they did not disrupt the progression of calcification in patients with aortic stenosis.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great rest of your week and we will catch you next week on The Run.

Dr. Greg Hundley:

Circulation June 15, 2021 Issue

14 juni 2021 | 26 min

Join Mercedes Carnethon as she interviews authors Brendon Bellows, Dhruv Kazi, and Kirsten Bibbins-Domingo to discuss two articles published in the special issue: “Cost-effectiveness of Hypertension Treatment by Pharmacists in Black Barbershops” (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051683 ) and “Scaling Up Pharmacist led Blood Pressure Control Programs in Black Barbershops: Projected Population Health Impact and Value” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051782.

Dr. Joseph Hill:

Welcome to Circulation on the Run. My name is Joe Hill and I'm the editor-in-chief of Circulation. In recent months, we witnessed horrific acts of discrimination and violence against African-Americans. We are shocked and appalled, but yet we also recognize that this is in many ways nothing new. At Circulation, we are highly committed, longstanding commitment to shining a bright light on these pervasive inequities. And we are not willing to simply catalog the woefully longstanding racism that pocks our society, but rather we intend to shine a bright light on solutions. And with that, we are launching the first annual issue on disparities in cardiovascular medicine. This will be released in mid June corresponding to the date of Juneteenth, which is the date in the 19th century when a group of slaves in Galveston, Texas was apprised of the fact that they were no longer slaves now for two years.

Dr. Joseph Hill:

I'm honored to have our three editors who are running this podcast and this issue with us, they are Dr. Mercedes Carnethon from Northwestern University, Dr. Karol Watson from UCLA, both of whom are associate editors with the journal. And I'm pleased that Michelle Albert, who is one of our senior guest editors at UCSF will be joining us. These three professionals have led this initiative and I would like to spend a few minutes talking with them about this. First let's turn to Michelle if I may. Michelle, what do you think is required from a workforce perspective to make headway, to eliminate these disparities?

Dr. Michelle Albert:

Thank you, Dr. Hill. And I would first say that it is an honor to have been able to participate in this disparities issue focused on African-Americans and health. First, I think that it is important for our audience to understand that the metrics actually behind a workforce. In cardiovascular medicine, only 13% of fellows are underrepresented fellows, meaning black or African American, Hispanic, or Latinx, native Americans, Alaska natives, and Pacific Islanders. And only 9% of faculty are UIM in cardiovascular medicine. This stems from a pipeline or pathway issues that go all the way back to kindergarten and middle school. Indeed, over the last three decades only, although there's been a 50% increase in applications for blacks and Hispanics, the applications have only increased by 1.2% and there has been a drop in Alaska native and American Indian applications by 30%.

Dr. Michelle Albert:

So with regards to how improve these statistics, we have to have multifaceted approaches related to understanding pipeline barriers, which include things like lack of encouragement, lack of role models and paying attention to recruitment, but not just the only recruitment at the pre-medical level, immediate pre-medical level, but way prior to the pre-med level, we have to engage middle-aged and high school students in STEM and thereafter at the pre-medical level, we have to make sure that students get the appropriate advice to ensure successful careers in college that would then engender successful applications to medical school.

Dr. Michelle Albert:

Once we get into the actual medical institutional systems, we have to address structural barriers to discrimination that exist, that impede the progress through pathways in medicine. And these barriers exist at the medical school level, the residency level, fellowship level and faculty to leadership levels. I would say just a couple of examples at the medical school level to address would be actually paying attention to the fact that MCAT scores, we need to pay attention to a whole range of MCAT scores that focus on success in medical school and not just a specific hard cutoff. In residency we need to focus on evaluation disparities for UIM versus non UIM that then set the pathway again for a lack of progress into extremely competitive specialties like cardiovascular medicine. At the fellowship level we know that only 6% of program directors actually value diversity as one of the top three entities when ranking applicants. Duke School of Medicine actually had a really innovative process of holistic review and at all levels there should be holistic review that pays attention to distance, travel and metrics as well as attributes.

Dr. Michelle Albert:

And at Duke for example, what they did was they tripled actually their UIM enrollment in cardiology fellowship from 9% to 33% after employing a holistic review process that focus less on metrics and more on a combination of metrics, distance traveled, et cetera. Once folks are in the pipeline we have to set up systems of support to help trainees and faculty thrive in clinical learning and work environments because we noted small differences and assess clinical performance, amplify to large differences and evaluations, grades, and awards that have gone toward consequences for our workforce. And then I would say these are not my recommendations here or not all inclusive. But two other things I think that we really need to pay attention to besides the mentorship and sponsorship is actually stemming isolation for trainees and faculty within our structures and systems as well as ensuring that we all have implicit bias training and also the effect of implicit bias training is measured over time on the impact on healthcare outcomes and our pipeline outcomes. I know that was a mouthful, Joe, but this is a very complicated topic.

Dr. Joseph Hill:

Well, it certainly is Michelle. And I think all our listeners know that you have been and are a major leader on an international scale around these topics. Thank you for your leadership. My next question has to do with building trust with black patients in terms of their willingness to engage with their physician and also participate in research studies and trials. Karol, Dr. Watson from UCLA, maybe you can comment on that.

Dr. Karol Watson:

Yes, I would be happy to. And I have to piggy back on what Michelle just said. You start off talking about trust, there has to be a trust between the patient and the provider, the researcher and the participant, and that trust really it's multifactorial as Michelle states, but it really does rely on having a workforce that looks like the patient population, having principal investigators that look like the participants. We have an issue with trust in medicine in many areas, but one of them is lack of trust amongst African-Americans. When surveys are done and they ask patients to endorse or not endorse certain statements, the statement I trust my healthcare provider, it's less likely to be endorsed by African-American patients than others. And much of that mistrust is well earned. We're all aware of some horrific medical injustices that were meted out to certain communities, including African-American communities.

Dr. Karol Watson:

We're all aware of the Tuskegee syphilis study, but there are many others. So without trust, there really cannot be a healthy, collaborative care model that ensures optimal patient outcomes. So I think one of the most important things that we have to stop doing is thinking of blaming the patient for being, "Nonadherent, non-compliant, difficult," because many things go into that equation and much of it is on our backs. And as Michelle says, we have to diversify our workforce to start off. And I think there are so many other levels of Michelle really nicely laid out, but there are really so many other levels and including getting more African-Americans into clinical trials and we can't just do the same thing we've always done and expect to get different results. So we say, "Oh, African-Americans just won't up for research." Well, maybe we're not making that research relevant, appropriate, and easy for them.

Dr. Karol Watson:

If we ask people to come to our research centers between 8:00 and 5:00, Monday through Friday, when they're working three jobs and they have to watch their grandkids and they have no one to help. That's a very difficult ask, when you're asking people who are struggling for basic needs and basic survival to do extra things. It's a very difficult ask and we have to make it easier for them because I am of a firm belief that everyone wants to do the right thing. They want to help medical professionals get the research needed, do the right thing to care for their own health, but it has to be accessible and that's something we haven't done a great job doing.

Dr. Joseph Hill:

Well, thank you. What a challenge and that's why I think this issue that the three of you have spearheaded has helped move that needle around those sorts of questions. So my last question is a broad one and maybe even the hardest one that I will throw to Dr. Carnethon and that is what are the biggest remaining threats? What does the future look like when you put your headlights on high beam to solve these problems?

Dr. Mercedes Carnethon:

Well, thank you so much Dr. Hill, and it's great to follow my colleagues who've offered wonderful insights from multiple perspectives. When we think about the path forward, we have to really consider how we got here. And we didn't get here solely through faults in one system, for example, academic medicine, we got here because of the broader systemic and structural issues that have led to differences in access, that have led to the mistrust we're talking about and that have led to fewer opportunities for academic advancement for black adults within this country. And the path forward is going to have to be a collaborative path. It can't just be the researchers and clinicians within academic medicine making a change because we can't make those changes and reach out in isolation of the context in which the patients who were seeking to help live in. So it requires partnerships with individuals at the community level, so that we can think about how we roll out effective interventions.

Dr. Mercedes Carnethon:

So those interventions that work one-on-one how do we get those out to the people who need them the most? That requires partnerships with the community and even changing the environments in which people live, making them healthier. It requires partnerships with academic institutions building off of the point that Dr. Albert made about needing to start and bolster the pipeline early so that we can get researchers and clinicians who look like the patients that they're trying to serve. And ending as well with Carol's point, when we run a study and we don't have representation from across a range of socioeconomic status from multiple individuals, black individuals, white, other races and ethnicities, we don't know how well those therapies are going to work, or whether there are unique situations that are going to lead them to be less effective in one group versus another. So I think I would end really with the point that the path forward to promoting equity is one that's going to involve partnerships across multiple different domains. And I do feel very hopeful that we can get there, especially as we're calling attention to these important issues right now.

Dr. Joseph Hill:

Well, I will end by saluting the three of you because you are in fact pointing away to a path forward and concrete things to make a difference. And it is my pleasure and honor to work with the three of you leaders. And I'm so proud of this issue, which will be a recurring issue and in June of every year. And thank you again for what you've done, you're making an important difference in our world.

Dr. Karol Watson:

And thank you so much for Dr. Hill for spearheading and supporting this effort. It is so important.

Dr. Mercedes Carnethon:

Yes, thank you.

Dr. Joseph Hill:

My pleasure.

Dr. Michelle Albert:

It's indeed an honor. And we have to lead by example, and I hope that we do.

Dr. Mercedes Carnethon:

Thank you so much.

Dr. Mercedes Carnethon:

I'm really excited as we move past our discussion amongst the editors to have an opportunity in this podcast to also speak with a team of authors who submitted two papers to our very special issue we have with us today, Dr. Brandon Bellows, Dr. Kazi and Dr. Kirsten Bibbins-Domingo who are sharing their findings about pharmacist led interventions to manage blood pressure among black Americans in barbershops. So thank you so much for submitting your important work to Circulation. I'd like to start with questions for you, Dr. Bellows. So your particular manuscript is addressing the cost effectiveness of hypertension treatment by pharmacists in black barbershops. Thank you for working on this very important work, because it really extends some of what we talked about earlier, which is the need to scale up and disseminate what we know to be effective interventions in populations. So can you tell us a little more about what you studied and what was unique?

Dr. Brandon Bellows:

Yeah, thank you so much. So we studied the value of a program to bring clinical pharmacists into black owned barbershops as you mentioned, and have the pharmacist partner with the barbers to manage hypertension in black men. As we know, black men are disproportionately impacted by both hypertension and cardiovascular disease. So our work was based on a randomized trial that was performed in barbershops in Los Angeles County. And this was led by the late Dr. Ron Victor. So we're really building upon his great foundation. In that trial they found that the pharmacist-barber collaborations substantially reduced systolic blood pressure by over 20 millimeters of mercury, relative to Barber's providing education alone over one year. So given that having pharmacist drive around barbershops and Los Angeles is a very expensive proposition, but we wanted to know if the potential benefits long-term would outweigh some of those high upfront costs and would it be a cost-effective to do this in Los Angeles? So really focused on the trial.

Dr. Brandon Bellows:

So to do this, we combined the data from the randomized trial with our computer simulation model to try and project long-term clinical outcomes. So upto 10 years, so for both blood pressure, cardiovascular disease events, as well as the economic outcomes. So total healthcare costs, costs of the program and so on. So what we found was that having pharmacists work with barbers and these black owned barbershops was a cost-effective way to reduce blood pressure in black men. Over 10 years, we projected that the program would cost about $2,400 more, and that's total healthcare costs than barbers providing education alone so they enter the control arm in the trial, and we found that they would prevent about 30% of cardiovascular disease events over 10 years. So the incremental cost effectiveness ratio or ICER, which is how we define cost-effectiveness was $43,000 per quality adjusted life year gained.

Dr. Brandon Bellows:

And this is below the threshold recommended by the American Heart Association of $50,000 per quality adjusted life year gained to define something as highly cost-effective. So doing this with a highly cost effective way to improve blood pressure in black men. So one thing that makes our study unique is that our computer simulation model allows us to explore different designs of the program to see how that might impact the cost effectiveness. So for example, if we were to use only generic antihypertensive medications, or if we were to decrease the length of the intervention from one year to six months, the pharmacist barber program was even more cost effective. So given the long-standing disparities in cardiovascular disease that have been experienced by black men in the United States, we're really hoping that how our research can help motivate healthcare payers to adopt these kinds of non-traditional approach delivering hypertension care, because if nobody's paying for it, then there's not going to be uptake in the community.

Dr. Mercedes Carnethon:

Yeah. Brandon, thank you so much for sharing that and sharing the details about what you found. I love this line of work because quite often we've spent a lot of time discussing and describing disparities, but less attention considering ways in which we can reduce disparities by reaching people where they are. So that brings me to you Kazi. So your study uses the same population, but addresses a slightly different question that I think is very relevant to our audience as we seek to try to promote cardiovascular health equity. So tell us a little bit about what you did in the same population and what you found.

Dr. Dhruv Kazi:

I want to also start out by acknowledging that the study is anchored in the vision and genius of the late Dr. Ron Victor, who ran the barbershop based blood pressure controlled studies in Dallas, and then in Los Angeles. And kind of motivated by his pragmatic optimism, this idea that we have a problem where others high rates of uncontrolled blood pressure in black men, but it is a problem that can be addressed through a novel intervention that will then have to be contextualized. He was open-eyed about the need for contextualization that even though there's a large 20 millimeter mercury reduction in blood pressure, any intervention, when we go beyond Los Angeles would have to be contextualized for geography and for payer. Would treating blood pressure in Dallas, or San Francisco, or Detroit, or Atlanta would look different from both the economics and the practical aspects of delivering this care in Los Angeles?

Dr. Dhruv Kazi:

So we set out to ask the question that if we were to make these barbershop based pharmacists led blood pressure control programs more widely available across the country in urban areas, metropolitan areas, and were able to enroll black men with uncontrolled blood pressure into these programs, what would the clinical impact be and what would the economic constraints be for these programs to be sustainable? We estimated that about 950,000 black men could be enrolled in a program of this nature. So that's about a third of black men with uncontrolled hypertension and that doing so on an annual basis would reduce about 8,600 or 8,600 major adverse cardiovascular events. That's about including 1800 MIs and 5,500 strokes. So quite a large number of events, but 40% of events in enrolled populations. And we then set out to ask, "Well, that's great. If we could deploy these programs at scale, there's the potential for substantial clinical impact, what would the economic constraints have to be for this program to be sustainable?"

Dr. Dhruv Kazi:

So if we imagine that this were not a delivery program but rather a pill, and you were willing to pay $100,000 to reduce per quality adjusted life here for blood pressure control medication, how much would we be willing to pay for this barbershop based program? And we found that approximately it would have to be delivered at a cost of $1,400 per patient per year. Now, $1,400 per patient per year is a substantial amount of money when you scale it up across the entire eligible population, but at the same time would require innovation and delivery that goes beyond pharmacists driving from one barbershop to another. So what we hope is that our work will stimulate this conversation around how can we take this intervention that is highly effective, that is potentially scalable and adapted in a way that we can afford to deliver it nationwide without losing effectiveness that we saw in the Los Angeles trial?

Dr. Mercedes Carnethon:

Thank you so much Dr. Kazi. And this just generates a lot of discussion as we really think about how we can bring interventions to people and how we can have an impact. So Kirsten, I'm so pleased that you were also able to join us as one of the senior authors, senior members of these research teams, because we really value your perspectives as well about where do the findings from this study situate us in the field. How do we move forward to achieve our goals of achieving equity and particularly among black patients and black adults in this country who we know have experienced significantly higher rates of hypertension and hypertension related disorders, we have a significant need here. So tell us how do we use this important information in order to make a difference?

Dr. Kirsten Bibbins-Domingo:

Thank you so much for having us and congratulations on this really important issue.

Dr. Kirsten Bibbins-Domingo:

I think what we see here in why these papers and this work is important is that it is really trying to take the important science that we're producing, trying to aim that addressing disparities and put it in the context that we could ideally rapidly translate it to actually help and address this issue. And with hypertension, we have both the urgency of declining rates of blood pressure control in the US as well as the persistent disparities that we see. So we have this effective intervention marrying a care provided by clinical pharmacists with community-based venues and partnership with black barbershops that is highly effective. The detailed studies led by Brandon really suggest that even in LA, pharmacists driving around this is a cost-effective intervention and that if we were to scale it, it could actually reach a lot of black men in the US and even though $1400 per person per year is a lot of money, it's actually not out of context of other things that we do that are high priority for our healthcare systems.

Dr. Kirsten Bibbins-Domingo:

So what we hope is that these two papers together help us to start to bring more people to the table to how we can translate now an effective trial, a trial that can effectively scale in a cost-effective way to thinking about what we could actually do. So how might this look? We think this is something that we hope health systems start to engage in. When they see disparities in the care for their members, for their patients, how could they think more creatively?

Dr. Kirsten Bibbins-Domingo:

How could payers, how could Medicaid for example, think about incentivizing different ways of delivering hypertension care? How could we think in other contexts about departments of public health or cities that really want to have a population-based approach to improving cardiovascular health? And money isn't everything, but is an important thing that many of these entities are thinking about and understanding both that this is a cost-effective intervention and that the amount per person to actually achieve this important role in cardiovascular health is not out of scale for other things that we prioritize in terms of health I think is important and that's what we hope people will take away from these important studies.

Dr. Mercedes Carnethon:

Wow, I really appreciate the time and attention that your team put into designing these really high impact research studies that achieve what our goal is, is to really think about ways in which we can address and eliminate disparities. I've really loved hearing about this work, and I hope that a broad audience receives it and really thinks about some of what we talked about before, which are the multiple different parties and disciplines that are required to come to the table for us to effectively address disparities. So thank you so much for spending time with us at our Circulation on the Run podcast, Dr. Kirsten Bibbins-Domingo from University of California at San Francisco, Dr. Brandon Bellows from Columbia University College of Physicians and Surgeons and Dr. Kazi from Beth Israel Deaconess Medical Center. So thank you so much for spending time with us today.

Dr. Dhruv Kazi:

Thank you for having us.

Dr. Brandon Bellows:

Thank you. It's been a pleasure.

Dr. Mercedes Carnethon:

And finally, I'd like to end by thanking our listeners for spending time with us today. We hope that you enjoyed the podcast, and we hope that you will enjoy the issue even more.

Dr. Greg Hundley:

Circulation June 8, 2021 Issue

7 juni 2021 | 25 min

This week's podcast features author Nicholas Mills and Guest Editor Allan Jaffe as they discuss the article "High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial." (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.052380)

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor/Director of the Pauley Heart Center and VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to examine cardiac troponin, high-sensitive cardiac troponin, and its association with myocardial infarction. But first, before we get to that, how about we grab a cup of coffee and start in and review some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I would love that. The first paper brings up the problem of stroke, remaining a devastating complication of transcatheter aortic valve replacement or TAVR. Now, this stroke risk has persisted despite refinements and the technique and increased operator experience, while cerebral embolic protection devices have been developed to mitigate this risk data regarding their impact on stroke and other outcomes after TAVR are limited.

Dr. Carolyn Lam:

Dr. David Cohen from Cardiovascular Research Foundation in New York and colleagues performed an observational study using data from the STS-ACC TVT registry, including more than 123,000 patients from almost 600 sites who underwent elective or urgent transfemoral TAVR between January 2018 and December 2019.

Dr. Greg Hundley:

Wow, Carolyn, this sounds like a really good use of the registry. What were the results?

Dr. Carolyn Lam:

Indeed, in this nationally representative observational study, the authors did not find an association between embolic protection device use for TAVR and in-hospital stroke in their primary instrumental variable analysis. And that's a technique designed to support causal inference from observational data with site-level preference for embolic protection device use within the same quarter of the procedure as the instrument.

Dr. Carolyn Lam:

However, they found a modestly lower risk of in-hospital stroke in their secondary propensity weighted analysis. These findings provide a strong basis for large-scale randomized control trials to really test whether embolic protection devices provide meaningful clinical benefit for patients undergoing TAVR. And this is discussed in a nice accompanying editorial by Dr. Tam and with Wijeysundera from University of Toronto.

Dr. Greg Hundley:

Very nice Carolyn. Well, my first paper comes to us from Professor Hua Zhang from Shanghai Children's Medical Center. Cyanotic congenital heart disease is a complex pathophysiological condition involving systemic chronic hypoxia and some cyanotic congenital heart disease patients are chronically hypoxic throughout their lives which heightens their risk of heart failure as they age.

Dr. Greg Hundley:

Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-Alpha. And Carolyn, this study aims to determine the effect of chronic hypoxia on cardiac metabolism and function in cyanotic congenital heart disease patients and its association with age. The authors investigated the role of hypoxia-inducible factor 1-Alpha in this process, and the potential therapeutic targets for this were explored.

Dr. Carolyn Lam:

What did they find Greg?

Dr. Greg Hundley:

In cyanotic congenital heart disease patients maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. In cardiomyocytes, specific HIF1-Alpha knockout mice, chronic hypoxia failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF1-Alpha and was responsible for cardiac metabolic maladaptation in animals exposed to chronic hypoxia.

Dr. Greg Hundley:

Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal chronic hypoxia animals. And so, Carolyn, perhaps future studies could test whether pioglitazone administration during puberty might improve cardiac function in cyanotic congenital heart disease patients. And this article is nicely accompanied by an editorial from Professor Ghofrani.

Dr. Carolyn Lam:

That's really interesting. For the next paper we're going from cyanotic congenital heart disease to plain old hypertension asking the question, What is the association of blood pressure classification using the 2017 ACC/AHA blood pressure guideline with risk of heart failure and atrial fibrillation? Well, this question was addressed by Dr. Kaneko and colleagues from University of Tokyo who performed analysis using a nationwide health claims database collected in the JMDC claims database between 2005 and 2018. Now note, this was more than 2 million patients followed for a mean of more than a thousand days in whom more than 28,000 incident heart failure, and more than 7,700 incident atrial fibrillation events occurred.

Dr. Greg Hundley:

Carolyn, this is a really large cohort a lot of events. What did they find here?

Dr. Carolyn Lam:

Among adults not taking anti-hypertensive medications and with no prevalent history of cardiovascular disease, stage one and stage two hypertension, according to the 2017 ACC/AHA blood pressure guidelines was associated with a higher incidence of heart failure and atrial fibrillation. The population attributable fractions for heart failure associated with stage 1 and stage 2 hypertension were 23.2% and 51.2% respectively. The population attributable fractions for atrial fibrillation associated with stage 1 and 2 hypertension were 17.4% and 34.3% respectively. The categorization based on 2017, ATC/AHA blood pressure guidelines may improve risk stratification for identifying adults at high risk for heart failure and atrial fibrillation.

Dr. Greg Hundley:

Wow Carolyn. Really useful data and something I love about our journal, a transition from a large cohort study on hypertension, and now we're going to delve into the world of preclinical science and talk about myocardial hypertrophy. Carolyn, exercise can induce physiological myocardial hypertrophy and former athletes can live five to six years longer than non-athletic control suggesting a benefit after regression of physiological myocardial hypertrophy.

Dr. Greg Hundley:

Accordingly, these authors led by Professor Yulin Liao from Nanfang Hospital and Southern Medical University hypothesized that anti-hypertrophic memory exists after physiologic myocardial hypertrophy has regressed increasing myocardial resistance to subsequent pathological hypertrophic stress. In this study, C57BL, six mice were submitted to 21 days of swimming training to develop physiological myocardial hypertrophy. Then after termination of the swimming events and exercise, the physiological myocardial hypertrophy regressed within a week. And these physiological myocardial hypertrophy regression mice termed the exercise preconditioning group or HP, and then sedentary mice as a control group underwent transverse aortic constriction, or a sham operation and were observed for four weeks.

Dr. Greg Hundley:

Finally, in these two groups, cardiac remodeling and function were evaluated using echocardiography invasive left ventricular hemodynamic measurements and histological analysis.

Dr. Carolyn Lam:

Wow. Exercise induced and I hypertrophic memory in the heart. That is so cool. Greg, could you summarize what they found?

Dr. Greg Hundley:

Yeah. And how about that exercise stimulus? The mice were swimming. Carolyn, these authors found that exercise-induced physiological myocardial hypertrophy can produce cardioprotective effect. And this cardioprotective effect continues to exist after the physiological myocardial hypertrophy subsides. And it's termed a phenomenon exercise hypertrophy preconditioning.

Dr. Greg Hundley:

Now, mechanistically, the investigators found that exercise hypertrophy preconditioning up regulates the expression of the long noncoding RNA Mhrt779 by increasing the three methylation of histone 3 at the A4 promoter of Mhrt779.

Dr. Greg Hundley:

Carolyn, also cardiac overexpression are knocked down of Mhrt779 respectively enhanced or weakened the anti hypertrophy effect of exercise hypertrophy preconditioning. The clinical implications of this research are that these results will likely stimulate further research into the mechanisms of exercise hypertrophy preconditioning, and Mhrt779 may be a potential therapeutic target for myocardial heart hypertrophy and heart failure in clinical practice.

Dr. Carolyn Lam:

Wow. Thanks so much, Greg. That was an incredible summary.

Dr. Carolyn Lam:

Let me tell you what else is in today's issue. There's an exchange of letters amongst doctors Mehmood Donkor, and Westermann regarding the article “Left Ventricular Unloading is Associated with Lower Mortality in Cardiogenic Shock Patients Treated with Venal Arterial Extracorporeal Membrane Oxygenation.” There's an ECG Challenge by Dr. Bhasin regarding “A Young Woman with Palpitations. Is It a Poison or Is It a Reality?”

Dr. Carolyn Lam:

In Cardiology News by Tracy Hampton, she describes new research, revealing mechanisms behind exercise-induced heart damage, new details behind muscle injury repair, and new insights on plasma membrane rupture during cell death. Very interesting. A new section there. There's a Perspective piece by Dr. Passman on “’Pill in the Pocket?’ Anticoagulation for Atrial Fibrillation. Is That Fiction, Fact, or Foolish?”

Dr. Greg Hundley:

Great, Carolyn. Well also in the mailbag, there's a Frontiers and medicine piece from Professor Rohatgi entitled “HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.” And then finally, Carolyn, a Research Letter from Professor Felker, entitled Probabilistic Re-adjudication of Heart Failure Hospitalization: Events in the Paragon-HF Study.” Well, Carolyn, what a great group of articles summarized. How about now we proceed to that feature discussion?

Dr. Carolyn Lam:

Let's go Greg.

Dr. Greg Hundley:

Well, listeners. We are now to our featured discussion today and we have with us one of our associate editors who has submitted a paper, Dr. Nick Mills from Edinburgh, Scotland. And then we have a guest editor. Sometimes he's been a feature author, but now he's serving as a guest editor, Dr. Alan Jaffe from Rochester, Minnesota. Welcome gentlemen.

Dr. Greg Hundley:

Well, Nick, could you start us off first and describe for us the hypothesis that you wanted to test, and then maybe also provide a little bit of context or background around the study that you and your team have just performed.

Dr. Nicholas Mills:

Thanks, Greg. I've been working for about a decade trying to understand how we can get the value from high-sensitivity cardiac troponin in our clinical practice. We've tried a number of different approaches to implement them for the benefit of patient care that I'm particularly proud of this trial. What we'd recognized that I think with the rollout of these assays across Europe and more recently in America is that they're excellent tests, but they do generate some diagnostic uncertainty in clinical practice.

Dr. Nicholas Mills:

But as we've got used to using them, we've learned that actually their major strength is that the confidence that they bring in ruling out myocardial infarction rather than ruling it in. And they allow us to make really early decisions often with a single test at the point of arrival, where we can say with absolute confidence that a patient does not have acute coronary syndrome and it's unlikely to have a problem in the next 30 days or one year based on just how low that high sense of high-sensitivity cardiac troponin result is. And I've been a strong advocate for using these tests in that way for some time. But the limitation has been that much of the work in this field has been observational. And so the patients were actually managed accordingly because of uncertain pathways. And there's always been some uncertainty as just how effective they are when in clinical practice, whether using these approaches are safe. And so we designed the Historic Trial to address that definitively in our hospitals in Scotland.

Dr. Greg Hundley:

Very nice Nick. So what was the study population and what was the design for this

Dr. Nicholas Mills:

Thanks Greg. So we use an interesting study design set wage cluster, randomized controlled trial, where rather than randomizing individual patients and randomized hospitals in Scotland, in order to do a trial like this, you need very detailed infrastructure because we wanted to enroll every consecutive patient, attending our emergency departments with symptoms, suspicions of acute cardiac syndrome. We embed it so into our care path, which allows our clinicians to enroll patients for us. We were keen to enroll all consecutive patients because we wants to be confident that our findings were truly generalizable at any included patients with complex comorbidities presenting that of ours who were sick unwell, which is often not the case; they've been observational studies. We randomized hospitals and follow up patients with acute coronary syndrome up for a year in order to determine whether the implementation of already changed clinical care and that was safe and did not lead to recurrent and in the future.

Dr. Greg Hundley:

Very nice. So Nick, in this randomization of hospitals, how many total patients did you encounter and then what were your study results?

Dr. Nicholas Mills:

So we enrolled 31,492 consecutive patients. I've crossed all seven hospitals implementing our early relapse pathway, reduced length of stay overall in the hospital. By just over three hours, we increased the proportion of patients who are directly discharged home from the emergency department by more than 50%. So that overall 71% of patients attending hospital with possible acute coronary syndrome were able to be discharged from the emergency department rather than being admitted unnecessarily for further investigations. But the critical result was, was that major change in the care pathway safe. We had a non-inferiority design. We had a very small number of safety outcomes at 30 days, and it was difficult to prove non-inferiority, but the event rate favored the implementation there.

Dr. Nicholas Mills:

They will have pathway with the 0.4% of patients we attend within 30 days of heart attack or dying from heart disease for our implementing it and 0.3% in and crucially, we followed everyone up for a year and were able to demonstrate that the safety outcome was not increased in those that we are able to that pathway one year with absolute confidence. And furthermore, there was no difference in re attendance or an all-cause mortality. We the two different arms of the trial. So we concluded that the early relapse pathway was effective and safe, and that using this approach we'd have major benefits from patients who can avoid unnecessary for healthcare providers in terms of reducing actual cost limitations.

Dr. Greg Hundley:

Fantastic. Well listeners, we're now going to turn to our guest editor, Dr. Alan Jaffe, and Alan, could you help us put into perspective these new data regarding high sensitivity, proponent, and also comment what attracted you to this article so much so that you feel it's needs to be published and circulated worldwide in the literature?

Dr. Allan Jaffe:

One of the important areas in the field of biomarkers is the movement just finally occurring. And Nick has been the forefront of this, of starting to do randomized trials. Observational data is just that it's observational. The patients are not created based on the information that is by the biomarkers. Patients can be missed if you're missing a sample, you exclude those patients. In addition, most observational trials, try and get informed consent. And by getting informed consent often miss the sickest patients. So what's desperately needed by the field. And which is just now starting with two or three ongoing randomized trials is just that a randomized trial where the investigators are forced to use the data, to manage the patient. And by using the step wedge design that Nick and his group has used in other trials as well, they guarantee that they don't miss patients either.

Dr. Allan Jaffe:

So that it's comprehensive and takes all into account. This is terribly important to then validate things like in this instance, the rule-out pathway. And I think these data do substantially confirm the fact that a single sample rule-out strategy using the cutoff value that Nick had previously established as optimizing the percentage of the population that can be included works well. It is unfortunate that the way in which they design their trial mist and design their non-inferiority outcome for safety was such that they ended up not finding significance to that. But I agree with Dr. Mills in the sense that the outcome adverse effects were so low, that despite that I think there's very important and reasonable data that this strategy is also safe.

Dr. Greg Hundley:

Very good. Well, Nick, thinking forward, what do you feel is the next study that needs to really be performed in this area?

Dr. Nicholas Mills:

I completely agree with everything Alan said. I think there's lots of really interesting approaches to find a group diagnosis, risk stratification of this really common condition. We need trials that demonstrate these approaches actually influence care and outcomes. For me, the challenge remains how to really harness these great tests to route the ruler of my cognitive function. I run about ads of patients with elevated cardiac troponin added due to an underlying condition that is an acute coronary syndrome. And we're starting to think about ways in which we can individualize our decision-making a little bit moving to walk away from binary thresholds, because values are influenced by age, by sex, by comorbidities like renal disease and preexisting heart failure about heart disease.

Dr. Nicholas Mills:

And by incorporating some of these patient factors into the interpretation of cardiac troponin. I think we can give clinicians better guidance on who to treat early with antiplatelet therapies and who needs invasive investigation than just simply saying that the troponin concentration is all positive or negative. And it's our challenge, I think, is how to harness that information, make it workable in clinical practice, and then demonstrate that by doing so we actually target effective therapies better, and that it makes a difference for patient care. So this is where we're working on at the moment. And I hope that in due course, we'll be able to do randomized trials in this space and that will move things forward again.

Dr. Greg Hundley:

Alan, do you have anything you'd like to add to that?

Dr. Allan Jaffe:

Yes. I think we're in a new era. We are finally starting to see there are now two or three randomized trials. It is time that the biomarker diagnostic studies graduate to a higher level of evidence, meaning randomized controlled trials. Nick is leading the way in that regard and I suspect and hope that subsequent trials, although observational trials may help inform which ones we should do, but that subsequent trials will continue to be randomized and generate the more robust data that randomized trials are capable of generating.

Dr. Greg Hundley:

Well, thank you both. And Nick, thank you for bringing us this research and also Alan, for evaluating it and providing this commentary today. It's quite exciting to have really this new information produced from a randomized trial, which evaluated the utility of a low high sensitivity treponema value in patients presenting to hospitals with chest pain syndromes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.

Circulation June 1, 2021 Issue

1 juni 2021 | 26 min

In this week’s podcast, articles “The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin” by Light et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and “Metabolic effects of empagliflozin in heart failure: A randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic) by Jensen et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are discussed.

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia,

Dr. Carolyn Lam:

Greg, it's double feature day. And guess what? Both papers that we're going to talk about are regarding the SGLT2 inhibitors, and really look at the mechanism of action of these amazing compounds, from both a pre-clinical and clinic point of view. That's all I want to say, because we've got to tune in, a very interesting discussion coming right up.

Dr. Carolyn Lam:

But first I'd like to ask you a question. What do you think is the association between health-related quality of life and mortality in heart failure around the world?

Dr. Greg Hundley:

Well, Carolyn, I would think that, actually, they might be linked.

Dr. Carolyn Lam:

That's a really clever answer. Thanks Greg. Well, the authors are actually going to tell you with this next paper. It's from Dr. Salim Yusuf from Population Health Research Institute and McMaster University in Hamilton, Canada, and colleagues, who looked at the global congestive heart failure, or GCHF study, which is the largest study that has systematically examined health-related quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, which is the largest study that has systematically examined health-related quality of life and its association with outcomes in heart failure, across eight major geographic regions, spanning five continents.

Dr. Greg Hundley:

Wow, Carolyn. So what did they find here?

Dr. Carolyn Lam:

Health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, or KCCQ, really differs considerably between geographic regions, with markedly lower quality of life related to heart failure in Africa compared to elsewhere. Health-related quality of life was also a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and with both preserved and reduced ejection fraction.

Dr. Carolyn Lam:

Indeed, this paper really highlighted a great need to address disparities that impact health-related quality of life in patients with heart failure in different regions of the world.

Dr. Greg Hundley:

Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn, and they're kind of similar, so we're going to do them back to back. The first study reports the results of the Sort Out X Trial, a large scale randomized multi-center, single-blind, two-arm, non-inferiority trial, with registry based follow-up designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34 positive antibody coated combo stent or DTS versus the Sirolimus-Eluting Orsiro Stent or SES.

Dr. Greg Hundley:

And the study comes to us from Dr. Lars Jakobson, from Arhus University Hospital. The primary endpoint target lesion failure, or TLF was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, all analyzed using intention to treat.

Dr. Carolyn Lam:

All right, Greg. So the DTS compared to the SES, what did they find?

Dr. Greg Hundley:

Thanks, Carolyn. So the DTS did not confirm non-inferiority to the SES stent for target lesion failure at 12 months. The SES was superior to the DTS, mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the two stent groups.

Dr. Greg Hundley:

Now Carolyn, in this same issue, we have another study evaluating endothelial function and implantation of intercoronary stents. And this second study comes to us from Professor Alexandra Lansky, from the Yale University School of Medicine and Yale Cardiovascular Research Group. And Carolyn, the study evaluated whether implantation of an intercoronary stent that facilitated endothelialization after the four to six weeks smooth muscle anti-proliferative effects post-stent implantation would be non-inferior to traditional drug-eluting stents.

Dr. Carolyn Lam:

Okay, another interesting study. And so, how did they do that? What did they find?

Dr. Greg Hundley:

Yeah, so Carolyn, a total of 1,629 patients were randomly assigned in a two to one fashion to the supreme DES stent, so 1,086 patients, or the DPDES stent, which was 543 patients. And there were no significant differences in rates of device success, clinically driven, target lesion revascularization, or stent thrombosis at 12 months.

Dr. Greg Hundley:

And the safety composite of cardiovascular death and target vessel revascularization or myocardial infarction was 3.5 versus 4.6% with the supreme DES stent compared to the DPDES stent. But target revascularization for this new stent was two and a half fold higher.

Dr. Greg Hundley:

So Carolyn looking at these two papers, what have we learned? So first, the Jakobsen, et al, tested whether the stainless steel COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive antibody could theoretically capture endothelial progenitor cells and regrow endothelium.

Dr. Greg Hundley:

And the investigators observed that this stent had higher, not lower or equivalent, target lesion revascularization relative to the current generation Cobalt-Chrome Stent that only eluted sirolimus.

Dr. Greg Hundley:

In the second study, Lansky and associates examined an approach which was touted as enhancing endothelial recovery, where the early erosion of material and release of drug was thought to allow earlier endothelial recovery enhancing vascular response. Non-inferiority of the rapid release was demonstrated, but rather than hints of superiority, there were signs of inferiority. Hereto, target lesion revascularization was problematic and was two and a half fold higher.

Dr. Greg Hundley:

And so, Carolyn, there's a wonderful editorial from Professor Elazer Edelman from the Massachusetts Institute of Technology entitled, “Karnovsky's Dictum that Endothelium is Good Looking and Smart,” where Dr. Edelman emphasizes that while some endothelial cells may have been present after deployment of these devices, perhaps a fully constituted functioning endothelium may not have been achieved.

Dr. Greg Hundley:

And as we know, it is a fully functioning endothelium with nitric oxide release, buried platelet adhesion that is most protective. It is a really provocative read that reflects on previous thoughts from Morris Karnovsky, who suggests preservation of endothelial function is optimized by minimizing injury to it. And so, Carolyn, these combined articles really highlight the current state of new developments within interventional cardiology to thwart re-stenosis and highly recommend them to our readers.

Dr. Carolyn Lam:

Wow, thank you, Greg. That was amazing. But you know what, so's this next paper, because it really provides novel insights into that enigma of the role that the epicardium plays in the pathogenesis of arrhythmogenic cardiomyopathy.

Dr. Carolyn Lam:

Now, to delineate the contributions of the epicardium to the pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian from University of Texas Health Science Center at Houston, Texas and colleagues performed a series of elegant mouse experiments using conditional deletion of the gene encoding desmoplakin in the epicardial cells of mice. Mutations in genes and coding desmosome proteins, including desmoplakin are known to be major causes of arrhythmogenic cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, very interesting. So what did they find here?

Dr. Carolyn Lam:

Epicardial derived cardiac fibroblasts and epithelial cells expressed paracrine factors, including TGF-β1 and fibroblasts growth factors, which mediated epithelial mesenchymal transition and contributed to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of arrhythmogenic cardiomyopathy. These findings really uncover contributions of the epicardial derived cells to the pathogenesis of arrhythmogenic cardiomyopathy.

Dr. Carolyn Lam:

Greg, there's a whole lot of other interesting stuff in today's series, as well. There's an exchange of letters among doctors Mehmood, doctors Moayedi and Dr. Birks regarding the article “Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Device.” There's an ECG challenge by Dr. Ezekowitz on a silent arrhythmia. How would you treat this patient? Go quiz yourself.

Dr. Carolyn Lam:

There is an AHA Update by Dr. Churchwell on how federal policy changes can advance the AHAs mission to achieve health equity. And finally, a Perspective by Dr. Talbert on rheumatic fever and the American Heart Association, The Nearly 100 hundred-Year War. Well, that wraps it up for the summaries. Let's go to the double feature, shall we?

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

Wow, today's feature discussion is really all about SGLT2 inhibitors, and that question that we're still asking, how do they work? And today, we are discussing two papers, very interestingly, looking at it from different aspects, one from a preclinical lens, finding a very novel target for SGLT2 inhibitors, and the other from a clinical lens, and really looking at the metabolic effects of the SGLT2 inhibitors in a way you've not seen before.

Dr. Carolyn Lam:

I'm very pleased to have with us the authors of these very exciting papers. We have Dr. Jesper Jensen from Herlev and Gentofte University Hospital in Denmark. We have Dr. Peter Light from University of Alberta, in Canada, and we have our associate editors, Dr. Thomas Eschenhagen from University Medical Center, Hamburg, and Dr. Justin Ezekowitz from University Alberta.

Dr. Carolyn Lam:

So, welcome gentlemen, thank you so much for joining us today. I suggest, let's start from the mice before we go to the men, and Peter, if you don't mind by starting us in, please tell us about this novel target you found, why you looked at it, how you found it, what it means.

Dr. Peter Light:

Hi, Carolyn, yeah, happy to discuss that. So, we all know that through numerous clinical trials, there's a very unexpected and exciting cardioprotective effect against heart failure with the SGLT2 inhibitors. And we decided to investigate some of the molecular mechanisms, which may underlie that protection. And in looking at the literature previously, and from my own lab's work, we're very interested in control of electrical excitability and ionic homeostasis in cells.

Dr. Peter Light:

So we investigated a known target or a known iron channel, which is involved in the etiology of heart failure as well as cardiac arrhythmias. And that would be the cardiac sodium channel. So, we investigated the effects specifically on a component of the cardiac sodium channel called the late sodium current, which is only induced in disease states, and they could be that during heart failure or ischemia, or can actually be in congenital conditions such as Long QT Syndrome Three, which involves certain mutations in this sodium channel.

Dr. Peter Light:

So we basically investigate the effects of empagliflozin, dapagliflozin and canagliflozin, in several different models of a sodium channel dysfunction, including mice with heart failure. And really what we've found is that this class of drug, and this is a class effect, it's not specific to just one of these SGLT2 inhibitors, what we found, they are very good inhibitors of this late current of the sodium channel. And in fact, they don't even affect the peak current at all.

Dr. Peter Light:

And when we did this and we analyzed the data, we found the IC 50s were in the low micromolar or even sub micromolar range for these drugs, which is exciting. And we extended those studies into cardiac myocytes and looked at calcium handling in those cardiac myocytes and saw that we get a very nice reduction in abnormal calcium handling in cardiac myocytes.

Dr. Peter Light:

We also used in silico molecular docking of these drugs to the cryo-EM structure of the NaV1.5, which is the cardiac sodium channel and identified that these drugs bind to a known region of that channel, which also binds the local anesthetics or anti-arrhythmic drug, Lidocaine, as well as the anti-anginal drug, Ranolazine.

Dr. Peter Light:

And finally, we showed that these drugs also reduce inflammation through the NLRP3 inflammasome in an isolated beating heart model. So collectively, we provide evidence that the late component of the sodium channel is a really important, or maybe a really important target for the molecular actions of this drug, and may underlie those observations received from the clinical trials relating both to heart failure, as well as sudden cardiac death.

Dr. Carolyn Lam:

Thomas, could you put this in context for us?

Dr. Thomas Eschenhagen:

Thanks, Carolyn. I mean, we immediately liked the story because as you said, and Peter as well, these drugs have amazing effects and every clinical paper and indeed some new ones, but it's really unclear how they do that. And what is, besides the established target, the SGL2 in the kidney, what could be the reason for all of this or some of this?

Dr. Thomas Eschenhagen:

And then, of course, other examples proposed, like the sodium hydrogen exchanger, but this story didn't go so far. So we saw now this data from Peter showing that, and this is, of course, for a pharmacologist, just like me, very important, it's very potent binding. It's not a binding which happens in a millimolar or high micromolar, but as Peter said in low micromolar range. So that makes it a very realistic effect, for example, much more potent than ranolazine.

Dr. Thomas Eschenhagen:

And, of course, now the question is, to which extent could this, now I would say, establish the effect on the late sodium current, explain some of the findings which came out of the clinical studies, and actually, a question I would have to Peter, now that I think most of you know, the late sodium current is a reason for the increased sodium for LQT3 syndrome, very rare.

Dr. Thomas Eschenhagen:

But, of course it would be tempting to say, okay, maybe that would be a very good drug, particularly for people with LQT3. Did you think about that, Peter? Is it something on your list, mexiletine has been tried.

Dr. Peter Light:

Yeah, so I think that it's a certainly intriguing possibility. In fact, in our study, we did test out several different Long QT3 mutations and saw a reduction in the late component as also sodium channel. It's tempting to speculate that, indeed, these could actually be a rather effective anti-arrhythmic drug in patients with these LQT3 mutations or specific ones. I would love to be able to test that in at least some of the genetic mouse models of Long QT3 and to see whether this concept holds water or not.

Dr. Carolyn Lam:

Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to now anti failure, and now anti-arrhythmic drugs? That's just amazing. Thank you, Peter. We should move on to this next paper, and this one all the way on the other spectrum, a clinical paper called Empire Heart Failure, Empire Heart Failure Metabolic, actually. Jesper, could you tell us about your trial and what you found?

Dr. Jesper Jensen:

Sure, thanks for the invitation to take part in the podcast, first of all. I'll tell you a little bit, we designed this study to try to get behind mechanisms, so the clinical benefits of the SGLT2 inhibitors in order to try to make a clinical outcome trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were competed very fast, demonstrating the clinical benefits in HFrEF patients.

Dr. Jesper Jensen:

So, the data of our study provides some detailed mechanistic insights to these findings. And from the literature, we know that SGLT2 inhibitors improve glucose metabolism in patients with diabetes, and these changes might not be surprising in the diabetes population, but moreover, alterations in glucose metabolism may not be the main mechanism for the early occurring clinical benefits.

Dr. Jesper Jensen:

However, we know that many of our heart failure patients without diabetes are insulin resistant as a metabolic feature of the heart failure, and the insulin resistance is associated with an increased risk of developing future diabetes, which in turn reduces the long-term survival and quality of life. So, the targeting insulin resistance in HFrEF patients is, therefore, of clinical relevance to our patients.

Dr. Jesper Jensen:

So, the population of the Empire HF Metabolic consisted of patients with chronic HFrEF, with or without type two diabetes, who are on a stable guideline directed heart failure therapy, and have also indicated on anti-diabetic therapy. And we randomized patients to receive empagliflozin 10 milligrams once daily, or matching placebo as an-add on for 12 weeks.

Dr. Jesper Jensen:

And this was a modest sized randomized control trial, including 120 patients. A very large proportion of patients received guideline directed heart failure therapy, and they generally consisted of the best one third of atypical HFrEF population, and only 10% had concomitant history of type two diabetes.

Dr. Jesper Jensen:

We then, at baseline and after 12 weeks, we formed an oral glucose tolerance test to assess the hepatic and a peripheral insulin sensitivity and performed a whole body DXA scan to investigate alterations in body composition. We know that patients lose weight when they get an SGLT2 inhibitor with and without diabetes, but we don't know what it consists of in a HFrEF population.

Dr. Carolyn Lam:

Tell us what you found after 12 weeks.

Dr. Jesper Jensen:

Yeah, so a large proportion, actually half of the patients without a history of diabetes, had a new onset diabetes, or impact glucose tolerance at baseline. So even though few have no diabetes, this population were at very high risk of developing future diabetes. And the main finding was that empagliflozin improved insulin sensitivity. So the hepatic insulin sensitivity was improved by 13% and the peripheral insulin resistance was improved by 20% compared to placebo.

Dr. Jesper Jensen:

And moreover, both fasting and postprandial glucose were significantly reduced. And regarding the body composition, patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly consisted of a loss in lean mass and no significant changes were observed in fatness, and this is from the DXA scan.

Dr. Carolyn Lam:

Hmm. Justin, could you shed some light on what the editors thought about this, and there's lots of questions still, huh?

Dr. Justin Ezekowitz:

Yeah, absolutely, Carolyn, and thanks Jesper for sharing this paper with Circulation. Thanks for summarizing it so well. I think the questions that come up and the reason why we liked it so much was we're all trying to understand mechanism of how these medications work so profoundly for our patients.

Dr. Justin Ezekowitz:

Now, in this predominantly non-diabetic population, the fact that the liver and the peripheral insulin sensitivity improves, how does that bear out for the fact that there is no fat loss in the early stages, yet that's all been linked to later improved exercise capacity and increased fat loss later on in life.

Dr. Justin Ezekowitz:

So, do you think those two are going to be linked if you went to say from 12 weeks beyond the 52 or two years down the road?

Dr. Jesper Jensen:

Yes, that is what we've seen from diabetes populations, at least. So you could imagine that the same would be the case also in the HFrEF primarily non-diabetic population, but again, we don't know. But early loss is the mass loss.

Dr. Justin Ezekowitz:

So Jesper, when you think about the peripheral insulin sensitivity improvement, is that largely indicating mostly muscle based insulin sensitivity improvement, and that would indicate that the muscles, perhaps, are functioning better in the short term with just a simple change in therapy.

Dr. Jesper Jensen:

Yeah, that could be a way to put it. I would agree upon that.

Dr. Justin Ezekowitz:

So thanks, Jesper, I think that may indicate the quality of life improvement that we may be seeing in the functional status there, Carolyn.

Dr. Carolyn Lam:

Yeah, but as you said, Justin, there just seems so many other questions. To Jesper, I want to know, what further might you want to do to find out what's happening with this? The loss of lean mass surprised me, frankly. I thought it would have been fat mass. So, what are you doing to look at that? And then to Peter, I want to go the other direction. What are you planning next that might bring this closer to humans and a clinical study? So maybe I'll ask Jesper to go first.

Dr. Jesper Jensen:

So, I definitely agree with you, Carolyn. We would also have to put our money on the fat from the beginning, before the study. So with respect to the weight loss, then a loss in lean mass is not preferable if it represents muscle. So however, the weight loss works to mediate the observed change in insulin resistance. And additionally, a significant loss in muscle would result in reduced insulin sensitivity. And we observed the opposite. Therefore, the observed loss in lean mass may be speculated to represent water and pointing towards the early diuretic effect SGLT2 inhibitors. So, the DXA scan is good at looking at body composition, but it has difficulties in separating lean mass from whether it's muscle or water, but combined with the findings on the insulin resistance, we speculate that the lean mass loss is more.

Dr. Carolyn Lam:

Thank you. And Peter, could you very quickly tell us what are next steps, in your view?

Dr. Peter Light:

Yeah, obviously we were studying mouse model of heart failure. We'd like to make a more of a translational step in the next experiments we do by studying human tissues. So getting access to ventricular tissue from ex-planted hearts, human hearts, too, and then measure electrical activity as well as some calcium imaging.

Dr. Peter Light:

Looking at some of these Long QT3 animal models would be another thing that we're going to do. And also start looking at to see whether we can get access to any electrophysiological data from electronic medical records to start looking for DCGs and measuring QT interval, for example, would be another nice step to that.

Dr. Peter Light:

And then, more of a drug development side of things, we are actively synthesizing new derivatives of these drugs and seeing whether we can enhance the cardio-protective effects on the late sodium current, but actually remove the ability to inhibit SGLT2. So we would no longer have a glucose-lowering drug, but we'd have a cardioprotective drug. So, it's all very exciting work going on right now.

Dr. Carolyn Lam:

You've been listening to Circulation on the Run. From Greg and I, don't forget to tune in again next week.

Dr. Greg Hundley:

Circulation May 25, 2021 Issue

24 maj 2021 | 20 min

Please join editorialist Padma Kaul and Associate Editor Karol Watson as they discuss the original research article "Preterm Delivery and Long-Term Risk of Stroke in Women: A National Cohort and Cosibling Study" and the editorial "Pregnancy as Oracle: What it Augurs for Women's Health."

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh Greg, today's feature paper is really important. It's about preterm delivery and the long-term risk of stroke in women. A very, very important cardiovascular risk factor that we don't talk about. This is important data from the national cohort and co-sibling study. So hang on, look out for it. But first, how would you take us through some of your spotted original papers?

Dr. Greg Hundley:

So Carolyn, my first paper comes to us from Dr. Guido Claessen from University Hospitals in Leuven. Exertional intolerance, Carolyn, is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension, and traditionally, the etiology has been attributed to central factors, including ventilation, perfusion mismatch, increased pulmonary vascular resistance and right heart dysfunction and uncoupling. So pulmonary endarterectomy and balloon pulmonary angioplasty provides substantial improvement of functional status and hemodynamics. However, despite normalization of these pulmonary hemodynamics, exercise capacity often does not return to age-predicted values. So by systemically evaluating the oxygen pathway, these authors aim to elucidate the causes of functional limitations of chronic thromboembolic pulmonary hypertension patients before and after these pulmonary vascular interventional procedures.

Dr. Carolyn Lam:

So very interesting. Tell us more, what did they find, Greg?

Dr. Greg Hundley:

Yeah, well Carolyn, they utilize cardiovascular magnetic resonance, as you know, one of my big interests, but guess what? They also did it with exercise and simultaneous invasive hemodynamic monitoring. The authors in doing so, sought to quantify the steps of the oxygen transport cascade from the mouth to the mitochondria in patients with this pulmonary hypertension. So they had 20 subjects with pulmonary hypertension and they compared those to 10 healthy individuals. Furthermore Carolyn, the authors evaluated the effect of pulmonary vascular intervention procedures, both endarterectomy or balloon angioplasty, on the individual components of the cascade in 10 of those 20 individuals.

Dr. Greg Hundley:

So what did they find? They found that in this chronic thromboembolic pulmonary hypertension condition, these patients, they have significant impairments of all steps in the oxygen utilization cascade, resulting in markedly impaired exercise capacity, the thick equation uncoupled. And pulmonary vascular interventions increased, peak VO2, by partly correcting the oxygen delivery, but having no impact on abnormalities in peripheral oxygen extraction.

Dr. Greg Hundley:

So Carolyn, this suggests that the current interventions only partially address patient's limitations and that additional therapies may improve functional capacity, such as improvement in skeletal muscle function and metabolism. So maybe one of your faves, cardiac rehab, perhaps could work on some of those peripheral factors in these patients. So, really interesting, very well accomplished study.

Dr. Carolyn Lam:

Nice, elegant and clinically impactful. Very nice. Well, the next paper is the same. We know that prenatal detection has benefits for infants with hypoplastic left heart syndrome and transposition of the great arteries. Well, this next paper describes the largest multicenter study to evaluate whether social economic quartile, public insurance, race or ethnicity, rural residence and distance from the residence are associated with the prenatal detection of critical congenital heart diseases in North America. This study is from Dr. Krishnan from Children's National Medical Center in Washington, DC and colleagues. Basically, what they found was that lower socioeconomic position, Hispanic ethnicity, and rural residence were all associated with decrease prenatal detection rates of hypoplastic left heart syndrome and transposition of the great arteries.

Dr. Greg Hundley:

Wow Carolyn, so social determinants of health, interesting. So how do we, as clinicians, apply these results?

Dr. Carolyn Lam:

Well, clinicians can use the findings of the study to focus efforts on improving overall prenatal detection rates for congenital heart disease. They can specifically improve health equity in prenatal detection and timing of prenatal detection by improving linkages between tertiary care centers and these populations and regions that were identified in this study.

Dr. Greg Hundley:

Very nice Carolyn. Well, I'm going to turn to the world of aortic aneurysms and this next paper comes to us from Dr. Maria Mittelbrun from Centro de Biología Molecular Severo Ochoa. Carolyn, it involves Marfan syndrome, which you know, is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene, encoding a large glycoprotein in the extracellular called fibrillin one. The major complication, again as you know, of this connective disorder is the risk to develop thoracic aortic aneurysms. To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are surgery. So here, the authors studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm dilation, and mitochondrial boosting strategies as a potential treatment to manage these aneurysms.

Dr. Carolyn Lam:

Wow, that's really fascinating. So what did they find?

Dr. Greg Hundley:

So Carolyn, just like in circulation, these wonderful translational basic science studies, the research here by these authors was performed in both mice and in patient samples from Marfans patients. So mitochondrial function of vascular smooth muscle cells was found to be controlled by the extracellular matrix and drive the development of aortic aneurysm in the Marfan syndrome. Interestingly, restoring mitochondrial metabolism with the NAD precursors nicotinamide riboside rapidly reversed aortic aneurysm in the fibrillin positive mice. Thus Carolyn, the clinical implications are that by potentially targeting vascular metabolism, a new available therapeutic strategy for managing aortic aneurysms associated with these genetic disorders, such as Marfan syndrome, may become available. Really interesting new development in the world of managing aortic aneurysm dilation in patients with Marfan syndrome.

Dr. Carolyn Lam:

Oh my goodness, that would be paradigm shifting. Wow, hope that's going to be pursued further. Well, this next one is from the preclinical world and this study really uncovered a metabolic transcriptional axis that explains how dividing cells coordinate metabolism with gene regulation in pulmonary arterial hypertension. So this is from Dr. Rabinovitch and colleagues from Stanford University School of Medicine who applied RNA sequencing to pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension with and without a BMPR2 mutation compared to control pulmonary artery smooth muscle cells, basically to uncover genes required for their heightened proliferation and glycolytic metabolism. The assessment of differentially expressed genes establish metabolism as a major pathway. The most highly up-regulated metabolic gene was aldehyde dehydrogenase family 1 member 3, an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular smooth muscle cells, but now demonstrated in pulmonary arterial hypertension. Isn't that cool?

Dr. Carolyn Lam:

The findings were basically like this, an increase in this particular aldehyde dehydrogenase family 1 member 3, underlined the heightened proliferation and glycolysis of pulmonary artery smooth muscle cells in patients with both idiopathic and hereditary pulmonary artery hypertension, while promoting survival of their endothelial cells under stress. The authors further uncovered the way this molecule interacted with genetic factors in doing so and then finally demonstrated that transgenic mice with the deletion in smooth muscle cells did not develop chronic hypoxia-induced pulmonary hypertension.

Dr. Greg Hundley:

Wow Carolyn, really new, inventive material from the world of basic science. So what's the take-home message?

Dr. Carolyn Lam:

So these findings really suggest that selectively disrupting the pivotal role of aldehyde dehydrogenase family 1 member 3 in pulmonary artery hypertension smooth muscle cells, note that was smooth muscle cells, not the endothelial cells, may be a important therapeutic consideration in patients.

Dr. Greg Hundley:

Very nice.

Dr. Carolyn Lam:

So Greg, let me tell you about some other articles in today's issue. There's an exchange of letters between Drs. Pengo and Kario 00:10:36 regarding the article Nighttime Blood Pressure Phenotype And Cardiovascular Prognosis, A Practitioner-based Nationwide JAMP Study.

Dr. Greg Hundley:

Great Carolyn, well also in the mail bag, we have a perspective piece from Professor Chang entitled Trial By Wildfire, The Need To Expand The Framework Of Environmental Determinants Of Cardiovascular Health From Climate Change To Planetary Health. Also, there's a primer from Professor Miano entitled The Fate And State Of Smooth Muscle Cells And Atherosclerosis. Then lastly, we have another article from the world of basic science, a research letter from Dr. Ieda entitled Overexpression Of GATA4, MEF2C and TBX5 Generates Induced Cardiomyocytes Via Direct Reprogramming And Rare Fusion In The Heart. Well, Carolyn, how about we get to the world of preterm delivery and onto that feature article?

Dr. Carolyn Lam:

I'm there already, let's go.

Dr. Greg Hundley:

Well, listeners. Now we are turning to our feature discussion and we're so excited today to have with us our editorialist for this article, Dr. Padma Kaul and our own associate editor, Dr. Karol Watson and we'll be discussing today, a paper related to preterm delivery and long-term risk of stroke in women. Padma, I'd like to start with you. Describe for us a little bit, the context for this study, and then what were the authors' study population and study design?

Dr. Padma Kaul:

So Greg, this is a study, which is a retrospective cohort study from Sweden and they looked at women who had given birth over a pretty long period of time, from 1973 to 2015. In over two million women, they looked at the association between preterm birth and the long-term development of stroke in the mothers. It's a really interesting study. What they did find is that preterm birth was associated with a higher hazard ratio for stroke, over 48 million person years of follow-up. The authors also did an interesting co-sibling analysis to supplement what the overall primary analysis. This was by looking at a subset of women who had at least one sibling in the cohort. The point of that was to assure that the association between preterm birth and stroke risk remained, even after you account for familial or genetic environmental factors. They do find that it was demonstrated even in the subset.

Dr. Greg Hundley:

Very nice, just a couple quick clarifying points. Were these ischemic strokes, were they hemorrhagic strokes? And then give me a little bit of definition. How did they define preterm?

Dr. Padma Kaul:

So preterm was in less than 37 weeks of gestation, and they looked at both hemorrhagic as well as ischemic strokes in the women. So they did an overall stroke endpoint as well as looked at whether these two types of strokes, whether the relationship stayed.

Dr. Greg Hundley:

And was there any particular age at which these strokes occurred?

Dr. Padma Kaul:

That's an excellent point. As I told you, that the time period of the study is pretty long. So they did stratify the follow-up period into 10 year segments, and they found that higher risk in the early part of the 10 and the 10 to 20 time periods. It stayed in the latter periods as well, but it was more so associated with a higher hazard in the early time periods, the 10 and the 20.

Dr. Greg Hundley:

Thank you so much, Padma. Well now listeners, we're going to turn to our associate editor, Dr. Karol Watson from UCLA. Karol, I know working on the editorial board at Circulation, you see many papers come across your desk. What attracted you to this particular manuscript? And how would you put the results from this study in the context of other studies that have really evaluated women's health in this situation?

Dr. Karol Watson:

That's a fabulous question. I think really so many great manuscripts come in and there are important features of many of them, but this one caught my eye for a couple of reasons. It was so incredibly well done. This is a huge, huge cohort of over two million women and it's from Sweden, where they keep really exquisite records, so we had so much data on this population. So we really got to know all about these soliton deliveries in Sweden, over a 40 year period. So the great cohort that was really well characterized, the really long follow-up. I love the co-sibling analysis that they talked about, they really did control for so many things, shared familial factors, shared genetic factors, covariates. So they just did a fabulous study.

Dr. Karol Watson:

So, in the whole realm of women's health, we are understanding that pregnancy is a great window into a woman's vascular future. So we now know so many things, we know that preterm delivery is amongst those pregnancy outcomes that we have to look for. So we have to look for pregnancy-induced hypertension, gestational diabetes, but also preterm delivery and pregnancy loss. So all of these things are telling us that a woman's vascular system is under stress and we have to do things to make sure they have good outcomes, because we know they're at greater risk.

Dr. Greg Hundley:

Very nice. So as leading experts in the era, Padma first to you, and then I'll come back to Karol. Padma, tell us, what do you think is the next area of research that needs to be explored in this topic area?

Dr. Padma Kaul:

I think that this is an observational study. So one of the things we have to recognize is how do we add to the evidence that this study has provided us? That I think, is to see if in other cohorts, similar pregnancy birth cohorts with longitudinal data, whether we observe the same patterns that we ever observed in Sweden. Sweden is actually quite unique in terms of the makeup of the population and these are historical trends. We do know that the characteristics of the mothers who are giving birth are changing over time. Women are delaying childbirth, they are getting heavier, they may have preexisting conditions. So I think to keep monitoring the health of the mothers and pregnancy factors is what is needed to move the field forward.

Dr. Greg Hundley:

Very nice, and Karol? Karol, would you like to add anything?

Dr. Karol Watson:

Yeah, I agree completely with what Padma says. The beauty of the Swedish cohort is how well characterized it is, but one of the limitations is it's a fairly homogenous cohort. So I would love to see similar data in other racial or ethnic groups. We'd also like to see, again, as Padma said, this is observational cohort study, so we don't know truly the causal validy here, although this is a really good study to identify this trend. I would love to think of ways why this might be, we really don't have a good handle on the pathobiology. We can surmise some things endothelial dysfunction, et cetera, but we just don't know for sure. The other thing I'd like to think of is ways we might address mitigating risk. If this truly is a risk factor, how are we going to help these women have better vascular outcomes. But again, a great study to start all these questions.

Dr. Greg Hundley:

Well, thank you Karol and Padma and listeners. We certainly want to thank both Drs. Kaul and Watson for their time today and also the author group under the direction of Dr. Casey Crump for submitting this article to us at Circulation reporting on this large cohort of women from Sweden, identifying a preterm delivery and long-term risk of both ischemic and hemorrhagic stroke.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Circulation May 18, 2021 Issue

17 maj 2021 | 27 min

This week, please join author Uwe Tietge and Associate Editor Anand Rohatgi as they discuss the article "High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events" (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050808)

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got a very interesting feature this week. It involves another paper in the line of the story of HDL, and looking at HDL and future cardiovascular events. But before we get to that, how about we grab a cup of coffee and jump in and review the other articles and the issue? And Carolyn, this week, maybe I'll go first.

Dr. Carolyn Lam:

Go, I've got my coffee.

Dr. Greg Hundley:

Very good. So Carolyn, this paper comes to us from Dr. Huso Hakala, from the University of Turku at Turku University Hospital, and the study pertains to cognition and cardiovascular disease. So Carolyn, as you know, cardiovascular risk factors such as high blood pressure, adverse serum lipids, and elevated body mass index, and midlife may harm cognitive performance. So importantly, perhaps the presence of cardiovascular risk factors since childhood, Carolyn, may impact cognition later in life. So these authors studied the associations of the cardiovascular risk factors from childhood to midlife, their accumulation and midlife cognitive performance. They gathered their data beginning in 1980 from a population-based cohort of 3,596 children who are aged three to 18 years that were repeatedly followed up for 31 years, and they assess blood pressure, serum lipids, body mass index, all in the follow-ups.

Dr. Carolyn Lam:

Wow. So accumulating risk, I suppose, Greg. So what did they find?

Dr. Greg Hundley:

Great. Carolyn, glad you asked. So consistently high systolic blood pressure or serum total cholesterol associated with worse midlife episodic memory and associated learning, compared to situations when blood pressure or cholesterol values were low. Obesity since childhood associated with worse visual processing and sustained attention compared to individuals or children that had normal weight. And an inverse trend association was observed for the cardiovascular risk factor accumulation with episodic memory and associated learning with visual processing and sustained attention and with reaction and movement time. So the take home Carolyn, is that, maybe we should be launching preventative strategies against some of these cardiovascular risk factors beginning in childhood, because perhaps they could benefit primordial promotion of cognitive health for those later in adulthood, maybe like you and me.

Dr. Carolyn Lam:

Oh, wow. Thinking back on my blood pressure, cholesterol and weight, I suppose, since childhood, yikes. Well, the next paper Greg is an important analysis from DAPA-HF. Now as a reminder in the DAPA-HF trial, the sodium glucose co-transporter two inhibitor dapagliflozin was shown to reduce the risk of cardiovascular death and a first episode of worsening heart failure, in patients with heart failure with reduced ejection fraction or HFpEF. In the current paper from Drs. Jhund and colleagues from University of Glasgow, they described the efficacy of dapagliflozin on the predefined secondary end point of total heart failure hospitalizations. That's the first and recurrent heart failure hospitalization and cardiovascular death. And this is so important because we know that patients with HFrEF are known to experience multiple episodes of heart failure during the course of the disease.

Dr. Greg Hundley:

So Carolyn, what did they find?

Dr. Carolyn Lam:

Well, they did this analysis by two methods in the first, which was the Lin, Wei, Ying and Yang or LWYY model the rate ratio for the effect dapagliflozin on recurrent heart failure, hospitalizations or cardiovascular death was 0.75.

Dr. Carolyn Lam:

And the second method, a joint frailty model, the rate ratio for total heart failure hospitalizations was 0.71 while for cardiovascular death, the hazard ratio was 0.81. The factors associated with more hospitalizations were, being a men, having a higher heart rate, NT-proBNP, New York Heart Association class type 2 diabetes, and a longer duration of heart failure with less hospitalization in those with higher systolic blood pressure and higher ejection fraction. So in summary, dapagliflozin in reduced the risk of total heart failure, hospitalizations and cardiovascular death. In fact, if you compare it to the time to first analysis, you can see that, that actually underestimated the benefit of dapagliflozin in HFpEF.

Dr. Greg Hundley:

Very nice Carolyn, well, my next paper comes to us from the world of basic science. And so Carolyn, neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocytes cell cycle exit and loss of the capacity for cardiac regeneration. Now the mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored.

Dr. Carolyn Lam:

Okay, Greg. So what did this current paper find?

Dr. Greg Hundley:

Right, Carolyn, so Dr. Ahmed Mahmoud from University of Wisconsin-Madison, they found that malonate, a competitive inhibitor of succinate dehydrogenase, promotes adult cardiomyocyte proliferation, revascularization of the infarct zone and myocardial regeneration following infarction. They also found that SDH inhibition by malonate is consistent with a metabolic shift from oxidative phosphorylation to glucose metabolism in the adult heart. So Carolyn, the clinical implications include the observation that transient inhibition of SDH may represent an important metabolic target to promote adult heart regeneration, following myocardial infarction.

Dr. Carolyn Lam:

Cool. Thanks Greg. Well, I've got another basic science paper. Let me try to tell you about la ribonucleoprotein domain family member seven. And I'm going to call that LARP7. Again, it's la ribonucleoprotein domain family members seven. Now LARP7 is a master regulator that governs the DNA damage response. The authors today, Dr. Zhang, from Xin Hua Hospital and Shanghai Jiao Tong University and colleagues aim to study its role in heart failure, pathogenesis by assessing LARP7 expression in human heart failure and in non-human primate and mouse heart failure models.

Dr. Greg Hundley:

Great, Carolyn. So what did they find?

Dr. Carolyn Lam:

LARP7 was essential for mitochondrial biogenesis energy production and cardiac function by modulating silent mating type information regulation to homolog-1, which is cert one, cert one homeostasis and activity. Now, reduction in LARP7 and diseased hearts due to activation of ataxia-telangiectasia mutated protein pathway contributed to the heart failure pathogenesis and conversely restoring LARP7 in the injured heart conferred myocardial protection. So in some, these results identified that this LARP pathway is a target or rather is a potential target for therapeutic intervention in heart failure.

Dr. Greg Hundley:

Great, Carolyn. One of the things I love about our journal is really the translational basic science that really could have future implications for how we manage patients with cardiovascular disease. So I, to follow, have another basic science article, and it comes to us from Dr. Florian Weinberger from the University Medical Center in Hamburg-Eppendorf. So Carolyn, human engineered heart tissue transplantation represents a potential regenerative strategy for our heart failure patients and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices and determination of the effective dose. So these authors performed studies in which cardiomyocytes were differentiated from three different human induced pluripotent STEM cell lines, including one reprogrammed under these GMP conditions. Protocols for human induced pluripotent STEM cell expansion, cardiomyocyte differentiation and engineered heart tissue generation were adapted to substances available in good manufacturing process quality. Engineered heart tissue geometry was modified and repair efficacy was evaluated at three doses in a cryo-injury Guinea pig model, human scale patches were epicardialy transplanted onto healthy hearts in pigs to assess the technical feasibility of this entire process.

Dr. Carolyn Lam:

Wow. And what did they find?

Dr. Greg Hundley:

Right, Carolyn? I mean, this is just so exciting, the practicality of how you implement some of these new strategies that we work on in the lab. So Carolyn, they found that human engineered heart tissue patch transplantation resulted in a partial re-muscularization of the injured heart and improved left ventricular function in a dose dependent manner in a Guinea pig injury model and human scale patches were successfully transplanted in pigs in a proof of principle study. So an exciting new front for engineered cardiac tissue transplantation. I mean, this is a really exciting article.

Dr. Carolyn Lam:

Wow, well, indeed. Thanks, Greg. Well, other than those wonderful papers in today's issue, we have an exchange of letters between Drs. Morgan and Lopes regarding initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure of left ventricular dysfunction and that's insights from the ischemia trial. Tracy Hampton does her wonderful review from the literature and it covers new research published in nature medicine, which indicates the impact of a Mediterranean diet on cardio-metabolic disease risks, which may be affected by an individual's gut microbes and goes all the way to network correcting therapeutic candidate for heart valve disease, which was published in science and even a newly discovered genetic arrhythmia syndrome, which was described in science translational medicine. That's a perspective piece by Dr. Kuwabara on the Japanese national plan for promotion of measures against cerebral vascular and cardiovascular disease.

Dr. Greg Hundley:

Great, Carolyn. Well, you've heard of mission accomplished. Well, Dr. Brooke has an On My Mind piece entitled mission unaccomplished, the optimal hyper, any hypertensive therapy. And then finally, Dr. Glembotski has a Research Letter entitled optimizing AAV9 for studies of cardiac chamber specific gene regulation. Well, Carolyn, what a great issue and integrating all the wonderful world of basic science in a translational fashion. Now, how about we get on and move toward our feature discussion?

Dr. Carolyn Lam:

Yep. HDL, here we come.

Dr. Greg Hundley:

Well, listeners, we are onto our feature discussion today and we're very excited to have with us today, professor Uwe Tietge from Stockholm, Sweden, and our own associate editor Anand Rohatgi from UT Southwestern. Welcome gentlemen. And Uwe, could you describe for us the hypothesis that you wanted to test and tell us a little bit about your study design?

Dr. Uwe Tietge

Okay. So thank you very much for inviting me and for having the opportunity to discuss this article with you today. So we've been for a long time interested in HDL function, and we have developed an HDL anti-inflammatory see, and we have tested it in some cross-sectional studies. And we have seen in this cross-sectional work, for example, in the acute mi or diabetes, are associated with significant reductions in HDL anti-inflammatory function. So we felt that the next important step would be to study this prospectively in the general population. So this is why we made use of the prevent cohort, which is a prospective general population study with white participants from Groningen, which is a city in the North of the Netherlands. Prevent stands for prevention of menial and stage disease, and prevent has a total number of participants of 8,592.

Dr. Uwe Tietge

So we first excluded all that had already experienced mi intrusion. And then we took all subjects, was the first cardiovascular disease events during follow up and matched controls for sex, age, smoking, and importantly also for HDL cholesterol levels. And we felt that such a design would allow us to truly identify changes in HDL function, independent of HDL cholesterol levels. So then finally we ended up with 340 match case control pairs.

Dr. Greg Hundley:

Uwe, sounds like a very interesting hypothesis. So what was your methodology and how did you perform your analysis? And then also describe for us, what did you find?

Dr. Uwe Tietge

The key method that we used was our essay determining the atrial anti-inflammatory capacity and the main outcome measured was incident cardiovascular disease. And in our case, that was deaths from cardiovascular disease, hospitalization from mi, PDCA, ischemic heart disease, or CABG. We did not have stroke in our study. So with respect to HDL function, we isolate HDL by means of PEG precipitation. And this is an established method that is widely used in larger cohort studies. We then take a primary industry that cells, humans, and we pre incubate them for 30 minutes with the individual engineer preparations. Then the agents removed and TNF alpha is added for another five hours. And after these five hours, we isolate RNA and determine BK1 and mRNA levels by quantitative real time PCR. Then we calculate the results relative to the [inaudible 00:16:09] or without the edit HDL. So when the empties data, we use statistical analysis to determine the perspective association in, based on HDL anti-inflammatory function and the outcome measure incident CVD.

Dr. Uwe Tietge

So to summarize the main findings of the study. So first of all, the anti inflammatory activity of HDL baselines intrusion in this study was significantly higher in controls than in cases. Next, the HDL anti-inflammatory activity was not correlated with any other CBD related biomarkers. Importantly also know it was HDL cholesterol at 8.1, but also not, for example, with triglycerides, or isolated CRP, and also not with [inaudible 00:16:58] capacity, which is another function metric of HDL.

Dr. Uwe Tietge

The further finding was that in conditional logistic regression analysis, we found that baseline HDL anti-inflammatory activity was significantly associated with future CV events, even in a fully adjusted model. Then finally, when we were adding this function of HDL to the premium, this form, or when we were replacing anti-inflammatory capacity in the score that improved risk prediction and interestingly adding cholesterol reflux and other HDL function, as said before, resulted in a further improvement.

Dr. Uwe Tietge

So the general conclusion was that of the HDL functional measures in the case of our actual study, this is the HDL anti-inflammatory activity has the potential to provide clinic information independent of conventional use biomark.

Dr. Greg Hundley:

Very nice who made. So we always think of HDL is the good cholesterol. And sounds like you're describing a whole nother process by which HDL could be beneficial. Well, Anand turning to you now. I know you see many papers come across your desk. What drew your attention to this particular manuscript and how does this new HDL anti-inflammatory capacity or activity impact the remaining science that we have that focuses on other beneficial effects of HDL?

Dr. Anand Rohatgi:

Thank you, Greg. And I would like to first start by thanking Dr. Tika to submitting his article to circulation and thinking about us for his studies. I will say when this came across my desk, I became extremely excited as HDL function is an area that is near and dear to my heart as well. And Dr. Tika is an international expert in this area. So we are quite excited. The reason why this really picked our attention at circulation is that this was really the first and large demonstration that this novel marker on anti-inflammatory capacity was linked to the incidents of cardiovascular events, so that it wasn't just the range and people who already had disease, but at baseline, in people who are otherwise healthy, it could predict those who would go on to be at higher risk of atherosclerotic events. So in this case, what we saw was a truly unique and novel cardiovascular marker.

Dr. Anand Rohatgi:

It was a significant translational study working in effort on the part of Dr. Tika and his research team to be able to do this, and so many participants, this is not an easy undertaking. So to be able to do this and show the results that they were able to show is really remarkable, which is really why it elevated to our interest at circulation. A couple of things in terms of the implications in science are that when they recorded this study, they intriguinly we found that there were really no other stablished risk factors, cholesterol levels, or other markers that are associated with this novel anti-inflammatory capacity, it really wasn't associated with high sensitivity CRP, a global marker of inflammation. And it wasn't associated with the only other HDL function that had been shown to be linked to cardiovascular events, cholesterol influx.

Dr. Anand Rohatgi:

So really what we have here is a truly novel marker that stands on its own. And it's not confounded by the usual things of obesity or other cardiovascular risk factors, and is clearly imparting different information than a global marker, like CRP. I'll extend that these observations to one or two concepts, when it comes to inflammation, there are a couple of things to think about. One is the timing of the inflammatory cascade. A lot of markers are studied at the time where people are in an acute disease state and pro-inflammatory already, and so that can actually have an effect itself on the markers. In this case, by self-report, the participants did not have any acute illness. And so the relationship we see here between anti-inflammatory capacity and cardiovascular events is presumably in the context of a healthy, low inflammatory state. So I think that's important. The other thing that's important, I think for our audience to know is that the inflammation can have tissue specific effects.

Dr. Anand Rohatgi:

So when you think of global markers like CRP or interleukin 6, those are flagged systemic levels of inflammation in your body, and they are also predictive. But when it comes to atherosclerosis, we think about specific tissue types, the endothelium, macrophages, dipocytes. And in this case, what this marker represents is specific activity at the level of the endothelium, which is a key player in the atherosclerotic process. So it really gives us new and novel insights into that process. And it highlights the potential to find maybe therapeutic targets that can be more precise in targeting the atherosclerotic process and improving outcomes. So those were some of the main things that we saw that were exciting.

Dr. Greg Hundley:

Very nice. Uwe, as an international expert. What do you see as the next study that needs to be performed that will perhaps use this new market?

Dr. Uwe Tietge

I think what we need here first would be validation in another cohort and ideally a cohort that involves different ethnicities because our participants were predominantly white. So in terms of generalization, I think this is the next step that we would need. In terms of making this essay applicable to clinical settings in the daily routine, so to speak, we need to simplify it. And this is another issue that we are currently working on, trying to have an easier essay that gives us quicker readouts and ideally, maybe not using primary industry, but something that is better standardizable. And I mean, when you think about next steps, then also identification of a certain biomarker, comes to mind. So something that would reflect the dimension, the activity component of the age that reflects its functioning. And can be used in daily routine and is applicable. It lies to take all the types of essays.

Dr. Greg Hundley:

Very good. Anand, do you have anything to add to that?

Dr. Anand Rohatgi:

Well, I agree completely. I think when you always see a novel marker, you want replication and validation, and I think extending this to other nonwhite cohorts is important. The prevent cohort with 70% men, and also add average out there were probably higher than contemporary populations, at least in the United States. So it'd be nice to see an extension of these observations and cohorts that reflect that diversity. Interestingly, cholesterol wheat blocks the other HDL functions that's been associated with events is not linked through vascular events, it's mostly linked to coronary events. So it would be really interesting to find out how the anti-inflammatory capacity relates to events related to other vascular beds outside of the coronary tree. And then I guess a question that I had for professor Tika is, do you think there might be certain groups of people either by disease or demographic that this might be more powerful formative? Or do you think you would have the same kind of information across the board?

Dr. Uwe Tietge

Yeah, that's a relevant question of course. When we divided our population by participant level characteristics, we saw that there are sex differences. So the predictive capacity seems to be a bit better in females are significantly better than females, which is in male. And also in participants with lower BMI, with ahigher BMI. And the third parameter was in participants with was lower for this one was higher this month. So yes, I expect that some parameters can play a role here and it would be very wise to explore these connections.

Dr. Greg Hundley:

Very good. Well listeners, what an excellent discussion. And we want to thank Dr. Uwe Tika and his team from Stockholm, Sweden, and also our associate editor, Dr. Anand Rohatgi for bringing to us this new research regarding this marker of anti-inflammatory capacity involving HDL, that demonstrates an inverse association with cardiovascular events.

Dr. Greg Hundley:

On behalf of both Carolyn and myself. We want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

Circulation May 11, 2021 Issue

10 maj 2021 | 32 min

This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up.

Dr. Carolyn Lam:

First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance.

Dr. Carolyn Lam:

What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen.

Dr. Greg Hundley:

Really interesting, Carolyn. Clinically, what are the implications today as we see these patients?

Dr. Carolyn Lam:

Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg?

Dr. Greg Hundley:

Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury.

Dr. Carolyn Lam:

Oh, wow. Interesting, Greg. what did they find?

Dr. Greg Hundley:

Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits.

Dr. Carolyn Lam:

Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic.

Dr. Greg Hundley:

Wow, Carolyn, really interesting. Can you summarize it for us?

Dr. Carolyn Lam:

Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy.

Dr. Carolyn Lam:

Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood.

Dr. Carolyn Lam:

Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find?

Dr. Greg Hundley:

Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production.

Dr. Carolyn Lam:

Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece.

Dr. Greg Hundley:

Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles?

Dr. Carolyn Lam:

Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation?

Dr. Carolyn Lam:

Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found?

Dr. Alexander Benz:

Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies.

Dr. Alexander Benz:

Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable.

Dr. Alexander Benz:

Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy.

Dr. Carolyn Lam:

Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation?

Dr. Lars Wallentin:

I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients.

Dr. Lars Wallentin:

This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments.

Dr. Carolyn Lam:

Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex?

Dr. Alexander Benz:

Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from.

Dr. Carolyn Lam:

Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable?

Dr. Lars Wallentin:

Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples.

Dr. Carolyn Lam:

Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish?

Dr. Alexander Benz:

Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this.

Dr. Lars Wallentin:

Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course.

Dr. Carolyn Lam:

Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion.

Dr. Carolyn Lam:

Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found?

Dr. Timothy McKinsey:

Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension.

Dr. Carolyn Lam:

You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found?

Dr. Timothy McKinsey:

Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction.

Dr. Timothy McKinsey:

We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction.

Dr. Carolyn Lam:

Very nice. If you could just give us a one-line on how will you find this hidden fibrosis?

Dr. Timothy McKinsey:

We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at extracellular matrix protein expression in the heart, there was really a profound increase in ECM protein expression in this mouse model, even though the staining for fibrosis was negative. That told us that there was this underlying hidden fibrosis.

Dr. Carolyn Lam:

Oh, that is really interesting. And so it is that form of fibrosis that was actually reversed, perhaps, by the HDAC inhibition, and that's what you showed. Would that be accurate to say?

Dr. Timothy McKinsey:

Yeah. So the HDAC inhibitor really had this profound ability to block that ECM remodeling, the hidden fibrosis, to the point where initially we thought it was an artifact. We thought maybe there was a mix-up of samples. It wasn't a mix up. It's just that the compound, this inhibitor of HDAC enzymatic activity, really has this amazing ability to block the formation of hidden fibrosis.

Dr. Carolyn Lam:

Oh, wow. Wow, Tom, I really, really loved your editorial where you put all of this in context and talked a little bit about the translational and clinical potential. Could you maybe share your thoughts here? I love the title by the way, Erasing Hidden Fibrosis.

Dr. Thomas Gillette:

Thanks. Thanks for that. Yeah, first of all, Tim, it was a really great piece of work, and it's actually really exciting because when we think of this diastolic dysfunction, and really it's the development of HFpEF, I think, that a lot of people are... It's the single most critical unmet need in cardiovascular medicine, is the treatment for HFpEF. That diastolic dysfunction, it's really that stiffness that Tim was measuring with his atomic force microscopy and those changes in ECM that really seemed to be critical, at least in that model.

Dr. Thomas Gillette:

And we know from other models as well that these underlying changes in fibrosis and stiffness, perhaps in the ECM, play a really important role, not only in the diastolic dysfunction, but also if you think about in strain as well, because I know in our models of HFpEF and this mouse model of HFpEF, we have the two-hit model published that Gabrielle, a Allie developed with Dr. Hale in Nature. It's that strain that we could measure that really seems to correlate well with the heart failure phenotype. And so it begs the question, has he caught a very early change in the ECM that's really critical to the development of this pathology? And is there a way that we could detect it early on in patients? Is there a way we could measure that in patients and really get a sense of who's progressing and how they're progressing?

Dr. Thomas Gillette:

Then there's a second point, and I mentioned a little bit in the editorial, I didn't go into it too deeply, and that is, it's really intriguing what this might mean for the development of the disease, because the matrix not only is involved in stiffness, but it's also a reservoir for growth factors, it helps recruit inflammatory cells, and inflammation plays a huge role in HFpEF. And so it begs the question, how many of those changes may proceed a lot of that pathology as well?

Dr. Carolyn Lam:

Wow, Tom, I really couldn't agree more. I made a big deal earlier about agreeing with Tim, calling this a diastolic dysfunction model rather than HFpEF, but I completely agree with you that the implications are for the development of HFpEF, and it needed the begs, the question of how many patients actually have this hidden fibrosis? And we know that in patients with HFpEF, there is a stage of advanced fibrosis where we feel patients don't respond to treatment as well. So have we caught an early phase that may be clinically applicable? I really loved the way you worded that. But finally, with Sergio, could you put it all together and what the editors thought of this paper? Why you invited Tom to write this editorial? And perhaps what next steps are?

Dr. Sergio Lavandero:

Okay, Tim, this is really a fascinating work. I have a long road, because in Italy, you develop the most important new concept. The new concept, the hidden fibrosis. The second important, originally, most of the HDAC inhibitors were developed for other diseases, originally for cancer. So now we have more data that, probably, this compound can apply to other diseases like cardiovascular disease. It was difficult to convince at the beginning some reviewers about the concept of hidden fibrosis, because it's not traditional. But finally, we asked to another expert to, "Okay, why don't you explain, please, this new technique?" For the future, Tim, what do you think? How can we evaluate hidden fibrosis in patients?

Dr. Timothy McKinsey:

Ideally, and you would have a non-invasive approach to assessing hidden fibrosis in patients. Obviously I know myocardial biopsies could be analyzed using the mass spec approach and atomic force microscopy, but not everyone is going to want to get a myocardial biopsy. So ultimately, we would like to correlate data that we obtain with biopsies, with circulating factors to see if there is a non-invasive surrogate circulating factor that correlates with the existence of hidden fibrosis. I think that would be very powerful clinically.

Dr. Sergio Lavandero:

What do you think the specificity of this research, because maybe it's too broad? What do you think?

Dr. Timothy McKinsey:

Yeah, that's a great point. There's a negative impression of general HDAC inhibition, because people just can't believe that you could inhibit a large number of HDAC enzymes throughout the body and not kill someone. But you can. And in our models you can use pretty low doses of these HDAC inhibitors and see efficacy. But obviously, the holy grail in this field would be to identify specific HDAC isoforms that regulate specific disease processes. So we have an active area of investigation where we're trying to tease apart the roles of different HDACs in the heart, with the ultimate goal of finding the HDAC or a subset of HDACs that regulate in fibrosis. Then you could selectively inhibit those and perhaps have a safer drug than a general HDAC inhibitor.

Dr. Carolyn Lam:

Thank you, once again. This is an amazing discussion and really, really an example of just the kind of papers we love publishing at Circulation. So novel and with such translational potential. Thank you, Tim, again, and Tom and Sergio. Thank you, audience, for joining us today. From Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

Circulation May 4, 2021 Issue

3 maj 2021 | 28 min

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, it's another double feature Tuesday and today we get to discuss two articles. One, some insights from the CREDENCE trial. And second, another article about left atrial appendage closure devices, some results from the PINNACLE FLX trial. But before we get to those, how about we grab a cup of coffee and dive into some of the other really interesting articles in this issue? Would you like to go first?

Dr. Carolyn Lam:

I would, because this next paper, right up your alley and I'm sure you'll like it. But first, we talk about mitral valve prolapse. Now, we know that's a frequent disease that can be complicated by mitral regurgitation, heart failure, arterial embolism, rhythm disorders, and death. Left ventricular replacement myocardial fibrosis is a marker of maladaptive remodeling and has been described in patients with mitral valve prolapse. However, the implications of this finding remain scarcely explored. So these authors, led by Dr. [Le] Tourneau from Hôpital Laennec in France, aimed at assessing the prevalence, pathophysiological and prognostic significance of left ventricular replacement myocardial fibrosis through late gadolinium enhancement by cardiac magnetic resonance in 400 patients with mitral valve products. I bet you like that, right Greg?

Dr. Greg Hundley:

Oh my gosh Carolyn, not only a favorite topic of cardiovascular magnetic resonance, but this is a really large patient population with mitral valve prolapse that underwent CMR. So tell us, what did they find?

Dr. Carolyn Lam:

So replacement myocardial fibrosis was observed in 110 patients, so that's 28% of the patients. It was associated with mitral valve apparatus alterations, left ventricular remodeling, and ventricular arrhythmia. The ventricular arrhythmias were more frequent in patients with replacement fibrosis, but were not associated with the grade of mitral regurgitation. In patients with trace or mild mitral regurgitation, the presence of replacement myocardial fibrosis was nonetheless associated with specific mitral valve apparatus alteration at normal left ventricular dilatation, not explained by volume overload and ventricular arrhythmias, suggesting the presence of a mitral valve prolapse-associated cardiomyopathy.

Dr. Greg Hundley:

Wow Carolyn, really interesting. So the late gadolinium enhancement and the evidence therefore of replacement myocardial fibrosis that was identified by CMR, maybe this particular study is suggesting that we might want to integrate that into the clinical workup of patients with mitral valve prolapse. Very interesting work, and great job on that fantastic CMR presentation. I must say, got to recruit you into the club.

Dr. Greg Hundley:

Well, my next paper is another wonderful paper from the world of basic science and it comes from Dr. Douglas Lewandowski at the Ohio State University College of Medicine. So Carolyn, the failing heart is energy starved with impaired oxidation of long chain fatty acids at the level of reduced carnitine palmitoyltransferase-1, or CPT-1, activity at the outer mitochondrial membrane. Recent work shows that elevated ketone oxidation and failing hearts as an alternate carbon source for oxidative ATP generation. So Carolyn, these authors hypothesized that another short chain carbon source, short chain fatty acids that bypass CPT-1, could similarly support energy production in failing hearts.

Dr. Carolyn Lam:

Wow. Okay, so what did they find?

Dr. Greg Hundley:

So Carolyn, the failing heart oxidizes short-chain fatty acids more readily than ketones, with short-chain fatty acids also displacing long-chain fatty acid oxidation to somewhat of a greater extent. So in particular, the short-chain fatty acid butyrate has a higher affinity for entry into mitochondrial oxidation at the enzyme, short-chain Acyl-CoA dehydrogenase than does the ketone 3-hydroxybutyrate at the hydroxy butyrate dehydrogenase and then also through the respective downstream metabolic pathways for each substrate. So Carolyn, failing hearts of rats and humans have increased levels of Acyl coenzyme A synthetase medium chain three enzyme, which can also oxidize short-chain fatty acids to enhance butyrate oxidation.

Dr. Carolyn Lam:

Wow, that really is interesting. I can't say that I would have predicted that result. So could you give us a clinical implication?

Dr. Greg Hundley:

You bet, Carolyn. A lot of basic science here. So here's I think what we can take home, and what we learned. So while ketones have been sought as a potential supplemental fuel to remedy the impaired oxidative metabolism of the failing heart, this study shows that failing hearts preferentially oxidize short-chain fatty acids over ketones and short-chain fatty acids may prove to be a more efficient energy source during pathological stress.

Dr. Greg Hundley:

Next, novel alterations in metabolic pathways, favoring short-chain fatty acid oxidation in the failing heart occur in patients with non-ischemic cardiomyopathy. Then finally, circulating ketones are not a unique, super fuel beyond the ability to bypass the inhibition of long-chain fatty oxidation in the failing heart, as do the short chain fatty acids.

Dr. Carolyn Lam:

Thanks, I like the way you broke down the clinical implications. Well, Greg, I've got a question for you. Have you ever thought that statins may do more than lower cholesterol, but depending on what you eat?

Dr. Greg Hundley:

Oh wow, Carolyn. We always hear about the pleiotropic effects of statins, but I never really thought that could depend on what you eat. Tell me, so what did these authors investigate?

Dr. Carolyn Lam:

Yeah, so this next paper is so interesting. It's from Dr. Hu from Huazhong University of Science and Technology in Wuhan, China and colleagues, who present a novel perspective on the story of the pleiotropic effects of statins, exactly like you said, Greg. They started with the premise that statins exert pleiotropic or cholesterol-independent effects by reducing geranylgeranyl pyrophosphate production. I'm not going to keep saying that, so geranylgeranyl pyrophosphate or GGPP, is how I'm going to refer to it.

Dr. Carolyn Lam:

So they developed a sensitive technique to quantify dietary GGPP, and conducted proteomics, RT-PCR screening, and western blot, to determine signaling cascades, gene expression, protein-protein interaction, and protein-membrane trafficking in wild-type and transgenic rats, focusing on models of pulmonary hypertension, given their interest in the potential therapeutic efficacy of statins in pulmonary arterial hypertension.

Dr. Greg Hundley:

Interesting, Carolyn. Really complex and sophisticated. So what did they find?

Dr. Carolyn Lam:

Okay, listen up. Red meat and soybean have a high content of GGPP and their ingestion increases GGPP plasma levels, but reduces the effects of statins in rat models of pulmonary hypertension. Ingestion of garlic extracts, rich in methyl-L-phenyl sulfonate, which is a natural inhibitor of GGPP production, decreases GGPP bioavailability, and rescues statin effects in pulmonary arterial hypertension models. So consequently, first of all, diet may influence the cholesterol-independent effects of statins and the data really raise a provocative question of whether populations in which the typical diet contains high amounts of soybeans of beef may benefit less from statins. All this is discussed in an elegant editorial by Dr. Thomas Eschenhagen from Germany, who really ends with saying the present study should be considered hypothesis-generating and stimulate retrospective analysis of clinical registries and existing large interventional trials to either validate or refute this hypothesis. Whatever the outcome, the study is a nice example of thorough scientific underpinning of the widely held maxim that we are what we eat.

Dr. Greg Hundley:

Oh, absolutely Carolyn. I think next time with my spaghetti, I'll have the-

Dr. Carolyn Lam:

Garlic.

Dr. Greg Hundley:

... sauce with the garlic, but I won't add the red meats. Especially if I'm taking a statin.

Dr. Carolyn Lam:

Oh, that's what I was afraid you might say. Oh well, let me tell you about other papers in this issue. There's an ECG challenge by Dr. Del-Carpio Munoz and entitled A Carousel ECG Confusion. There's an on my mind paper by Dr. Hammond, on the importance of shared decision making for return to play after COVID-19.

Dr. Greg Hundley:

Great, Carolyn. So, in the mailbag, there's a really nice research letter from Dr. Robert-Ebadi evaluating the impact of the age-adjusted D-dimer cutoff to exclude pulmonary embolism. It's from a multinational prospective real-life study or the RELAX-PE study. Well Carolyn, it's another double feature Tuesday. How about we get off to understand a little bit more about those insights from the CREDENCE trial, and then also left atrial appendage closure devices?

Dr. Carolyn Lam:

All right, come on with your garlic breath.

Dr. Greg Hundley:

Well listeners, we are onto our feature discussions and we are very fortunate, we're going to have two feature discussions. Our first feature really addresses high blood pressure. And we have with us today, Dr. Brendan Neuen from the George Institute of Global Health in Sydney, New South Wales, Australia. And our own associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern in Dallas, Texas. Welcome to you both. Brendan, we're going to start with you. Could you describe the hypothesis that you wanted to test and what was your study population and your study design?

Dr. Brendan Neuen:

Well, thanks Greg. In this study, what we wanted to assess was the blood pressure lowering effects of the SGLT-2 inhibitor canagliflozin in people with type two diabetes and chronic kidney disease. The reason we thought that this is important is because what we know about the blood pressure lowering effects of these drugs is largely based on people with normal kidney function, with relatively less data in people with chronic kidney disease. So we aim to assess both the blood pressure lowering effects of SGLT-2 inhibition in chronic kidney disease, as well as treatment effects by baseline blood pressure and other blood pressure defined variables. This was conducted in the CREDENCE trial, which was a large primary renal outcome trial of the SGLT-2 inhibitor, canagliflozin, which enrolled about 4,400 people with type two diabetes and chronic kidney disease with a urine albumin to creatinine ratio greater than 300 milligrams per gram and a GFR greater than 30 at enrollment. This was a high risk hypertension population, about 30% of patients had apparent treatment resistant hypertension, about 60% of people had a GFR less than 60 and about 20% of people were on four or more blood pressure lowering agents. So really high burden of hypertension in the CREDENCE trial.

Dr. Greg Hundley:

Very good. Tell us a little bit about that design. So is this a randomized trial?

Dr. Brendan Neuen:

So CREDENCE was an event-driven randomized, double blind, placebo controlled, international trial. It was the first primary renal outcome trial of an SGLT-2 inhibitor, the primary results of which were reported in the New England journal in 2019. What this trial did, was it randomized participants, as I mentioned, with a GFR of greater than 30 and significant albuminuria and type two diabetes to either canagliflozin 100 milligrams or matching placebo in a one-to-one ratio with primary outcome overall of doubling of serum creatinine, kidney failure, cardiovascular or renal death. The trial was conducted in several, I think, 20 or 30 countries overall and enrolled at approximately 4,400 people, with participants followed for a median of about two and a half years.

Dr. Greg Hundley:

Excellent. So Brendan, tell us, what did you find?

Dr. Brendan Neuen:

So we found a couple of important findings with regards to blood pressure. Firstly, what we found was that canagliflozin reduced systolic blood pressure by about three and a half millimeters of mercury in the overall trial population. But most importantly, this blood pressure lowering effect was consistent across the number of blood pressure defined subgroups, including in people on multiple numbers of blood pressure lowering agents. So irrespective of the number of blood pressure lowering agents at baseline, and also irrespective of a history of apparent treatment-resistant hypertension at baseline, that was important. We also, secondly, found that the blood pressure lowering effective SGLT-2 inhibition was present very early at the first trial visit at three weeks. This effect was sustained over the duration of the trial.

Dr. Brendan Neuen:

Thirdly, we also found that canagliflozin reduced the risk of kidney failure and cardiovascular events, regardless of the number of blood pressure lowering agents at baseline and regardless of blood pressure, history of resistant hypertension. Finally, there is this often important question of how do these drugs reduce the risk of kidney failure and heart failure. So we did a mediation analysis, looking at to what extent the blood pressure lowering effect of this drug explains the treatment effect on these important outcomes. We found that only about less than 10% of the treatment effect on kidney failure and cardiovascular events was explained by blood pressure lowering.

Dr. Greg Hundley:

Very interesting and strong, powerful results. Well, now we're going to turn listeners to our associate editor, Dr. Wanpen Vongpatanasin. Wanpen, I know you see a lot of papers come across your desk at circulation, really focused on blood pressure and its lowering. What struck you about this paper, and then how do you put into context the results that Brendan just describe for us with all the other results that you see in new blood pressure lowering strategies?

Dr. Wanpen Vongpatanasin:

Yes, so I think this is very important study and add to a body of literature showing that the canagliflozin, like many SGLT-2 inhibitors, inducing significant lowering of blood pressure. If anything, because CREDENCE is not designed to be hypertension study the effects of blood pressure lowering my even be underestimated because the backup ground therapy allowed to be changed throughout the trial, depending on physician judgment. Also, I think the effects of many studies start to look at effects of SGLT-2 inhibitor on out of office blood pressure, like home blood pressure, or 24 blood pressure. Some even that we have published over the years, show more pronounced blood pressure lowering effects when measure outside the office. So I think that it is very interesting study but it could be not just only the drug that we use cardiovascular and renal outcome, but maybe a new class of antihypertensive medication that we could use for that purpose, although it has to be tested.

Dr. Greg Hundley:

Very nice. Well, Brendan, I want to turn back to you and then we'll come to Wanpen. Brendan, what do you think as a followup study to yours, what do you think is the next study that needs to be performed in this space?

Dr. Brendan Neuen:

Thanks, Greg. I think there's so much we still need to know about the blood pressure lowering effects of these drugs in people with advanced CKD. It would be very interesting to look at the DAPA-CKD trial, to look at the blood pressure lowering effects in people with advanced CKD not due to diabetes, so nondiabetic kidney disease. These patients also have a high burden of hypertension and whether or not these effects are also present in this population would also be important to know, and study patients with even more advanced kidney disease. That is being done in the EMPA-KIDNEY study with empagliflozin. Those results should be known in the next 12 to 24 months.

Dr. Brendan Neuen:

So, I'm studying this further in people with kidney disease. And also as Wanpen mentioned, looking at effects on blood pressure phenotype, you know, 24 hour blood pressure dipping status would also be important though, blood pressure variability, all those things can add to our understanding of the effect of these agents on blood pressure.

Dr. Greg Hundley:

Excellent. And Wanpen, do you have anything to add?

Dr. Wanpen Vongpatanasin:

Yes. I think one also very important study that helps someone with carrying in the future is in the CREDENCE, the people who are already treated with a mineralocorticoid receptor antagonist were excluded. So whether among resistant hypertension group, adding canagliflozin will be beneficial in those groups already treated MRA and lower cardiovascular outcome in already treated with MRA will be very interesting to see.

Dr. Brendan Neuen:

Yeah, I think that's a really important point to point out about the design of the CREDENCE trial, that patients who were on MRAs were excluded from the trial initially. This was due to early concerns that canagliflozin might increase the risk of hyperkalemia. I think that risk has now been put to bed in the other SGLT-2 inhibitor trials. We've got more data looking at the effects on serine potassium coming out soon, hopefully, but the other trials in which enroll more patients on MRAs, it will be very important to look at the blood pressure lowering effects in these populations.

Dr. Greg Hundley:

Excellent. Well, listeners, we've heard a great discussion today and we want to thank Brendan Neuen for bringing this wonderful science to us through circulation at the American Heart Association. We also want to thank our associate editor, Wanpen Vongpatanasin for being present today and helping us discuss how, in patients with type two diabetes and chronic kidney disease, describing that the blood pressure lowering effect of canagliflozin occurs early and appears sustained over the long term and therefore perhaps canagliflozin and can be used or considered as an adjunct blood pressure lowering medicine in addition to perhaps its protective effects on the kidney and other cardiovascular-related issues. Well now listeners, we've got another feature to get onto. So we're going to get to that second feature discussion right now.

Dr. Greg Hundley:

Well listeners, we are now turning to our second feature discussion and we're so fortunate today to have with us Dr. Saibal Kar from the Los Robles Regional Medical Center in Los Angeles, California, and our own associate editor, Dr. Mark Link from UT Southwestern in Dallas, Texas. Welcome gentlemen. Saibal, let's start with you. Could you describe for us the hypothesis that you wanted to test and what was your study population and your study design?

Dr. Saibal Kar:

Dr. Hundley, or if I could allow to call you Greg, thank you very much for asking me this question. The hypothesis was that we do know that the WATCHMAN device does prevent ischemic strokes. We do know that the first generation device has a few limitations. So there were some modifications made to the new WATCHMAN device, which is now called the WATCHMAN FLX. We thought that these changes should translate into better safety and better efficacy. So, that was the hypothesis of the study. The study population was patients with nonvalvular atrial fibrillation with a CHADS-VASc score of three or more, who had high risk of bleeding or patients who cannot take long-term anticoagulants. The study design was a single arm, prospective multicenter study with endpoints, which were based on performance goals from previous clinical trials.

Dr. Greg Hundley:

Excellent. Before we get to your results, Saibal how many patients and how many centers participated in your trial?

Dr. Saibal Kar:

So as the national principal investigator, I've never seen a study which was enrolled so fast. So the intended population was 400 patients in 29 centers and before half those centers could be activated, the study was over in four months.

Dr. Greg Hundley:

Congratulations. I think all of us that have ... especially in this pandemic era for recruiting so well, and tell us, what did you find?

Dr. Saibal Kar:

So what we found is that there were two endpoints, a safety endpoint and the efficacy endpoint. So the first thing that we found is that of the 400 patients, we could actually implant in 395 patients, device actually, which made the primary success rate over 98%. regarding the safety endpoint, we had a safety margin around 4% based on a performance score and set about 2.5, but the actual safety event rate was 0.5%, which was only two minor ischemic events, peri-procedural. There were no pericardial effusions in the first seven days, and there was no device embolizations at any time period, so that was the primary safety endpoint. So we were actually clearly safer than the first-generation device.

Dr. Saibal Kar:

When it comes to efficacy, it was an anatomical efficacy and we set the primary goal for the previous generation to be 99%. We've made a delta to make it about 97% effective, but we actually achieved an effective closure in 100% of patients. When I say effective closure, I mean that anyone with a peri device leak of less than five millimeters. Going into a little bit of granular detail, we actually found out that 90% of the patients actually had no leak at all. So we did at least achieve both the anatomical as well as the safety endpoints.

Dr. Greg Hundley:

Excellent. Well, listeners, we're now going to turn to our associate editor, Dr. Mark Link and Mark, I know you have many papers that pass through your hands. What attracted you to this paper. Then, these results really sound significant. Can you describe what impressed you also with the results of this study and how do they relate to other studies pertinent to implantation of devices in patients with atrial fibrillation?

Dr. Mark Link:

Yeah, we were interested in this paper at CERT because it's the next generation of the WATCHMAN. The numbers of patients that are being implanted with this device to prevent strokes is dramatically going up, but it's not a perfect device. So we were, as the EP community, very interested in the next generation device. We're obviously also interested in other competitors' device, but it's clear that the WATCHMAN is probably the world's leader in this time. So we knew that many of our people reading this magazine, reading the circulation, would want to see how the next generation turned out, was it really safer. That was really the primary goal of this study, it's really a safety study more than an efficacy study because the efficacy was defined by echo criteria, not by clinical criteria of stroke, which is the ultimate criteria. It was a well done study and the results came out more positive than I think even the investigators thought it was going to come out. So we liked it and that's why we did our best to get it published in circulation.

Dr. Greg Hundley:

Very good. So it sounds like great new innovation and very, very safe, especially relative perhaps to the first-generation device. So Saibal, can you tell us in just a few words, what do you think is the next study to be performed in this space? After you answer, Mark, we'll turn to you and basically ask the same question.

Dr. Saibal Kar:

Thank you very much, Greg. Transcatheter left atrial appendage closure has been approved by the FDA, specifically the WATCHMAN device, for patients who are candidates for long anticoagulation, but have limitations to long-term anticoagulation and therefore not for all-comers and there's a reason for that. The time has now come to actually evaluate this device for all-comers. That means all patients with nonvalvular atrial fibrillations who are suitable for anticoagulants. Therefore, the next best study is the CHAMPION trial. This study is going to be a randomized trial of the WATCHMAN FLX versus NOACs, or more correctly DOACs, in all-comers, patients with nonvalvular atrial fibrillation who require long-term anticoagulants. It's a 3,000 patients clinical trial with a one-to-one randomization to WATCHMAN FLX or the continuation of DOACs and the primary endpoints will be estimated at three years with a follow-up up to five years. Our goal is to show that we are non-inferior in comparison to stroke and death, and superior respect to long-term bleeding.

Dr. Greg Hundley:

Very good, and Mark?

Dr. Mark Link:

Yeah, I agree. The CHAMPION trial is the obvious next trial that everyone wants to see the results of, comparing this device to DOACs. Another trial or data I'd like to see is the immediate post-procedural anticoagulation. It's still an area that we don't have enough data to know how to treat these patients. Traditionally, they've been treated with warfarin and anti-platelet agents, but many of the patients getting this WATCHMAN have a relative contraindication to anticoagulation. So I'd like to see some data on shorter term duration of anticoagulation post-implant.

Dr. Greg Hundley:

Very good. Well listeners, we've had a wonderful discussion here and we want to thank the lead author, Dr. Saibal Kar and also our own associate editor, Dr. Mark Link, for really providing us with new information that this left atrial appendage closure device met the primary safety outcome in 99.5% of all of those implanted within seven days, what a remarkable finding. So, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run. This program is copyright of the American Heart Association, 2021.

Circulation April 27, 2021 Issue

26 april 2021 | 31 min

Dr Carolyn Lam:

Welcome to Circulation on the Run! Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr Carolyn Lam:

Greg, we got double features today. Now, the first one's all about fruit and vegetables. Now, before you switch off, this is a very important one, okay? So, listen on. And the second is on the EMBRACE heart failure trial. Now, this was a late breaker, very important, more data on empagliflozin, that SGLT2 inhibitor. So really, really fun discussions coming right up. But first, can I dig into one of the papers that I'm really dying to tell you about?

Dr. Greg Hundley:

Absolutely.

Dr Carolyn Lam:

Okay. This is all about the diagnostic performance of high-sensitivity cardiac troponin T strategies, that super hot topic. We know that European data support the use of low high sensitivity troponin measurements or a 0/1 hour algorithm for myocardial infarction or to exclude MACE among emergency department patients with possible acute coronary syndrome. However, there's really very modest U.S. data to validate these strategies. This study today from Dr. Allen and colleagues from University of Florida, really evaluated the diagnostic performance of an initial high sensitivity cardiac troponin T measure below the limit of quantification. And that is six nanograms per liter, a 0/1 hour algorithm, and their combination with heart scores for excluding MACE in a multi-site U.S. cohort. And this is the largest prospective multi-site U.S. study of high sensitivity troponin T strategies to date.

Dr. Greg Hundley:

Wow, Carolyn you've really piqued my interest. So what did they find?

Dr Carolyn Lam:

Okay. And initial high sensitivity, cardiac troponin T below that level of quantification of six nanograms per liter was associated with a negative predictive value of 98.3% for 30-day MACE. Okay. That was that value itself. Now the 0/1 hour algorithm rolled out 57.8% of patients with a negative predictive value of 97.2% for 30-day MACE. The addition of a low-risk heart score to that initial high sensitivity troponin T level below that six nanogram per liter and the 0/1 hour algorithm improved the negative predictive value for 30-day MACE to 99% and 98.4% respectively.

Dr. Greg Hundley:

Wow. Carolyn, it looks like a really comprehensive analysis of the high sensitivity troponin. So tell us what are the clinical implications of this study?

Dr Carolyn Lam:

So these data seem to imply that when used without a risk score and initial high sensitivity troponin T below six nanograms per liter, or a 0/1 one hour algorithm, may not have sufficient sensitivity or negative predictive value to exclude 30-day MACE in the U.S emergency department patients. But the addition of that low-risk heart score to those measures improves the negative predictive value, but rolls out fewer patients. And so in totality, these results suggest that in the U.S. Emergency departments, adding a risk score to either of these strategies really increases their safety.

Dr. Greg Hundley:

Boy, great new information in our journal. Well, Carolyn, I'm going to switch to the world of basic science and start to evaluate in this next paper, the regulation of cellular signatures in children with dilated cardiomyopathy, and the work comes to us from Dr. Stephanie Dimmeler from Goethe University in Frankfurt. So Carolyn, Stephanie's team performed single nuclei RNA sequencing with heart tissues from six children with dilated cardiomyopathy. One was age 0.5, 1.75 and another at 5, 6, 12, and then 13 years of age. And they did this to gain insight into age and disease-related pathophysiology, pathology, and molecular fingerprints. And the goal was to gain further insight into dilated cardiomyopathy, which is a leading cause of death in children with heart failure.

Dr Carolyn Lam:

Cool. So what did they find Greg?

Dr. Greg Hundley:

Right, Carolyn. So, the number of nuclei in fibroblast clusters increased with age in dilated cardiomyopathy patients, a finding that was consistent with an age-related increase in cardiac fibrosis quantified by cardiovascular magnetic resonance imaging.

Dr. Greg Hundley:

Now Carolyn, fibroblast of the dilated cardiomyopathy patients over six years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans and a switch in thrombospondin isoforms and signatures for fibroblast activation. Additionally, Carolyn, a population of cardiomyocytes with a high pro-regenerative profile was identified in infant dilated cardiomyopathy patients, but was absent in those children that were greater than six years old. And this cluster in these infants showed high expression of cell cycle activators, such cyclin D family members increased glycolytic metabolism and any oxidative genes and alterations in beta adrenergic signaling genes.

Dr Carolyn Lam:

Wow. That sounds like a magnificent and elegant study. Could you boil it down to the take home messages?

Dr. Greg Hundley:

You bet. Carolyn. Great question. So two points first, infants with a predominantly regenerative cardiomyocyte profile, may preferentially receive treatment strategies to support cardiac regeneration while patients with a pattern associable with cardiac fibrosis may benefit from an early anti-fibrotic therapy to avoid diastolic dysfunction. And second, despite the impracticality of performing these large cohort studies in children with dilated cardiomyopathies, tailored pharmacological treatment is possibly realistic. For example, based on the expression of beta adrenergic signaling genes.

Dr Carolyn Lam:

Oh wow. That is super cool. That's Circulation for you, publishing these amazing basic science papers with very big clinical implications. Well, I've got another basic science paper for you and this time I've learned a new word actually. It's called O-GlcNAcylation. I should get you to say it after me. I had to get our editor-in-chief Joe Hill to teach me to say that, O-GlcNAcylation. So, cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Now, in this paper, co-corresponding authors, Dr. Anderson and Umapathi from Johns Hopkins University provide a new genetic mouse model to control myocardial O-GlcNAcylation independent of pathological stress. Their data actually provided evidence that excessive O-GlcNAcylation caused cardiomyopathy, at least in part due to defective energetics. Enhanced O-GlcNAcase activity was well-tolerated. And conversely, attenuation of O-GlcNAcylation was beneficial against pressure overload induced pathological remodeling in heart failure.

Dr. Greg Hundley:

Interesting, Carolyn. So what are the clinical implications of these findings?

Dr Carolyn Lam:

Well, the data really provide new proof of concept that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy, and they also suggest that attenuation of this excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

Dr Carolyn Lam:

Shall we go on and sort of wrap up on what else is in this issue? Because I'd like to talk about highlights from the Circulation family of journals that Sarah O’Brien really beautifully summarizes, talking about everything from Circulation: Arrhythmia & Electrophysiology, to [Circulation:] Cardiovascular Quality & Outcomes. It's just a beautiful piece where we get all the highlights. Must read. There's also a Perspective piece by Dr. Gillis on Rhythm Control in Atrial Fibrillation: Is Earlier the Better?, and that discusses the EAST-AFNET 4 and early AF trials.

Dr. Greg Hundley:

Very good, Carolyn. Well, from the mailbox, professors Pan and Liu exchange letters regarding a prior response to a letter regarding the article Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program. Also, Dr. Arbus-Redondo has an EKG challenge entitled, Dual Chamber Pacemaker after Sinus Node Dysfunction and an Enlarged Right Atrium. Is it what it seems?

Dr. Greg Hundley:

And then finally, Dr. Corrado has a very nice Research Letter, entitled, Serial versus Single Cardiovascular Screening of Adolescent Athletes.

Dr. Greg Hundley:

Well, Carolyn, I'm dying to hear about fruits and vegetables. How about we get onto those featured discussions?

Dr Carolyn Lam:

Cheeky, cheeky, Greg. Here we go.

Dr Carolyn Lam:

Oh, I'm so excited about today's featured discussion because it's about my favorite thing, fruits and vegetables. Okay, wait a minute, everybody. Before you start rolling your eyes, this is a really important one. Have you ever asked yourself, what is the optimal intake levels of fruit and vegetables for maintaining long-term health? Well, guess what? We're about to find out and I'm so pleased to have the first author of today's feature paper, Dr. Wang Dong, and he's from Harvard medical school and Brigham Women's Hospital. We also have our Associate Editor, Dr. Mercedes Carnethon from Northwestern University and our Associate Editor who is also the editorialist to this paper, Dr. Naveed Sattar from University of Glasgow. So welcome, everyone. Dr. Wang, please tell us what you did in this study and what were your main results?

Dr. Wang Dong:

Thank you, Carolyn. So, basically, in this study, we analyzed the data from two long running cohort study. That is the Nurses' Health Study and Health Professional Follow-Up Study. So these two study includes more than 100,000 participants who had been followed for up to 30 years. And we also include a meta-analysis that includes in total 26 studies and about two million participant from 29 countries, and had countries around the world. So, basically, the major finding from this study is, of course, the intake of fruits, vegetable is inversely associated with the risk of death from all cause and the different kinds of cause-specific mortality. And we have a very interesting finding that is intake of about five servings per day, that can be translated into two serving of fruits and three servings of vegetables per day, was associated with the lowest risk of total mortality. So that's an optimal intake level for fruits and vegetable.

Dr. Wang Dong:

And another important finding from this study is, not all foods that some people consider to be fruits and vegetables can offer the same health benefits. For example, in this study, we found that starch vegetables such as peas and corn, and some fruits juice and potatoes are actually not associated with any benefit in terms of longevity. On the other hand, if you look at green living vegetables such as spinach, kale, and fruits that's orange color fruits and vegetables, that's rich in beta-carotene and vitamin C such as citrus fruits and berries, carrots they're associated with a substantial reduction in the risk of total mortality. That's a major finding from this paper.

Dr Carolyn Lam:

Oh, I just love it. I mean, just like such wholesome, beautiful findings from a wonderful study. Now, if I could ask you, cause I think the first thing everyone's going to say is, okay, these are associations. I mean, what'd you do about the residual risks? Could you maybe describe how you try to address some of these things like, is taking in fruits and vegetables just a surrogate for people who, I don't know, exercise more, for example?

Dr. Wang Dong:

Yeah. So in original data analysis, we actually have extensive data collection of all kinds of foods, lifestyle, risk factors, medication use, any health-related variables. So we carefully adjust for a large number of confounding factors. So actually another thing I want to point out, most all of these health-related lifestyle factors actually are inverse confounding factors in this kind of analysis. So when you adjust for other confounding factors, it's tend to attenuated your inverse association. So the review from confounding actually wouldn't be a major explanation for this association.

Dr Carolyn Lam:

Oh, that's great. And by the way, I think I misspoke. I'm not sure if I said residual confounding or residual risk just now, but you absolutely read me right, that I meant residual confounding. So thanks. Now that we've got that out of the way, if I could ask Mercedes, please. I mean, ah, another fruits and vegetables paper, I mean, what made this one different that we said we have to have it at Circulation.

Dr Mercedes Carnethon:

Well, thanks so much, Carolyn. And thank you Dong, for your team's outstanding work. I know what excited me about it was the demonstration of something that we have adopted into our lexicon, that one needs five fruits and vegetables. So I was excited to see you quantify it. In particular, the question I have for you is, did you see that these patterns of association of fresh fruit and vegetable intake were consistent across the age range and in both sexes?

Dr. Wang Dong:

Yes, of course. In total, this acts as a stratification variable. So basically, in our original data analysis, we did the analysis in the Nurses' Health Study, which all the participants are women, and in the Health Professional Follow-Up study, in which all the participants are men, would be analyzed separately and we found very consistent results in both cohorts. Then will be the meta-analysis to meta-analyze the results from these two cohorts. It comes out age, actually if you look at the paper, I think in one of the supplemental table, with the age stratified analysis, to look at the a better association if it still holds in different age group. And we did found that the results is pretty consistent in different age groups. And also, I would point out this meta-analysis provides further support to show that this results is generalizable in different people with different social economic status, demographics status also from different background.

Dr Mercedes Carnethon:

Thank you so much, Dong. it brings me to what Naveed wrote about in his editorial, that food is medicine and I just really loved that and loved the implications of that. So, I don't know, Naveed, if you've got some comments to make? Questions?

Dr Naveed Sattar:

Yeah, thanks Mercedes. No, I really love this as well because clearly the cardiovascular community, we do lots of trials. Lots of us are nihilists and just look at trials, but actually it's hard to do trials in the food and the dietary area, but these data are very consistent. I think there are multiple potential mechanisms that may explain this. We all have to eat every day, so it's a big part of our lives. Increase fiber intake, increase potassium, micronutrients, food displacement, the more fruit and veggies you eat, the less you'll eat of other things that perhaps are not as protective. And actually, part of the motivation to write an editorial was to put all that into context in terms of mechanisms. And particularly fiber, I think we underestimate the importance of fiber, but then it was also to discuss, well, if this is true, how do we help people make the changes?

Dr Naveed Sattar:

And at the level of policy, at the level of high risk groups, and my own particular favorite is really communicating dietary change in the clinic. And one of the things I often try, and we put this in a kind of headline figure in the editorial, was actually getting people to try to undergo the palate test or the retraining their palates. I have lots of patients, who, would you believe, in the west of Scotland, never really eat fruit and veg, and I really pushed them to say, "Look, would you please try? And it might take a few weeks for you to retrain your palate". And lots of people come back saying, "Ah, you're correct. And my God, now I like banana and I now like salad."

Dr Naveed Sattar:

So actually, there's lots of tips that we can do to help people increase from their average of two to three intake, which is the vast majority of population, to four to five, but it's a gradual process and it requires good communication with our patients and to compel them that these changes might take time, but that if they make these changes, they can get to a point where they really enjoy eating fruit and veg and all the multiple health benefits that come, which this paper has now showed, Mercedes.

Dr Naveed Sattar:

I think for me, that was the real nub of this.

Dr Carolyn Lam:

Naveed, I just love the way you express it. And indeed, everyone take up that editorial and look at that beautiful figure. I love the colorful fruits and vegetables on top because it also reminds us, and this paper shows, we are not talking about potato chips, and was it those, corn and peas. But, you know, we're talking about nutrition and fiber and the good stuff. Oh, this is just amazing. I wish we could go on forever, but we have a double feature this issue. And I just want to end by saying, thank you, thank you all of you, for being on the show today. It was such an important topic and I really loved the discussion as I'm sure the audience did. Thank you.

Dr Mercedes Carnethon:

Thank You.

Dr Naveed Sattar:

Thanks very much.

Dr. Wang Dong:

Thank you so much.

Dr Carolyn Lam:

I am so pleased to have with us today, a friend, a deeply admired colleague and the corresponding author of today's feature discussion, Dr. Mikhail Kosiborod from Saint Luke's Mid America Heart Institute.

Dr Carolyn Lam:

Welcome, Mikhail. And thank you for publishing this beautiful paper on EMBRACE heart failure with us. I know that this was presented as a late-breaking trial at the Heart Failure Society of America meeting, and it's a very much anticipated paper, but maybe I could start with it's all about SGLT2 inhibitors these days. So please tell us how does EMBRACE add to this accumulating knowledge that we have on SGLT2 inhibitors and heart failure?

Dr. Mikhail Kosiborod:

Well, first of all, Carolyn, thanks so much for publishing our trial in Circulation. And you're right, SGLT2 inhibitors have been taking the world of cardiometabolic medicine and heart failure by storm over the past few years. EMBRACE is a very unique trial because it really, took this world of rapidly developing technology in heart failure and heart failure monitoring, and coupled it with one of the hottest topics in heart failure today in terms of drug management, which is the advent of SGLT2 inhibitors and the emergence SGLT2 inhibitors as a efficacious therapy, not just for prevention of heart failure, but also treatment of heart failure. Because as you know, pulmonary artery pressure and hemodynamic status are one of the strongest predictors of patient outcomes, both in terms of symptoms, hospitalizations, and deaths in heart failure. And we know actually that monitoring and intervening on elevated pulmonary pressure in this patient population may lead to hospitalizations and possibly even death.

Dr. Mikhail Kosiborod:

But up until recently, it's been very difficult to monitor pulmonary pressures and to use them as an outcome in heart failure trials, because you will have to use invasive monitoring, essentially a right heart catheterization to get that data. Well, now we can actually have this implanted sensors like CardioMEMS, which are the sensors that we use in EMBRACE-HF trial. So, the question we wanted to ask is, we know SGLT2 inhibitors in DAPA-HF and EMPEROR-Reduced trials, clearly reduce the risk of cardiovascular death and hospitalization for heart failure, worsening heart failure, but the mechanisms have been hotly debated. Is there a possibility these agents can actually have an impact on hemodynamic status and pulmonary pressures? And that's the key central question that we tried to address and EMBRACE-HF trial by using this novel technology at the time, now it's been around for a few years, to noninvasively measure pulmonary pressures and use it as a primary outcome in our trial.

Dr Carolyn Lam:

Mikhail, first of all, hats off, it was a very, very clever idea to look at these patient populations who already have CardioMEMS right, and then perform this randomized trial. I mean, when I saw this, I was like, "Aw, man, how come I didn't think of that? That's just like so clever, but it's just so Mikhail to be ahead of the curve." But I'd like to remind the audience, this was a prospective randomized trial, the pre-specified outcomes, right? So maybe you could describe that in a greater detail and then the results. Yeah.

Dr. Mikhail Kosiborod:

Absolutely. Well, Carolyn, first of all, once again, thank you very much. You're being very kind. We do think it was a very novel clever idea and that you're absolutely correct, as this was very rigorously designed, randomized, double blind placebo controlled investigating trial within this study and 10 sites in United States. And the patients had to have heart failure, either with reduced or preserved ejection fraction, about half-and-half actually, as it turned out to be once it's all said and done with the trial. Because they had to have implanted CardioMEMS for clinical indication previously, they were quite advanced in terms of their heart failure. So more than half of the patients were in NYHA class III or IV, they had elevated brain natriuretic peptide levels, they had hybrid symptoms as you would expect. And essentially the patients were screened, and if they were eligible, randomized to use a empagliflozin-placebo in a double-blind fashion.

Dr. Mikhail Kosiborod:

And they were monitored actually for a couple of weeks prior to randomization to get a baseline pulmonary artery diastolic pressure. They were then treated for 12 weeks with empagliflozin, 10 milligrams a day, or a matching placebo. And we were measuring pulmonary pressure twice a day, every day for the 12 week treatment period, and then at the end of the treatment period, the treatment was stopped, but we actually continued to measure pulmonary pressure for one additional week again, twice a day, every day. So we actually saw what happened for one week after the treatment was stopped. And, as I mentioned before, the patient population was quite advanced from a heart failure standpoint. These were patients that were adequately managed with guideline-directed medical therapy for heart failure. Of course, about half of those patients have, have HFpEF. Did I mention before was the standard of care is not a thoroughly defined?

Dr. Mikhail Kosiborod:

And essentially what we observed was quite remarkable, which is average pulmonary artery diastolic pressure at baseline was about 22 millimeters of mercury across the patient population, and in patients treated with empagliflozin, there was quite a rapid reduction in pulmonary artery diastolic pressure that we saw almost immediately within one week as compared with placebo. And that divergence of curves in terms of pulmonary artery diastolic pressure continued over the entire 12-week treatment period. And by the end of the treatment period, there was nearly two millimeter of mercury difference in favor of empagliflozin, with lower pulmonary artery diastolic pressure in patients with empagliflozin compared with placebo. And also interestingly, even after the treatment was stopped for an additional week, those curves continued to diverge, with even greater lowering of pulmonary artery diastolic pressure in patients that received empagliflozin. So, I think to our knowledge, this is the first evidence from a randomized clinical trial, randomized double blind placebo controlled clinical trial, that SGLT2 inhibitors, in this case, empagliflozin, have essentially direct the congestion effect towards a lower pulmonary artery pressure rapidly and with effect amplified over time.

Dr Carolyn Lam:

Yes. Congratulations and beautifully present it there. Now, if I could ask a few more questions now, because the things will come up there. What happened to the diuretic dose? Is this depend on diuretic dose? Are there any subgroups that appeared to benefit more?

Dr. Mikhail Kosiborod:

No, excellent question, Carolyn. So first of all, we monitored average daily furosemide equivalent dose continuously throughout the trial, and what we observed was that there was no difference in diuretic dose, essentially, between the two groups from a loop diuretic management standpoint. Now, remember this patients are getting frequent pulmonary pressures with diuretics being adjusted all the time. But if you look at what happens over time, that's one of the figures in the paper you see essentially the flat lines in both groups. And coupling that with the fact that pulmonary pressures continue to diverge for another week after the treatment was stopped, at least in my mind, suggests that this hemodynamic benefits as we observed with empagliflozin as compared with placebo was lowering of pulmonary pressures is likely not simply due to diuretic effect. It just cannot be explained only by diuretic effect. I think these findings are very much in line with the analysis that we had in DAPA-HF trial with the analysis that recently were published from EMPEROR-Reduced, showing that you just can't explain what you see with heart failure benefits with SGLT2 inhibitors simply by diuresis.

Dr Carolyn Lam:

Fascinating. Well, how about the question of diabetes?

Dr. Mikhail Kosiborod:

Yes. So in terms of subgroups, that you mentioned, we did do subgroup analysis. Now I will say that the subgroup analysis have to be interpreted with a great deal of caution in this trial, because the entire trial had about 65 patients, so it's a small trial. It was really powered to look at the entire patient population and look at the primary end point of the diastolic pressure. Nevertheless, as I mentioned before, we had half-and-half reduced and preserved EF and we did not see a statistically significant heterogeneity in the treatment effect when we look at patients with reduced to preserved EF, so that hopefully both for outcome trials in preserved EF heart failure, we'll see, of course, what happens with that. And in terms of diabetes we saw a bit greater effect in patients with diabetes as compared to patients without diabetes, in terms of pulmonary artery pressure reduction.

Dr. Mikhail Kosiborod:

But again, I would just strongly caution interpretation of those subgroups because certainly when we look at clinical outcomes in those DAPA-HF and EMPEROR-Reduced, we see no such difference. We see that the benefits, right, the hard clinical outcomes, benefits, are quite consistent regardless of diabetes status. I will say one other thing, which I think is really important. If you look at the pulmonary artery pressure trajectory in patients treated with placebo in EMBRACE-HF, you see that they actually go up over time. And this is in patients that have frequent monitoring of blood pressures, our own guideline-directed medical therapy are closely watched by predominantly heart failure cardiologists and their teams to make sure that they're well-managed. And despite that, you see this increase in pulmonary pressure over time, and that's just another reminder to us that heart failure is a progressive disease despite best available therapy.

Dr. Mikhail Kosiborod:

These patients deteriorate over time, which is why treatment, novel advancements, treatments like SGLT2 inhibitors and their effective implementation is just so important because we know the benefits occur very early. We saw one week here, when we start seeing separation of curves, certainly see a significant difference by 12 weeks with pulmonary pressure. But of course we know with clinical outcomes, we see within a few weeks of randomization, already a significant benefit in reducing CV death and hospitalization for heart failure, both in DAPA-HF and EMPEROR-Reduced trials. So I think that's a critical point for clinicians to keep in mind at the time of the death.

Dr Carolyn Lam:

Mikhail, those are just such important and practical take-home messages. Thank you again. In the last minute though, I just really, really have to go back to that very clever method. Could I just pick your brain? I mean, it's like a very clever population. This CardioMEMS population that maybe what's in the future plans? Give us a sneak peek!

Dr. Mikhail Kosiborod:

Well, Carolyn, very insightful as always. I really think of it as a novel platform for drug development and heart failure. I think this is the proof of concept. This is really the first time we did something in the heart failure space was with monitoring of pulmonary pressures that shows that drugs that work for hard clinical outcomes actually do something meaningful on hemodynamics. We've struggled for such a long time in heart failure to have a good surrogate endpoints that would be reflective of clinical outcomes. This may be it. It may be one of them. And I think EMBRACE-HF is a good concept proving study that can say, if you have a compound and you think that compound may be effective for heart failure. So of course the congestion is so important that we know correlates so well with clinical outcomes

Dr. Mikhail Kosiborod:

When we started to trial all the way back to late 2015, very few patients had this device. It's not lots of patients have this device. And testing novel treatments to try to understand will there promise in heart failure, and even making go-no-go decisions, in terms of drug development, I think is starting to become a potential future development, which we should at least seriously consider in the heart failure space.

Dr Carolyn Lam:

Wow, Bravo. And Mikhail, I mean. Okay, audience, listen, you heard it right here. This is amazing. Thank you once again for publishing with us and congratulations on the beautiful paper.

Dr Carolyn Lam:

And from Greg and I, thank you audience for joining us again today, you've been listening to Circulation on the run. Tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021.

Circulation April 20, 2021 Issue

19 april 2021 | 25 min

For this week's Feature Discussion, please join author Marco Vinceti and Associate Editor Wanpen Vongpatanasin as they discuss the article "Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Dr. Greg Hundley:

I'm Dr. Greg Hundley, co-host and Associates Editor, Director of the Pauley Heart Center, Richmond, Virginia, VCU Health

Dr. Carolyn Lam:

Dr. Greg, today's feature paper, super, super exciting. Everyone has to listen to it because it's about blood pressure and sodium intake. But you think you've heard it all? You haven't. You have to listen to this feature discussion, and I'm sure you'll learn a lot, just like I did. Seriously. But before that you got your copy, I got mine. Let me tell you all about microRNA. Shall I?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

MicroRNA, we know, have a remarkable influence on the physiology of the heart and the remodeling of diseased hearts through canonical RNA interference mechanisms. Now, the authors of today's paper, co-corresponding authors, Dr. Fu and Deschênes from Ohio State University in Columbus, Ohio, investigated if microRNA one or mir-1 specifically binds with cardiac plasma membrane proteins, and they revealed an evolutionarily-conserved direct binding between this mir-1 and an inward rectifier potassium channel called cure 2.1. Now, this is endogenously existing in cardiomyocytes.

Dr. Carolyn Lam:

Now, the authors then used inside out and wholesale patch clamp recordings to show the biophysical modulation of cardiac electrophysiology by mir-1. They further studied the mechanism of this physical interaction and investigated its pathophysiologic relevance by using mir-1 deficient transgenic mice. In total, their study demonstrated a novel mechanism of microRNA ion channel biophysical modulation that regulates cardiac arrhythmia risk.

Dr. Greg Hundley:

Wow, Carolyn really sophisticated work involving the pathophysiology of some of these arrhythmias. What are the take home message?

Dr. Carolyn Lam:

Ah, I'm glad you asked. Let me circle back to what I said earlier. Cardiac electrophysiology is regulated by microRNAs. We knew about the canonical RNA interference mechanisms, but that needs hours to days to regulate gene expression. But now we have the newly discovered biophysical mechanism that quickly, and that is within seconds or minutes, modulates the function of the ion channels. These microRNAs could prevent or trigger arrhythmias through biophysical modulation of the ion channels, even before its RNA interference regulation of protein expression occurs in diseased hearts.

Dr. Greg Hundley:

Wow, Carolyn. Really interesting new basic science. Such an asset for our journal. Well, I'm going to switch and talk a little bit about really, really high coronary artery calcium scores, something that sometimes we see. The work comes from Dr. Michael Blaha from Johns Hopkins University in Baltimore, Maryland. Carolyn, as you know, there are limited data on the unique cardiovascular disease and non-cardiovascular disease and mortality risk of primary prevention individuals with very high coronary artery calcium scores. What do we mean by very high? These are scores greater than or equal to a thousand. That's especially true in comparison to rates observed in secondary prevention populations. In this study, the investigators compared the hazard ratios for coronary artery calcium scores greater than a thousand in comparison with calcium scores of zero, those from 400 to 999, and they looked at this for those with cardiovascular disease, non-cardiovascular disease, and also evaluated mortality outcomes.

Dr. Carolyn Lam:

Oh, wow. That's interesting and those are very high coronary artery calcium score. What did they find?

Dr. Greg Hundley:

Thanks, Carolyn. After full adjustment, coronary artery calcium scores greater than or equal to a thousand demonstrated a 4.7 to a seven and a half increase in the hazard ratio for outcomes compared to individuals with calcium scores of zero, a 1.6 to 1.3 four-fold increase compared to those with calcium scores in the 400 to 999 range. Carolyn, with increasing coronary artery calcium scores, the hazard ratios increased for all event types with no apparent upper coronary artery calcium threshold. For example, a coronary artery calcium of a thousand correspond to an annualized 3-point MACE rate of 3.4 per a hundred person years and that's similar to that of a for EA population of 3.3 and higher than lower risk for EA subgroups.

Dr. Greg Hundley:

Carolyn, these results raise the thought that as we're thinking and putting together future guideline statements, should we consider a less distinct stratification algorithm between primary and secondary prevention patients for these very high coronary calcium scores? The high scores in the primary prevention group for this study really mirrored those four EA scores that you see in patients that are undergoing secondary prevention. They've already had a heart attack. Should we start thinking about for these very high scores, really aggressive preventive pharmacotherapy, just like we would in a patient that was undergoing secondary prevention?

Dr. Carolyn Lam:

I like that explanation. Thanks, Greg. Well, this next one really speaks to my favorite topic, sex differences in cardiovascular physiology and disease outcomes. Greg, here's the quiz question. Do you think progesterone receptors in cardiac cells play a role in determining the difference between you and me? Co-corresponding authors Dr. Porrello from Murdoch Children's Research Institute in Melbourne, Australia and Dr. Hudson from the Berghofer Medical Research Institute in Brisbane, Australia, and their colleagues, hey performed single nucleus RNA sequencing to capture transcriptional changes across multiple cardiac cell populations during the human heart development from fetal stages to adulthood. Their data revealed six specific transcriptional mechanisms governing maturation of multiple cell types in the heart, including a previously unrecognized role for the progesterone receptor in human cardiomyocyte maturation. These data really provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.

Dr. Greg Hundley:

Oh, great, Carolyn. Very nice. Well, Carolyn, my next paper really involves an assessment of air pollution. As you know, many of the studies today have really focused on short-term exposures to air pollution. But this group headed by Dr. Yazdi at the Harvard T.H. Chan School of Public Health began to evaluate long-term or chronic exposure to air pollution. Carolyn, the study examined the relationship between the long-term exposure to find particulate matter with an aerodynamic diameter of less than 2.5. micrometers also from nitrogen dioxide and from ozone, and they evaluated all three of those relative to hospital admissions for four cardiovascular and respiratory outcomes: myocardial infarction, ischemic stroke, the development of atrial fibrillation or flutter, and the development of pneumonia. They looked at this in the Medicare population within the United States.

Dr. Carolyn Lam:

Hmm, interesting. What did they find?

Dr. Greg Hundley:

Okay, Carolyn, so a couple things. First, long-term exposure to that fine particulate matter was associated with an increased risk of all outcomes with the highest effect seen for those that incurred a stroke. The findings translated to 2,536 cases of hospital admissions with ischemic stroke per year, which can be attributed to each one unit increase in fine particulate matter levels among the study population. Also, the nitrogen dioxide was associated with an increase in the risk of admission for stroke and atrial fibrillation. Then, the ozone was associated with an increase in the risk of an emission for a pneumonia.

Dr. Greg Hundley:

Carolyn, what this study showed, at lower concentrations, a chronic exposure, long over time of all these pollutants, were consistently associated with an increased risk for all of the study-related cardiovascular and cardiopulmonary studied outcomes. New important information regarding long-term as opposed to short-term exposure of these pollutants.

Dr. Carolyn Lam:

Yikes, yikes. Important to pay attention to. Thanks, Greg. Let me now go to the other articles in today's issue. There is a beautiful Perspective piece by Dr. Shah titled Transcatheter Closure of the Patent Foramen Ovale: Not Always an Open or Shut Case. There is a Research Letter by Dr. Davis on engrafted human induced pluripotent stem cell derived cardiomyocytes undergoing clonal expansion in vivo.

Dr. Greg Hundley:

Great, Carolyn. I've got two publications to discuss. First, Dr. Ransom has an EKG challenge entitled Palpitations in the Clinic. Then, finally, our own editor in chief, Dr. Joe Hill has a wonderful in memoriam to Dr. Jim Willerson, a prior editor-in-chief of circulation, and really a guiding light for many of us in cardiovascular diseases for much of his life. Well, Carolyn, on that note, how about we now transfer to that feature discussion and learn a little bit more about sodium intake and high blood pressure.

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Carolyn Lam:

Now, most of us would agree that dietary sodium has a role in the modulation of blood pressure levels. That we've agreed on. However, we still debate over the magnitude of the effect, who it applies to, and the importance of sodium-driven blood pressure changes for global disease burden. Well, today's feature paper does a lot to address many of the remaining questions that are revolving around sodium intake and blood pressure. I'm so pleased to have with us the corresponding author of the feature paper, Dr. Marco Vinceti from University of Modena and Reggio Emilia in Italy, as well as our associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern. Welcome both. Marco, if I may and begin with you, please, could you tell us the inspiration for your study and what you did?

Dr. Marco Vinceti:

Thank you by the way, for inviting me and good morning to everybody. Our inspiration was being aware that as you already say, there may be an association, there is an association between sodium intake and blood pressure, but that maybe not all the details about such relation are being explored and carefully investigated, also for the lack of adequate statistical tools. Also, because we know that health endpoints and exposures, both dietary and environmental factors, I mean, may have a relation that is not linear, that is, just has some kind of different shape, U-shaped curve, J-shaped curve, and so on. Our thought was to investigate better this relation between sodium intake and blood pressure, even in a category of people which is wide. Also, there isn't such a large consensus about the relation; that is, people without high blood pressure and to shape that association using new statistical tools in non-linear fashion, if appropriate.

Dr. Carolyn Lam:

Very nice. Could you tell us what was special about your study design? Because it is true that the methodology you used was very unique and then perhaps the top line of what you found.

Dr. Marco Vinceti:

We took advantage of from a recent, let's say, discovery. I don't know if the term is correct, but we consider it like a discovery, of a colleague of ours at the Karolinska Institute of Stockholm. He is a statistician named Nicola Orsini. He published it in 2019. A new tool, a new approach, call it a one stage dose response meta-analysis that is able to shape the relation between exposures, in this case, sodium intake, and health endpoints or outcomes. We're talking here of continuous endpoint such as blood pressure. We can maybe talk about an outcome, almost outcome hypertension, even in the whole range of exposure from very low intake up to a high intake.

Dr. Marco Vinceti:

Until recently the only meta-analysis that you could perform was just comparing high versus low sodium intake across trials or observational studies. But in each trial, the high exposure category is different from another trial so you are comparing across trials categories that are not the same categories, are not corresponding each other. This is a major limitation. So far, there are no publication able to shape the entire range of exposure, the result of experimental studies. For experimental studies, I mean the gold standard in medical research, in human medicine that are randomized controlled trials.

Dr. Carolyn Lam:

I love that. That is really spot on, I think, of what makes your meta-analysis so important. Could you maybe then now tell us about the results?

Dr. Marco Vinceti:

Well, yes, the results, if I go back to one last detail about our statistical approach, if I can add, in addition to what I said before, we also wanted to use extensively what in 2016, the American Statistical Association just declare it, that to avoid the systematic use of p-values and statistical significant testing, just a black and white approach or something which is statistically significant or not statistically significant, and to shape the relation in a smooth, in a different way, looking graphically their religion and not having a dichotomous black and white approach, exactly as recommended by the American Statistical Association in it's very important statement in 2016.

Dr. Marco Vinceti:

About the results. I think that the main results were that the relation was, unfortunately, I will say linear. Because we were looking at non-linear association and that we tried in any way to find out if there was some kind of non-linearity in the association and I'm saving unfortunately only because we used a tool that is suitable to test a non-linear association. But we found evidence confirming here at previous meta-analysis and previous studies that say that there is a linear association between intake, that is exposure to sodium, and blood pressure. But this association also holds for people without hypertension, participant in these trials without high blood pressure. This put there that this consensus is not exactly well established all over the world; that there are investigators claiming that in people without hypertension, there is no relation, particularly for diastolic blood pressure and sodium intake. Our analysis showed, in my opinion clearly, that such association exists also, even if it is slightly weak, let's say in terms of strength compared with people with hypertension, with at least a high blood pressure.

Dr. Marco Vinceti:

There is an association for people with and without high blood pressure for diastolic and systolic blood pressure, and it exists across the entire range of usual exposure in the Western world. Because we were talking about mainly Western population. Most studies were carried out in Europe, in Australia and North America. The large majority or the 85 trials, which is the largest amount of trials ever analyzed in meta-analysis so far, were carried out in Western population. In those populations, the relation exists and is really detectable across the entire range of association even at very low intakes.

Dr. Carolyn Lam:

Wow, thank you. Thank you so, so much, Marco. So indeed a large, extremely well done meta-analysis, 85 trials, basically showing a positive and approximately linear association between dietary sodium consumption and blood pressure. Wow!

Dr. Carolyn Lam:

Wanpen, please. I mean, Marco is so just delightful in sort of saying that we'd look really hard for that J and U shape that everyone else talks about. We didn't find it, but that's exactly, I think, why we editors found this paper so, so important. Wanpen, I know you can express this better than me, so please.

Dr. Wanpen Vongpatanasin:

Sure. I agree. This is a very important study for the precision in comparing different levels of sodium intake and what it means for blood pressure. Also, I liked the paper that examine the different cutoffs that for example, the paper has a project in blood pressure that recommend by the American Heart at different levels of 1,500 milligrams a day was just the usual American diet about 3.5 grams a day, and in some subgroups even more. We can get pretty good idea and what it's translate into a blood pressure reduction.

Dr. Wanpen Vongpatanasin:

The thing that I particularly like is there's no threshold. I think that's fascinating and I think that's really important. The data, at least part of, I think, inertia in the public too, at least for me as a physician, I saw many remarks saying, "Oh, if it's part of the problem we had before, without these type of techniques, we usually give a general blanket. Sodium restriction, lower blood pressure by a few millimeters. Why do we even bother? But here you can see a dose response relationship without plateau. It really tells us that the more you eat, the more you're going to get into this kind of problem. I think this is really important and perhaps we'll push the certain population that address and consume a lot of salt to rethink about it.

Dr. Carolyn Lam:

Wanpen that was just really, really nicely put. I know that Marco was just nodding and appreciating as well. I know you had some questions from Marco too. Would you like to ask them?

Dr. Wanpen Vongpatanasin:

Yes. Based on the information from your study, would you give a recommendation a little bit differently, or how would you ... you've changed your view in terms of preexisting guidelines from European or from the United States?

Dr. Marco Vinceti:

I think that our results are really strengthening the most recent guidelines from both the U.S. and in Europe. I'm talking about the American Health Association guideline of limiting sodium intake below or at least at 1.5 gram per day, about the national recent sodium dietary allowance reference values of coming not beyond the 2.3 gram, and the European Food Safety Authority it's not just a recommendation, it's a risk assessment of indicating 2 gram per day the ideal intake of sodium. I would say the AHA was absolutely right in pointing out the opportunity to reduce to 1.5 gram and even lower, I would say. It's not a general assessment that we're one of the sodium and the Human Health Association. It's not a general risk assessment of sodium, but we know that hypertension, high blood pressure is a major, probably the major driver of all cardiovascular diseases. In our opinion, keeping this threshold, let's say, and even attempting to go below, we know how difficult it is in public health. That is absolutely correct.

Dr. Carolyn Lam:

I completely agree. That's the amazing public health message of this very important paper. As you said, it supports the guidelines, but it also suggests, I mean, should we just be saying, go as low as you can? We don't see a threshold so that's really, really fascinating.

Dr. Carolyn Lam:

Oh, may I ask maybe, cheekily, I recall, you mentioned Marco, that you had a lot of press about this paper and the publication and circulation. We would love to hear about that. Could you share with the viewers?

Dr. Marco Vinceti:

I can tell you that this is not to use or to ask, to be able to publish in such a top journal and you are not only the according to Web of Science, number one journal in the world in the cardiovascular community, let's say, but everybody. Even in the journal of medicine. I mean, I'm a public health physician, and anybody in my world, in Italy, and of course, not only Italy, I'm talking about my country, well knows this journal and what is publishing in such a journal is like some kind of an endorsement of what you are telling.

Dr. Marco Vinceti:

We received a lot of attention not only in my medical school, in my university, but also for the local press. From the national press a lot of people call me and ask for interview and even from the media. This is something that, particularly in this period of what everybody, I'm a public health physician is talking about COVID-19 and this is the emergency of course. Having the capacity to look at usual traditional disease but so important, that probably haven't received enough attention during the last months, I think is very important because I hope we are not forgetting that these are the major health issues, even in this period that is so difficult for an effect of disease for the COVID-19 outbreak.

Dr. Carolyn Lam:

Thank you so much Marco. I mean, I wish the whole audience could see the smiles you have put on all of our faces. Really, the credit all goes to you and your team for fantastic work done. We are privileged to have published this very important paper in circulation. And so thank you very, very much once again, to both of you for being on the show and to the audience for listening in today.

Dr. Carolyn Lam:

From Greg and I, you've been listening to Circulation on the Run. Thank you for joining us today.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation April 13, 2021 Issue

12 april 2021 | 22 min

For this week's Feature Discussion, please join authors Erik Näslund, Mehran Anvari, Editorialist Philip Schauer, and Associate Editor Ian Neeland as they discuss, in a panel forum, the articles: "Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Severe Obesity: A Nationwide Cohort Study," "Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease: A Population-Based Retrospective Cohort Study," and accompanying editorial "After 70 Years, Metabolic Surgery has Earned a Cardiovascular Outcome Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Director of the Pauley Heart Center in Richmond, Virginia with VCU Health. Well, Carolyn, another double feature this week and investigating the world of metabolic, or as we also know, bariatric surgery and the impact of bariatric surgery on cardiovascular outcomes.

Dr. Greg Hundley:

But before we get to that double feature discussion today, how about we grab a cup of coffee and we jump into some of the other articles in the issue. I'll go first this week, Carolyn. The first article comes from Professor Andreas Schuster from University Medical Center in Göttingen. Carolyn, as you know, right heart catheterization using exercise stress represents a key method for the diagnosis of heart failure with preserved ejection fraction but carries the risk of that invasive procedure. These authors hypothesized that real time cardiovascular magnetic resonance exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary non-invasive alternative for diagnosing HFpEF.

Dr. Carolyn Lam:

Wow, Greg, you know how I love talking about HFpEF? I actually managed this paper. Could you just describe what they found? It's so exciting.

Dr. Greg Hundley:

Yeah, Carolyn. Even the methods are interesting here, where these authors created a situation where you're riding a bicycle and obtaining an MRI scan at the same time. Let's get to the results. The HFpEF stress trial, prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion with E to E primes greater than eight, New York Heart Association class greater than or equal to two. To then, undergo echocardiography, right heart catheterization and then this real time pedaling a bicycle CMR exam at rest and during exercise stress. And so what they found Carolyn, the real time CMR allowed a highly accurate identification of HFpEF during physiological exercise and qualifies, perhaps, as a suitable non-invasive diagnostic alternative to the invasive procedures. So Carolyn, I think these results will need to be confirmed in a multicenter prospective approach, but really interesting innovation here, in this particular study.

Dr. Carolyn Lam:

So Greg, the paper I want to talk about, actually, is the first indicative critical role of cardiac macrophages in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage micro RNA-21 as a key molecule for the pro-fibrotic role of cardiac macrophages. Now, this comes from Dr. Engelhardt from Munich, Germany, and colleagues who show that within the myocardium, micro RNA-21 has the strongest expression in cardiac macrophages. Where it is also the single strongest express micro RNA among all micro RNAs. Targeted genetic deletion of micro RNA-21 in macrophages of mice prevented their pro-inflammatory polarization and subsequent pressure overload-induced cardiac fibrosis and dysfunction. Analysis of intercellular communication using cell sequencing identified the cardiac fibroblasts as the primary recipient cell of intercellular signals that emanate from activated cardiac macrophages and that are controlled by micro RNA-21.

Dr. Greg Hundley:

Oh, Carolyn, really interesting findings. What are the clinical implications?

Dr. Carolyn Lam:

Ah, glad you asked? What this implies is that interference with the activation of cardiac macrophages represents a promising therapeutic strategy in myocardial remodeling and dysfunction. In fact, synthetic oligonucleotide inhibitors against micro RNA-21 are currently undergoing clinical testing against fibrotic disease. This is really, really fascinating.

Dr. Greg Hundley:

Well, Carolyn, my next paper also comes from the world of basic science and it's from Dr. Anke Tijsen from Amsterdam University Medical Center, University of Amsterdam. Carolyn, as you know, titin, the largest protein in human, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to cardiomyocytes. Mutations that disrupt the titin transcript are the most frequent cause of hereditary heart failure. These investigators evaluated the role of titin and specifically a class of circular RNAs for regulating splicing of key muscle genes in the heart.

Dr. Carolyn Lam:

Fascinating. Tell us what do they find.

Dr. Greg Hundley:

Yeah, Carolyn. In this study, the authors found that the back splice junction formed by circular RNAs creates a unique motif, which binds SRSF10, to enable it to regulate splicing. And furthermore, they show that one of these circular RNAs, cTTN1, distorts both localization of, and splicing of, RBM20. Carolyn, the authors demonstrate with this work that circular RNAs formed from the titin transcript are essential for normal splicing of key muscle genes by enabling splice regulators, RBM20 and SRSF10. This shows that the titin transcript also has regulatory roles besides its well-known signaling and structural function. So, really interesting new work involving titin.

Dr. Greg Hundley:

Well, Carolyn, as we transitioned to the other articles in the issue, I want to tell you about Dr. Maskoun. He has a cardiovascular case series entitled, A Plumbing and Electrical Problem: An Unusual Cause of Syncope.

Dr. Carolyn Lam:

I like that title. Well, there's also a perspective fees by Dr. Lindman on unloading the stenotic path to identifying medical therapy for calcific aortic valve disease, talking about its barriers and opportunities.

Dr. Carolyn Lam:

Tracy Hampton reviews the literature and fascinatingly highlights papers like how DNA base editing treats Hutchinson-Gilford progeria syndrome in mice, how some researchers have identified the protein involved in cardiac repair, which is the ZEB2 protein and more information on mapping early heart formation in the embryonic mouse heart.

Dr. Carolyn Lam:

We've got a research letter by Dr. Levine. This one is so fascinating. It's about the cardiac effects of repeated weightlessness during extreme duration swimming and how that compares with spaceflight. Is that cool?

Dr. Greg Hundley:

Yeah.

Dr. Carolyn Lam:

Anyways, this was just such a power-packed issue. Now, let's just go to our feature discussion. Shall we? I can't wait, Greg.

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Well listeners, we have got another exciting feature discussion today on this April 13th issue. We have with us Erik Naslünd from Karolinska Institute in Stockholm, Ari Doumouras from McMaster Institution in Ontario, Canada, Ian Neeland our own associate editor from Cleveland, Ohio, and Phil Schauer from Pennington Biomedical Research Center-LSU. Welcome gentlemen. Let's start with you today, Erik. Could you describe for us, what was the hypothesis that your study wanted to address and what were your study population and design?

Dr. Erik Naslünd:

Well, what we want to study was if metabolic surgery affects the outcome in patients with previous myocardial infarction. And in Sweden, we are lucky that every Swede has their personal identification number, which is connected to essentially anything that we do, including all healthcare and we then have several registries. One is in a metabolic surgery registry, and then we also have one for cardiovascular disease called SWEDEHEART. What we did was, we went into these registries and we found patients who had undergone metabolic surgery. And then, we went to the SWEDEHEART registry and we looked at those patients who'd had a previous myocardial infarction. And then, we were able to get a match cohort, the same BMI and so on, in the SWEDEHEART registry. We were able to compare these two. We got a cohort then of roughly 500 patients who'd had metabolic surgery without a prior myocardial infarction and 500 who'd had a myocardial infarction. We then, assessed to see what the outcome was.

Dr. Greg Hundley:

Very nice. And can you describe for us your results?

Dr. Erik Naslünd:

Yeah, what we found was... Our main outcome measure was in the major adverse cardiovascular event and we found that, that was lower in the group that underwent metabolic surgery. We also then looked at death, which was also lower. We also looked at the risk for new onset of heart failure, which was also reduced. We also then assessed the risk for a major complication of the surgery in the group that had undergone metabolic surgery. We compare that to our surgical registry and we found that that was essentially the same. There was not really difference in terms of outcomes in terms of severe complications after the surgery.

Dr. Greg Hundley:

Excellent. Now, Ari, you also have a study that is involving bariatric surgery or metabolic surgery. Could you describe for us your hypothesis and your study population and design?

Dr. Aristithes Doumouras:

Yes. Thanks, Greg. Our hypothesis, first and foremost, was very similar to Erik's that patients who underwent metabolic surgery, who already had a history of heart disease when compared to a group that didn't receive bariatrics or metabolic surgery would decrease the future cardiovascular risk through a MACE outcome. Our secondary hypothesis we had, that was that those with heart failure would actually have a greater effect of metabolic surgery because of the decrease in obesity compared to those without heart failure or patients with ischemic, just ischemic heart disease with no heart failure.

Dr. Aristithes Doumouras:

The setting of the study was Ontario, Canada, where we have a centralized bariatric surgery network called the Ontario Bariatric Network. Like Erik, in Ontario, we're able to have multiple databases that are connected. They have one unique identifier for each patient. And so we looked at all patients who underwent bariatric surgery in Ontario during a timeframe. To note, we have a very large private system. Most bariatric surgeries, more than 95%, happen in the public system so we're able to track a lot of our bariatric surgery patients and don't lose a lot. We tracked all of our bariatric patients and matched them, on a one-to-one ratio, with very similar patients who also had heart disease and access to cardiology care, access to family physician care and followed them over 10 years. And so the design was a retrospective matched cohort in this way, comparing these two groups.

Dr. Greg Hundley:

Thank you, Ari. And Ari, what did you find?

Dr. Aristithes Doumouras:

Once again, like Erik, we found that there was a lower rate of MACE outcomes in the patients who underwent metabolic surgery and the absolute values were actually quite high. The absolute risk difference between the two groups was 8% and actually that went up to almost 19% in patients with heart failure. There was no action causing interaction between ischemic heart disease and heart failure, so they were the same. And the risk was about 40% lower for future MACE events in the surgery group.

Dr. Greg Hundley:

Wow, a large difference. Ian, as an editorialist for Circulation, the American Heart Association, you see a lot of papers come across your desk, what attracted you to these two manuscripts?

Dr. Ian Neeland:

When I first read these excellent papers, I thought that first of all, it was globally diverse. One study was in Europe, the other one in North America. And nevertheless, they showed strikingly similar relative risk reductions in MACE. One of them showed between 40 to 50% and so did the other. That was one really striking thing, was the consistency of a risk reduction despite being globally diverse with different systems in each country. Second of all, the absolute risk reduction was astounding. Assuming you could translate the absolute risk reduction to a clinical trial, to real-world experience, you're looking at a number needed treat between five to 12 for MACE, which is astounding and much greater than many of the evidence-based therapies we have today. The magnitude of the findings were striking and the ability to generalize globally were really interesting.

Dr. Greg Hundley:

Thank you, Ian. Well listeners, we also have an editorialist that can help us put all of this in context of what we known previously about bariatric surgery or what we are calling metabolic surgery. So we're going to turn to Phil. Phil help us put the results of these two studies in the context of cardiovascular medicine specialists or even family practitioners, internists that are managing patients with cardiovascular disease that happened to be morbidly obese.

Dr. Phillip Schauer:

Yeah, Greg. Well, these are both outstanding observational studies. And congrats to Erik and Ari and their teams for putting these studies together. Now, what's unique about these studies, is that I think these are the first to actually look at metabolic surgery for secondary prevention. Now, there are nearly 30 studies looking at metabolic surgery as primary prevention. These are all observational. They're not prospective randomized trials, but they all show, nearly all of them, show mortality reduction and MACE event reductions. These two studies are the first to show that metabolic surgery is good for secondary prevention. This is really important because I think, up till now, cardiologists have been very reluctant to refer patients to metabolic surgery. Patients who've already had a heart attack because of the least perceived operative risk and surgeons have been reluctant to operate on these patients. And both Erik and Ari have showed that the perioperative risks were remarkably low for this population, operative mortality way below 1%.

Dr. Phillip Schauer:

And so within a very short period, within a year or two, the mortality reduction, by far, supersedes any perioperative risk. I think this is really very good news. We now have quite a large amount of observational data in the primary prevention side. These two studies, nearly identical, showing mortality, MACE event reductions, as Ian pointed out, 40 to 50%. That's a lot. That rivals almost anything else out there in terms of mortality reduction, whether it's an SGLT2 inhibitor, a GLP-1, or a statin, I mean, people dance in the street when you see a five and 10% reduction. With surgery, it looks like we're seeing 40 to 50%. So, this is remarkable news but we do have a little more work to do. Perhaps we can talk about that, your next question.

Dr. Greg Hundley:

What a great lead-in Phil. So listeners, striking results with this surgical intervention for patients with cardiovascular disease that have morbid obesity. Erik, let's start with you, but we'll go through all of our expert panelists here. Erik, what do you think is the next study that needs to be performed in this sort of area of research?

Dr. Erik Naslünd:

Well, I mean, the obvious answer to that is that we need to do a randomized control trial to verify these results. That's the number one. Number two, I think, we also need to tease out, if we can, which are the most suitable patients. And is there a difference between the most commonly performed metabolic surgery procedures. That's where I would suggest that you need to do next.

Dr. Greg Hundley:

Ari, how about you?

Dr. Aristithes Doumouras:

I agree with Erik. I think everyone's going to say the same thing. That I think a randomized trial is the next step when looking at bariatric surgery and the role of secondary prevention-based patients, as these are all observational studies. And they just need to be confirmed. We're starting on a pilot study for this exact randomized trial at our institution and obviously looking for more partners later on, but yeah, that's definitely the next step in the process for sure.

Dr. Greg Hundley:

Ian, what would you like to add?

Dr. Ian Neeland:

No, I definitely agree an RCT is needed. I think one that combines both primary and secondary prevention patients is important to try to understand that the difference. One could imagine that secondary patients may actually derive much greater benefit than prime prevention patients given their baseline risk. And if one can show that the operative morbidity, mortality is low in both populations, as both papers showed observationally, then I think there's a lot of benefit there. I also think it's important to try to randomize people to different procedures, to really try to understand is it the gastric sleeve? Is it the bypass? And which one has greater benefit in the setting of a RCT as well as how do the risks and safety outcomes differ between those two in the real-world RCT setting.

Dr. Greg Hundley:

Very nice. Well, Phil we've heard randomized trials, maybe also, do we need longer follow-up?

Dr. Phillip Schauer:

Yeah, Greg. In the title of my editorial, and I hope that the listeners actually do read it, is after 70 years, metabolic surgery has earned a prospective randomized trial, and it's true. This field is 70 years old, there's not a single prospective large randomized controlled trial. There are quite a few small studies that were powered for biomarkers, but not hard clinical end points. We need this and it is doable. For example, for coronary artery bypass surgery, there's over a hundred prospective randomized controlled trials. So we definitely need this type of study. It needs to be long follow-up, probably five years or more. As Erik and Ari pointed out, it should have a mixture of primary and secondary prevention.

Dr. Phillip Schauer:

I'll share with you right now, I'm working with a group in the US. Along with Steve Nissen, a very noted cardiologist, Bob Eckel, who's currently the president of the American Diabetes Association and a number of other experts. David Aterburn, Sonia Thomas, who are working together to try to develop a study. The question is who will fund this? And frankly, we've been talking to various funding organizations. And frankly, we need the help of the cardiology community to help us support this. This information is very important.

Dr. Phillip Schauer:

If I may say one more thing, it's interesting the entire field of obesity treatment, everybody who has obesity gets treatment to cause weight loss. Yet in 2021, we do not have data that shows that weight loss actually reduces morbidity and mortality. The closest thing we have is a look ahead trial, and it looked at weight loss via a lifestyle intervention. After 10 years, they got 6% weight loss, 6% weight loss is not enough. With metabolic surgery, we can get 25 to 30% weight loss. So we need to do this study, not just to show that metabolic surgery is effective, but to show that weight loss itself could actually reduce morbidity and mortality. And frankly, it's not just cardiovascular. The second most common cause of death in these studies is cancer. And that's the other interesting thing that should be looked at. Hopefully, we can get organizations like NCI to come in and support this initiative.

Dr. Greg Hundley:

Thank you. Well, listeners, what a wonderful discussion today, really a feature symposium. And we want to thank Erik Naslünd, Dr. Aristithes Doumouras, Ian Neeland and Phil Schauer for their time and expertise and sharing that with us today. Especially on this topic of bariatric, but now maybe more commonly called metabolic surgery, where these two studies have been demonstrating efficacy of these procedures now in patients with cardiovascular disease and even those post myocardial infarction.

Dr. Greg Hundley:

On behalf of Carolyn and myself, I want to wish you another great week ahead and we will catch you in that next week, on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation April 6, 2021 Issue

5 april 2021 | 27 min

For this week's Feature Discussion, please join authors Igor Klem, Pasquale Santangeli, Mark N.A. Estes III, and Associate Editor Victoria Delgado as they discuss, in a panel forum, the articles: " The Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients with Non-Ischemic Cardiomyopathy," "Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias," and "Cardiac Magnetic Resonance Imaging in Nonischemic Cardiomyopathy: Prediction Without Prevention of Sudden Death."

Dr. Carolyn Lam:

Welcome to Circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate editor, Director of the Pauley Heart Center in Richmond, Virginia. Well Carolyn, this week we've got another sort of double feature with a forum and our focus is going to be on myocardial scar that's observed with late gadolinium enhancement during cardiovascular magnetic resonance and the two author groups we'll be discussing the impact of that scar on the development of ventricular arrhythmias. But before we get to that, how about we grab a cup of coffee and jump into the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I certainly would. Although I have to say, can't wait for the double feature. I love those, and this is right up your alley too. All right. But first, the first paper I want to talk about provides new randomized trial information regarding the benefits of catheter ablation in atrial fibrillation in patients who also have heart failure. Now, this is a sub-study of the CABANA trial.

Dr. Greg Hundley:

So Carolyn, remind us a little bit about the CABANA trial first.

Dr. Carolyn Lam:

I thought you might ask. Well, CABANA randomized 2,204 patients with atrial fibrillation who were 65 years or older or less than 65 with one or more risk factors for stroke at, it was huge at 126 sites, and they were randomized to ablation with pulmonary vein isolation or drug therapy. Now of these, 35% of 778 patients had New York Heart Association Class II or higher at baseline, and really formed the subject of the current paper. Although this sub-study was not specifically designed to evaluate patients with heart failure with preserved ejection fraction, about 91% of the patients with a clinical diagnosis of heart failure participating in CABANA for whom such data on injection fraction were available, really had an ejection fraction of above 40% and fully 79% had an ejection fraction above 50%. So excitingly, this is really majority talking about, have HFpEF. Now, what did they find well in patients with New York heart Association Class II or III heart failure at trial entry, most of whom did not have a reduced ejection fraction.

Dr. Carolyn Lam:

There was substantial clinical outcome benefits with the ablation over drug therapy with a 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding or cardiac arrest. Benefits were evident for both all-cause mortality and atrial fibrillation reduction. However, the effects on heart failure hospitalization were small and not significant. Authors also caution that these results should not be viewed as practice changing until they are reproduced in a confirmatory trial of ablation in the same population. And this is beautifully discussed in an editorial by Lynda Rosenfeld and Alan Enriquez from Yale University School of Medicine.

Dr. Greg Hundley:

Oh, wow. Thanks Carolyn. Well, my first paper comes from the world of basic science and it's from Professor Thomas Braun, from the Max Planck Institute for Heart and Lung Research. So Carolyn, vascular smooth muscle cells show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states, but critical information is missing about the physiological signals that promote formation and maintenance of contractile vascular smooth muscle cells in vivo. So BMP-9 and BMP-10 are known to regulate endothelial quiescence after secretion from the liver and right atrium. And these investigators are studied the role of BMP-9 and 10 for controlling formation of contract, all vascular smooth muscle cells.

Dr. Carolyn Lam:

Greg, talking about vascular smooth muscle cells always reminds me of their role in pulmonary hypertension, am I right?

Dr. Greg Hundley:

Yes, Carolyn. So these investigators found that in mouse models, BMP-9 and BMP-10 act directly on vascular smooth muscle cells for induction and maintenance of their contractile state, and surprisingly the effects of BMP-9 and 10 in vascular smooth muscle cells are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner. And therefore, just as you suggest, Carolyn, these results may offer new opportunities to manipulate blood pressure in the pulmonary circulation.

Dr. Carolyn Lam:

Thank you, Greg. Well, my next paper provides the first proof of principle of gene therapy for complete correction of Type 1 Long QT syndrome.

Dr. Greg Hundley:

Ah, so tell us a little bit about Type 1 Long QT syndrome, Carolyn.

Dr. Carolyn Lam:

Okay. Well Type 1 long QT syndrome is caused by loss of function variants in the KCNQ1 and coded potassium channel alpha sub-unit. And that is essential for cardiac repolarization providing the slow delayed rectifier current. Now no current therapies target the molecular cause of this Type 1 long QT syndrome. Well, this study from Dr. Michael Ackerman colleagues from Mayo Clinic Rochester really established a novel dual component suppression and replacement KCNQ1 gene therapy approach for Type 1 long QT syndrome. And it's the type that contains the KCNQ1 short hairpin RNA to suppress endogenous expression and a codeine altered short hairpin RNA immune copy of this KCNQ1 for gene replacement.

Dr. Carolyn Lam:

So this very novel approach rescued the prolonged action potential duration in inducible pluripotent STEM cell cardiomyocytes derived from four patients with unique Type 1 Long QT syndrome, causative, KCNQ1 variants. So it's super cool. Just go have a look.

Dr. Greg Hundley:

Well, thanks Carolyn.

Dr. Carolyn Lam:

I want to also tell you about other things in the mail bag. We have ECG Challenge by Dr. Dai on “Severe Arrhythmia Caused by a Chinese Herbal Liqueur. What's the Diagnosis?” I'm not going to tell you. You have to go see. We have Dr. Karen Sliwa writing a beautiful Joint Opinion paper from the World Heart Federation and American College of Cardiology, American Heart Association, and European Society of Cardiology on "Taking a Stand Against Air Pollution, the Impact on Cardiovascular Disease."

Dr. Greg Hundley:

Well, thanks Carolyn. So I've got a couple other articles. First Professor Yacoub has a global rounds describing and working towards meeting the challenges of improving cardiovascular health in Egypt. Those are really interesting features to learn about cardiovascular care worldwide. Next there's an In Depth article by Professor Thum entitled, "Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases, Roadmap to the Clinic." And then finally, a Research Letter from Dr. Bottá entitled, "Risk of Coronary Artery Disease Conferred by Low Density Lipoprotein Cholesterol Depends on Apologetic Background." Well, Carolyn, what a great issue and how about now we proceed on to that double feature?

Dr. Carolyn Lam:

Oh, I can't wait. Thanks Greg.

Dr. Greg Hundley:

Well, listeners, we are here for a really exciting feature discussion today that's going to focus on imaging, in particular magnetic, resonance imaging, and some new findings in that era and how those findings may pertain to ventricular dysrhythmias. With us today, we have Dr. Igor Klem from Duke University who will be discussing a paper, Dr. Pasquale Santangeli from University of Pennsylvania, our own associate editor, Dr. Victoria Delgado from Leiden and an editorialist, Dr. Mark Estes from UPMC in Pittsburgh. Welcome to all of you. Well, Igor, we're going to start with you. Could you tell us what was the hypothesis for your study and what was your study population in study design?

Dr. Igor Klem:

Yes. Good morning, Greg and thanks for the invitation. We wanted to know if you have a patient who you diagnosed with non ischemic cardiomyopathy based on clinical grounds and you refer him for a cardiac MRI study with contrast, what is the additional information that you get from the MRI study? And so we wanted to compare, and that's primarily related to the findings on scar imaging with late gadolinium enhancement. And we wanted to compare that to one of the most robust clinical parameters in cardiology, which is left ventricular ejection fraction, and in particular using a cutoff of 35%, which somehow in our clinical management has sort of as established as a break point for many clinical decisions.

Dr. Igor Klem:

And so we created a registry among three centers of patients who undergo a cardiac MRI study, where we found an LVEF of less than 50% and we followed them for a number of outcomes. One is all caused death. And then we wanted to separate a little bit the events into those who have cardiac mortality to look at a little epidemiology because in those patients, we have two major adverse events: one as heart failure related mortality. One is arrhythmia related mortality.

Dr. Greg Hundley:

And how many subjects did you include?

Dr. Igor Klem:

We included about a thousand patients from three centers and coming to the major findings of our study, we found that both left ventricular ejection fraction, as we know, is a robust marker of all cause mortality and cardiac death. And so it was the presence of myocardial scar on cardiac MRI. But the major difference was in relation to the arrhythmic events. We founded left ventricular ejection fraction in particular, when we use the 35% cutoff actually had very little predictive power to inform us who is at risk of arrhythmic events. In contrast, there was a very strong and robust relationship or multiple statistical methods to stratify patients who are at risk for sudden cardiac death, appropriate ICD shock, as well as arrhythmic cardiac death.

Dr. Greg Hundley:

Very good. Well, Pasquale understand you also performed a research study utilizing cardiovascular magnetic resonance. Could you describe for us your hypothesis as well as what was your population and your study design?

Dr. Pasquale Santangeli:

Thank you, Greg. And of course, thanks to the editor for the interest in our paper. I need to thank also the first call authors Daniele Muser and Gaetano Nucifora for putting together a registry of 70 institutions throughout the U.S., Europe, and Japan and the our hypothesis came from a clinical need. We do know that patients with idiopathic ventricular re we ask, which includes not sustain a weakness like PVCs or non-sustained VT. Very few of them, but there is a group of them that have a higher risk of ending malignant and up comes in terms of your ethnic events over follow-up. And prior studies have shown that by doing an MRI and showings and the detecting scar related announcement, there is an increase with how we make events of a follow-up. However, if you do look at those studies late, an answer's been reported in up to 70% of these patients, which you never view is a highly practical way of re-stratifying these patients, because you have a risk factor that is present 70% of those, then it's hard to use it for clinical decision-making.

Dr. Pasquale Santangeli:

So in this registry, which you put it again at 686 patients with panel data idiopathic, not sustained ventricular arrhythmias, which were defined by a normal WBC gene status, a normal echocardiogram and a normal stress test. We looked at whether there is a specific pattern of late announcement. So how basically I believe lands, and it looks on the MRI, they may predict better or outcomes over follow-up. And again, we use a composite and Pauline the full cost mortality, but associated cardiac arrest due to ventricular fibrillation or a hemodynamically unstable BP, or in a subgroup of patients that underwent ICD therapy. We also looked at, I approve SED shocks.

Dr. Pasquale Santangeli:

The groups were divided in three different categories. The first one, which is a larger group of 85% of patients and no late announcement. The second group, the one with late announcement, which represents the remaining 50% of 15% of patients, we divided it into a ring light pattern, which was defined as that word says, as a ring like distribution of the lead announcement in the mid-market segments, which involves a three consecutive continuous segments in a short axis view. It looks like really at least half the ring or three-quarters of the ring.

Dr. Pasquale Santangeli:

And the other group is the one that had the leader announcement without a ring light pattern. And it's interesting that the third and the latest announcement was not that similar between the ring light and the one without ring light late announcement. What we did find though for our follow-up the patient with a ring light pattern, a significantly higher rate of the primary composite endpoint, which happened in the median follow-up about 61 months so it was quite long. And the composite outcome occurred in 50% of patients in the ring light group versus 19% in the no ring light a positive announcement group and a 0.3%. So really, really rare in patients. So then concluded that of course, late announcement does provide some information in general, particularly the type of announcement that increases the risk significantly. Probably although this has to be confirmed prospective fashion patient with a ring light pattern may benefit from other forms of interventions, including potentially defibrillator therapy in a prophylactic fashion.

Dr. Greg Hundley:

Very nice. So now listeners, we're going to turn to our associate editor. One of the imaging experts here at Circulation, Dr. Victoria Delgado. Victoria, you see a lot of papers come across your desk and as an imaging expert, what attracted you to these two papers? And what do you think are their significance?

Dr. Victoria Delgado:

Thank you, Greg. I think that these two papers are important because right now, if we follow the clinical guidelines, we decide implantation. For example, of an ICD based on the ejection fraction, and we see that in many patients based on ejection fraction, they may not benefit ever from an ICD because they don't have arrhythmias. What other patients who do not meet the criteria often injection fraction below 35%. They may have still arrhythmias. So the article by Igor highlights the relevance of the amount of burden of late government Huntsman with CMR, in patients with non ischemic cardiomyopathy, which are sometimes very challenging patients on how to decide when we implant an ICD or not. We need sometimes to base the decision on genetics.

Dr. Victoria Delgado:

If we have an on the other hand, the paper of Pasquale, these were patients with normal echocardiogram. So what patient, having arrhythmias where we don't see on echocardiogram, that is the first imaging technique that we usually use to evaluate these patients. We don't see anything, but CMR can give us more information in terms of structural abnormalities and particularly not only the burden of scar, but also the pattern of the scar. And we have seen in other studies that for example, not only for ICD implantation, but for ventricular tachycardia ablation. The characteristics of that scar and some areas where these are short of panel that can be targeted for that ventricular tachycardia ablation can lead to much more precise treatment if you want of these patients.

Dr. Greg Hundley:

Thank you, Victoria. So it sounds like listeners we're hearing late gadolinium enhancement, regardless of EF could be forecasting, future arrhythmic events. And then also the pattern of late gadolinium enhancement, where contiguous segments in a ring-like fashion may also offer additional prognostic information. Well, now we're going to turn to our editorialists and as you know, listeners at Circulation, we'll bring in an editorialist to really help put things together and uniquely here today, we have Dr. Mark Estes, who is really not an imager per se, but like many of us uses the information from imaging to make clinical decisions. Mark, how do you see this late gadolinium enhancement as perhaps a new consideration for placement of devices?

Dr. N.A. Mark Estes:

Greg, that's one of the key questions. There's no doubt, not only based on these two studies, which extend our prior information about LGE and patients with valid and non ischemic cardiomyopathies that scar burden is important in predicting not only total mortality, but arrhythmic events. All of the criteria that were used in the original ICD studies, which include the definite, the Skuid half Danish and made it our it trials use only ejection fraction and functional status, no imaging. These are legacy trials. Now, many of them, a decade or more older. And the treatment of advanced heart failure has progressed to the point that the total mortality is dramatically lower than it was at the time of these studies. In some instances down to 4 or 5% per year. The studies are important in that they identify a subgroup of patients with low ejection fractions, less than 35%, who might qualify for ICDs, who are unlikely to benefit.

Dr. N.A. Mark Estes:

They also identify a group of patients with preserved ejection fraction greater than 35%, less than 50 in whom the risk of sudden death may be substantial. And it extends prior observations about patchy, mid Meyer, cardio wall fibrosis, subendocardial, subepicardial and important ways. But the key issue here, and it was alluded to with Pasquale's comments about prospective validation, is that when one has a risk stratifier and identifies a high risk population that has to be linked to an unequivocal therapy, it improves survival. And we don't have that link quite yet.

Dr. N.A. Mark Estes:

Prospective randomized trials are unlikely to be done in the low ejection fraction because they would probably be considered unethical. Given the trials that have shown the benefit you can't randomize to defibrillator versus an implantable loop recorders. I think the future really lies in risk stratification for people with preserved ejection fractions greater than 35%, less than 50 using LG in that patient population. Currently, I think the best information we can give to clinicians is to stick with the AHA guidelines, which is PF less than 35% with dilated, nonischemic class II symptoms who have had optimal medical therapy for at least three months using perhaps in that patient population LGE for shared decision-making in patients about the magnitude of the risk. And I think that's as far as we can go pending future studies, and there is one which we can discuss later on the CMR study at just that preserved ejection fraction LGE randomizing to defibrillator versus ILR.

Dr. Greg Hundley:

Thank you, Mark. So listeners just really quickly, let's go back to each of our experts and ask them, you know, in 20 seconds, Igor, Pasquale, Victoria, and Mark, what's the next study that needs to be performed in this space? Igor, we'll start with you.

Dr. Igor Klem:

Well, number one, following on Mark's comment on the less than 35% population, I think that it's unlikely that they're randomized clinical trial is ethical in this population, but we may consider a wealth of registry data by now that shows that there is a subgroup of patients who have a lower risk or lower benefit from an ICD. I think in the preserved ejection fraction above 35%, maybe up to 45%, 50%. That's an interesting study that's coming up. Maybe there's more trials that can provide us that robust information that we need today in order to change the guidelines to risk stratify, not based on the LVF, but on the presence of scar or maybe subgroups of scar.

Dr. Greg Hundley:

Pasquale?

Dr. Pasquale Santangeli:

Yes. So I think of course, one of the major studies is the one already alluded by this, which is a prospective study that links as specific therapy like ICD or even additional risk factors like we've been using program's stimulation some of these patients to further risk for the five to see what they can benefit.

Dr. Pasquale Santangeli:

Based another one that I think is important for the study that we did is a mechanistic more study to understand why the ring light pattern was there, as opposed to other patterns. We do believe we think that some of these patients may have an initial form of lb dominant arrhythmogenic paramount. There wasn't really a detective before and ran. Now, if we actually extending our study and have a registry to try to screen also the family members or patients with ring light pattern to understand whether there is a familiar component to it, because really we do not see this type of pattern that commonly and it'd been associated with lb dominant. Magnetic kind of alpha in some others, small studies.

Dr. Pasquale Santangeli:

So that's the other part to dig in a little bit more into the field type for these patients to understand why one pattern versus another happens and whether that gets main to, to explain why there's a higher risk in one population versus another.

Dr. Greg Hundley:

Victoria.

Dr. Victoria Delgado:

Yeah. Following what has been said. I think that from the imaging point of view, we are always criticizing in a way that we increase the burden or the cost of healthcare. But I think that these studies or any randomized study where MRI or echo is used in order to design a therapy and show the value of using that imaging technique to optimize the health care costs is important. So I will not add much on which sort of populations, but probably patients within non ischemic cardiomyopathy with preserved ejection fraction that do not fulfill the recent scores, for example, in hypertrophic cardiomyopathy to be implanted with an ICD. But probably if we see a lot of scar on a AGE where specific patterns that can help to decide which are the patients that have benefited from an ICD implantation, for example.

Dr. Greg Hundley:

Thank you. And finally Mark.

Dr. N.A. Mark Estes:

But I think all the major points have been hit here. And unfortunately we have a bit of a dilemma. And that dilemma is that these legacy trials for ICDs, which selected based on low ejection fraction and functional class II were done at a time when contemporary heart failure treatment was not as good as it currently is pharmacologically. And it's been reflected with a lower total mortality. When the mortality in this patient population gets down to the 4 and 5% per year, it's unlikely that any intervention for prevention of sudden death is going to impact on that total mortality.

Dr. N.A. Mark Estes:

So I do think that the registries hold a lot of promise, giving us insights into the subgroup of patients that previously would have been selected for defibrillators who may not have as much benefit or who may benefit the most. And I think that they will play an important part in perhaps refining the risk stratification with greater sensitivity and specificity in the patient population, less than 35%. I think the CMR guide trial is going to be a critical trial and looking at ICDs in the patient population between 35 and 50%, but we need to be mindful of one thing. And that in the Danish trial, they get a sub study looking at about 240 patients using LGE. And they found that ICD in patients with LGE that was positive, did not make a difference in survival or total mortality. So again, we need to get the data. I think the best clinical practice has come out of the best clinical evidence. You'll clearly be limitations to what we can do, but I think in the future, we'll have much better data to make these judgment calls.

Dr. Greg Hundley:

Very good. Well listeners, we want to thank our panelists, Dr. Igor Clem, Pasquale, Santangeli, Victoria Delgado, and Dr. Mark Estes for this wonderful discussion related to magnetic resonance imaging, late gadolinium enhancement, and how it may be useful in identifying those at risk for future arrhythmic events. On behalf of both Carolyn and myself, want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation March 30, 2021 Issue

29 mars 2021 | 28 min

For this week's Feature Discussion, please join authors Michael Ackerman, Christopher Haggerty, editorialist Michael Rosenberg, and Associate Editor Nicholas Mills as they discuss the original research articles “Artificial Intelligence-Enabled Assessment of the Heart Rate Corrected QT Interval Using a Mobile Electrocardiogram Device,” “ Deep Neural Networks Can Predict New-Onset Atrial Fibrillation From the 12-Lead Electrocardiogram and Help Identify Those at Risk of AF-Related Stroke,” and “Trusting Magic: Interpretability of Predictions from Machine Learning Algorithms.”

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this week's feature, it's kind of a new thing for us. It's more than our double feature; it's actually a forum, where we're going to have two papers discussed, we'll have both authors represented from each of those two papers, we'll have an editorialist, and we'll have one of our associate editors. And the topic, Carolyn, just to keep you in suspense, is really on machine learning and actually how that can be applied to 12 lead electrocardiograms. But before we get to that, how about we grab a cup of coffee and start off on some of the other articles in this issue? Would you like to go first?

Dr. Carolyn Lam:

Yes, I would, but you're really keeping me in suspense. But first, let's focus on health related quality of life. We know that poor quality of life is common in heart failure, but there are few data on heart health related quality of life and its association with mortality outside of the Western countries. Well, until today's paper. And it's from the Global Congestive Heart Failure, or GCHF study, the largest study that has systematically examined health-related quality of life as measured by the Kansas City cardiomyopathy questionnaire 12, or KCCQ, and its association with outcomes in more than 23,000 patients with heart failure across 40 countries, in eight major geographic regions, spanning five continents.

Dr. Greg Hundley:

Wow, Carolyn. That KCCQ 12, that has been such an interesting tool for us to use in patients with heart failure. So what did they find in this study?

Dr. Carolyn Lam:

Really important. So the health-related quality of life differs considerably between geographic regions with markedly lower quality of life related to heart failure in Africa than elsewhere. Quality of life was a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and in both preserved and reduced ejection fraction. So there are some important clinical implications, namely that health-related quality of life is an inexpensive and simple prognostic marker that may be useful in characterizing symptom severity and prognosis in patients with heart failure. And there is certainly a need to address disparities that impact quality of life in patients with heart failure in different regions of the world.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I'm going to turn to the world of basic science and bring us a paper from David Merryman from Vanderbilt University. So Carolyn, myocardial infarction induces an intense injury response, which ultimately generates a collagen dominated scar. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process post myocardial infarction. Now Carolyn, serotonin 2B receptor signaling has been shown to be harmful in a variety of cardiopulmonary pathologies, and could play an important role in mediating scar formation after MI. So Carolyn, these investigators employed two pharmacologic antagonists to explore the effect of serotonin 2B receptor inhibition on outcomes post myocardial infarction and characterized the histological and micro structural changes involved in tissue remodeling.

Dr. Carolyn Lam:

Oh, that's very interesting, Greg. What did they find?

Dr. Greg Hundley:

So Carolyn, serotonin 2B receptor antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated in their results by decreased scar thickness and decreased border zone area. Serotonin 2B receptor antagonism resulted in collagen fiber redistribution to a thinner collagen fiber. And they were more anisotropic. They enhanced left ventricular contractility and the fibrotic tissue stiffness was decreased, thereby limiting the hypertrophic response of the uninjured cardiomyocytes.

Dr. Carolyn Lam:

Wow. That is really fascinating, Greg. Summarize it for us.

Dr. Greg Hundley:

Yeah, sure. So this study, Carolyn, suggests that early inhibition of serotonin 2B receptor signaling after myocardial infarction is sufficient to optimize scar formation, resulting in a functional scar, which is less likely to expand beyond the initial infarct and cause long-term remodeling. The prolonged presence of the antagonist was not required to maintain the benefits observed in the early stages after injury, indicating that acute treatment can alter chronic remodeling. So Carolyn, it's really going to be interesting to see how this research question is pursued in studies of larger animals, including us, or human subjects.

Dr. Carolyn Lam:

Wow, that is really interesting. And so is this next paper. Well, we know that genetic variation in coding regions of genes are known to cause inherited cardiomyopathies and heart failure. For example, mutations in MYH7 are a common cause of hypertrophic cardiomyopathy, while mutations in LMNA are a common cause of dilated cardiomyopathy with arrhythmias. Now, to define the contribution of non-coding variations, though, today's authors, led by Dr. Elizabeth McNelly from Northwestern University Feinberg School of Medicine in Chicago and colleagues evaluated the regulatory regions for these two commonly mutated cardiomyopathy genes, namely MYH7 and LMNA.

Dr. Greg Hundley:

Wow, Carolyn. So this is really interesting. So how did they do this and what did they find?

Dr. Carolyn Lam:

You asked the top questions, because the method is just as interesting as the findings here. They used an integrative analysis that relied on more than 20 heart enhancer function and enhancer target datasets to identify MYH7 and LMNA left ventricular enhancer regions. They confirmed the activity of these regions using reporter assay and CRISPR mediated deletion of human cardiomyocytes derived from induced pluripotent STEM cells. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. Extending the strategy genome-wide, they identified an enhancer modifying variant upstream of MYH7. One specific genetic variant correlated with cardiomyopathy features derived from biobank and electronic health record information, including a more dilated left ventricle over time. So these findings really link non-coding enhancer variation to cardiomyopathy phenotypes, and provide direct evidence of the importance of genetic background. Beautiful paper.

Dr. Greg Hundley:

Very nice, Carolyn.

Dr. Carolyn Lam:

But let me quickly tell you what else is in this issue. We have an ECG Challenge by Dr. Lutz on flash pulmonary edema in a 70-year-old; there's an On My Mind paper by Dr. Halushka, entitled (An) Urgent Need for Studies of the Late Effects of SARS-CoV-2 on the Cardiovascular System.

Dr. Greg Hundley:

Ah, Carolyn. Well, in the mailbox, there are two Research Letters, one from Dr. Soman entitled (The) Prevalence of Atrial Fibrillation and Thromboembolic Risk in Wild-Type Transthyretin Amyloid Cardiomyopathy, and a second letter from Dr. Berger entitled Multiple Biomarker Approaches to Risk Stratification in COVID-19. Well Carolyn, now let's get on to that forum discussion and hear a little bit more about using machine learning in the interpretation of a 12 lead ECG.

Dr. Carolyn Lam:

Wow, can't wait. Thanks, Greg.

Dr. Greg Hundley:

Well listeners, we are here today for a double feature, but this double feature is somewhat unique, in that we are going to discuss together two papers that focus on machine learning applications as they relate to the interpretation of the electrocardiogram. With us today, we have Mike Ackerman from Mayo Clinic, Chris Haggerty from Geisinger, Mike Rosenberg as an editorialist from University of Colorado, and then our own Nick Mills, an associate editor with Circulation. Welcome, gentlemen. Well, Mike Ackerman, we will start with you first. Could you describe for us the hypothesis that you wanted to test, and what was your study population and your study design?

Dr. Michael Ackerman:

Thanks, Greg. The hypothesis was pretty simple, and that is could an artificial intelligence based approach, machine learning, deep neural network, could that solve the QT problem? Which is one of the big secrets among cardiologists, which, as you know, one of your associate editors, Sammy Biskin, published a sobering paper over a decade ago, showing and revealing the secret that cardiologists are not so hot at measuring the QT interval, and heart rhythm specialists sometimes don't get it right either. And we all know that the 12 lead ECG itself is vexed by its computer algorithms at getting the QTC just right, compared to those of us who would view ourselves as QT aficionados. And so we were hoping that a machine learning approach would solve this and help us glean, one, a very accurate QTC, as accurate as I can make it when I measure it, or core labs that do QT measuring for living.

Dr. Michael Ackerman:

And two, could we get that QTC from just a couple of leads to be as accurate as what the whole 12 lead ECG would be seeing so that we can move it to a mobile smartphone enabled solution? And so that was our hypothesis going forward, and we studied a lot of patients. And that's something that machine learning and the power of computation does, that in my world, I'm used to studying a hundred or a thousand patients with congenital long QT syndrome and thinking that I've assembled a large cohort, but for this study, we started with over two and a half million ECGs from over 650,000 people. And then ultimately, through training, testing, and validation of about 1.6 million ECGs from over a half a million individuals to sort of teach the computer or have the AI algorithm get the QT interval not too hot, not too cold, but just right. And as we'll discuss, I think we hit the mark.

Dr. Greg Hundley:

Thanks so much, Mike, what did you find?

Dr. Michael Ackerman:

Ultimately, we were able to show that with this drill, we could get the deep neural network derived QTC to be give or take two plus minus 20 milliseconds from what would the standard of care, and that being a technician over-read QTC. But then we took, I would say, pretty unique to AI studies, as many AI studies, just do training, testing, and validation for study number one. And then a future paper of a prospective study. But we did that prospective study within this single paper with a subsequent about two year enrollment of nearly 700 patients that I evaluated in our genetic heart rhythm clinic at Mayo Clinic. And half of those patients have congenital long QT syndrome, half did not. And what we showed was that the deep neural network derived QTC from a mobile ECG approximated the subsequent or the just prior 12 lead ECG within one millisecond, +/- 20 millisecond territory.

Dr. Michael Ackerman:

And it's ability to say is the QTC above or below 500, which we all know is sort of a warning sign, that's a very actionable ECG finding, do something about it, that that 500 millisecond cutoff by the deep neural network gave us an area under the curve of 0.97, which from a screening perspective, that AUC is far higher than a lot of AUCs for a lot of screening tests done in the cancer world and so forth. And so we think we are very close to what I've called a pivot point, where we will soon pivot from the way we've been doing the QTC since Eindhoven over a century ago to a fundamentally new way of deriving a QTC that's precise and accurate and mobile enabled.

Dr. Greg Hundley:

Very nice, Mike. So using machine learning to accurately assess the QTC from just two leads of an electrocardiogram. Well Chris, you also have a paper in this issue of circulation that pertains to another application of machine learning and looking at the electrocardiogram. Can you describe for us your study population, study design, and then also the question you were trying to address?

Dr. Christopher Haggerty:

Sure. Yeah, thanks Greg. Great to be here with you all today. Very similar to Mike's study, the motivation for us was we believe very strongly that there's opportunities with using deep learning applied to ECG data to uncover not only new knowledge latent in the ECG itself related to the current patient context, but also to try to predict future outcomes, future events. And that was really our motivation, was to take that paradigm of looking forward, in this case to predict new onset of atrial fibrillation within a year. We used our Geisinger patient cohort, which is a largely rural population in central Pennsylvania. We have very longitudinal data for a lot of our patients, which allows us to have this kind of design going back in our electronic health records, in this case, our ECG database to 30 plus years.

Dr. Christopher Haggerty:

Similar big numbers that Mike described, and in our case, 1.6 million ECGs over 430,000 patients used to train the model. And we had several different study designs that we employed. One just being a simple proof of concept, asking can we accurately predict new onset atrial fibrillation one year? And then a second study design that was intended to simulate a real world deployment scenario. Obviously the main rationale for trying to predict atrial fibrillation is to then be able to treat and try to prevent stroke. And so we tried to, as best we can in a retrospective fashion, simulate a scenario in which we might use this model to identify patients who went on to have a presumably AFib associated stroke.

Dr. Greg Hundley:

And what did you find, Chris?

Dr. Christopher Haggerty:

So I think there are three main findings that we highlighted here. So first, obviously we were building on the great work that Mike and some of his colleagues at the Mayo Clinic have done, showing that looking at AFib using deep neural networks needs to be feasible. We extended it in this case by looking out further than just an acute sense, looking at that one-year outcome. And we had an area under the curve for our proof of concept of 0.85. So area under the curve of 0.85 to identify patients with new onset of atrial fibrillation within one year in our millions of ECGs. Looking at it another way, the second main finding was that that one year prediction was shown to have prognostic significance beyond that one year, which is really interesting and warrants a lot of further study. Looking over 30 years of follow-up, patients predicted to be at high risk at baseline had a hazard ratio of 7.2 for developing atrial fibrillation, compared to those deemed to be low risk.

Dr. Christopher Haggerty:

And then really the third, and I think perhaps the most exciting finding that we had here, was this simulated stroke experiment that we had, where we identified patients from an internal stroke registry and identified patients who had new diagnosis of AFib at the time or up to a year after the stroke. So we can assume that they were an AFib associated stroke. And subsequently, or I should say previously, had an ECG that we could use to run through the algorithm to predict their atrial fibrillation risk. And we showed that the model performed well in this setting, that of the 375 strokes that we identified, for example, over a five-year period in our registry, we were able to identify 62% of them within three years based on that ECG. So a number needed to screen for an atrial fibrillation associated with stroke about 162, which compares favorably well to other screening techniques that are out there, obviously. So we took that as a great proof of concept that this type of AI technique might have benefits for screening for atrial fibrillation and preventing strokes.

Dr. Greg Hundley:

Well congratulations, Chris. Well, we're now going to turn to our associate editor, Dr. Nick Mills. And Nick, you have a lot of manuscripts come across your desk. What attracted you to these two papers, and what are the significance of the results as they apply to ECG applications as we move forward?

Nick Mills:

Thanks, Greg. Yeah, this is a rapidly growing field, where the availability of data scale with digital archiving and lots of really interesting new methodologies are available to our researchers. So we are receiving a lot of content in this area. What I loved about these two papers is not just the quality of the work, but also the really tangible benefits, potentially, for patients. So AI does not need to be complex, but it does need to solve a tangible problem. I guess what we look for in the journal, beyond the kind of innovation and methodology, is quality, and these studies used prospective validation, really reliable end points, ascertainments, transparency, reporting, all the things that we know are important for high quality clinical research. I think the idea that we can bring QT monitoring to the drug store on a portable device for our patients is potentially transformative. I also think that to take a technology, the electrocardiogram that we've been using for over a century, and provide new insights that go way beyond my ability to interpret the ECG, that might help us recommend a different course of action for our patients is also just really exciting.

Dr. Greg Hundley:

Very nice. Thank you, Nick. Well Mike ... we're going to turn to Mike Rosenberg now, listeners. And Mike wrote a wonderful editorial, and I would invite you to work through this. As you have an opportunity to read the journal and interact with it. Mike, there are two different types of machine learning, I think, that you described were used by the two respective investigative groups. Could you describe those for our cardiology listeners? What were the differences in those two approaches?

Dr. Michael Rosenberg:

Yeah, sure. And thank you for the opportunity to write the editorial. Two very fascinating papers. I should say that they both use the same approach of what's called supervised learning, where you basically have a set of data inputs, and you're trying to predict a labeled outcome. And what I talk about in the paper is that what we've learned is if you have enough data and enough computing power, you can predict almost anything highly accurately. What's interesting about the two papers, and what I sort of tried to contrast in the editorial, is that the one from the Mayo Group and Dr. Ackerman, was basically predicting what's already a known biomarker for sudden death, which is the QT interval. And essentially, almost trying to automate that process of predicting it accurately and in a way that, in essence, could allow a home monitoring of patients for QT prolongation, which obviously would be a huge benefit for clinicians, all those alerts and things, to be able to have patients taking drugs that are known to prolong the QT interval and feeling comfortable that if they have any prolongation, it could be detected accurately.

Dr. Michael Rosenberg:

The second one, which is sort of interesting, and in contrast is from the Geisinger Group and Dr. Haggerty, was the approach of ... where actually the prediction itself is actually the biomarker. And we don't actually know exactly what it's using, which I talk about a little bit of what that means and the implications clinically, but in essence, what they showed was that it actually is a very good biomarker and on par with what a lot of us would consider to be very strong predictors of agents. So I think it was two very interesting approaches to, again, applying the same type of machine learning, but really approaching it one from a more discovery side and another from sort of validated or almost automating something that we do on a daily basis.

Dr. Greg Hundley:

Thank you, Mike. So Mike, just coming back to you again, as we read the literature, and most of us are clinicians or researchers practicing, what should we look for when these new machine learning manuscripts and research studies come out as to gauge, "Ah, this is a really good study," or maybe not so much?

Dr. Michael Rosenberg:

Yeah. And it's a good question. I think one of the biggest challenges, as I talked about, is interpretability. I think in the clinical world, we're used to understanding the code for the variables that go into our risk prediction model. And so I think first and foremost is can I even understand what this is predicting or am I sort of expected to take the predictions as sort of a black box, it is what it is type of approach? I think that there's other things that I just look at when I'm reviewing these manuscripts. I mean, as I sort of mentioned, what these models are really doing, it's not anything magical. What they're doing is identifying patterns in the data and then using those to make predictions, again, toward whatever label that you've assigned them to.

Dr. Michael Rosenberg:

It's important that your data sets are split and that you're training at one data set and then testing it in one that's separate. And again, you can't ignore epidemiology. Is the data set that you're training it reflective of the population that you're going to be using those models in? And we know from outside of healthcare, there's issues with models that have been trained in one population where it's potentially biased or it's potentially offering predictions that are using information we may not necessarily want to use. Recidivism is a big example of that. So I think that that's, first and foremost, it's sort of taking a step back as a clinician and saying, "If this was a biomarker that someone was proposing to use to predict some new disease, what would I expect to use to evaluate that?" And that's probably what I would start with.

Dr. Greg Hundley:

Excellent. Well, I'm going to turn back and go back to our panelists here, listeners. And we're going to ask each of our panelists in about 20 seconds to describe for us what they think is the next most important aspect of research in their respective areas. So first I'll start with Mike Ackerman. Mike, can you tell us what's coming next in this area of assessment of QT prolongation or other aspects of the electrocardiogram?

Dr. Michael Ackerman:

I think next is implementing this in the real world. We are having our suite of the AI ECG as a hypertrophic cardiomyopathy detector. We've shown that as an ejection fraction detector, and now as a QT detector in AFib, from our work and Chris's work. And for the QT itself, I think where we are is we're really, really close to now having a mobile enabled digital QT meter. And a digital QT meter, once FDA cleared, then allows the QTC to truly emerge as the next vital sign. And it really deserves to be a vital sign. We use it as a vital sign. We know I want to know my patient's QTC every bit as I want to know his or her weight, blood pressure, saturation. It's an actionable finding, and we're now getting really close. We're just on the cusp of having a true digital QT meter.

Dr. Greg Hundley:

Excellent. Chris?

Dr. Christopher Haggerty:

I think for us to, in part address some of the comments that Mike brought up about the reproducibility of these types of models, we're very keen to demonstrate the prospective capabilities of our models to enroll patients in a prospective fashion, run their ECG through our predictor, and then screen them for AFib to determine how well we actually do moving forward, instead of just relying solely on our retrospective data. So we're very excited to do that. We're ramping up for that trial now and hope to be able to demonstrate similarly positive findings from our technique.

Dr. Greg Hundley:

Great. How about you, Nick?

Nick Mills:

I'd like to see the same quality and rigor applied to the implementation of these technologies as we have to other important areas in cardiovascular medicine. I think that's a really important step, not just to develop the tools, but to demonstrate their value. But I also think what we've done so far is relatively simplistic. We've taken an ECG and we've ignored almost all the other information that we have in front of us. And as these algorithms are trained and evolved, these and other vital clinical biomarkers and information, and integrating them into these neural networks will really enhance their performance for predicting things that are less tangible, like sudden death in the future or stroke.

Dr. Greg Hundley:

And then finally, Mike Rosenberg.

Dr. Michael Rosenberg:

Yeah, I actually see two challenging areas in this field. One is the access to data. And I think one of the things that a lot of companies are realizing is that even if they make hardware, that the data may be more valuable than the technology that they're getting the data from. So I think one is figuring out ways to get access to data so that people can reproduce findings from these studies. And the second is deliverable. A bottle like this is not like the CHADS-VASc score that I can calculate in my head in the clinic. I mean I need a way to actually run these models within an EHR, within a computer system like that. And I think it's going to be a big challenge to take a model like this and to deploy it at scale the way we would with the drug or any other innovation.

Dr. Greg Hundley:

Fantastic. Well listeners, we want to thank Mike Ackerman from Mayo Clinic, Chris Haggerty from Geisinger, Mike Rosenberg from University of Colorado, and Nick Mills from University of Edinburgh for really providing us with a wonderful discussion regarding the use of machine learning applications in one study to predict the QTC interval from two leads that may be applicable to wearable devices. And in the second study, predicting the future occurrence of atrial fibrillation and even stroke as an adverse event in people at risk.

Dr. Greg Hundley:

On behalf of both Carolyn and myself, I want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021.

Circulation March 23, 2021 Issue

22 mars 2021 | 29 min

For this week's Feature Discussion, join author author Hannah Valantine and Senior Associate Editor Biykem Bozkurt as they discuss the Original Research Article "Cell-Free DNA to Detect Heart Allograft Acute Rejection."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, I think we've got an interesting feature this week.

Dr. Carolyn Lam:

Oh boy, we sure do. This one is one of those potentially practice changing landmark papers. I'll give you a clue. It's about using cell-free DNA to detect heart allograft acute rejection in transplantation. Huge, huge, but you got to wait. Listen to the summaries of this week's exciting issue first. Greg, you want to go first?

Dr. Greg Hundley:

Yes. And I can't wait for that feature discussion. I think that's going to be one of our top papers this year, but first onto some of the summaries. So my first article comes to us from Dr. Pilar Alcaide from Tufts University School of Medicine. So Carolyn, despite the well-established association between T-cell mediated inflammation and non ischemic heart failure, the specific mechanisms triggering T-cell activation during the progression of heart failure and the antigens involved are poorly understood. So Carolyn, these authors hypothesize that myocardial oxidative stress induces the formation of isolevuglandin modified proteins that function as cardiac neoantigens to elicit CD4 positive T-cell receptor activation, and then promote heart failure.

Dr. Carolyn Lam:

Oh, that's really interesting. Inflammation in heart failure is a hot topic. Tell me more.

Dr. Greg Hundley:

So Carolyn, these authors discovered that TCR antigen recognition increases in the left ventricle as cardiac dysfunction progresses, and they identified a limited repertoire of activated CD4 positive T-cell chronotypes in the left ventricle. Mechanistically, cardiac pressure overload resulted in reactive oxygen species dependent dendritic cell accumulation of isolevuglandin protein adducts, which induced robust CD4 positive T-cell proliferation.

Dr. Greg Hundley:

So collectively, Carolyn, these results demonstrate an important role of reactive oxygen species induced formation of isolevuglandin modify cardiac neoantigens that lead to TCR dependent CD4 positive T-cell activation within the heart. And therefore, these results help understand the relationship between T-cell mediated inflammation and heart failure.

Dr. Carolyn Lam:

Wow. Super. Thanks, Greg. I'm moving all the way from basic science now to talk about intensive lifestyle interventions, which we know are first line approaches to effectively treat obesity and manage the associated cardio-metabolic risk factors. However, to date, whether effective lifestyle based obesity treatment in primary care works, we need more data. And this is what this paper provides.

Dr. Carolyn Lam:

This comes from Dr. Katzmarzyk and colleagues from Pennington Biomedical Research Center in Los Angeles. And what they report is the PROPEL Trial, which randomly allocated 18 clinics equally to usual care or an intensive lifestyle intervention, and subsequently enrolled 803 adults with obesity from participating clinics. The usual care group continued to receive their normal primary care, while the intensive lifestyle intervention group received 24 months of high intensity lifestyle-based obesity treatment in a program, embedded in the clinic setting and delivered by health coaches in weekly sessions initially and monthly sessions from months seven through 24.

Dr. Greg Hundley:

Well, Carolyn, sounds like a really practical study here. So what were these results?

Dr. Carolyn Lam:

Yes, Greg, this was a pragmatic trial. And although pragmatic, this lifestyle intervention was consistent with national guidelines, and participants receiving the PROPEL intensive lifestyle intervention lost significantly more weight over 24 months than those receiving usual care. Results also demonstrated clinically relevant improvements in high density lipoprotein cholesterol, total to HDL cholesterol ratio, metabolic syndrome severity, and fasting glucose. The PROPEL model may therefore be a viable option to deliver effective obesity and cardio-metabolic risk factor treatment in primary care.

Dr. Greg Hundley:

Well, Carolyn, what an interesting article. A lot that we can take home from that. Well, I'm going to switch and talk to you about blood flow restoration and its effect on venous thrombosis and vein wall injury. And this article comes to us from Dr. Farouc Jaffer from the Massachusetts General Hospital at Harvard Medical School. So Carolyn, up to 50% of patients with proximal DVT will develop the post-thrombotic syndrome, which is characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. While catheter based interventions, enabling restoration of blood flow, have demonstrated little benefit on post-thrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. So here, these authors in experimental and studies, they examined whether restoration of blood flow has a restricted time window for improving DVT resolution.

Dr. Carolyn Lam:

Oh, very interesting, and potentially a significant clinical implications, huh? Tell us about it.

Dr. Greg Hundley:

Well, Carolyn, there were two types of studies performed in mice and those in human subjects in the ATTRACT pharmacomechanical Catheter-Directed Thrombosis trial. So in the series of experiments in mice, within a restricted therapeutic window, restoration of blood flow improved DVT resolution. And then in the human studies, the pharmacomechanical catheter directed thrombolysis did not improve the PTS scores for patients having a symptom onset to randomization or SOR time of less than four days or greater than eight days. So therefore, further studies are warranted to examine the value of time restricted restoration of blood flow strategies to reduce post-thrombotic syndrome in patients with deep venous thrombosis.

Dr. Carolyn Lam:

Interesting. Thanks. Greg. My next paper is related, also talking about anticoagulants. And this time, the authors led by Dr. Hijazi from Uppsala Clinical Research Center in Sweden evaluated the risk benefit balance of antithrombotic therapy according to kidney function in the AUGUSTUS Trial. As a reminder, in the AUGUSTUS Trial resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, whereas aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or PCI treated with a P2Y12 inhibitor.

Dr. Greg Hundley:

Carolyn, thanks for reviewing for us the AUGUSTUS Trial results. So what did they find in this study?

Dr. Carolyn Lam:

So what they did is they looked at patients with atrial fibrillation and ACS and/or a PCI, and found that apixaban, as compared to vitamin K antagonists, displayed a consistent safety and efficacy profile, irrespective of kidney function, without significant interaction and in accordance with the overall trial.

Dr. Carolyn Lam:

Next, they found that aspirin, relative to placebo, on top of oral anticoagulation and a P2Y12 inhibitor resulted in more bleeding, irrespective of kidney function again, and with an even greater increase among those with a GFR more than 80.

Dr. Carolyn Lam:

These findings can help clinicians perhaps make informed decisions on the antithrombotic therapy in patients with atrial fibrillation and kidney disfunction, with ACS and/or a PCI.

Dr. Greg Hundley:

Very nice.

Dr. Carolyn Lam:

All right, Greg. Well, tell you what, let's go onto the other papers in this issue. I would like to tell you about a letter to the editor from Dr. Saleh on carotid atherosclerosis thickness, a proxy for cardiovascular disease events. There's an ECG challenge by Dr. Liu entitled, intriguingly, A Noteworthy Electrocardiogram, and this really describes new SD segment elevation and its differential diagnosis. To refresh, look up the paper.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I have a research letter to tell you about from Dr. Lanz entitled One Year Outcomes of a Randomized Trial, Comparing a Self-expanding to a Balloon Expandable Transcatheter Aortic Valve. And then finally, Dr. Maron has a very nice perspective piece entitled Exploring New and Old Therapies for Obstructive Hypertrophic Cardiomyopathy Mavacamten in Perspective. Well, Carolyn, I can't wait to get to this week's feature discussion. How about you lead us through that?

Dr. Carolyn Lam:

Me too. Let's go, let's go. I could not be more thrilled to be doing today's feature discussion. And I have to admit I'm feeling very star struck because I'm with two of the women I think are most at my own respect. And the first is Dr. Hannah Valantine, and she is professor from Stanford University now and also at NIH, and she's the corresponding author of today's incredible paper. And the next guest is of course, Dr. Biykem Bozkurt, senior associate editor of circulation from Baylor College of Medicine.

Dr. Carolyn Lam:

Welcome, ladies. On the topic today, it's really landmark. We could be talking about a new gold standard that may replace the endocardial myocardial biopsy. Wow. So if I could just start off, Dr. Valantine, could you please tell us about your study? What is cell-free DNA?

Dr. Hannah Valantine:

Yes. Thank you. It's a wonderful opportunity to be doing this podcast, and thank you for the interest on the technology. If you can imagine, when you put an organ transplant, essentially what you're doing is a genome transplant. You're transferring the genome of the donor into the recipient.

Dr. Hannah Valantine:

Now, we all have single nucleotide polymorphisms, otherwise known as SNPs, that are unique to the donor DNA, and that are unique to the recipient DNA. So that once we put that organ in and there is a teeny little bit of damage, little fragments of DNA come out of the donor organ into the recipient circulation, and we can pick that up, circulating in the plasma. And that's why we call it donor derived cell-free DNA.

Dr. Hannah Valantine:

So, you know the SNPs that belong to the donor, and you know the SNPs that belong to the recipient. You extract the DNA from the plasma of the recipient and you sequence it. And bingo, you can tell what the percentage of that cell-free DNA is coming from the donor, and that is the basis of the test.

Dr. Carolyn Lam:

Oh my goodness. I love that explanation. It's so lucid, and it's reminding me of what happened when I was pregnant. It's the same technology that's used, I think, in prenatal testing, in oncology in some cases, but this is the first time that you've shown it in a multicenter approach in cardiac transplantations. So could you please tell us about that?

Dr. Hannah Valantine:

Yes. Well, we first did this work in a single center when I was at Stanford, where we developed the technology, myself and a couple of colleagues in bio-engineering. But when you do a study, as you know, in one center, doesn't mean it's necessarily transferable or trans label into multicenter.

Dr. Hannah Valantine:

So when I went off to NIH, I transferred the technology there and did something else that was rather unique. I put together a consortium of the five local heart and lung transplant centers in the DC area. And we enrolled patients from each of those five centers into this study. And in the heart cohort, which is what is reported here, we were able to take blood samples on a serial basis. And there were 171 of them in the study. So, what happens is that we genotype the donor and the recipient of each of those 170 patients at the beginning, before the transplants, so that we could then know and monitor their cell-free DNA as they progress at serial time points after the transplant. And that's the way we were able to confirm the value of this test.

Dr. Hannah Valantine:

I can describe to you what the findings were. So what we found is that the cell-free DNA started to rise a lot earlier, before the heart biopsy showed a rejection. So it was just remarkable, because of the serial samples, we were able to look back and say, well, was there an elevation of the cell-free DNA before the positive biopsy? And that was definitively the case.

Dr. Hannah Valantine:

As you know, there are two types of rejection, antibody, mediated, rejection, and cellular driven rejection. And antibody mediator rejection, quite frankly, is the Achilles heel of organ transplantation because it's difficult to pick up and it occurs, that means it's diagnosed late, and it's really resistant to treat.

Dr. Hannah Valantine:

So what we found in this study is that the cell-free DNA was elevated for at least a couple of months before the heart biopsy actually showed the presence of antibody mediated rejection. And that has significant implications for the management of patients. And there are some other characteristics of the cell-free DNA that distinguish cellular and antibody mediated rejection. That is really important because the two types of rejection are treated differently. That's a great excitement of the results of this study.

Dr. Carolyn Lam:

Oh my gosh. I'm just tingling. My hairs are standing, just listening to you explain that. I really think we have a true liquid biopsy now for cardiac transplant rejection.

Dr. Carolyn Lam:

But Dr. Bozkurt, you're such an expert in heart transplantation. Could you frame it for us, just how significant these findings are?

Dr. Biykem Bozkurt:

This is transformative. So first, I would like to congratulate Dr. Valantine and her team for pioneering and leading this concept for such a long time. And now with this validations study, for providing the framework for the future studies for alternative strategies, implementation of how we're going to do this, as the liquid biopsy in lieu of endomyocardial biopsy.

Dr. Biykem Bozkurt:

So the findings that I think are truly practice changing are, yes, this study validates the ability to detect rejection. The second very interesting finding is predict the rejection almost three months before that we're able to detect it by histopathology. Third, for the first time, being able to detect antibody mediated rejection, as well as cellular. Fourth, being able to eliminate the necessity in approximately 81% of the patients with a very high negative predictive value.

Dr. Biykem Bozkurt:

Now, but I'm going to pose this question to Hannah. What is the gold standard now? Because in the historical past, we used to rely on histopathology to be diagnosed myocardial infarction. Now, we know that Troponin-I is a driver or Troponin-T or cardiac troponin. The profile of this is so, I would say, impressive, both for its negative predictive value. And I do realize the sensitivity and specificity is over 80%. And in the positive predictive, when we use the biopsy as the gold standard, the numbers are not as high as a negative predictive value, but if we add the clinical, those who've had the LV dysfunction, those who developed rejection subsequently, three months later, it is performing quite well.

Dr. Biykem Bozkurt:

So what now is going to be the gold standard? I'm thinking, shall we start calling things allograft injury and go and embrace the injury drum now with this profiling, and then trying to determine whether we can intervene early and prevent rejection? And I guess my question is, what's the next step?

Dr. Hannah Valantine:

Thank you for that lovely summary. This clearly, at this point, I would say the gold standard should be the cell-free DNA because in the study we switched it on its head. And we said, if the cell-free DNA is the gold standard, then how sensitive is the heart biopsy? And it wasn't very sensitive. And this is something that we've known for many years.

Dr. Hannah Valantine:

And I'll tell you a little anecdote that has driven my passion over the last 35 years to come up with a better diagnostic tool. When I was first an assistant professor and using echocardiography to study whether or not we could replace the biopsy, I had a patient who in whom I noticed had diastolic dysfunction. And my protocol was if we saw diastolic dysfunction, we actually did a biopsy. And to cut a long story short, I ordered these biopsies, and the biopsy was negative. And in retrospect, I think he had antibody mediated rejection. But the sad part of it is that after a few weeks I got a call from his wife to inform me that she found him dead in bed.

Dr. Hannah Valantine:

And so this has really motivated me to really find something better. And to your question, the cell-free DNA should be the gold standard. The problem is that physicians are human, and there is often takes a lot of time for adoption. So even though the data speaks for itself, that adoption piece is a social, psychological factor that to be overcome. But actually, we've had a really interesting experience in the context of COVID-19 when we were not able to do elective procedures, many centers have reverted to the cell-free DNA technology, and guess what? The patients are doing very well, as we documented in this study. So I think we're going to see a huge paradigm shift in the management of patients with cell-free DNA being the gold standard.

Dr. Hannah Valantine:

But I think that's not all because you asked the very important question about what's next and what's next about this research is to figure out, using the same technologies, why it is that black patients reject their organs so much more than white patients. And in this study, I hope you noticed that 44% of the cohort are African-American. And so it opens the door now to study this area. And then the third implication is that we can use cell-free DNA to actually look at other mechanisms and develop the technology. For example, DNA methylation profiles will come on board very shortly that can teach us more about where the damage is happening and add to the diagnostic tools.

Dr. Biykem Bozkurt:

I have another burning question. The peripheral gene expression profiles that also are available clinically to be able to characterize these patients. How do you see the difference in the cell-free DNA versus gene expression? And in this study, both the donors and the recipients were genotyped. Do you see the necessity of having to do so? Whether the current, you know, snip analysis will allow us not having to genotype patients, which may have an implication on the cost, as well as the practicality of how to implement this on the clinician bedside.

Dr. Hannah Valantine:

Absolutely. As you know, there are now several ways to get around having to genotype the donor by using an array of 260 or so SNPs known that are common in the population. And you can use that. And when you use that technology, it's equally sensitive. So that is what is going to move this forward in terms of clinical utility, so that we don't have to do that. So it's an extension of the technology. I like to do the recipient and donor genotyping because there's so much more research. So from the research perspective, it's useful to continue this technology. But for the application, yes, we're going to be able to do it without the genotyping, and rapidly.

Dr. Hannah Valantine:

And even beyond that, there are now new technologies coming up that we could use. For example, DVPCR, that could be translated into more rapid, an even more rapid test. Right now, the test takes about a day and a half to come back. My goal ultimately would be to have a point of contact test that we could actually use right there to make the diagnosis on a sample of the patient's plasma. So lots of new things coming out. This is just the beginning.

Dr. Biykem Bozkurt:

We're also excited about the possibility of the cell-free DNA, being able to predict coronary artery vasculopathy and/or other clinical events. So I'm sure your team is going to come up with results in regards to the future prognostication regarding the clinical events. So any, perhaps, prediction as to what we shall see those who don't decay, especially after 28 days? I'm very intrigued by those patients, which I think was a subgroup in your study.

Dr. Hannah Valantine:

Yeah. So that's absolutely right. What we are seeing is that those in whom the cell-free DNA remains relatively elevated, because what we find is that immediately after transplant, in the first 24 hours, the cell-free DNA diminishes and to a baseline low level. And then when there is rejection, we see these spikes, but when it's remains elevated, this might be a predictor of ongoing injury, an injury to the vascular dithulium that then sets up the familio for allograft vascular disease. And so we're chasing that hypothesis. The trouble is that the end point takes a while to develop, which is good for the patients. And so look out for future studies that where we will look at the correlation of the cell-free DNA as a predictor of allograft vasculopathy.

Dr. Hannah Valantine:

The other really interesting thing goes back to mechanism. You mentioned the question of consistently elevated cell-free DNA. And so I'm asking myself the question, whether this three floating cell-free DNA can actually act as a trigger of the immune response and therefore lead to damage and rejection. And that again is research that's ongoing, which will have significant implications for patient care. And it might actually help us in understanding why it is that African-American patients reject their organs. Because even those that are doing well in this study, they had relatively higher levels of cell-free DNA throughout the course, and did not decay as in the same pattern as the white patients. So lots of exciting work to come.

Dr. Carolyn Lam:

Oh my goodness, this is just a mind blowing discussion. So might not just be a marker, but even a target for rejection or anti-rejection therapy. And as a trialist, I'm already thinking ahead. Might we see future trials with raised cell-free DNA, but no evidence of rejection on biopsy, and whether or not treating these patients would actually improve outcomes?

Dr. Carolyn Lam:

So this is incredible. I wish we had all day to chat, and I think I really cannot let this end without at least saying something about Dr. Valantine, your work in diversity, and to just thank you on behalf of everybody for really forging this, and especially as part of Circulation. As you know, we have an issue focused on disparities, and we're just incredibly privileged to have you on the podcast today. Biykem, please would you add some last words?

Dr. Biykem Bozkurt:

I second those sentiments. We're grateful to Dr. Valantine for being a trailblazer for our transplant patients, for our community, to enhance the diversity, and for scientific excellence in all fronts. So thank you, Dr. Valantine.

Dr. Hannah Valantine:

Thank you very much. I'm humbled by your comments and very appreciative, and thank you for the support of this work.

Dr. Carolyn Lam:

Thank you, audience, for listening today. You've been listening to Circulation on the Run. Thank you for joining us, and don't forget to join us again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021.

Circulation March 16, 2021 Issue

15 mars 2021 | 28 min

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature involves interleukin-6 and a phenome-wide association study. So we have a lot to look forward to, but before we do that, how about we grab a cup of coffee and jump into the other articles in this issue? I could start first because I've got to tell you about some results from the ODYSSEY outcomes trial. And Carolyn, this comes to us from Professor Gregory Schwartz at the University of Colorado School of Medicine. Well, Carolyn, this study pertains to LDL lowering. As you know, recent international guidelines have lowered the recommended target levels of LDL cholesterol for patients at very high risk for major cardiovascular events or MACE.

Dr. Greg Hundley:

However, uncertainty persists as to whether additional benefit results from achieving LDL-c levels below some of these conventional targets. Now inferences from prior analyses are limited because patients who achieve lower versus higher LDL-c on lipid lowering therapy differ in other characteristics prognostic for MACE, and because few achieved very, very low LDL-c levels. So to overcome these limitations, these authors performed a propensity score matching analysis of the ODYSSEY outcomes trial, which compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving intensive or maximum tolerated statin treatment.

Dr. Carolyn Lam:

Sensible question, and what did they find?

Dr. Greg Hundley:

Well, Carolyn, the main finding of the study was that after accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-c levels less than 25 milligrams per deciliter did not appear to derive further reduction in the risk of MACE compared to those who achieved LDL-c levels of say 25 to 50 milligrams per deciliter. So, Carolyn, the take-home message is that recent international guidelines have lowered LDL-c goals for patients at very high risk for MACE to levels less than 55 milligrams per deciliter, and in some cases, maybe less than 40 milligrams per deciliter. However, any potential benefit of achieving LDL-c levels significantly below these goals to those very low, less than 25 really remains uncertain.

Dr. Carolyn Lam:

Very interesting. Thanks Greg. Well, my paper is about the HOST-REDUCE-POLYTECH-ACS trial. Got your attention? All right. I'll tell you what it is. It's an investigator-initiated, randomized, open-label, adjudicator-blinded, multicenter, non-inferiority trial, which compared the efficacy and safety of durable polymer versus biodegradable polymer, drug-eluting stents. And these investigators led by Kyung Woo Park from Seoul National University Hospital looked at 3,413 patients with acute coronary syndrome. At 12 months, the primary endpoint of patient oriented composite outcome, which was a composite of all-cause death, nonfatal myocardial infarction, and any repeat revascularization, occurred in 5.2% of the durable polymer group and 6.4% of the biodegradable polymer group. And so that met the non-inferiority P value of less than 0.01. the key secondary end points of device oriented composite outcome, which is a composite of cardiac death, target vessel MI, or target lesion revascularization occurred less frequency in the durable polymer versus biodegradable polymer groups, and this was mostly due to a reduction in target lesion revascularization. The spontaneous nonfatal MI and stent thrombosis rates were very low with no significant difference between the groups.

Dr. Greg Hundley:

Well, Carolyn, you know one of my favorite questions, so what's the take-home message here?

Dr. Carolyn Lam:

In patients with acute coronary syndrome receiving PCI durable polymer drug-eluting stents were non-inferior to biodegradable polymer drug alluding sense with regards to patient-oriented composite outcome at 12 months. I think that's the significant take-home message, and it's accompanied by an editorial where all this is discussed, and this editorial is by Doctors Byrne and Hanratty from Dublin.

Dr. Greg Hundley:

Very nice, Carolyn. Well, Carolyn, I am going to turn to the world of basic science and discuss phospho-lamin phosphorylation and how that may regulate vascular tone, blood pressure, and hypertension in both mice and men. And it comes to us from Dr. Michael Shattuck from King's College, London. So Carolyn, it's long been recognized that smooth muscle Na,K-ATPase modulates vascular tone and blood pressure. However, the role of its accessory protein phospho-lamin has not been characterized. So Carolyn, the aim of this study was to test the hypothesis that phospho-lamin phosphorylation regulates vascular tone in vitro, and this mechanism plays an important role in the modulation of vascular function and blood pressure in experimental models, both in vivo and in man.

Dr. Carolyn Lam:

Okay. So what did they find?

Dr. Greg Hundley:

Carolyn, these authors found that in aging wild type mice, phospho-lamin was hypo-phosphorylated, and this correlated with the development of aging induced essential hypertension. In human subjects, they identified a non-synonymous coding variant, a single nucleotide polymorphism RS-61753924, which causes the substitution of R-70 C and phospho-lamin. The R-70 C mutation prevented phospho-lamin phosphorylation at searing 68. This variance rare Alleo was associated with increased blood pressure in middle-aged men. So Carolyn, taking together these translational animal and human studies demonstrate the importance of phospho-lamin phosphorylation in the regulation of vascular tone and blood pressure and suggest a novel mechanism for aging-induced essential hypertension.

Dr. Carolyn Lam:

Interesting. And I suppose opening the door to translationally preventing this hypertension. Very interesting. Well from the next paper we switch to cardiac troponins, and you know these are the cornerstone of diagnosing acute myocardial infarction. But have you ever wondered, what is the duration of ischemia necessary to induce a measurable release of the cardiac troponins, or the very early release kinetics of cardiac troponins following an ischemic event? Well, this study is the first to report the early release kinetics of cardiac troponin concentrations, following different durations of experimental coronary balloon occlusion in humans.

Dr. Greg Hundley:

Ah, Carolyn. So how did they do this?

Dr. Carolyn Lam:

So 34 patients with N geographically normal coronary arteries were randomized into four groups with different durations of induced myocardial ischemia from zero to 30, 60, 90 seconds. Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected prior to balloon inflation and every 15 minutes for the first three hours and every 30 minutes for the next three hours. Cool, huh?

Dr. Greg Hundley:

Yeah. So did any of the patients suffer complications?

Dr. Carolyn Lam:

So the first thing to report is none of the patients had any complications, but what they found, and this was from authors, Dr. Iverson from Copenhagen, Denmark and colleagues. This is what they found increased cardiac troponin concentrations were detected by all three high sensitivity assays, be they high sensitivity troponin T by the Roche assay, high sensitivity troponin I by the Siemens essay, or high sensitivity troponin I by the Abbot essay. All assays detected a cardiac troponin increase after only 30 seconds of ischemia. High sensitivity troponin I by Siemens rose faster and reached a higher peak. Copeptin levels did not significantly change. So these interesting findings are accompanied by an editorial by Christopher deFilippi and Nicholas Mills discussing how the findings challenged some of our assumptions and may help shape future care pathways and the classification of ACS.

Dr. Greg Hundley:

Carolyn, so more in the evolution of high sensitivity troponins. Well, I'm going to shift to my last article of the day, and it focuses on eccentric remodeling and ischemic cardiomyopathy, and comes to us from Professor Konstantinos Drosatos at the Lewis Katz School of Medicine at Temple University. So Carolyn, these authors have shown that cardiomyocyte Krüppel-like factor or (KLF)-5 regulates cardiac fatty acid oxidation, and as heart failure has been associated with altered fatty acid oxidation, they now investigated the role of cardiomyocyte (KLF)-5 in lipid metabolism and the pathophysiology of ischemic heart failure.

Dr. Carolyn Lam:

Wow, Greg. What did they show?

Dr. Greg Hundley:

Well, Carolyn, they found that (KLF)-5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of (KLF)-5 in mice with myocardial infarction prevents ceramide accumulation, alleviates eccentric remodeling, and increases left ventricular ejection fraction. Thus, the authors suggest that (KLF)-5 may emerge as a novel therapeutic target for the treatment of ischemic heart failure. Well, Carolyn, we've got some other articles in the issue, and I'm just going to tell you quickly about an in-depth article entitled, “Cardiovascular Disease and Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options” that come to us From Dr. Marx, and then I'm going to turn it over to you.

Dr. Carolyn Lam:

Yes, we've got an exchange of letters between Doctors Grace and Mital regarding the article, “A Validated Model for A Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.” There's an ECG challenge by Dr. Peng on an irregular complex tachycardia. And there's this very interesting on-my-mind paper by Dr. Skolnik simply entitled, Gratitude. And I just have to tell you a bit about it, and I'm quoting from it now, “…having two surgeries for a large aortic aneurysm and aortic regurgitation, I am also left with an overwhelming sense of gratitude for living in the age in which I'm living. While some focus on what is wrong in the world, at least for today, my focus is on what is right.” Now, please read that paper. It's just such a beautiful piece. And, finally, there's a perspective piece by Dr. Sandhu entitled, “The Affordability of Guideline-Directed Medical Therapy, Cost Sharing, and How Cost Sharing is a Critical Barrier to Therapy Adoption.” Well, looks like it's a wrap. Greg, let's get on to our feature discussion, shall we?

Dr. Greg Hundley:

You bet. Well, listeners, we are now coming to our feature discussion today, and we're very fortunate to have with us today, Dr. Martin Dichgans and Dr. Marios Georgakis both from Munich, Germany. And we also have Dr. Svati Shah from Duke University, one of our associate editors. Welcome to you all. And I'll start with you Martin, could you explain to us a little bit of the background behind this study and what was the hypothesis that you wanted to test?

Dr. Martin Dichgans:

Yes, of course. We are interested in stroke, and more broadly, in cardiovascular disease, and inflammatory cytokines and inflammatory mechanisms in general play a major role in cardiovascular disease and particularly in arthrosclerosis, which connects a cardiac disease and stroke and also multiple other disorders. So that was our starting point. And we previously noted the importance of specific inflammatory cytokines in stroke, which is all primary area of research. We then quickly became aware of the central position of IL-6, which is downstream of IL-1β in the inflammatory cascade, and recognized not only that there's a lot of data on IL-6 in cardiovascular disease already, but that IL-6 actually is implicated in multiple inflammatory conditions, including autoimmune diseases, vascular, as I mentioned, and also metabolic disorders. And we noted that IL-6 receptor inhibition is already in use in some of these disorders, particularly in the treatment of autoimmune diseases, but not yet in use in cardiovascular disease.

Dr. Martin Dichgans:

So we asked ourselves whether there would be any repurposing potential, and also whether there would be an opportunity to explore the safety profile in its full width using genetic data because, and this I didn't mention, we have a background in genetics, a large interest in genetics, and you might have noticed that previously there has been a wealth of genetic data coming out, both on stroke, but also on cardiovascular disease in general. So also including other phenotypes, like for instance, and it has now become possible via a methodology called Mendelian randomization to utilize these genetic data and explore causal relationships between exposures such as IL-6 levels or specific cytokines and outcomes such as ordinary-after disease or stroke, and even go one further and explore the therapeutic potential, and also the full width phenotypes that could be relevant in such a scenario. So what we did is we took advantage of large scale genetic data from the UK biobank and data on specific outcomes available in the UK biobank to dive into the questions we were interested in.

Dr. Greg Hundley:

Martin, that was a wonderful explanation. So could you describe, what was the aim of your study?

Dr. Martin Dichgans:

In brief, the aim was to use large scale genetic data to explore the repurposing potential and safety profile of IL-6 receptor inhibition in the general population.

Dr. Greg Hundley:

Very nice. Describe your study design.

Dr. Martin Dichgans:

So the study population was the UK biobank, which is a population-based sample of, in this case, 340,000 unrelated individuals. And what we did is we performed the phenome-wide association study. So we looked across all available phenotypes that are systematically encoded in the UK biobank, and which included both clinical outcomes and biomarkers, in this case about 1,400 clinical outcomes and 360 or 70 biomarkers and endophenotype of human disease in this biobank. And again, explored relationships between IL-6 receptor inhibition and the effect on these outcomes.

Dr. Greg Hundley:

Very nice. Well, Marios, let's turn to you. Could you describe the results? What did you find?

Dr. Marios Georgakis:

Yes. Hello from my side as well. So, as Martin mentioned, we explored associations between genetically down-regulated IL-6 signaling and 1,400 clinical outcomes, as well as with 360 biomarkers in another, I would say hypothesis reapproach. So, following corrections from output testing, we found significant associations with genetically down-regulated IL-6 signaling activity with 16 clinical outcomes and 17 biomarkers. As we had shown in the past, genetically down-regulated IL-6 signaling activity was associated with several cardiovascular phenotypes, specifically atherosclerotic phenotypes, primarily including coronary artery disease manifestations, but also for example, abdominal aortic. Interestingly though, we also found a significant association with a lower risk of type two diabetes, as well as with a lower glycated hemoglobin, another finding that was consistent not only in the UK biobank, but also in two cohorts that we use for validation. So in the past, there have only been data from small observational studies and small case series in patients with rheumatoid arthritis supporting these findings, but to date, no data from large clinical trials.

Dr. Marios Georgakis:

Furthermore, we find significant associations between genetically down-regulated IL-6 signaling and higher total cholesterol, but also higher HDL cholesterol levels, but no association with LDL cholesterol. This further supports associations of IL-6 signaling downregulation with, let's say more favorable argument among the profile. Now, why is this important? This is a very interesting finding because previous clinical trials had suggested that IL_6 receptor inhibitors might lead to increases in total cholesterol levels, which would, of course, be an undesired side effect for people who'd ever envisioned using IL-6 receptor inhibitors in the context of lowering cardiovascular risk.

Dr. Marios Georgakis:

Here, however, we show, and our results support, that this increases primarily the results of the effects of IL-6 signaling bar down-regulation on HDL and not LDL levels. On the negative side, and finally, we found significant associations between genetically down-regulated IL-6 signaling and the number of potential side effects, particularly strong associations with bacterial infections, such as cellulitis and urinary tract infections, which is probably also related to the identifed association with the lower risk of neutropenia. So while these are well-described side effects of IL-6 signaling and condition in the context previous clinical trials, this, we believe, disagreement with our findings adds additional confidence to, let's say, the validity phenome-wide association state.

Dr. Greg Hundley:

Very nice Marios. Really appreciate this exciting work. And now we want to turn to our associate editor, Doctor Svati Shah. And Svati, you have many papers come across your desk, what attracted you to this paper? And then how do you put the results that these men have presented into context with other papers in this area of investigation?

Dr. Svati Shah:

Yeah. Great question, Greg, and thanks for having me. I thought this paper was really important, but I want to start at a broader level, and that's why it's attracted my attention is, I think genetics can not sort of inherently appeal to the broad Circulation reader. It can feel somewhat esoteric. We do these genome-wide association studies, these whole-exome association studies, and we find new genes and we're really excited about them as people who live in the genetic epidemiology realm. But when we think about the broader circulation readership and the broader cardiology readership, how does this really relate to how I take care of patients, and what might be important for me in my cardiovascular realm? And I think this paper really highlights the power of human genetics and how we really understand things that have clinical utility.

Dr. Svati Shah:

And let me just expand on that really briefly. And that is, in the human genetics realm, we can look at what we call human knockouts. We're not actually doing gene editing in humans, but looking at people who have loss of function variants. They're emulating a drug for example. And we also have PheWAS, which is a phenome-wide association study, where we say, "We're just going to look at lots of different clinical things and biomarkers and try to understand things that are associated." And then finally we have Mendelian randomization, which allows us at a very statistical level to really assess causality. We know there are things that are correlated with each other, but we don't necessarily know that they're causal, and this is a statistical way for us to potentially assess causality. I say that very carefully because it's a statistical way to do that.

Dr. Svati Shah:

And what's really cool about this paper is they combine PheWAS and Mendelian randomization, but with a very clinically important aspect. What are the potential good side effects, the on-target things that we want to try to address with these potential drugs, like tocilizumab, and what are potential side effects of these potential drugs. And in this case, because they combined PheWAS, they're able to look across all kinds of things. So the things that we already know about, they're not looking at a drug per se, but they're emulating a drug by looking at these genetic variants to say, "Okay. Well, we're going to look across all these different clinical factors." So it's not only things that have been evaluated in these clinical trials, but even just beyond that. And then the Mendelian randomization piece allows them to be able to say, again, statistically, are these causal. So if you antagonize these receptors, does it 'cause' these downstream effects. So, that's what was really cool to me about this paper. Is it really highlights the potential for human genetics in a very short term translational clinical potential.

Dr. Greg Hundley:

What a wonderful explanation for our listeners here. Well, let me ask each of you, Martin, Marios, and then Svati, what do you see as the next research endeavor in this space? Martin, you first.

Dr. Martin Dichgans:

And I completely agree with Svati that we have to utilize genetics in order to improve our means of treating patients, and I think that's obviously our aim here. And what this study shows, and let me just briefly also confirm what you said, we were intrigued by how the genetic data reflect what we see, for instance, in clinical trials. Just to expand a little bit on that aspect, the seven genetic instruments, which consisted of seven snips, single nucleotide polymorphism, when we looked at the effects of genetic lowering in this context on upstream and downstream, known upstream and downstream biomarkers of IL-6 signaling, this really very much matched what we know from clinical trials with tocilizumab so with pharmacologically lowering IL-6 signaling. Again, giving us confidence that it's informative and we will see with genetics what we are going to expect in the future in clinical trials.

Dr. Martin Dichgans:

So now getting to your point here and providing an answer, what we see as the next step, we should, for instance, combine the genetic data we have here with genetic data on other approaches to see whether, and maybe Marios can be more specific about this, whether by combining two different approaches, for instance, LDL lowering and targeting residual inflammatory risk, whether we could in future clinical trial provide additional benefits to high-risk patients with a cardiovascular disease. And I think that will be a very important area. Also, I think we should extend this approach to other inflammatory cytokines that have come up in Mendelian randomization analysis to explore their potential in future clinical trials.

Dr. Greg Hundley:

Marios?

Dr. Marios Georgakis:

Yeah. So just to add a little bit on Martin's summary, I would say here that now that we have established the efficacy of anti-inflammatory approaches in lowering cardiovascular risk, both with clinical trials, but also with showing genetic and clinical evidence, I think that the next step is first to identify the proper clinical scenario where anti-inflammatory approaches targeting IL-6 signaling would be used for reducing cardiovascular risk in order to design the proper clinical trials. And secondly, as Martin mentioned, to explore whether targeting IL-6 signaling would, one, pass additive benefits on Kruppel available approaches such as lipid-lowering approaches, and second, to see whether the risk-benefit balance of anti-inflammatory targeting IL-6 signaling would be acceptable in the clinical setting.

Dr. Greg Hundley:

And Svati.

Dr. Svati Shah:

Yeah. It's hard to follow up on those comments. I'll say, since I am very interested in diabetes and insulin resistance, the cholesterol story is fantastic, but I think the fact that they see effects on, again, statistical lowering of hemoglobin A1C and type two diabetes is fascinating to me. I would take it even a little step further. I think we need clinical trials. These data are very suggestive. It sort of flips the story almost. We've seen, even in some of the clinical trials of these drugs, that there are beneficial metabolic effects with regards to glucose, although some of the data are contradictory. So flipping it and saying, we know that inflammation is complex and we know that IL-6 has pro and anti-inflammatory roles in inflammation, and we know that diabetes with regards to inflammation is very complex, but maybe these drugs potentially are useful in type one and type two diabetes. So I think we need carefully designed clinical trials, potentially, to understand the role of blocking inflammation, and in particular IL-6 signaling, in patients who have diabetes.

Dr. Greg Hundley:

Excellent. Well, listeners, we want to thank Dr. Martin Dichgans, and Dr. Marios Jojakas, and our own associate editor, Dr. Svati Shah for bringing us this study incorporating phenome-wide association and Mendelian randomization to identify a relationship between down-regulated IL-6 signaling with subsequent clinical cardiovascular outcomes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021.

Circulation March 9, 2021 Issue

8 mars 2021 | 27 min

This week features two Feature Discussions. In our first feature discussion, Nikkil Sudharsanan and Associate Editor Ntobeko Ntusi as they discuss the article "Variation in the Proportion of Adults in Need of BP-Lowering Medications by Hypertension Care Guideline in Low- and Middle-Income Countries: A Cross-Sectional Study of 1,037,215 Individuals from 50 Nationally Representative Surveys." Then in our second feature discussion, join author Aloke Finn and Associate Editor Jeffrey Saffitz as they discuss the article "Microthrombi As A Major Cause of Cardiac Injury in COVID-19: A Pathologic Study."

One addendum to the Feature Discussion with Drs. Sudharsanan and Ntusi:

· Dr. Sudharsanan wanted to clarify that treatment needs were determined for each country based on multiple blood pressure measurements taken on the day of the survey; however, all the estimates were based on BP measured on just one day, rather than over several weeks as is done in clinical practice. This is related the final question posed in the first Feature Discussion.

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Greg Hundley Associate Editor for the Pauley Heart Center in Richmond, Virginia at VCU Health.

Dr. Carolyn Lam:

Guess what, Greg, it's another issue with a double feature. We are going to be discussing microthrombi as a major cause of cardiac injury in COVID-19.

Dr. Greg Hundley:

Yes, Carolyn and our second discussion will be centered on blood pressure lowering in low and middle-income countries. But how about you and I both grab a cup of coffee and jump into the other articles in this issue.

Dr. Carolyn Lam:

Sure thing. I got my coffee and let's start with gestational diabetes. Now, we know that leads to an earlier onset and heightened risk of type 2 diabetes, which is a strong risk factor for cardiovascular disease. But Greg, do you think that attaining normal glycemia following gestational diabetes can ameliorate the access risk?

Dr. Greg Hundley:

Carolyn, that's a really great question. I would think so but how about you tell me what these authors found.

Dr. Carolyn Lam:

Yep. This next paper it's from Dr. Gunderson from Kaiser Permanente, North California and colleagues. They exactly sought to answer the question and realize that it was unclear whether attaining normal glycemia can ameliorate the excess cardiovascular disease risk that's associated with gestational diabetes. So they evaluated gestational diabetes history and glucose tolerance after pregnancy and found out whether or not it was associated with coronary artery calcification in women. The obtained data from the CARDIA study which is a US multicenter community-based perspective cord of young black and white adults age 18 to 30 years at baseline.

Dr. Carolyn Lam:

This is what they found. Women without previous gestational diabetes showed a greater increase in the risk of coronary artery calcification associated with worsening glucose tolerance. However, women with a history of gestational diabetes had a twofold higher risk of coronary artery calcification across all subsequent levels of glucose tolerance. Midlife atherosclerotic cardiovascular disease risk among women with previous gestational diabetes is therefore not diminished by attaining normal glycemia. And this is discussed in an accompanying editorial by Dr. Jennifer Green from DCRI entitled Cardiovascular Consequences of Gestational Diabetes.

Dr. Greg Hundley:

Carolyn, well, sounds like I was wrong but our next paper, it's going to review for us a little bit about IgE. Remember that immunoglobulin associated with itching. So Carolyn immunoglobulin E or IgE belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor in pathological cardiac remodeling and heart failure or a non. So in this study, the investigative team measured serum IgE levels and cardiac IgE receptor expression in diseased hearts from humans and mice.

Dr. Carolyn Lam:

Oh, Greg, I'm itching to find out what this study showed.

Dr. Greg Hundley:

Yes, Carolyn, going from the quizmaster now to is it comedy now? Serum IgE levels were significantly elevated in patients with heart failure as well as in two mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin two infusion. Now, interestingly Carolyn, IgE receptor expression levels were also significantly up-regulated and failing hearts from human and the mouse model.

Dr. Greg Hundley:

Carolyn, the authors found that IgE induction plays a causative role in pathological cardiac remodeling at least partially via the activation of IgE receptor signaling in cardiac myocytes and cardiac fibroblasts. So future studies are needed to determine if therapeutic strategies targeting the IgE receptor axis and as to whether they may be effective for managing IgE mediated cardiac remodeling.

Dr. Carolyn Lam:

Fascinating. I never thought of IgE involved in cardiac remodeling. Now, this next paper really interesting. Regulators are always evaluating the use of non-interventional real-world evidence studies to assess the effectiveness of medical products. The RCT DUPLICATE Initiative was formed to use a structured process to design real-world evidence studies to emulate randomized control trials and compare results. Now, this paper represents the first 10 trials emulations in RCT DUPLICATE, and it's from Dr. Jessica Franklin from Brigham and Women's Hospital and Harvard Medical School in Boston and her colleagues. And they did this to evaluate cardiovascular outcomes of antidiabetic and antiplatelet medications.

Dr. Greg Hundley:

Wow, Carolyn. So how does they do this?

Dr. Carolyn Lam:

So they use patient level claims data from US Commercial and Medicare-PEERS and implemented inclusion exclusion criteria of the trial selected primary endpoints and compare the populations to emulate those of each of the corresponding randomized controlled trials within the trial mimicking populations, they then conducted propensity score matching to control for more than 120 pre-exposure con founders.

Dr. Greg Hundley:

So Carolyn, were they able to emulate their randomized clinical trial results?

Dr. Carolyn Lam:

Now, despite the attempts to emulate the trial design as close as possible, there were still differences between the randomized control trial and the corresponding real-world evidence study population. The regulatory conclusions were equivalent in six of 10 studies. The real-world evidence emulations achieved a hazards ratio estimate that was within the 95% confidence interval from the corresponding trial in 8 of 10 studies. Agreement between the trial and real-world evidence findings varied depending on which agreement metric was used.

Dr. Carolyn Lam:

Interim findings indicated that selection of active comparative therapies with similar indications and use patterns enhance the validity of the real-world evidence. And so, even in the context of active comparators concordance between trial and real-world evidence findings was not guaranteed partially because trials were not emulated exactly. More trial emulations are needed to understand how often and in what context real-world evidence findings will match the trials. And yet these initial findings of RCT DUPLICATE really indicate circumstances when real-world evidence may offer causal insights where trial data is either not available or cannot be quickly or feasibly generated

Dr. Greg Hundley:

Well, Carolyn, that is really interesting findings there because we're all trying to decide what to do with these large data sets and combining the results of millions and millions of data points and very interesting findings in this study. How about we see what else is in the issue?

Dr. Carolyn Lam:

Absolutely. Well, let me start. There's an exchange of letters among doctors Villarreal, Cárdenas Suri, [and] Navarro-Castellanos regarding the Multi-system inflammatory syndrome in children. The ECMO needs and Kawasaki disease likeness. There's also an ECG challenge by Dr. Pillai entitled "A Tale of Two Blocks".

Dr. Greg Hundley:

Well, Carolyn, I've got a very nice In-Depth review from Dr. Van Belle regarding transcatheter aortic valve replacement in bicuspid aortic valve stenosis. And there's a Research Letter from Dr. Lew entitled “Short-Chain Enoyl-CoA Hydratase Mediates Histone Crotonylation and Contributes to Cardiac Homeostasis.” And then finally, Dr. Nordin Hanson from Amsterdam has a very nice piece on the Clinical Implications of Basic Science Research entitled “DAMPening Mortality in COVID19: Therapeutic Insights from Basic Cardiometabolic Studies on S100A8/A9.” Well, Carolyn, how about we check out the double feature.

Dr. Carolyn Lam:

Definitely let's go, Greg.

Dr. Greg Hundley:

Well listeners, we are here for our first feature discussion on this March 9th issue and we have with us Nikkil Sudharsanan from Heidelberg and also our own Associate Editor Ntobeko Ntusi from Cape Town. Welcome gentlemen. Nikkil, could you please describe for us the hypothesis that you wanted to test your study population and your study design?

Dr. Nikkil Sudharsanan:

Yeah, so for our hypothesis, we really wanted to know, depending on which hypertension treatment guideline you chose, what implications does it have at the population level for the number of people in low and middle-income countries that would require treatment or that you would want to place on treatment. And we were really looking at not just one country, but a whole range of 50 low and middle-income countries. And so our study population is actually from this pretty remarkable data source that combines the World Health Organization surveillance data for many countries with other sources of data, to try to create a comparable almost low and middle-income country super dataset that's specifically designed to answer questions around cardiovascular disease. So our study population was really based on population representative samples for each of the 50 countries we considered. And in most of the countries we focused on the adult population. So those ages 30 and above.

Dr. Greg Hundley:

And your total sample was over a million participants, correct?

Dr. Nikkil Sudharsanan:

Yeah, it's a really huge sample. And I think it's a testing to some of these data sources, especially the ones in India and Brazil, but collected just really large sample sizes that contributed to this huge global population.

Dr. Greg Hundley:

Very nice Nikkil. And what did you find?

Dr. Nikkil Sudharsanan:

So the big finding is we actually went into it not knowing how the choice or how strong the choice of a blood pressure treatment guideline would be on the number of people that required treatment and were really surprised to see that we took more treatment guidelines, the 2018 American College of Cardiology, American Heart Association guidelines, the kind of typical 140 by 90 blood systolic diastolic blood pressure threshold that you see as part of a lot of guidelines. The UKs NICE guideline and then the WHO Hearts guideline, which is based on their pen and package of essential non-communicable disease interventions.

Dr. Nikkil Sudharsanan:

And we started a really, really pronounced difference in the proportion and size of the adult population that you would recommend or place under hypertension treatment, depending on which of these guidelines used to decide who gets treatment across these countries. So at the top, we found the American College of Cardiology, American Heart Association guidelines, and for the countries we were considering it put about 27% of women and a really high 35% of men as recommended for blood pressure treatment.

Dr. Nikkil Sudharsanan:

And then very closely followed to that was the 140, 90 threshold. So it was still high, but not as high, I would think it was around 26% of women and 31%. And then between these two guidelines and the UK NICE and WHO Hearts, there was a really big drop-off in how many people would actually be recommended for blood pressure treatment.

Dr. Nikkil Sudharsanan:

The NICE guideline, for example, only have 12% of women and about 16% of men and the WHO Hearts is by far the lowest, which only about 10% of women and 11% of men. So I think our first really striking finding was that this choice is not trivial. And depending on which guideline you actually choose to decide who gets treatment in that country, it has really big implications for how many people in that country are going to need treatment.

Dr. Greg Hundley:

Very good. And Ntobeko, how do you put the results of this study in the context with other research perform to study hypertension?

Dr. Ntobeko Ntusi:

Thank you, Greg. So we know that although more than 80% of the global battle of Cardiovascular Disease, okay. As in low and middle-income countries, the data around respecters for cardiovascular disease has largely come from high-income countries. And the INTERHEART study was really the first publication about 15 years ago to try and address this question. And it was very apparent both in the INTERHEART study as well as the INTERHEART Africa study of hypertension was one of the key respecters not only for my myocardial infraction, but for cardiovascular disease in general.

Dr. Ntobeko Ntusi:

In the INTERHEART study hypertension having a hazard ratio of two and the population attributable risk of 17%. And then the INTERHEART Africa study having a hazard ratio of over six. And this paper is really an important application in my view, showing that in a comparison of over a million individuals from 50 countries, there is great variation in the proportion of individuals that need to be treated for hypertension, based on the choice of guideline and definition of hypertension. And if you look at figure one, this is variable from anywhere from 9% to 35%.

Dr. Ntobeko Ntusi:

The other important contribution of this paper is that the proportion of the population that needs to be treated for hypertension increases with age, which is something that we know but strikingly more than 60% in those over the age of 60 years. And for me, they are really great core key messages that I think are important contributions from this publication. The first one being that the choice of hypertension treatment guideline significantly influences the denominator of what you consider to be hypertensives in your population. The second one is that many people in low and middle-income countries are still unaware of their status of elevated blood pressure and the need for treatment. And I think this is a key point to emphasize.

Dr. Ntobeko Ntusi:

The third important message is that these first two points I've made have got huge implications for the scale-up costs and healthcare system capacity and that countries need to choose definitions for diseases. And this needs to be aligned with national health policy as well as available resources. And then finally, a key part of the discussion, which I asked the author to address was really around our understanding of the barriers to optimal management of blood pressure in low and middle-income countries and how these gaps can be oppressed. And they speak to the economic and human resources, the health policy, the importance of population screening and importantly education at every level.

Dr. Greg Hundley:

Very good. Nikkil I'd like to come back to you and then maybe 20 seconds or so, what do you think is the next study that needs to be performed really in this area of research?

Dr. Nikkil Sudharsanan:

I think there may be two, one is to really build on this in terms of what we showed this is the proportion of people that would require treatment and that's how it varies across these guidelines. I think it's important to also tie that to the resource implications directly, like Dr.Ntusi said, to actually show this guideline would require this many resources versus this many for that guideline. I think that will really help countries in deciding what's actually feasible guideline to implement.

Dr. Nikkil Sudharsanan:

And the second one, which is I think a much more challenging study to do is just a study of all these guidelines are based on mostly data from high-income countries. And even among these high income countries, there's these discussions on what the appropriate level for treatment is and what point you should initiate treatment. And it seems like this really has not been done with low and middle-income country populations. So we're arguing about four different guidelines that were built for high-income country populations. And I think it would be really important to see some sort of trial or long-term observational study actually in terms of averting cardiovascular disease events which guidelines actually makes the most sense for these countries.

Dr. Greg Hundley:

Very good. Ntobeko, anything to add to that?

Dr. Ntobeko Ntusi:

I think I agree completely with Nkkil and I think this paper has a number of really important strengths, and I think those strengths and key contributions have to be taken in the context of one significant limitation and how we interpret these results. And that's the fact that when we normally see a patient in the clinic to diagnose hypertension, we would take two or three blood pressure measurements. In this study, they only took a single blood pressure measurement and that's the basis for the conclusions and for me a key limitation, but nonetheless, I think a very important contribution.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Nikkil Sudharsanan from Heidelberg and Ntobeko Ntusi from Cape town for bringing us this important study, indicating that worldwide there's substantial variation really in the proportion of adults in need a blood pressure lowering medication, depending on which hypertension guideline is used. Well, let's move on now to our second feature discussion.

Dr. Greg Hundley:

Listeners, we are now to our second feature discussion and we have with us Dr. Aloke Finn from the Cardiovascular Path Institute in Gaithersburg, Maryland and our content editor expert for pathology, Dr. Jeff Saffitz from Beth Israel Deaconess. Welcome gentlemen. Aloke, could you describe for us, what was the question you wanted to address with this researching? What was your study design and your study population?

Dr. Aloke Finn:

Great. Greg, thanks for your interest in our article and for highlighting it. We were really interested in understanding what the pathologic causes for cardiac injury were in people hospitalized with COVID-19, as you know, it's been reported in the literature that people with COVID-19 with cardiac injury do worse than those without cardiac injury, but the mechanism is not still well understood. So the study design was really based upon a collaboration with a group from Italy in the Lombardy region, where they had had a terrible outbreak in 2020, as you remember in February. And they had a number of hospitalized. People die from COVID-19 infection, and they too were interested in understanding the pathologic causes of chronic injury. We got IRB approval and those hearts were sent to us during the middle of this pandemic in the February, March time. And we were able to examine 40 of those hearts and report our pathologic findings. And these were unselected cases of hospitalized patients dying of COVID-19.

Dr. Greg Hundley:

That was great. And tell us a little bit what were your study results?

Dr. Aloke Finn:

So we, first of all, did an analysis based upon the presence of myocardial necrosis. So that was the sort of the selection factor, which hearts had myocardial necrosis which parts didn't have myocardial necrosis. We found that 35% of the hearts in this 40 cases had myocardial necrosis. Now, we divided those into the type or pattern of myocardial necrosis. Was it acute myocardial infarction? Was there a large area of infarction greater than one centimeter squared or was there focal myocardial necrosis less than one centimeter squared. It's small areas of focal myocardial necrosis. We've found that most cases of patients dying of COVID-19 with myocardial necrosis had focal myocyte necrosis. Not large areas but small areas of myocyte necrosis. And we looked for the cause of those necrosis, majority of those cases with focal myocyte necrosis had microthrombi as the cause of that necrosis. So that suggests the major mechanism of myocardial injury in COVID-19 patients is microthrombi.

Dr. Greg Hundley:

Very nice. Well, Jeff, let's turn to you. How do we put the results of this study in the context with perhaps other pathologic studies that have been obtained from hearts of individuals that succumb to COVID-19?

Dr. Jeffrey Saffitz:

It's a very important question. And I want to say that at the outset, there have been many papers published focused on the pathologic findings of COVID-19 patients who have come to autopsy. And I have to say that the quality of these papers has been quite variable. In many cases, the pathology being shown is actually post-mortem artifact. In other cases, the interpretation of the pathology is incorrect. And so I think we have to be very careful in a study like this to make sure that what is being reported is actually valid and meaningful in the context of the important clinical questions being posed. And in this case, I can say the pathology was really extremely impressive and very convincing.

Dr. Jeffrey Saffitz:

Another important aspect of this study has to do with the comparison of the composition of the microthrombi that were identified in patients dying from COVID-19 versus patients who have other types of coronary thrombosis, but in a different setting. And here, there were some interesting observations that provide insights, not only into mechanism of thrombosis, but also potential information about how one might want to target antithrombotic therapy in these patients. So I would really like to hear more from Dr. Finn on this interesting aspect of this study.

Dr. Aloke Finn:

Jeff, thanks for your comment and your question. I think I agree with you, this was another interesting aspect of the study. What was done was that were able to examine the constituents of thrombi, different types of thrombi both in the setting of patients who had COVID-19 and non COVID-19 STEMIs as well as microvascular thrombi described in the COVID-19 patients, as well as embolized thrombi that embolized a small microvascular within the heart. And what we essentially found was that these thrombi, that are COVID microthrombi are distinct in their constituents. Distinct in that they had more fibrin and more compliment activation than the other types of thrombi that we're studied. So I do think this begins to unravel the question about how are these thrombi forming and are they different from the type of thrombi we normally treat? And the answer is, yes.

Dr. Greg Hundley:

Very nice, Aloke. What study do you think needs to be performed next in this space? And after you, I'll ask Jeff the same question.

Dr. Aloke Finn:

Greg, I would like to know whether or not therapies like anticoagulant, anti-compliment, antiplatelet therapies can decrease the risk or the effect of the COVID-19 on myocardial injury. Is will we see a benefit to anticoagulant or antithrombotic strategies in the study? I think that is the natural next question to ask.

Dr. Greg Hundley:

Very nice. And Jeff, anything to add?

Dr. Jeffrey Saffitz:

Yeah, well, I'm an experimental pathologist, so I'm always interested in disease mechanisms. And I would like to understand more about how these microthrombi form, the role of endothelial cell injury, the role of cytokine storm and other factors which we know are contributing. I think in the end having a more fundamental understanding of these mechanisms will provide important insights, not only in trying to manage heart disease, but in fact, other organ system disease, which is likely being mediated by a similar mechanism in the kidney and potentially in the brain and other organs as well. So I think this is a great example about how autopsy can provide really critically important information in a new human disease and set the stage for subsequent studies that will really provide important dew information.

Dr. Greg Hundley:

Excellent. Well listeners, we want to thank Dr. Aloke Finn from Gaithersburg, Maryland, Dr. Jeff Savitz from Boston, Massachusetts for this excellent discussion and revealing the pathologic results of 40 hospitalized patients from Italy that expired after COVID-19 highlighting the cause of myocardial necrosis and how it was related to the presence of microthrombi.

Dr. Greg Hundley:

On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation March 2, 2021 Issue

1 mars 2021 | 30 min

This week, join author authors John J.V. McMurrary and Milton Packer, and Associate Editor as they discuss their Perspective article "How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction? A Redefinition of Evidence-Based Medicine."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, this feature discussion is going to knock you off your seat, because it did me. It's about treatment sequencing in HFrEF and discussing it with some luminaries on the field, Dr. John McMurray and Dr. Milton Packer. You are going to love it. I loved it. But I'm going to make you wait. How about you grab some coffee and let's start with some of the other papers in today's issue first.

Dr. Greg Hundley:

All right, Carolyn. How about if I go first? I'm going to start with a paper from Dr. Liam Brunham from the University of British Columbia. Well, Carolyn, the high density lipoprotein or HDL hypothesis of atherosclerosis has been challenged by clinical trials of cholesterol ester transfer protein, or CETP inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of HDL cholesterol, or HDL-C, declined drastically during sepsis. And this phenomenon is explained in part by the activity of CETP, a major determinant of plasma HDL-C levels. So Carolyn, these authors tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts in animal models of sepsis.

Dr. Carolyn Lam:

Huh. Interesting. And what did they find?

Dr. Greg Hundley:

Well, Carolyn, results from both the human UK Biobank and the mouse model experiments suggested that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.

Dr. Carolyn Lam:

Wow. So is this ready for clinical applications somehow?

Dr. Greg Hundley:

Well, Carolyn, two conclusions from this work. First, high density, lipoprotein cholesterol, a commonly used biomarker for cardiovascular risk assessment, may also predict risk of death from sepsis. And then second, cholesterol ester transfer protein inhibitors that have been tested in clinical trials of cardiovascular disease could be repurposed and studied in clinical trials of sepsis.

Dr. Carolyn Lam:

Ooh, exciting. Well, Greg, for my paper, I'm going to ask you a question. Have you ever thought about what the temporal changes in medical prevention and adverse outcomes are in patients with symptomatic peripheral artery disease after revascularization? Well, wait no longer. Our next paper addresses that. It's from Dr. Sogaard from Aalborg University Hospital in Denmark and colleagues who identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark from 2000 to 2016. And this is what they found.

Dr. Carolyn Lam:

First, the profile of patients with PAD who underwent lower extremity revascularization changed towards older age and a higher prevalence of comorbidity. Despite increases in age and co-morbidity, medical prevention of adverse events improved substantially over time, particularly in the first part of the study period and among patients who used medications chronically.

Dr. Carolyn Lam:

Now in contrast, initiating treatment after revascularization increased modestly among treatment-naive patients. Now concurrently, prognosis improved for almost all adverse outcomes in patients of both sexes, all age groups, and in all high-risk co-morbidities. In particular, the risks of myocardial infarction and cardiovascular death declined by more than 40%.

Dr. Greg Hundley:

Well, Carolyn, are there any other findings with clinical implications here?

Dr. Carolyn Lam:

Yes. So that was the good news earlier. But despite overall improvements, significant disparities remain. Less than 40% of treatment-naive patients initiated cardioprotective therapy after revascularization, underscoring the need for raising levels of awareness and education in the vascular community, general practitioners and patients of this. Major amputations also remained unchanged and thus more work is needed to understand relationships between the preventive measures, revascularization and amputation.

Dr. Greg Hundley:

Great summary, Carolyn. My next paper comes from Dr. Rachael Cordina from the Royal Prince Alfred Hospital, University of Sydney. Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well-defined. So the investigators here aim to study neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry and postnatal clinical factors.

Dr. Carolyn Lam:

Okay, you got our attention. What did they find, Greg?

Dr. Greg Hundley:

Thanks, Carolyn. So participants with a Fontan circulation, without a pre-existing major neurological disability, were prospectively recruited from the Australia and New Zealand Fontan registry. And the investigators found that neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller grey and white matter brain volume. Understanding, therefore Carolyn, modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Dr. Carolyn Lam:

Indeed. Well, this next paper I want to talk about is the first detailed endothelial cell cysteine-S self-hydrome.

Dr. Greg Hundley:

Self? S self-hydrome? What is that, Carolyn?

Dr. Carolyn Lam:

Good. I needed to catch your attention. Let me tell you about it. So in vascular endothelial cells, cysteine metabolism by cystathionine gamma-lyase, or CSE, generates hydrogen sulfide- related sulfane sulfur compounds. And these exert their biological actions via cysteine-S self-hydration of target proteins. So the paper we're talking about today by Dr. Fleming from Goethe University in Germany and colleagues, they aimed to map the S self-hydrome, which is the spectrum of proteins targeted by this hydrogen sulfide-related sulfane sulfur compounds, or H2Sn, in human endothelial cells. And they did this using liquid chromatography and tandem mass spectrometry.

Dr. Carolyn Lam:

So here's what they found: vascular disease was associated with mark changes in the S self-hydration of endothelial cell proteins involved in mediating responses to flow. Integrins were most effected by S self-hydration and the modification of beta-3 integrin resulted in reshuffling of the intramolecular disulfite bonds to preserve its extended and open confirmation. Loss of beta-3 integrin self-hydration, on the other hand, inhibited endothelial cell adhesion, impaired mechanosensing and attenuated flow induced phase with dilation. Thus, short term H2Sn supplementation could improve vascular reactivity in humans, highlighting the potential of interfering with this possibly to treat vascular disease.

Dr. Greg Hundley:

Very nice, Carolyn. You know, just more from the world of hydrogen sulfide and endothelial function. Thanks so much. Well, the next paper I have comes to us from Dr. John McEvoy from Johns Hopkins University School of Medicine. So Carolyn, recent clinical guidelines support intensive blood pressure treatment targets. However, observational data suggests that excessive diastolic blood pressure lowering might increase the risk of myocardial infarction. Therefore reflecting, does a J or U-shaped relationship exist when we're following the treatment of diastolic blood pressure? So Carolyn, these authors analyzed 47,407 participants from five cohorts with a median age of 60 years. First to corroborate prior observational analysis, the authors used traditional statistical methods to test the shape of association between diastolic blood pressure and cardiovascular disease.

Dr. Carolyn Lam:

Okay. So was it J or U?

Dr. Greg Hundley:

Okay, Carolyn. So interesting, traditional observational analysis of the cohorts suggested a J-shaped association between diastolic blood pressure and myocardial infarction. However by contrast, linear MRI analyses demonstrated an adverse effect of increasing diastolic blood pressure increments on cardiovascular disease outcomes, including myocardial infarction. Furthermore non-linear MRI analyses found no evidence for a J-shaped relationship. Instead confirming that myocardial infarction risk decreases consistently per unit decrease in diastolic blood pressure, even among individuals with low values of baseline diastolic blood pressure. So Carolyn, in answer to you, no, the J or U-shaped curve does not exist.

Dr. Carolyn Lam:

I suppose depending which way you look at it. Very interesting. Well, let's finish up with what else is in today's issue. There's an AJ update by Dr. Elkin on COVID-19 at one year, the American Heart Association president reflect on the pandemic. A white paper by Dr. Zannad on challenges of cardio kidney composite outcomes in large scale clinical trials. A research letter by Dr. Kass on the reduced right ventricular sarcomere contractility in HFpEF with severe obesity. Another research letter by Dr. Messas on the feasibility and performance of non-invasive ultrasound therapy in patients with severe symptomatic aortic valve stenosis. A first in human study.

Dr. Greg Hundley:

Right, Carolyn. So I've got an exchange of letters from Dr. Vazgiourakis addressing a prior publication entitled Right Heart Dysfunction in COVID-19 Patients: Does Mechanical Ventilation Play an Additional Role? And then finally, an exchange of letters from Drs. Carrizales-Sepúlveda and Topalisky regarding the prior paper, The Spectrum of Cardiac Manifestations in COVID-19. Well, Carolyn, I'm really excited to get to that feature that you explained to us right at the beginning. Very exciting.

Dr. Carolyn Lam:

So am I. So am I. Thanks, Greg.

Dr. Carolyn Lam:

Wow. Today's feature discussion could not be more star-studded in my point of view. We are talking about the very, very hot topic of how do we sequence treatments in heart failure with reduced ejection fraction now? A really hot topic because just last year in 2020, we suddenly got a bonanza of positive trials and everybody's grappling with how to put it all together.

Dr. Carolyn Lam:

Now who better than the two authors I'm going to talk to today, Professor John McMurray from University of Glasgow and Professor Milton Packer from Baylor University Medical Center in Texas. So welcome both. John, Milton, I'm almost tripping over myself to talk about this because this is an amazing perspective piece. Everybody must get your hands on it and even look at the figure while you're listening to this. We're going to divide today's discussion into just three simple questions. Why do we need a new sequencing approach? How in the world do you come up with a new sequencing approach? Based on what? And finally, what is that new approach that you're both proposing? So maybe I'll start off with you, John. What's wrong with what we've been doing?

Dr. John McMurray:

So Carolyn, I think we've maybe neglected the fact that while we think of, for example, cancer as something that's incredibly urgent to diagnose and to treat as fast as possible, to give the patient all those life-saving therapies, we haven't had the same urgency in our treatment with heart failure. And our existing approaches, as you know, being largely one of start with the first treatment that was ever tested in the trial, up titrate to the pill dose, take your time, then on the second, third and so on. And of course, what that means is that it takes months for patients to be treated with all of the fantastic life-saving options that we have available for them. And we know that that's failing.

Dr. John McMurray:

We've seen from numerous registries, CHAMP registry in particular springs to mind, where that's simply not happening. It's probably taking too long. It's too complicated for both the doctor and the patient, and we need to change it. And I suppose Milton will tell you his view, but I think my view and I think his as well, was that the SGLT2 inhibitor story really brought this question, I think, to the fore because here is our fourth life-saving drug that if we do things the same way might not get started for six months. And we really felt that we need to rethink what we're doing. Milton, I'm sure, will say whether he agrees with that. But I think that was sort of where the starting point was.

Dr. Carolyn Lam:

Great. But if I could interject a bit, so now we're talking about that left side of the panel, where in your beautiful article where you're showing, we start with ACE inhibitors and ARBs, and then go on to beta blockers and mineralocorticoid receptor antagonists, and so on. I would love to know, and Milton I'm sure you'll add, is it the sequence that's wrong? Or is it really just the timing? Or the fact that we're just all too lazy? What do you say to people who go, "But that's how the trials were done." Especially because you guys both led those amazing trials of ARNIs and SGLT2 inhibitors. It's just awesome.

Dr. Milton Packer:

So Carolyn, what's really amazing is that everyone assumes that that's how the trials were done. But two things, one, just because we did things in a certain way, developed things in a certain way, doesn't mean we have to prescribe them in a certain way. I mean, we developed digitalis before all of them and so does that mean we need to use digitalis in everyone? But a lot of the early trials, all the patients were, or most of the patients were, on cardiac glycosides.

Dr. Milton Packer:

There are four things that we've learned from the large-scale clinical trials. One is the order of drugs does not matter with respect to efficacy. The beta blockers work the same whether people are getting ACE inhibitors or not, MRAs are not effected by background therapy. Neither is neprilysin inhibitors. They work pretty much the same regardless of background therapy, so you don't have to sequence them in the order in which they were developed.

Dr. Milton Packer:

Two is low doses, low starting doses of these drugs seem to work amazingly well, perhaps surprisingly well. And the third thing is that they work very early. So in a lot of the clinical trials, nearly all the trials that were carried out, there was a meaningful separation of the curves and in effect size in the first 30 days of all of these trials. And in many of the trials, in the first 30 days, patients were still on the starting dose. Hadn't been uptitrated.

Dr. Milton Packer:

The last point is that these drugs can influence each other's safety profiles. So the result of all of this was for us to rethink what the sequence should be based not on how the drugs were developed, but how they might be most logically used with respect to relative efficacy, safety and ease of use.

Dr. John McMurray:

So, Carolyn, to go back to your question then is sort of what Milton is saying is that it's a bit of both of the things you asked about. It is about timing, but it's also about the order of the drug. And that last point Milton made is very important about the potential synergies in terms of making it easier to use treatments, but timing is critically important as well. I mean, we do tend in the conventional approach to therapy recommended in the guidelines to perhaps spend too much time trying to reach that target dose, and then doing that before moving on to the second drug. So again as Milton pointed out, if you're getting early benefit from all of these treatments, fundamentally what you want is as many of these treatments started as quickly as possible as you can do safely. And that may be facilitated by some of the synergies between treatments as we, I think, rather provocatively suggested in the new algorithm, might even be possible to start two treatments at once.

Dr. Carolyn Lam:

Okay. Now I know everybody's really, really wondering what that new algorithm is, but I'm going to lengthen the pain a little bit more because this is critically important. You've already started discussing the how did you come up with an algorithm. It seems a lot of, yeah, very reasonable approaches, but could you give us specific examples of actual scientific interrogation of the data from the trials that you've led, frankly, to show us these points, that maybe support that we can come up with a reasonable new approach? Those points that Milton very rightly put, the treatment benefit of each class is independent. Give us some examples of that. The dose issue, the side effects, how one could help in that too. Could you give us some examples?

Dr. Milton Packer:

Oh, my God. So let me say that there's so many pieces of evidence and please read the article. We try to summarize as much of them as possible. But in all of the major clinical trials, there was a separation that occurs within 30 days. That's true across every single major trial. Anyone who thinks that the treatment effects of these drugs are delayed, that it takes months to evolve, we're getting statistical significance within two to four weeks across all of the drugs.

Dr. Milton Packer:

Second is, in many of the trials, for example, COPERNICUS trial with carvedilol, the trials with MRAs, even the trials with ACE inhibitors, during that first 30 days when the curves were separating, patients hadn't been uptitrated. They started on low doses and remained on relatively low doses and the curves were separating. So we knew that the drugs had early effects at low doses, low starting doses. And we also have randomized trials that really tell us that if you go to high doses for some of these drugs, you get a little bit more benefit, but you don't get as much benefit as starting another drug with a different mechanism at a low dose.

Dr. Milton Packer:

And lastly, we know that some of these drugs actually prevent the side effects of others. There's evidence that neprilysin inhibitors and SGLT2 inhibitors mitigate the hyperkalemia produced by spironolactone and aplerno. So these are just a few examples.

Dr. John McMurray:

Sorry, Carolyn. To add a couple more, we obviously know that the treatments work independently. We primarily knew that from subgroup analyses, but also from trials like RALES for example, where spironolactone was tested in addition to an ACE inhibitor, but very, very few patients were on a beta blocker. Subsequently we tested different a MRA in patients who were taking both an ACE inhibitor and a beta blocker, and the benefit was essentially the same. And of course, our very first trial with an ACE inhibitor, the CONSENSUS trial, was actually done in a population where more than half of the patients were on a very large dose of an MRA. So you can sort of put all the trials together in a type of jigsaw and figure out that these drugs all clearly work independently.

Dr. John McMurray:

And then maybe the only other thing I would mention, because it's perhaps relevant to the new algorithm, is that we do have another key trial, which is, a trial I think often forgotten about, the CIBIS III, which was a study that tested whether or not you could start treatment with either a beta blocker or with and ACE inhibitor in patients with HFrEF, showing that you could start with a beta blocker in patients who had not yet received an ACE inhibitor and do that safely and efficaciously. So there's a lot of material out there that you can sort of put together to answer all of these questions.

Dr. Carolyn Lam:

Great. And now drum roll. Okay. What is the new algorithm? John, you want to introduce it? Or Milton? Up to you.

Dr. Milton Packer:

John can start. That's fine.

Dr. Carolyn Lam:

Well, which one, Carolyn? I suppose the one in the Circulation article is a three-step algorithm. It starts with the combination of a beta blocker, based as I mentioned, so there's three plus an SGLT2 inhibitor. So again, thinking about synergies, thinking about tolerability, thinking about size of effect and thinking about repetity of onset of benefit. So I think most of us would agree, beta blockers are incredibly effective treatments, life-saving treatments, reduce the risk of sudden death. We know that you can start a beta blocker safely as first-line therapy. We do know that there may be more intolerance in patients who are volume overloaded. So why not give a treatment that has a modest, initial diarrhetic effect when you're starting the beta blocker? In other words, the SGLT2 inhibitor. SGLT2 inhibitors work extremely quickly. There's no dose up titration needed. So they seem like the perfect combination to start with.

Dr. Carolyn Lam:

In step two, we suggested moving then to sacubitril valsartan, which in itself is two more drugs combination of an angiotensin receptor blocker and their prolines inhibitor. And then there's the third and final step. We suggested using a mineralocorticoid receptor antagonist. But Milton and I have had a lot of discussion about this. I think we're not saying that all those are necessarily the three steps for all patients. There may be different approaches in different people depending on patient's characteristics. But really the point here was, the provocative statement was we should be able to do this quickly in all patients. And this in fact was an approach to get all four of those drugs started potentially within four weeks.

Dr. Milton Packer:

So Carolyn, the mantra here, our motto going forwards, is four drugs in four weeks.

Dr. Carolyn Lam:

Okay.

Dr. Milton Packer:

An angiotensin receptor blocker, a beta blocker, an MRA, an SGLT2 inhibitor. Four drugs in four weeks. And if you're going to start all four drugs in four weeks, in all honesty, the order probably doesn't matter that much. John and I happen to think that if you have to define a first step, a combination of a beta blocker and an SGLT2 inhibitor simultaneously as step one makes a lot of sense. And then you can follow up with sacubitril valsartan and an MRA.

Dr. Milton Packer:

But here's the thing that's really important: do not take months to follow up. What we're proposing in this algorithm is you start a beta blocker and an SGLT2 inhibitor on day one, and you then follow through with sacubitril valsartan and an MRA within the next couple of weeks. But here's what's really important and we really need to emphasize this: this is a algorithm that assumes that someone's not on any of these drugs already. And of course, most of these patients are taking some of these drugs already. But the other thing that's really important is that we're also assuming that physicians are being very meticulous about background use of diuretics, so that patients really have to be maintained in a clinically euvolemic state in order to make this algorithm work.

Dr. Carolyn Lam:

Okay, well, I'm picking myself off the floor because it certainly was provocative. I love it. I love it for that. It's the first time I've ever seen any algorithm start with a beta blocker and SGLT2 inhibitor. You first go, "Where's the ACE and how come the new kid on the block is right on top?" So I really like that because it must challenge our current thinking. In other words, if we just look at the data for what it is, let's see how we could think it over. So salute you for that. But let me just press on a little bit. So four drugs in four weeks. That's really great. Are there any particular patients you may say the ARNIs come on top or the MRAs? Specific situations or...?

Dr. Milton Packer:

Well, Carolyn, as John has already said, the physicians need to understand the principles, but the application of those principles have to be individualized. So if a patient has a borderline blood pressure, you would probably be well advised to put the MRA before sacubitril valsartan. Depending on renal function, you may decide to advocate one drug a little bit earlier or preferentially compared to another. There are hundreds of individualized nuances, but to get tied up in these is to miss the point of our paper. The point of our paper is that we need to do things quickly... Four drugs, four weeks... And we need to not rely on our historical testing in order to determine the optimal sequence. If you embrace those conclusions, then patients and physicians can individualize their care to the greatest optimal degree. But our current approach, which is a historically-driven algorithm that takes six months to execute, it doesn't work.

Dr. John McMurray:

Carolyn, we obviously did give a lot of thought to the initial treatments, and we did realize that it would potentially be a surprise to people. But just to reiterate, I don't think there's much debate about the incredible benefits of beta blockers, the size of that benefit. We know that the benefit is apparent within 30 days. So Milton and we had Henry Krum's very nice paper about that in JAMA from the COPERNICUS trial, but we're seen it in the other trials. You know that SGLT2 inhibitors have had early benefit. You think about these two drugs being used in a newly presenting patient with HFrEF, probably don't even need to do any electrolyte monitoring, provided your patients not volume overloaded or recently decompensated. That patient's very unlikely to have any significant intolerance to these two treatments.

Dr. John McMurray:

They don't, in those sorts of patients, substantially reduced blood pressure in either drug, beta blockers certainly don't affect kidney function. SGLT2 inhibitors have minimal effect on kidney function. If your GFR is relatively normal, you probably don't even need to check it. And of course, there's no effect on potassium. So in terms of getting two treatments onboard quickly that will have a rapid benefit, are likely to be well-tolerated in the type of patient that we just described, and where they might have monitoring necessary is minimal, then this seemed to be the best option. And as Milton said thereafter, it's maybe less important what order you do it in as opposed to the speed with which you do it. And you're right, you would definitely probably tailor this approach according to the patient characteristics, but this was a general starting point to stimulate debate, which it seems to have done.

Dr. Milton Packer:

So Carolyn, there's something important. If you believe in what we've proposed, then at the end of four weeks, every patient with heart failure and reduced ejection fraction would be on low starting doses or four foundational drugs. Our estimate is if doing that would provide them with a substantial benefit, maybe 70, 75% of the benefit of bringing all of those doses to target doses. And if you can do that, you can do all four drugs at starting doses at four weeks and provide that magnitude of benefit really quickly? That has a big impact on patients. And that has a big impact on public health.

Dr. Carolyn Lam:

Wow. Just thank you so much for igniting this debate. I wish we could go on forever. I just had to share that when we editors looked at this paper, it did spur a very robust debate. But as you can see, we're publishing it as you've proposed it because we do see where you're coming from. It is very interesting. And I just want to reiterate what you both just said, to listeners out there, remember this is referring to a patient who is compensated. Diuretics are still part of it. Remember that the key message is to get everyone on the four foundational therapies within four weeks. And I just love the way you pushed the boundaries with this. Really, really appreciate it. Milton, you look like you want to say something else. If you'd like closing words, I'd love to...

Dr. Milton Packer:

We really thank Circulation for having the courage to do this. And please understand, John and I strongly feel that this is the start of a debate. This is the start of a discussion. This algorithm is a proposal to get people to start thinking differently. This is not the final word on the subject by far. We think this is the beginning of a very important discourse that will evolve over the next year or more. And we just wanted to remind people what the clinical trial evidence actually shows about these drugs, because we think it has been frequently misunderstood much to the detriment of patients with heart failure.

Dr. Carolyn Lam:

Yes. And John, any last words?

Dr. John McMurray:

I would go back to where I started, Carolyn. In a way, what's important here is to inject a sense of urgency back into the way in which we treat patients with heart failure and reduced ejection fraction. It deserves that sense of urgency, as I mentioned that, for example, cancer does. And also thank you for summarizing, I think, what we tried to get across absolutely accurately.

Dr. Carolyn Lam:

Okay. So John, Milton, so far I take it. I take your points well, but as a practitioner, what I would do, frankly, is if I have a patient that I'm starting a beta blocker and an SGLT2 inhibitor, I would surely just start an ACE inhibitor perhaps, or ARNI, at the same time. I don't see why I need to delay it. How about that? Even faster?

Dr. John McMurray:

Okay, well, I'll let Milton answer the faster, but I would say one thing, Carolyn, the new algorithm doesn't mention ACE inhibitors or angiotensin receptor blockers as a monotherapy. Because I think those days are gone. I really do think that we shouldn't go through that cycle of starting a RAS blocker, uptitrating it, then switching to an ARNI because that's a waste of time. You're delaying the introduction of life-saving therapy. And this is the whole point to, again, get that sense of urgency across in implementing all of these treatments as quickly as possible.

Dr. Milton Packer:

And Carolyn, if you want to go faster, that would be fine. Maybe we shouldn't have proposed four drugs in four weeks. We should have proposed four drugs in four days. But Carolyn, I think that changing the way people think is a gradual process. Perhaps four drugs in four weeks is a good starting point. If everyone feels comfortable with that and understands why we are proposing that, then in another six months or so, Circulation can invite John and I to come back and propose four drugs in four days. But let's see what happens.

Dr. Carolyn Lam:

Kudos. Thank you so much. Well, thank you once again, John and Milton. That was an incredible discussion. A beautiful paper.

Dr. Carolyn Lam:

Thank you so much, listeners. I'm sure you enjoyed that as much as I have or probably more. But thank you and please don't forget to tune in again next week. From Greg and I, here's Circulation on the Run.

Dr. Greg Hundley

This program is copyright of the American Heart Association, 2021.

Circulation February 23, 2021 Issue

22 februari 2021 | 19 min

This week, join author Chintan Dave and Associate Editor Naveed Sattar as they discuss the risk of cardiovascular outcomes in Type 2 Diabetes patients following the addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-IRA therapy.

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I love today's featured paper. It's a question everybody's asking. It's about cardiovascular outcomes, potential benefits, following the addition of SGLT2T2 inhibitors versus sulfonylureas to baseline GLP-1 receptor agonist therapy. Now, okay, I'm going to keep you waiting because that was just a hook. We got to get to us summaries first. And I'm going to start. The first original paper I want to describe is an analysis of myocardial infarction from the ischemia trial. And it looks at the impact of different definitions on the incidents, prognosis and treatment comparisons.

Dr. Carolyn Lam:

Because I know you're going to ask, I'm going to tell us a little bit about ischemia. So in an ischemia and initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic, heart disease, and moderate to severe myocardial ischemia. The most frequent component of the composite cardiovascular end points was myocardial infarction. So in the current report from Dr. Chaitman and colleagues from St. Louis University school of medicine, the aim was to compare treatment effects on the primary and major secondary competent end points in the ischemia trial using the pre-specified primary and secondary MI definitions.

Dr. Greg Hundley:

So Carolyn, what were those two EBI definitions, the primary and secondary?

Dr. Carolyn Lam:

Right. Now, I'm going to try to simplify this. So, for procedural MI, the primary MI definition use CK-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin.

Dr. Greg Hundley:

Great, Carolyn. So what did they find?

Dr. Carolyn Lam:

So procedural MI definition had an important impact on event frequency and subsequent prognosis. When the pre-specified secondary MI definition was applied, the conservative strategy had a significantly lower composite event rate for the primary and major secondary trial end points, due to an increased number of procedural MIs in the invasive strategy. Furthermore, spontaneous Type One MI events associated with increased risk of cardiovascular death were reduced with an invasive strategy, which is either PCI or CABG.

Dr. Greg Hundley:

Nice, Carolyn. Well, my first paper actually is a favorite topic of yours, HFpEF. And it really involves the central command and the regulation of exercise rate response. It comes to us from Dr. Ben Levine and colleagues at the University of Texas Southwestern Medical Center in Dallas.

Dr. Carolyn Lam:

Yay.

Dr. Greg Hundley:

All right, Carolyn. So chronotropic incompetence is common in HFpEF. And it's linked to impaired aerobic capacity. Whether upstream, autonomic signaling pathways are responsible for raising exercise heart rate are impaired in patients with HFpEF, That's really unknown.

Dr. Carolyn Lam:

Yep. It is something that we wonder. And so what did Dr. Levine find?

Dr. Greg Hundley:

Thanks Carolyn. So the central command, so vaguely mediated and the metabo-barrow receptor function, which is sympathetically mediated in patients with HFpEF, We're not different from healthy senior controls, despite significantly lower peak whole body exercise, heart rates. So these results, Carolyn, demonstrate key reflex autonomic pathways, regulating exercise, heart rate responsiveness are actually intact in patients with HFpEF. Great new work from Dr. Ben Levine.

Dr. Carolyn Lam:

And I love the way you summarized that. Thank you, Greg. Well, my next paper is the first report implicating the cross priming function of dendritic cells in immunopathology after Type Two MI. And that includes inflammation, fibrosis and functional decline.

Dr. Greg Hundley:

So tell us a little bit more Carolyn about these dendritic cells?

Dr. Carolyn Lam:

Ah-ha so I was ready for that question. So after ischemic injury to the myocardium, dendritic cells respond to cardiomyocyte necrosis present the cardiac antigen to T-cells and potentially initiate a persistent auto-immune response against the heart. So cross priming dendritic cells may have the ability to activate both CD4-positive helper and CD8-positive cytotoxic T-cells in response to necrotic cells. And may thus be crucial players in exacerbating auto-immunity targeting the heart.

Dr. Carolyn Lam:

So, in this study, authors led by Dr. Sattler from Imperial College, London, performed some elegant mouse experiments and showed that cross-priming dendritic cells were present in the heart and activate it after ischemic injury. Depletion of these dendritic cell cross priming function, inhibited accumulation, and activation of cytotoxic T-cells and stopped myocardial immunopathology and functional decline. So with cross-priming, these authors provided a targetable pathway to prevent activation of T-cells cyto-toxicity and persistent post Mia immunopathology exacerbating heart failure risk.

Dr. Greg Hundley:

Oh, beautiful. Carolyn, what a great description there. So my next paper comes to us from Dr. David Park from the New York University school of medicine. So Carolyn elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling of the left atrium that begets atrial myopathy and arrhythmias. At present the underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. So the purpose of this study for these investigators was to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans, as well as mouse models. And explore the role of ETV1 in atrial electrical and structural remodeling.

Dr. Carolyn Lam:

Ah, another study involving both animal and human models. Very important subject too. So what were the results?

Dr. Greg Hundley:

Well, Carolyn, evidence from both the Cleveland Clinic, Biobank Human Subjects Repository and the animal science experiments revealed that ETV1 is downregulated in the left atrium during cardiac pressure overload. Thereby contributing to both the electrical and the structural remodeling that we observe in the left atrium during cardiac pressure overload.

Dr. Carolyn Lam:

Nice. Well, let's quickly finish up with what's in the mailbag. We've got a research letter by Dr. Randi on the lack of evidence of AEs to expression and replicative infection by SARS-CoV-2 in human endothelial cells. There's another by Dr. Stokes on the association of cigarette and electronic cigarette use patterns with levels of inflammatory and oxidative stress biomarkers among US adults. And another research letter by Dr. Hemelsoet on screening for Fabry disease in male patients with arrhythmia requiring pacemaker or ICD.

Dr. Greg Hundley:

Thanks Carolyn. So I've got a paper it's a cardiovascular case series from Dr. Workman that involves a case of presyncope after transcatheter aortic valve replacement. Dr. Özeke has an ECG challenge reminding us that common things occur commonly. Dr. Zaha has a Perspective entitled, "Mending Broken Hearts, a New Treatment Paradigm for Immune Checkpoint Inhibitor Induced Myocarditis." And then finally, Dr. David Goff, the director of the NHLBI has a wonderful perspective piece (Special Report). And it really addresses some results from the Bethesda conference at the National Heart Lung and Blood Institute and the American Heart Association. And it was co-sponsored the bending curve of cardiovascular disease mortality, the Bethesda plus 40 years Symposium.

Dr. Greg Hundley:

The report, Carolyn, summarizes the relevant research, policy, and practice opportunities discussed at the symposium, including participant led discussion that explored the challenges and barriers in promoting cardiovascular health, across lifespan. And established a potential framework for observational research interventions that would begin in early childhood. Well, Carolyn, how about now we jump forward to that feature discussion.

Dr. Carolyn Lam:

All right, now we can go.

Dr. Greg Hundley:

Well, listeners, we are to the feature discussion today. And we have with us Dr. Chintan Dave from Rutgers University in New Jersey, and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. Welcome gentlemen. Chintan, could you explain to us some of the background information that went into the construct of your study and then what hypothesis did you want to test?

Dr. Chintan Dave:

So just for background, so we know that artheriscraotic cardiovascular events in heart failure typically occur in higher prevalence in patients with type two diabetes. What's been really exciting in recent years is that certain second-line therapies, namely SGLT2 inhibitors and GLP-1 receptor agonist in these large cardiovascular outcome trials have shown to reduce the incidents of cardiovascular events. So from these trials, we can infer that SGLT2 inhibitors typically reduce heart failure hospitalizations, and also have an impact on 3P-MACE, which is just the composite of cardiovascular death, non-fatal MI and non-fatal stroke hospitalizations. While GLP-1 receptor agonist tend to reduce, also have an impact on 3P-MACE, but they also have some modest benefits in heart failure hospitalizations as well.

Dr. Chintan Dave:

So now that we know that these agents reduce cardiovascular risk, what's not known is, whether or not, if we can use these agents together to further maximize a reduction in cardiovascular events. So in the cardiovascular outcome trials the dual use of SGLT2 two inhibitors and GLP-1 receptor agonists was rare and ranged from between 0% to 5.3%. So as a starting point, we said, "Okay, let's look at observational data to see what happens when you add SGLT2 inhibitors to patients who are already using GLP-1 receptor agonist." And we hypothesized that, given the orthogonal pharmacodynamic effects on cardiovascular risk, adding SGLT2 inhibitors to existing GLP-1 receptor therapy should further reduce cardiovascular events.

Dr. Greg Hundley:

Very good. And can you describe for us your study population and study design?

Dr. Chintan Dave:

Sure. So we used three databases in the US. Two of these databases were commercial claims data, which is typically your employer based insurance plans, which have patients between the ages of 18 and 64. And we supplemented that data with Medicare fee for service claims, which have patients over the age of 65. So within these three databases, we identified patients who have a diagnosis of type two diabetes and are already a GLP-1 receptor therapy or GLP-1RAs and initiating either SGLT2 inhibitors or sulfonylureas.

Dr. Chintan Dave:

And after we identified this patient population, we controlled for several pertinent variables that could be considered confounders, including socio-demographic variables, diabetes complications, and cardiovascular conditions. And we had two primary endpoints. The first primary end point of interest was a composite cardiovascular endpoint, which is defined as the composite of non-fatal MI or nonfatal stroke hospitalizations in all cause mortality. The reason we used all cause mortality instead of cost specific mortality is basically because we didn't have information on cause of death. So we have to resort to a more generic definition of mortality in the composite cardiovascular endpoint. The second primary endpoint that we used was heart failure hospitalizations. So we then in this population, estimated hazard ratios using basically a time to event framework.

Dr. Greg Hundley:

Okay. And what were your results?

Dr. Chintan Dave:

So after applying the eligibility criteria in all three databases and after doing a one-to-one propensity score matching, we had 12,500 patients who initiated SGLT2 inhibitors and 12,500 patients in the sulfonylurea groups. For the true primary end points the addition of SGLT2 inhibitors to baseline GLP-1RA therapy was associated with a 22% decrease in the incidents of composite cardiovascular end point or an adjusted hazard ratio of 0.78. And the caught 95% confidence intervals were statistically significant. For the endpoint of heart failure hospitalizations, we noted a 36% decrease in the risk of heart failure hospitalizations with the adjusted hazard ratio being 0.64. And again, that was statistically significant as well.

Dr. Chintan Dave:

The CCE or the Composite Cardiovascular Endpoints was driven primarily by non-statistical decreases in the risk of MI by about 25%, in all cause mortality by about 32%. But we also found no effect on stroke, which is also in line with what others have reported. The other thing we looked at was also to look at any evidence for heterogeneity in treatment effects by presence of cardiovascular diseases. And we found no statistical significant difference in that aspect. The last thing we looked at also was to look at any evidence of heterogeneity by baseline cardiovascular disease in the patient groups. And we found no evidence to that effect.

Dr. Greg Hundley:

Very nice. Well, Naveed help us put this study in perspective with some of the other research that I know you're familiar with related to the use of SGLT2 inhibitors and GLP-1 receptor agonists.

Dr. Naveed Sattar:

Yeah. Thanks Greg. So as we all know, the biggest gains in diabetes in the last few years is these two costs of the trucks SGLT2 inhibitors and GLP-1. We believe and the evidence suggests that SGLT2s, are more cardiorenal in its benefits, and GLP-1 more atherothrombotic. So the hope is that if you combine these drugs, you get additional benefits, but there are no trials that have actually tested this. So this particular paper being kind of first observational, look at adding an SGLT2 versus another drug on top of a GLP-1, tries to get at that particular question. And it provides an early hint that yes, if you add an SGLT2 on top of the GLP-1, you get additional benefits. Giving us some insight that yes, you combine these two classes of drugs, you might get additional benefit in one drug on its own.

Dr. Naveed Sattar:

Of course, this is not trial. Some of our readers are going to be nihilist and will not believe the data because it's not a trial, but that's fine. But it's done as well as it possibly can. This observational propensity analysis is well matched. The data have some kind of external validity in the sense that the greatest benefits or risks reductions, but for heart failure post-acquisition, which is what we would believe ratio to inhibitors. So there is some sense of validity here, but clearly colleagues, they want to know, and I actually had a patient in the clinic on Tuesday who was on a GLP-1 and actually was an SGLT2. And I wanted to add the GLP-1. And this kind of evidence provides me some evidence of confidence that yes, by adding both drugs, I might get additional benefits in that one drug on its own.

Dr. Naveed Sattar:

So what you're going to ask next, Craig, and I'll give my answer first. What we really need to do now is actually do the trials. And I think the trials will predominantly work, adding GLP-1 on people who are on SGLT2, because I think more people will be initially an SGLT2 because it's a oral therapy. Then we'll add GLP-1. Although we do have a new oral GLP-1 in play as well. So, that's the kind of paradigm we're in. Some hints, the combination gives you more than the single drug and I think that's really quite promising for people.

Dr. Greg Hundley:

Very nice. So Naveed suggesting a clinical trial to confirm some of these results. Chintan, do you have anything to add? What study do you think or what area of investigation in this field do you feel is next in line?

Dr. Chintan Dave:

Yeah, I mean, I would just start by saying that I agree with everything that Naveed said in the sense that this is a starting point. And that I think the key take home from this study that sort of is going to be published is basically that not only do SGLT2 inhibitors reduce the cardiovascular events in patients using GLP-1 therapy, but the fact that the magnitude of this reduction is very similar. What was noted in cardiovascular outcome trials of SGLT2 inhibitors for GLP use was very minimal. In other words, you can super impose the cardiovascular benefit profile of the SGLT2 inhibitors, which were seen in trials two patients using GLP-1 therapy.

Dr. Chintan Dave:

Now the converse is what needs to be done next, basically, where we need to look at what happens when you add GLP-1 receptor agonist, to SGLT2 inhibitors, as Naveed just said. And he raised a really good point in that more patients are going to be on SGLT2 inhibitors, because they want to avoid GLP-1 receptor agonist because they don't want to use injectable therapies. Of course we have oral semaglatites maybe that may mitigate these issues. But the fact that that aspect is still unknown, could potentially be really good idea for future studies. So that potentially would be a nice, good step.

Dr. Greg Hundley:

Excellent.

Dr. Naveed Sattar:

Can I see one last thing, Greg? There is a trial coming this year called AMPLITUDE‐O, which is a GLP-1 trial, which does have a fair number of people on base than SGLT2s. We might be able to get a curly hint at that ongoing trial in the next six months to a year.

Dr. Greg Hundley:

Excellent. Well, we want to thank both Chintan Dave from Rutgers and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. And really presenting information from US Claims databases highlighting the addition of SGLT2 inhibitors to GLP-1 receptor agonists and finding there was an association with a further reduction of cardiovascular risk relative to the use of GLP-1 agonists alone. On behalf of both Carolyn and myself, we want to wish you a great week. And catch you next week On the Run. This program is copyright of the American Heart Association, 2021.

Circulation February 16, 2021 Issue

15 februari 2021 | 28 min

This week, Circulation on the Run highlights the articles that are part of the Go Red for Women issue. Please join Senior Associate Editors Sana Al-Khatib and Biykem Bozkurt as they provide summaries for the articles found in this special 5th Edition of Go Red for Women.

TRANSCRIPT BELOW

Dr. Sana Al-Khatib:

Greetings. And welcome to this podcast that will showcase the contents of the Fifth Annual Go Red For Women Issue of Circulation. I am Sana Al-Khatib. I am a Professor of Medicine at Duke University and an electrophysiologist. And I am a Senior Associate Editor for Circulation. And I'm delighted to introduce my co-editor for this issue, Dr. Bozkurt.

Dr. Biykem Bozkurt:

Thank you, Sana. I'm Biykem Bozkurt, Professor of Medicine from Baylor College of Medicine in Houston. And I'm also a Senior Associate Editor at Circulation. And we're delighted to do this podcast. We'll be covering very exciting articles. We're very proud of our Go Red For Women Issue.

Dr. Sana Al-Khatib:

And you're exactly right, Biykem. We are indeed excited about the content that we will be sharing with you. And I will actually start with a couple of articles, tackling arrhythmias and covering some important topics in this field. So the first paper is actually an original research article that summarizes the results of sex and the outcomes of catheter ablation in the CABANA trial. And as you know Biykem, CABANA was a randomized clinical trial of patients who were either older than 65, or if they were younger than 65. They had to have risk factor, at least one risk factor for stroke. And those patients who had AFib were randomized to catheter ablation strategy versus pharmacologic strategy. In this particular secondary analysis of the CABANA trial, the authors looked at association between sex and outcomes of catheter ablation. And this is a really important question in the field of electrophysiology because several prior studies had suggested that women may be at an increased risk of adverse events and complications from invasive procedures.

Dr. Sana Al-Khatib:

So it was really good to see the results of this analysis and some of their findings were as follows. They enrolled 819 women in CABANA Biykem, which is a really good number because it accounted for 37% of patients enrolled in that trial. And this is something that we all strive to do in terms of enriching clinical trials with good women representation. And 1,385 of the patients were men. And compared with men, women had some baseline characteristics that were different. They were older. They were more likely to be symptomatic to present with paroxysmal atrial fibrillation. And when they looked at the outcomes of women, they found that the risk of complications was actually pretty infrequent in both sexes. And there was no indication that women had a higher risk of complications, so that was really reassuring to see. And you may recall that in the main trial and when they analyze data based on the intention to treat principle, they found no significant difference in the primary endpoint between ablation and pharmacologic therapy.

Dr. Sana Al-Khatib:

And just as a reminder, the primary endpoint was a composite outcome of deaths, disabling stroke, serious bleeding, or cardiac arrest. And in this secondary analysis focused on sex differences, they again found no difference in that primary outcome between ablation and pharmacologic therapy, regardless of sex. But when they looked at the risk of recurrent AFib, that was definitely significantly reduced in patients undergoing ablation. And that was true for men as well as for women although it seemed that difference was even larger for men.

Dr. Sana Al-Khatib:

I would have loved to see some data on quality of life Biykem, but these results are definitely reassuring and certainly indicate that in our female patients that we see in practice who are symptomatic with atrial fibrillation, passive ablation should certainly be considered as one of the treatment options. So with that in mind, I'm going to switch gears and share with you some of the results from his second paper in the Go Red For Women Issue that presented the results of an analysis of the engage a SME 48 trial. And that analysis aimed to examine the efficacy and safety of edoxaban in women versus men.

Dr. Sana Al-Khatib:

And this was a really large trial. They included 21,105 patients. Again, representation of women was pretty good at 38%. And they enrolled patients with AF who had a chart score of at least two. And they randomized them either to a higher dose of edoxaban, lower dose of edoxaban or warfarin. And the primary endpoint of the trial, where the composite of stroke or systemic embolism looking at efficacy and ISTH defined major bleeding, looking at safety. And not surprisingly, there were some differences in the baseline characteristics between men and women, with women being older, having lower body weights, more likely to have hypertension, renal dysfunction, but less likely to have diabetes, coronary artery disease. What was interesting Biykem, is that when they looked at the pretreatment endogenous factor Xa activity, this was significantly higher in women at baseline compared with men. But when they looked at the treatment effect of edoxaban, it appeared to be greater in women, such that when you look at the resulting endogenous factor Xa activity, after a treating these patients, the end result was actually similar between the two sexes, two to four hours after the dose.

Dr. Sana Al-Khatib:

But then also when you look at the treatment effect, they found a similar reduction in the risk of stroke, systemic embolism, and major bleeding with edoxaban in women versus men. However, actually women assigned to the higher dose of edoxaban, experienced a greater reductions in hemorrhagic stroke, intracranial bleeding and life-threatening or fatal bleeding compared with men. So these are really important findings, very interesting findings because, intracranial bleeding, life-threatening bleeding, really dreaded outcomes of anticoagulant therapy in patients with atrial fibrillation. So very exciting results. With this, I will turn over to you Biykem.

Dr. Biykem Bozkurt:

Thank you, Sana. We also have great papers on ischemic heart disease. There's a fascinating research paper on coronary optical coherence tomography, and cardiac MRI to determine the underlying causes of MINOCA, myocardial infarction with non-obstructive coronary arteries in women. This I find it almost like having a magical mirror showing exactly what's happening inside the heart, in the setting of MINOCA, which is seen in approximately six to 15% in my cases and disproportionately affecting women. The investigators performed coronary optical coherence tomography, which captures very small micrometers structures with very high resolution providing information on tissue composition.

Dr. Biykem Bozkurt:

They also did cardiac MRI in approximately 116 women diagnosed with MINOCA by cat. The optical coherence tomography identifies a culprit lesion in approximately health, surprise, which was most commonly plaque rupture. TMR was abnormal in approximately three quarters with an ischemic pattern in health, non-ischemic pattern in approximately 20% like myocarditis, takotsubo or non-ischemic cardiomyopathy with the combined non-ischemic cardiomyopathy with the combined OCT and MRI, they were able to identify hypothesized cause for MINOCA in approximately 85%, and they couldn't identify any abnormality in about 15. Overall with both modalities, ischemic etiology was determined to be the cause in approximately three quarters, non ischemic etiology, in about 20% and no mechanism could be identified as 15%.

Dr. Biykem Bozkurt:

We also had a resource letter, which I find to be quite complimentary to the topic, this time, examining coronary vascular response to vasoactive breathing maneuvers in ischemia with no obstructive coronary arteries or INOCA. This time assessed by another fancy modality oxygenation sensitive cardiac MR in female patients with recurrent chest pain, with no obstructive coronary artery by coronary angiography. By comparison of 20 women with INOCA, chest pain without any obstructive disease to 20 age matched healthy volunteers, they found no differences in LV volumes function, LV mass, or global oxygenation. But women with INOCA had significantly higher regional variations in response to these breathing and breath holding maneuvers, suggesting heterogeneous coronary vasomotor activity.

Dr. Biykem Bozkurt:

This regional heterogeneity suggested alterations in microvascular dysfunction, which is rather unique and supports the concept of the microvascular dysfunction, which may explain the presence of ischemic symptoms in the absence of epicardial coronary disease, but also in the absence of global coronary perfusion abnormalities, which have been reported and have been discorded in some of the former literature. So this study also implies a potential role for this perhaps new diagnostic modality, the oxygen sensitive cardiac MR, to have a potential investigator role for future clinical studies in patients with the INOCA. The third patients on the realm of ischemic heart disease reports analysis, highly awaited analysis on the trends in returns events, following myocardial infarction among US women and men by using administrative records from approximately 1.4 million hospitalized patients with MI between the dates of 2008 and 2017.

Dr. Biykem Bozkurt:

And following them for returned to MI CHT events, heart failure hospitalization, and all-cause mortality within a year post Mi. The investigator has reported the following, the baseline and recurrent event rates for MI and coronary heart disease event rates were higher for men than women. Heart failure hospitalization rates were higher in women than men. The good news is though the rates of recurrent MI, recurrent coronary heart disease events, heart failure hospitalization, all-cause mortality within a year after MI, declined considerably both in men and women and with proportionately greater reductions for women than men. However, this should not create any complacency because the rates remained still quite high and coronary heart disease is still the number one killer for both men and women. I know we have fascinating papers on sex differences in sudden cardiac arrest. So I will turn the mic to you, Sana for you to comment on those.

Dr. Sana Al-Khatib:

Thank you very much, Biykem. A really interesting papers that you presented there. So when it comes to sudden cardiac death, which is an area that is near and dear to my heart, we actually have two very interesting papers. The first paper is an original research article that examined sex differences in outcomes among resuscitated patients with out of hospital cardiac arrest. And those were patients who were successfully resuscitated from arrest and were enrolled in the continuous chest compression trial. And they applied a rigorous statistical analysis to their data, looking at this association while adjusting for important factors. They also looked at DNR status, withdrawal of life sustaining therapy, order status to see if there are any inner actions there. And they included 4,875 successfully resuscitated patients, of whom 1825 were women. Again, good representation of women here, 37%. And a bit more than 3000 of their patients were men, against some differences in baseline characteristics between women and men, with women being older, they were less likely to receive Bystander CPR and had a lower proportion of cardiac arrests that were witnessed or had shockable rhythm.

Dr. Sana Al-Khatib:

So when they looked at survival to hospital discharge, that was significantly lower among women compared with men. So you're looking at a survival that was 36.3% in men versus 22.5% in women. So that's actually a really big difference. And it's going to be important to understand better and look at more granular data that would account for that difference. They also looked at the association between sex and survival at discharge, and they found that this was modified by DNR and withdrawal of life saving therapy status, such that women had significantly reduced survival at discharge, among patients who were not made DNR, didn't have a withdrawal of life support order. And so they highlight these differences and really push for the need to try to understand reasons for these so that we can work on improving prognosis and outcomes for women.

Dr. Sana Al-Khatib:

The second paper is really interesting. This was a research letter that looked at sudden cardiac arrest in young women. And although several prior studies have looked at sudden cardiac arrest in men versus women. This particular one was focused on young women, defined as women younger than 40 years of age. And this actually delved into that pair sudden death expertise center registry, which is a prospective population-based registry that collects data on cardiac arrest in Paris and its suburbs. And they looked at those cardiac arrests occurring between 2011 and 2018. Their definition of sudden cardiac arrest was closure. And they had 14,210 sudden cardiac arrests that were recorded with 1062 young, meaning under 40 years of age victims of whom three 36 were women. And they found that the mean age at the sudden cardiac arrest was 31.3 years.

Dr. Sana Al-Khatib:

And the interesting findings were as follows, sudden cardiac arrest was the first manifestation of any underlying disease in 89 cases. So 63%. So that was actually a high number. Of course, looking at risk factors, those were not surprising in terms of the presence of hypertension, hyperlipidemia, diabetes, overweight, smoking, 22 patients had a previous history of cardiovascular disease. Only 16.5%, were mainly non-ischemic heart disease. Minority had family history of sudden cardiac arrest at a young age and under the age of 50. And the vast majority of those events occurred at home and only five really occurred in the setting of vigorous exercise or sports. Initial shockable rhythm was found in 73, meaning 29% paces and so on and so forth. They really provide more information about the circumstances of the cardiac arrest that would be really interesting to look at.

Dr. Sana Al-Khatib:

And finally, when they looked at cardiac etiologies, those were observed in about 50% of the cases, including non-ischemic cardiomyopathy, ACS, non-structural heart disease, coronary syndrome, MINOCA was uncommon, actually only one case and so on and so forth. So definitely I invite you to delve more into the content of this paper, to learn more about this condition. Biykem, I will turn over to you.

Dr. Biykem Bozkurt:

Fascinating results and quite striking. We have a very interesting study that I think is going to be of interest to our listeners on which actually portrays what happens to the heart in the setting of metabolic syndrome during pregnancy. The investigators want to find out if obesity or metabolic syndrome could disrupt the physiological adaptive cardiac remodeling that happens normally during pregnancy. This is an important question because as you know, Sana, there has been a significant increase in the prevalence of obesity and metabolic syndrome in women of childbearing age with more than 30% of females in their reproductive years being obese. So in this study, investigators compared pregnant female mice who develop metabolic syndrome after 50% fat diets to non-pregnant female mice or pregnant female mice that are non-metabolic and being fed by controlled diet. And the pregnant mice with metabolic syndrome had increased cardiac mass, pathological hypertrophy and fibrosis, and up regulation of fetal genes associated with pathological hypertrophy.

Dr. Biykem Bozkurt:

And they also showed that the mice had cardiac dysfunction when challenged by angiotensin two infusion after delivery. So these suggests that metabolic syndrome or obesity could disrupt the physiological adaptation that is expected during pregnancy and may result in pathological cardiac remodeling that could predisposed not only to future cardiovascular complications, but also added risk to adverse outcomes during pregnancy.

Dr. Biykem Bozkurt:

Another paper that is, which I find to be very important is drug discontinuation clinical trials. As you know, women are underrepresented across cardiovascular clinical trials and in several observational studies, women have been reported to be less likely than men to adhere to prescribed medication, including cardiovascular medications, which may contribute to worse prognosis. The reasons for this has been unclear. And the investigators in this study examined the association between sex and premature study drug discontinuation and withdrawal of consent in 11 large-scale TIMI trials with approximately 200,000 subjects. After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation and withdrawal of consent. Importantly, this was not explained by differences in comorbidities neither by reporting of adverse events.

Dr. Biykem Bozkurt:

This is important because we always attributed the differences in drug discontinuation to the differences in pharmacodynamics and pharmacokinetic profile and the woman experiencing higher incidence of adverse drug reaction with cardiovascular drugs. This was not the case in this study. And moreover the difference was not restricted to certain medications. It was seen in a wide range of study drugs, such as antiplatelets, anticoagulants, lipid-lowering drugs, antidiabetic medications. And also there was a large sex difference in regional representation. The drug adherence in North America demonstrated a significantly higher discontinuation in women than in men. The difference was relatively modest in Europe, Middle East Africa and Asia. And there was no difference between the two sexes between men and women in South and Central America. These results may suggest that there are potentially attributable reasons due to differences in access to health care, social, economic, cultural factors, non study related costs, transportation, family obligations, as well as concerns about drug safety and confidence in the healthcare system that may have played a role. Back to you, Sana.

Dr. Sana Al-Khatib:

Very interesting results, Biykem. So the next paper is actually a research letter that I really enjoyed reading, looking at sex differences in blood pressure associations with cardiovascular outcomes. And what the authors did is they studied more than 27,000 participants. 54% of whom were women. And these people had no baseline cardiovascular disease, but they had standardized systolic blood pressure measurements performed in one of four community-based cohort studies, for example, Framingham, Eric, so on and so forth. And when they looked at the sex pooled analysis, the threshold for incident MI and heart failure, was 120 to 129 millimeters mercury and for stroke was 130 to 139. In sex specific analysis, interestingly though, they observed increasing cardiovascular disease risk beginning at lower threshold of systolic blood pressure for women than for men. The incidents of cardiovascular disease proportionately increased beginning at a lower range of systolic blood pressure in women compared to men.

Dr. Sana Al-Khatib:

And in multi-variable adjusted analysis, the presence of a systolic blood pressure of 100 to 109 relative to a systolic blood pressure of less than 100 was associated with incident cardiovascular disease in women, but not men. So really interesting findings. And the authors actually states that maybe these findings could be related to differences in vascular anatomy, physiology between men and women, but they say that taken together their findings along with prior results, suggest that maybe the possible need for a lower sex specific definition of optimal systolic blood pressure for women. So really interesting. So they push for people to really do some research to validate these findings and explore these ideas further.

Dr. Sana Al-Khatib:

And then the last paper that I will present as to do with sex stratified, a gene regulatory networks. And basically looking at these to examine female key driver genes of atherosclerosis. And what the author said is that for years, we have known about sex differences in CAD with women developing more stable atherosclerosis than men. However, the underlying vessel biology had been unknown, and so they were trying to shed some light on this. And they integrated female gene regulatory networks with some single-cell RNA sequencing of the data from human atherosclerotic plaque and single-cell RNA sequencing of advanced atherosclerotic lesions in knockout mice.

Dr. Sana Al-Khatib:

And basically what they found is that by comparing sex specific GRNs, they observed clear sex differences in network activity. Within the atherosclerotic tissues, genes, more active in females were associated with missing chemo cells, endothelial cells, whereas genes, more active in males were associated with the immune system. And they determined key drivers of these GRNs being active in female with CAD being predominantly found in smooth muscle cells. So it was really interesting because they say, well, if we, based on these novel insights into molecular mechanisms that underlie sex differences, within atherosclerosis, perhaps, people can develop sex specific therapeutic targets. So I thought that was really interesting, Biykem. Back to you.

Dr. Biykem Bozkurt:

Very interesting, indeed. The final paper I want to comment on a very interesting research letter on temporal trends in proportion of women, physician speakers at major cardiovascular conferences. The investigators collected data on approximately 80,000 speakers from large annual cardiovascular conferences. They selected the ones that had more than 2,500 attendees, such as ACC, AHA, ESC, TCT, HRS, and they show that between 2015 and 2019, the proportion of women speakers increased modestly over time. But unfortunately the invasive fields such as EP interventional cardiology had the lowest proportions of women speakers in single digits. Speaker roles also varied by gender with more men serving in all the roles than women. Furthermore, all high-profile interventional on EP talks were given by men. Non-invasive specialties were more balanced. Women comprise approximately 46 to 50% of high profile speakers in non-invasive conferences. But across the board, women were poorly presented among late-breaking clinical trial presentations, almost in all conferences.

Dr. Biykem Bozkurt:

So overall the investigations concluded that though they were below, but gradually increasing in woman physician speakers at major cardiovascular conferences all the time. It appears that more women were often being tasked with giving more presentations, not more high profile ones. And they underlined the policy of women in high profile roles and almost near absence from the podium at late-breaking clinical trial presentations, reflecting exclusion of women in major roles at national meetings, underlining the need for structural and cultural change. So overall, fascinating papers, which we believe will add significantly to the field. On behalf of my co-editor, Dr. Dr. Sana Al-Khatib, I would like to thank our contributors, the authors, co-authors, investigators for their submissions, the Circulation Staff, a special call out to Sara O'Brien for creation of a very impactful Go Red for Women Issue, [and] our editors for making this endeavor successful and our listeners for joining.

Dr. Sana Al-Khatib:

I also want to thank everyone and thank you Biykem. It was indeed a pleasure to work with you on this issue. Thank you. And thanks to all.

Dr. Biykem Bozkurt:

Thank you.

Dr. Greg Hundley:

On behalf of Carolyn and myself, We want to wish you a great week and we will catch you next week On the Run. The program is copyright of the American Heart Association, 2021.

Circulation February 9, 2021 Issue

8 februari 2021 | 33 min

This week features Two Feature Discussions. In our first discussion, author Thomas Metkus and Guest Editor Allan Jaffe discuss the article "Myocardial Injury in Severe COVID-19 Compared to Non-COVID Acute Respiratory Distress Syndrome." Then in our second discussion, author Naveed Sattar and Guest Editor Ileana Piña discuss the article "Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor, Director of the Pauly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Guess what? Double feature again, this episode with the first talking about empagliflozin and its effect on left ventricular volumes in patients with type two diabetes, pre-diabetes, and HFrEF, and this is the sugar DM heart failure study.

Dr. Greg Hundley:

Carolyn, the second of our double feature Tuesday is a paper that involves myocardial injury in severe COVID-19 compared to non-COVID acute ARDS. Well, let's grab a cup of coffee and Carolyn this week, I'm going to jump into my first paper, which comes to us from Dr. Are Kalstad from the University of Oslo at the Oslo University Hospital. Carolyn, this study tested the hypothesis that the daily addition of 1.8 grams of N-3 PUFA to standard of care, secondary prophylaxis in elderly patients who have survived a acute MI would reduce the risk of subsequent cardiovascular events during two years of follow-up.

Dr. Carolyn Lam:

Interesting, Greg and a clinically important question. So what did they find?

Dr. Greg Hundley:

Yes, Carolyn. They enrolled 1,027 subjects who were randomized in this investigator initiated, multi-center randomized clinical trial of adding that 1.8 grams of n-3 PUFA, 930 milligrams of EPA, and 660 milligrams of DHA versus placebo, which was a corn oil supplement, daily to the standard of care in 70 to 82 year old patients with recent, so within two to eight weeks, acute myocardial infarction. The authors found that they could not detect reduction in clinical events in these elderly patients with the recent acute EMI treated with the 1.8 grams of n-3 PUFAs daily for two years. So, a negative study, Carolyn.

Dr. Carolyn Lam:

Surely, we'll add to that debate that's just so interesting surrounding the PUFAs. But let's go onto another paper I want to tell you about, it provides novel insights into the complex crosstalk between the cardiac endothelial cells and cardiomyocytes during cardiac repair after myocardial infarction. This paper is from Dr. Taleb and colleagues from Park Inserm in France. Their study suggested a deleterious role for endothelial indoleamine 2,30-dioxygenase-1, which I'm now going to abbreviate as IDO, which is an enzyme involved in tryptophan catabolism. They found that the specific deletion of IDO in endothelial cells enhanced cardiomyocytes survival and contractility leading to cardiac function improvement. The IDO dependent effects were mediated by endothelial cell production of kynurenine. The study in essence found that therapeutic strategies targeting cardiac IDO could, in fact, constitute an innovative approach to curb cardiac dysfunction following MI. This was followed by an editorial by Drs. Ma and Wang from Thomas Jefferson University.

Dr. Greg Hundley:

Very nice, Carolyn. Great studies again from the world of basic science. Well, my next paper comes to us from Professor Gerasimos Filippatos from the University of Athens Hospital. Carolyn, this was a sub-study of the FIDELO-DKD trial that evaluated the effect of the nonsteroidal selective mineralocorticoid receptor antagonists finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type two diabetes with optimized renin angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. Here the authors report the effect of the finerenone on individual cardiovascular outcomes and in patients with and without a history of atherosclerotic cardiovascular disease.

Dr. Carolyn Lam:

This is a much anticipated paper. Very excited for you to describe the findings, Greg.

Dr. Greg Hundley:

Thanks, Carolyn. Among patients with chronic kidney disease and type two diabetes, finerenone reduced the incidents of the composite cardiovascular outcome, that included time to cardiovascular death, myocardial infarction stroke, or hospitalization for heart failure. Additionally, there was no evidence of differences in treatment effect based on pre-existing cardiovascular disease status.

Dr. Carolyn Lam:

Emerging therapies. Isn't that awesome? Well, some other papers in this issue, there's a White Paper (Frontiers) about the therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing PCI, a North American perspective, 2021 update by Dr. Angiolillo. There's a Research Letter on the gradient of risk and associations with cardiovascular efficacy of ertugliflozin by measures of kidney function, and these are observations from VERTIS-CV trial by Dr. Cherney. There's also a sub-study analysis from Explorer HCM, and that is entitled “Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy.” This is by Dr. Saberi. There's another Research Letter on COVID-19 myocardial pathology evaluation in athletes with by CMR and that's by Dr. Clark.

Dr. Greg Hundley:

Very nice, Carolyn. I have an exchange of letters from Dr. Alkhalil and Kuzemczak, as well as Dr. Navarese regarding the article, “Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: A Network Meta-Analysis of 52,816 Patients From 12 Randomized Trials.” Next, there's another exchange of letters from Dr. Kastrati and Ferracane regarding the article, “Comparative Efficacy and Safety of the Same Oral P2Y12 Inhibitors in Acute Coronary Syndromes.” Dr. Karabinos has a nice ECG challenge. It's a bizarre down sloping ST segment elevation challenge. Finally, Carolyn, there's a Perspective piece from Dr. Okorodudu entitled, “Exposure to Cardiology as a Strategy to Increase Black Men Involvement in Medicine.” Well, Carolyn, how about we get on to those two feature discussions?

Dr. Carolyn Lam:

Oh, yes. Exciting. Let's go.

Dr. Greg Hundley:

Well, listeners, we are here for our first feature discussion today on this February 9th. We have with us Dr. Tom Metkus from Johns Hopkins and Dr. Allan Jaffe from Rochester. Tom, can you tell us what was the background that really framed this study and what hypothesis did you want to address?

Dr. Thomas Metkus:

This study really arose out of a time and a place in the COVID pandemic. If you can all turn your clocks back to late last spring, we were all enmeshed in the clinical care of many patients with COVID here in the United States, depending on your geography, and also reading an increasing number of reports from other centers that had been enmeshed in the pandemic for some time about myocardial injury, elevated troponin, different aspects of cardiac disease in patients with COVID-19. My background is as a cardiac intensivist, dual boarded in cardiology and critical care, and so this was of particular interest to me, specifically so in that my clinical practice at the time was in a COVID ICU. I spent much of the day every day taking care of these patients, so conceptualizing what myocardial injury meant, what's the pathogenesis, and what does it mean, was an open-ended question at the time. There are certainly many reasons to think that COVID-19 is particularly cardiotoxic. There's obviously the pro-thrombogenic nature of the illness. There's the inflammatory nature of the illness.

Dr. Thomas Metkus:

Yet, we also found that clinically, there was certainly many patients with COVID-19 who acted like they had myocardial injury from ARDS and pneumonia and we had investigated this in some prior studies prior to the pandemic. Really, the aim of the study was to clarify to the extent that we could and contribute to the growing body of knowledge about what is the prevalence and prognostic significance of myocardial injury in COVID-19. We felt that we had a unique lens on this because we also had a cohort of patients with generic ARDS who had cardiac biomarkers assessed, gave us a nice opportunity to do that.

Dr. Thomas Metkus:

Our hypothesis, that was really based on our clinical gestalt at the time from being in the ICU every day with COVID-19 patients, was that there are assuredly COVID-19 patients who have unique features of myocardial injury, myocarditis or malignant arrhythmias, or requiring mechanical support. But perhaps more, or at least a majority have myocardial injury that looks and acts an awful lot like it would in a sepsis patient, in an ARDS patient. We hypothesized that myocardial injury in COVID-19 would be more similar than different to the generic ARDS population. As such, we drew a population of patients with COVID-19 from our health system here across several hospitals, and did a bit of a comparison with our historical cohort of ARDS patients.

Dr. Greg Hundley:

Great description, Tom. Tell us a little more about that study population. You said there was going to be a comparison. What were some of the outcomes that you wanted to evaluate?

Dr. Thomas Metkus:

Right. This question alludes to an important point as we try to delve and do inference around the COVID literature in general, which is to say the pandemic is heterogeneous across geography and across time. In looking at this study, or indeed any study, and understanding of the study population where these ambulatory patients or intubated patients or patients on the ward, for example, as well as any comparison group are these sepsis patients, pneumonia patients, influenza patients, it's just imperative to do inference and to place the study in context. This study, we sought to look at only intubated patients, and that was partially driven by clinical interest, partially driven by the ability then to provide a comparison to our ARDS cohort. So, intubated patients with COVID-19.

Dr. Thomas Metkus:

The comparison group is from a study of acute respiratory distress syndrome patients. Primary lung injury patients that were drawn in turn from NHLBI sponsored areas, network clinical trials. That was a study that was a secondary analysis that we did where we checked troponin levels in everybody. A true cross sectional assessment. That's important in that there's a selection bias, isn't there, when you just look at patients who had troponin drawn in the context of clinical care? So, I think for this study in particular, it's important to note that the comparison group of ARDS patients was truly cross-sectional and that it was a population defined who had biomarkers assessed in the entirety; whereas our COVID-19 population was intubated patients who had troponin checked at the point of clinical care.

Dr. Thomas Metkus:

Now, to address some of the potential biases that are inherent in that assessment of exposure, we purposefully looked at only patients who had troponin assessed within 24 hours of intubation, really to sync up time zero in a sense. It's also important to note the time course of the pandemic. These patients were all in the late spring and very early summer. This was really before steroids, before the recovery trial, before steroids became standard of care. And really, health systems wonder a fair bit of duress at that time and indeed, as many of the listeners will know, the outcomes for hospitalized patients have improved since then for many reasons. But it's only to point out that this study was a place in geography and a place in time, and there are certainly implications about that that I'm sure we'll focus on subsequently.

Dr. Greg Hundley:

How many subjects did you enroll and what were your study results?

Dr. Thomas Metkus:

Our COVID-19 patient population here in the Johns Hopkins Hospital included 243 patients. All of them were intubated with COVID-19, so severe disease. Of those, we reported that just over half had clinical troponin levels greater than the upper limit of normal. We assessed the main clinical factors associated with elevated troponin in that patient population, which are largely similar to other reports and they include chronic kidney disease, lactate levels of the marker of malperfusion, ferritin fibrinogen levels as markers of systemic inflammation. We showed as have others that there's a graded increase in mortality with increasing amounts of myocardial injury. Then, probably what I would found the most interesting component of the study is that when we did covariate adjustment for features of critical illness, renal failure, lactate, how severe your hypoxemia was, vasopressor use, age, and sex. Age, sex, and multi-organ dysfunction in a sense.

Dr. Thomas Metkus:

The association of troponin with mortality attenuated quite significantly. That's similar to what we found in a general ARDS population and consistent with a paradigm of myocardial injury in the non-cardiac critically ill. I think the final finding that we would emphasize is that after you adjust for those mediating factors, the incidence of myocardial injury in COVID-19 was at least comparable to that in the general area's population. It gives an idea to place myocardial injury in context, in my view, as a function of critical illness in most COVID-19 patients. Surely, not all. There are patients with unique syndromes, but in many or most.

Dr. Greg Hundley:

Well, Alan, let's turn to you. Help us put these results that Tom has described for us really in the context of what we're learning about the heart and in patients with COVID-19.

Dr. Allan Jaffe:

Well, let me start by saying that as a cardiologist, too, at the Mayo Clinic in Rochester, Minnesota, we've studied previously patients with acute respiratory failure. In point of fact, although most of you are not quite as old and may not remember, when we first started seeing ARDS patients, many of the same issues that are here today for COVID, came up. For example, and people may not remember this, we actually did a randomized trial of anti-platelet therapy in patients with ARDS because we were convinced that thrombosis was ubiquitous and was a frequent contributor to the illness that we saw. So that if one thinks about it in another sense and says, "If you'll correct for modern day technology that gives us some additional insights, how different really is COVID ARDS from standard ARDS." I think what this paper has substantiated is that there are lots and lots of similarities that exist. I think that's important because it keeps us from chasing around and looking for some additional issues for us to try and take care of or treat additionally.

Dr. Allan Jaffe:

That said, I think the way to conceptualize it is some of the troponin elevations are because patients who have chronic heart disease get COVID and they may have those elevations right at admission. There's an acute component having to do with critical illness that is nicely described in this manuscript. Then, there are those unique clinical features, whether you think it's myocarditis, I'm not sure how common myocarditis, type 2 MI, ischemia, a variety of things, and maybe a new type of myocarditis that we're finding with some very peculiar cells that we see in interstitium with or without increases in troponin. But I think it puts it into the bucket of saying, treat these patients conventionally and look for the other complications. I think that's a terribly important message that I was attracted to when I read this paper. So, thank you, Tom.

Dr. Greg Hundley:

Very good. Well, Tom, what do you see as the next study really to be performed in this space? I'll ask you first and then come back and gather some of Allan's thoughts.

Dr. Thomas Metkus:

Absolutely. I love that framing about kind of COVID in the heart, which is to say that there are some things that are direct pathogenic related to COVID and there are some things that are secondary, and then there are some things related to patients with underlying heart disease coming to care. I think the next set of studies that can help us disentangle this are related to that paradigm in that more multimodal phenotyping, biomarker phenotyping, but also echo phenotyping and MRI phenotyping, we're starting to see those come down the pike to say, here's the biomarker evidence of myocardial injury, but what does that mean, functionally? What does that mean from an imaging perspective? The second important facet for the next series of studies will be the long-term follow-up. We know from the general critical care literature, that there is indeed a powerful and important entity of the post critical illness syndrome, and in COVID that's come to be called long COVID or the long hauling. We've known that even patients with general critical illness get that and to the extent that the heart plays a role in that, it implies one needs to follow these patients prospectively.

Dr. Thomas Metkus:

I think the other implication of this work for the next set of studies is that there are many biases that can be brought to bear when reviewing the pandemic literature and assuredly an editorial team sees the entire spectrum of them, but they would include, as I alluded to, careful selection of patients assuring meaningful classifications of exposure at a uniform time assuring adequate comparison groups. That's really going to be the key to doing good inference. Then, the final thing I'll add is that the next set of studies should and will integrate clinical research and clinical epidemiology with causal inference principles with using what we're learning from the basic science community, to have conceptual models about how has COVID affecting the heart at the cellular level, et cetera, et cetera, et cetera. In a sense, that community of researchers that you see coming together in this pandemic is why doing this work is very rewarding and I think meaningful. I think those are all features of the next set of studies that should include indeed epidemiologic analysis, randomized trials, and basic science analysis.

Dr. Greg Hundley:

Allan, do you have anything to add?

Dr. Allan Jaffe:

Well, I want to endorse the idea that one of the problems in this field is that patients present at different times with different clinical syndromes, because some of them have been at home, some of them have been hospitalized, some of them are recognized de novo late. One of the things that's necessary as a consistent repetitive approach so that we get consistent data, not only on each COVID patient sequentially, but also on the control group that is important. The other point I'll emphasize that Tom mentioned is that individuals who have elevated troponins who are critically ill with ARDS and most likely with COVID as well, have some sort of underlying cardiovascular disease. Often once those patients leave the hospital there, the troponin is out of sight and out of mind. COVID is reminding us by showing us the panoply of additional clinical syndromes that exist post-hospitalization. That as with ARDS, I would argue, that's a mistake. These patients need to have follow-up with cardiology to investigate what that underlying cardiovascular component is.

Dr. Greg Hundley:

Great. Well listeners, we want to thank Dr. Tom Metkus from Johns Hopkins om Johns Hopkins and Dr. Allan Jaffe from the Mayo Clinic in Rochester, Minnesota for bringing us this study regarding intubated patients with COVID-19, indicating that the myocardial injury shares many similarities to that experienced by patients with ARDS. Now listeners, we will turn to our second feature discussion on this February 9th.

Dr. Greg Hundley:

Well, listeners, welcome to our second feature discussion today. We have with us, Dr. Naveed Sattar from Glasgow, Scotland, and our guest editor, Dr. Ileana Pina from Detroit Medical Center. Welcome to you both. Naveed, we'll start with you. Could you describe some of the background that helped you formulate this study and what hypothesis did you want to address?

Dr. Naveed Sattar:

Yeah, thanks Greg. When I was watching the empirical outcomes study, I almost fell off my seat when I saw the results in heart failure, hospitalization. I actually, I sent a text to John McMurray who wasn't actually at the meeting and I sit next door to John McMurray who's obviously preeminent heart failure. I worked also with many of the fantastic heart failure colleagues, Mark Pietri, Cardic Joon and colleagues. At that time I felt, well, actually it wouldn't it be lovely, I was aware of MRI studies they've done on other drugs in heart failure and I thought, well, if this drug effects improves heart failure, well potentially, although we didn't have it amply reduced at the time or have heart failure, they've come subsequently. Perhaps it changes, lead to cardiac remodeling.

Dr. Naveed Sattar:

So we've designed the randomized placebo control trial of empirical fluorescent versus placebo and 105 patients who had heart failure with ejection fraction below 40%. We wanted big 4th ventricles as Professor McBuddy would tell me, we have lots of debates about these things to really give us adequate power follow-up for at least 36 weeks to see if we can see improvements in left ventricular installment volume or global longitudinal strain, which were our primary outcomes.

Dr. Greg Hundley:

Very nice. Great overview of the study design. Who did you enroll? I know patients with an ejection fraction less than 40%, but equal numbers of men and women, was this ischemic heart disease?

Dr. Naveed Sattar:

I think the majority of patients were male about two-thirds average age, 68, pretty much like the empirical reduced to that by half population. About 80% here had type two diabetes, about 20% had pre-diabetes. The other characteristics, the majority had class 2, NYHA Class IV heart failure, minority Class III. About a third were already on arnes. Also, the background theoretically was fantastically well.

Dr. Naveed Sattar:

The other critical thing we really did, we excluded people with atrial fibrillation because that really affects the quality of the MRI. Our group and it's a brilliant journey to be, I'm not a heart failure expert, but working with all these colleagues, they have brilliant experience in this. They know the mistakes to avoid, and one of them is, do not include people with atrial fibrillation because your MRIs will just not be readily interpretable. Also, it needs to be big enough. It needs to have big enough volumes to begin with to be able to see a change. It needs to be long enough to potentially see the remodeling. All that experience of John, Mark and Pandeep were put together in a really tight protocol. When the results came, I almost, again, fell off my seat because well, it worked. I guess, you're going to ask me about the results and what we find.

Dr. Greg Hundley:

Absolutely. Tell us about those results. We're waiting to hear.

Dr. Naveed Sattar:

Two primary outcomes were really what we saw was a reduction in the left ventricular and systolic volume index and by six mils per meter squared, and the diastolic volume index by 8.2 mils per meter squared. We didn't see a change in global longitudinal strain. We did not see changes in KCCQ or six minute walk test, but actually the reality is we now know the size of this chart is underpowered to see changes in six minute walk tests or KCCQ, in lieu of another trial that has some changes in that, but we didn't see them and I think our study was done ... I can tell you, Greg, the amount of work that went in this study, the quality control that people should look at the supplement when it comes out, the degree of attention to imaging protocols and quality control was, I think in my experience, unparalleled.

Dr. Naveed Sattar:

The team really pulled out all the stops to get this, but so the reductions in the volumes, that's probably the key thing. We think that this may reflect the reverse cardiac remodeling and that we think then fits in what you see with other drugs that benefit patients with heart failure. Because the bigger the volumes, the more people tend to die with heart failure or get readmitted. If you shrink the ventricles, that probably their contractility improves. What the actual mechanism is, I don't know, but I'm sure Ileana probably come in there in terms of discussing potential pathways. The final thing I should say is just for the internal validity or external validity, NT-proBNP did come down, suggesting less left ventricle wall stress. Schematic also went up. All the things that we've seen in the big trials was there so I think we've done a really strong, robust trial.

Dr. Greg Hundley:

Thank you, Naveed. Well, Ileana, as a guest editor, what attracted you to this paper? Then, how do you put the results from this study in the context with some of the other publications related to SGLT 2 inhibition in patients with heart failure?

Dr. Ileana Piña:

I think all of you know, that we, the heart failure community is pretty excited about these drugs and what they're doing. I also nearly fell off my chair when I saw the first EMPA-REG and I saw those curves splitting. Then, I further did that when the DAPA data came out and you see these curves split up almost immediately. What was attractive about this paper is that we really don't know how this happens. We think we do, but we really don't. We don't think necessarily that it's the glucose excretion, because that maybe happens in diabetics, but not necessarily in the non-diabetics. Yet the drugs seem to work in both. But remodeling is such a fascinating concept. I personally happen to love the concept of reverse remodeling. It's something that we in the heart failure community really believes that if we can reversely remodel the ventricle, then outcomes will get better.

Dr. Ileana Piña:

We really link them. Your proBNPs were elevated but not huge. This wasn't a very sick debilitated population. This was primarily Class II. Pretty well-medicated in background, you didn't necessarily give the doses clearly, but pretty well with percentages of RAS inhibition and everything else. Now you see that the volumes are coming down and you say, "Wow, is that what's it doing?" If it happens that quickly, because remember, we've got to explain why the curves of heart failure, hospitalizations split up almost immediately. You did show in your time of follow-up that these changes occurred during that follow-up. I am actually not at all surprised that you didn't see anything in the KCCQ because we know that first of all, the patients weren't that sick to start with so it's hard to see improvement when you don't have a lot of sickness and a six- minute walk. This group, for a six-minute walk, is going to have a very wide standard deviation. A six-minute walk doesn't really distinguish the people who are doing well. To me, it's more for the sicker.

Dr. Ileana Piña:

The fact that neither of these things change doesn't bother me at all. But I think that the next step before Greg asked me, is what's the outcome. In other words, can you tie that reverse remodeling directly to an outcome, be it mortality, which is getting argued out there, whether all the drugs are the same? Or just even the heart failure hospitalization, which I think is a very important outcome in this population. You did it well, you did it carefully, you can tell the data's very clean. You did do a little bit better with the women, so I can't scold you for that as I usually do, because you've had about 30 some percent women, which is very similar to what the big EMPEROR trial has had. I'm always fighting to get more women in the trial.

Dr. Ileana Piña:

At some point you may want to examine the reverse remodeling by gender, by sex, actually and see, even though you have a small number, you have 105 patients, you may not have enough data. But I think in the future, because we do believe that women remodel differently and reversely remodeled differently. That would be very interesting to see if there's any differences.

Dr. Greg Hundley:

Thank you, Ileana. Naveed, do you have anything to add? Ileana's really laid out on a nice course to follow forward. Do you have anything to add to her comments?

Dr. Naveed Sattar:

No, I completely agree with all of them. I think the key thing is nice that this came out straight after EMEPEROR-reduced and a year after that, for heart failure with the team that, John and colleagues were led out. I was involved in the EMPEROR-reduced so that the mechanism helps. I think clinicians buy into this concept. It does what they think drugs do to improve heart failure outcomes. I think that helps and it might help prescribing, get people the confidence that these drugs do work in a mechanism that works.

Dr. Naveed Sattar:

The only thing that I think we would love to have done is if doing the MRIs even sooner, how quickly do these actual volumes change? We think it's reverse remodeling, but maybe we need another trial doing MRIs at one month, three months just to see how quickly these volumes do actually change. Because I still think that's a bit of doubt. But having said all that, I've loved this journey working with my fantastic Hatfield colleagues, a brilliant team in Glasgow. We're now thinking about the next trial. Let's see where we get to in terms of algorithms and trials, but the diabetes, heart failure, kidney disease fraternity coming together is fantastic. I'd loved being part of that journey. So great.

Dr. Ileana Piña:

There's another interesting observation in your data was a hematocrit. It's really tiny, but the signal is there, which to me has also been fascinating. We see a lot of anemia in this population. A benefit in the hematocrit, I think, is really important. The fact that you did this with MRI, I don't think this is a good echo study, to do this with echo. I think you need the reliability and the precision of an MRI.

Dr. Naveed Sattar:

Yeah, I agree. We have other data coming up, Ileana, in terms of renal blood flow, because you've mentioned that as well at the same time, which we haven't yet analyzed. There's a lot more data which needs a good Biobank and pick some of these mechanisms. So, yeah, fantastic.

Dr. Greg Hundley:

Well listeners, this has been an excellent discussion and we want to thank Dr. Naveed Sattar from Glasgow and our guest editor, Dr. Ileana Pina from Detroit Medical Center, bringing us these results regarding the administration of empagliflozin and favorable changes in left ventricular volumes in patients with heart failure and a reduced ejection fraction.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021.

Circulation February 2, 2021 Issue

1 februari 2021 | 29 min

This week feature a Double Feature of Discussions. In our first discussion, author Larry Allen and Associate Editor Justin Grodin discuss the article "An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial." Then in our second discussion, author Benjamin Scirica and Associate Editor Sandeep Das discuss the Research Letter "Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Dr. Greg, I really love these double features that we have in 2021. Let me tell you about the first one. We are going to be talking about the EPIC heart failure trial. That's the electronically delivered patient activation tool for intensification on medications in HFrEF. Very important results.

Dr. Greg Hundley:

Yes, Carolyn. And the second feature is going to evaluate an algorithm based cardiovascular risk management program to improve lipid and hypertension control. But before we get to the double feature, how about we grab a cup of coffee and start with some of the other articles in the issue?

Dr. Carolyn Lam:

My coffee is right here and I want to talk about, guess what? SGLT2 inhibitors again for this first paper. Dapagliflozin, as we know, reduces the risk of end stage renal disease in patients with chronic kidney disease. We saw that in the DAPA-CKD trial. However, the primary and secondary preventive effects of SGLT2 inhibitors on cardiovascular outcomes have not been studied in patients with chronic kidney disease, with and without diabetes.

Dr. Greg Hundley:

Well Carolyn, remind us a little bit, what were the end points in the DAPA-CKD trial?

Dr. Carolyn Lam:

Okay, well yes. DAPA-CKD as a reminder, randomized more than 4,000 participants with chronic kidney disease to dapagliflozin, 10 milligrams daily or placebo. The primary endpoint was a composite of sustained decline in GFR of more or equal to 50% or end stage kidney disease or kidney or cardiovascular death. The secondary end points were a kidney composite outcome, the composite of hospitalization for heart failure or cardiovascular death and all cause death. Now the current paper is a pre-specified subgroup analysis where authors led by Dr. John McMurray from University of Glasgow, divided patients into primary and secondary prevention subgroups according to the history of cardiovascular disease. And results showed that dapagliflozin reduced the risk of the primary composite outcome to a similar extent in the primary and secondary prevention groups. This was also true for the composite of heart failure hospitalization or cardiovascular death and all cause mortality. The combined cardio renal benefits of SGLT2 inhibitors in patients with chronic kidney disease with and without diabetes therefore are substantial, whether there is history of cardiovascular disease or not.

Dr. Greg Hundley:

Not very nice, Carolyn. Well, my paper comes from Dr. Pradeep Natarajan and his colleagues at the Massachusetts General Hospital. And Carolyn, this study evaluated whether premature menopause is associated with CHIP. For our listeners, CHIP stands for clonal hematopoiesis of indeterminate potential and it is the age related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy. And previously it's been shown associated with accelerated atherosclerosis.

Dr. Carolyn Lam:

Yikes. Greg, is pretty much our menopause associated with CHIP?

Dr. Greg Hundley:

Well Carolyn, the investigators, among 19,606 women, they identified 418 or 2.1% with natural premature menopause and 887 or four and a half percent with surgical premature menopause. Premature menopause, especially the natural premature menopause was independently associated with CHIP among post-menopausal women. Natural premature menopause, therefore may serve as a risk signal for predilection to develop CHIP and CHIP associated cardiovascular disease.

Dr. Carolyn Lam:

Interesting. Okay. Well, my next paper really provides the first evidence for endogenous induction of type-1 protein kinase A disulfide formation in the heart and this occurring after ischemia and re-profusion in both humans and mice.

Dr. Greg Hundley:

Ah Carolyn, so tell us more about this interesting paper.

Dr. Carolyn Lam:

Well, this is from Dr. Simon from University of Oxford and colleagues who used high spatial and temporal resolution imaging modalities in conjunction with an interesting redox dead type-1 protein kinase A knock-in mouse model and demonstrated that disulfide modification targets this type-1 protein kinase A to the lysosome where it acts as a gatekeeper for two poor channel mediated calcium release and prevents inappropriate triggering of calcium release from the sarcoplasmic reticulum. In the post ischemic heart, they found that inhibition of lysosomal calcium release by these oxidized molecules was crucial for limiting infarct size and preserving cardiac function during re-profusion. All this thus offering a novel target for the design of cardio-protective therapeutics. This is discussed in an editorial by Doctors Westenbrink, Nijholt, and deBoer from University Medical Center Groningen.

Dr. Greg Hundley:

Thanks, Carolyn. Very nice. Well, my last paper comes from Dr. Nicholas Marston and colleagues from the TIMI study group at Brigham and Women's Hospital of the Harvard Medical School. Carolyn, genome wide association studies have identified single nucleotide polymorphisms or SNIPs that are associated with an increased risk of stroke. The authors sought to determine whether a genetic risk score could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors across five trials involving the spectrum of cardiometabolic disease.

Dr. Carolyn Lam:

Interesting. And these genetic risk scores are very hot. What did they find?

Dr. Greg Hundley:

Thanks, Carolyn. Among 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up of two and a half years. Across a broad spectrum of subjects with cardiometabolic disease, a 32 SNIP genetic risk score was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation, but lower CHA2DS2-VASc two scores, the genetic risk score identified patients with risk comparable to those with higher CHA2DS2-VASc two scores.

Dr. Carolyn Lam:

Wow, that really is impressive. Well, guess what? We've got some other articles in today's issue. There's a beautiful White Paper about the definitions and clinical trial design principles for coronary artery chronic total occlusion therapies and this from the CTOARC consensus recommendations by Dr. Rinfret and colleagues from McGill University. There's a Research Letter entitled, The Randomized Control Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients with Type II Diabetes. And this is from Dr. Hong and colleagues from Yonsei University College of Medicine in Korea.

Dr. Greg Hundley:

Thanks, Carolyn. Well I have an exchange of letters from Doctors Albiero and Xie regarding the previously published paper, Patent Foramen Ovale Could be a Source of Paradoxical Embolism and Lead to Adverse Outcomes in Hospitalized Patients with COVID-19 Pneumonia and DVTs.” There's also a Perspective piece to the 2020 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease from Dr. Bavry. And finally Carolyn, Dr. Tung has an ECG Challenge entitled, “Narrowing the Differential Diagnosis for a Wide Complex Tachycardia.” Well, how about we get on to both of our double features.

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Greg Hundley:

Well listeners, we are here for our first feature discussion and we have with us today, Dr. Larry Allen from University of Colorado and our own associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical School in Dallas, Texas. Welcome gentlemen. Larry, could you walk us through the background that really formulated your hypothesis? And then what was the hypothesis that you wanted to test with your study?

Dr. Larry Allen:

Well, thanks again for having me. I'm a heart failure doctor. The research group that I work with has spent a lot of time on patient empowerment and think about medication prescribing for HFrEF as shared decision making. Thinking about this as a discussion between the patient and me, rather than me deciding what to do. As you know, patients are now coming into the office because they've seen direct to consumer advertising around medications, but typically those are very biased. They're advertisements that are for only patented drugs. And what I'm really trying to think about is what is my patient's overall regimen in terms of heart failure?

Dr. Larry Allen:

And so we developed a tool which was a three minute video to tell patients that they should come into their visit and be excited to have discussions about their medicines and then a one page checklist that basically said, "Here's what an optimal regimen of medicines looks like for a patient with heart failure and reduced ejection fraction and nobody's really on a perfect regimen, but these are all the possibilities that you could have." Our hypothesis was that if we delivered that to patients before the clinic visit, that it would lead to better prescribing of these drugs. Essentially we imparted on a randomized trial within our healthcare system to do that and that's what we're discussing today, the results of the EPIC heart failure trial.

Dr. Greg Hundley:

Very nice, Larry. Tell us a little bit, what patients did you enroll in your trial? And then what outcomes did you work to assess?

Dr. Larry Allen:

We're part of the UC Health System, which has 12 hospitals, but a number of cardiology clinics across the front range of Colorado. Our entire system is on a single instance of the EPIC electronic health record so we're now able to essentially automatically identify all the patients in our system who have HFrEF. We generated lists of patients who had HFrEF who were going to see a cardiology provider in clinic and then we identified them ahead of time, enrolled them in the study prospectively. And the enrollment was for them to agree to be randomized in the study and then for us to be able to collect data on them.

Dr. Larry Allen:

The patients were kind of a wide range of HFrEF. They were an average of 65 years old, about 70% of the patients were male and reflected the race and ethnicity of Colorado with 11% Blacks and about 7% Hispanics. And everybody in the study had an ejection fraction of 40% or less on their last echocardiogram or other recent cardiac study. And then they were randomized to either get this three minute video sent to them as an email or as a text link that kicked them over to the one page checklist. And then we had them come in. A 145 patients came to clinic having got the information and a 145 patients just came to clinic like usual.

Dr. Greg Hundley:

Very nice. What did you find, Larry? What were your results?

Dr. Larry Allen:

Yeah, so we found not surprisingly that the majority of patients who were in usual care had no change to their medical regimen. What we found in the patients who received the EPIC heart failure three minute video and checklist, we saw about a 19% absolute increase in intensification of guideline directed medical therapy. And then we found that most of that was actually an increase in beta blocker dose prescribing. To some extent, the cheapest therapy that could be increased on a drug that people are already on.

Dr. Greg Hundley:

Very good. Well Justin, we'll turn to you. Help us put the results from Larry's work in the context of A, management of patients with heart failure and reduced ejection fraction and then also B, tell us a little bit about what attracted you to this article and maybe even where you see some of this going next.

Dr. Justin Grodin:

Thanks, Greg. And Larry, obviously I want to echo Greg's comments by thanking you for your submission. This was a paper that we thought obviously very highly of. Greg, for your first point, we've got novel therapies, but really one of the major issues now is not can we find a newer, better drug? I think we've all come to this realization, it's scalability and implementing these therapies into our regular practice, like beta blockers, RAS inhibitors and mineralocorticoid receptor antagonists. And as Larry said, the problem now is not the quality of our therapies, it's really scaling it and getting it to everyone. It's also increasing these therapies to optimum dosages in patients that can tolerate it over time.

Dr. Justin Grodin:

And then, to answer your second question, I think some of the things that struck us by this was that this is a wonderfully simple intervention that truly does empower patients. The majority of our interventions to optimize medical therapy has been targeting the physicians, the APP, the nurses, et cetera. This is beautiful in that it empowers the patient and we are putting the ball in their court. And I think to kind of dovetail with your third question, this is a health system clinical trial and I think that tells us a few things. I think one, it provides the framework on how one could perhaps implement that in their health systems. And we'll have to see if this is something that could translate to other health systems across the country or multiple centers. But I think really the intrigue with this work is that it all comes back to empowering the patients.

Dr. Greg Hundley:

Very nice.

Dr. Larry Allen:

Greg, I wanted to just add one thing that in the heart failure community, there's this argument going back and forth about whether the lack of optimization of guideline directed medical therapies is due to intolerance or whether it's due to therapeutic inertia. And one of the things I like about this study is on face value, we're empowering patients, but the fact that by asking patients to get involved in prescribing decisions, I think one of the take home messages is that this is partially about therapeutic inertia and that as clinicians, we have a lot of things we're dealing with. And if patients come in to the clinic visit and they're motivated to make these changes actually, we can intensify the therapy.

Dr. Greg Hundley:

Very good. Larry and Justin, both one at a time here quickly, in the last minute that we have, what do you see as the next study, Larry, that needs to be performed in this space?

Dr. Larry Allen:

I see two things quickly. One is, as Justin mentioned, validating that this kind of intervention, while simple can be pragmatically deployed in other health systems and in other contexts. The second thing is how do we integrate this kind of small intervention with the larger overall care of patients? One of the concepts that I've talked a lot about over the years with others, including Len Stevenson, is this concept of an annual heart failure review, where rather than seeing people on multiple short visits where we tackle small issues, we actually create a little bit of time to stand back and take a global view of heart failure therapy and how that heart failure therapy fits into the goals of care for the patient, the other medical problems they have and where they're headed.

Dr. Greg Hundley:

Very good. Justin, anything?

Dr. Justin Grodin:

Greg, I have to agree with Larry. I think he hit the nail on the head with his first comment. At least for me from an editorial standpoint is really we like to see how generalizable this is and really this implemented in other health systems. I think that's the logical next step. I can tell you, at least from our discussions at our medical center about this manuscript since it's been published at Circulation is, is there something like this we could implement in our own health system? Or in the health systems that we're affiliated with?

Dr. Larry Allen:

And I would just add that this research and the intervention was funded by the American Heart Association under the strategically focused research network for heart failure and so we've made the interventions public they're online at the research website we have, patientdecisionaid.org.

Dr. Greg Hundley:

Well fantastic. Well listeners, we want to thank Dr. Larry Allen from University of Colorado and our associate editor, Dr. Justin Grodin from UT Southwestern, for bringing us this article, demonstrating a process that facilitates patient physician interactions to improve the administration of guideline based therapy to patients with heart failure and reduced ejection fraction. And so we're going to wind up this feature discussion and we will head to our next feature.

Dr. Greg Hundley:

And we have with us Dr. Benjamin Scirica from Brigham and Women's Hospital and our own associate editor, Dr. Sandeep Das from UT Southwestern. Benjamin, could you tell us a little bit about the background information that you used to formulate your hypothesis that you wanted to test for this study?

Dr. Benjamin Scirica:

Thanks so much first for the invitation. It's a great honor to obviously be in Circulation and to be part of this podcast. We started with the recognition that in our practice, which is similar, I think to a lot of the United States, we are not doing as good a job as we could in terms of care for a lot of the chronic cardiovascular conditions we see. And hypertension and high cholesterol are one of those clear areas where we know there are very good guidelines with clear indication for therapy in specific situations and that these drugs that are available are predominantly generic. But when we looked at our registries, we found that we were not doing as well as we thought. We felt that there are a lot of reasons for that.

Dr. Benjamin Scirica:

A lot of it was based on the fact that for something good to happen, the right thing to happen, you have to have a patient and a doctor in the same room, the doctor has to recognize that there's a problem. They have to know that there is something they can do about it. They have to be able to convince the patient or educate the patient that they should start this new therapy. They have to know how to start the therapy and then have the ability to follow up and make sure that there is longitudinal care for these chronic diseases.

Dr. Benjamin Scirica:

And that's a lot to ask for any of us when we have 15 minutes to see the patient, we may only see the patient a couple times a year at most. And so we felt that our hypothesis is, could we design a program, would be delivered remotely, that would not require a doctor in the middle of all of these decisions and that we could scale by using lower cost resources, non-licensed healthcare coordinators or navigators and pharmacists who could follow very clear treatment algorithms to be able to identify patients and prescribe the right medicines to patients at the right time, based on their cardiovascular risk.

Dr. Greg Hundley:

What was your study design? And what was your study population?

Dr. Benjamin Scirica:

This is an active, ongoing quality improvement program where our hypothesis is that by doing this, we could improve patients' lipids and cholesterol prescriptions compared to prior. And we did some analysis and we saw that a lot of these patients had not been on optimal therapy for many years, even though they've been in our system. With the limitations of not having randomization, we identified these patients and through different clinics in the different hospitals, and would either have patients referred to us by providers or more commonly go and find them within the registries and identify the patients and contact them and have them enter our program where they would usually take somewhere between eight to 12 weeks to be actively managed, to get to their goals and then they'd enter a maintenance program. The report that we do now is that the story of the first 5,000 patients who we enrolled in our program of whom about 35% were still in management at the time we presented these ongoing results.

Dr. Greg Hundley:

Roughly how old were these participants? And what was the breakdown in terms of gender or sex distribution?

Dr. Benjamin Scirica:

We found that about 12% were over 75 years old, a little over half were female. We had 71% who are non-Hispanic Caucasian and 8% who were non-English speaking. In terms of their cardiovascular risks, about a third of the patients had established cardiovascular disease, about a quarter of the patients had diabetes and about a third had an LDL of more than 190 milligrams per deciliter, but no history of ASCVD or diabetes. And then for hypertension, we really would take anybody whom the physician felt required further blood pressure management, because their blood pressure was over 130 over 85.

Dr. Greg Hundley:

And what did you find?

Dr. Benjamin Scirica:

We found that of the 5,000 patients that we enrolled, about 4,000 were in the lipid program, a little over 1,400 we're in the hypertension program, so some patients were in both programs and in the lipid patients, in those patients who achieved maintenance, we increased lipid therapy, any lipid lowering therapy, from about 78% up to 97%. And that was predominantly through statins but we doubled the use of ezetimibe from 9% to 17%. We saw a small increase in PCSK9 inhibitor use from 1% to 3%. And if we looked at LDL reductions, it was a 52 milligram per deciliter reduction in LDL from an average LDL of a 125 down to 73 in those folks who achieved maintenance. For blood pressure, again, in those patients whom we successfully treated who are about 600 patients, we saw a 14 millimeter systolic blood pressure reduction and a seven millimeter mercury diastolic blood pressure reduction.

Dr. Greg Hundley:

Wow. Well Sandeep, what drew your attention to this? And then also, how do you put the context of these results with others that really are working in this wing of data science in cardiovascular medicine?

Dr. Sandeep Das:

Great question. We have a large body of literature that suggests that the use of these fantastic evidence based therapies like statins, like blood pressure medications is poor and we really struggle to improve those numbers. I wanted to applaud Ben and his group for really taking on, in a robust way, an important topic and subject. The other thing that really attracted me to this study, there was a hypertension expert here named Ron Victor back when I first started as a fellow. Fantastic researcher and he did a project called Colloquia called the Barbershop Project about leveraging pharmacists and barbers to improve the blood pressure control of African American men in the community.

Dr. Sandeep Das:

The idea is that you get out there, you got to go to where the patients are rather than expecting them to come to you. And you got to figure out ways to engage them, activate them, get them to participate in their own care. A fantastic study, but the one thing that always, we discuss that study, the thing that always jumps out is, well how do you scale it? How do you use it in a real practice? To me was also a very exciting aspect to this. The goal is to take steps to generalize from clinical trials to real world practice, because we got to get this to patients.

Dr. Greg Hundley:

Very nice. Well Ben, coming back to you, what do you see as next steps for your research here? And then even in the field?

Dr. Benjamin Scirica:

The first is, are there other disease areas we can do this in? I think the second part is how to test different techniques to try to improve the ability to scale it to broader populations and keep the cost down. And I think it is a combination of trying to find the right tools, whether they're digital or not and the right techniques to be able to activate patients, educate them, such that they are asking the question, "How come I'm not on these medicines? How come I'm not on this?" And I think we could do a lot in terms of AB testing in there. The part that I think is challenging in these healthcare studies and quality improvement studies, is that randomization would be great. How can we do it streamline? Do we need to get consent? Can it just be that approved drug A can be tested against approved drug B because there is clear equipoise. And I think by doing that, we could lower the bar for really pragmatic randomization in practice and be able to have much more rapid cycles of improvement and optimization on therapy.

Dr. Greg Hundley:

Very good. Sandeep, do you have anything to add?

Dr. Sandeep Das:

I'll echo Dr. Scirica's called arms here that we need to have a way to do this, do trials in this space pragmatically. I agree with that strongly. I did have a few thoughts on next directions. I work in a population of the urban poor of Dallas County with a lot of my clinical time and these patients have poor health literacy so I think that one question, not question but suggestion or comment to Ben and his group would be to think hard about how you would expand this to lower resource setting or to people that would be a little harder to reach. And even as sort of an aspirational goal, how do you expand it into the community? The other question that I would have is how much of this can we get by with adherence interventions? It's one thing to prescribe, but it's another thing to figure out how to get people to adhere to meds.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Ben Scirica for Brigham and Women's and Dr. Sandeep Das from UT Southwestern, bringing us this really interesting research that has been providing early results of a remotely delivered pharmacist led lipid and hypertension management strategy that dramatically increased medication compliance and improved hypertension control and lipid management.

Dr. Greg Hundley:

On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation January 26, 2021 Issue

25 januari 2021 | 25 min

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature discussion, actually our whole issue, is going to involve the flozins, empa, dapa, et cetera, but that feature discussion will get some results from the EMPEROR-Reduced trial. Well Carolyn, how about we grab a cup of coffee and this is your area, so we're going to let you run with it today.

Dr. Carolyn Lam:

Man, and I can't wait to talk about this. Yes, the sodium-glucose cotransporter 2 inhibitors or SGLT2 inhibitors, are indeed now the foundational therapies for patients with heart failure with reduced ejection fraction. Initially developed to improve glucose control in patients with type II diabetes, SGLT2 inhibitors have beneficial cardiovascular and renal effects in patients with diabetes, HFrEF, chronic kidney disease. Well, today's issue contains two pre-specified subgroup analyses from DAPA-HF and EMPEROR-Reduced, both trials evaluating SGLT2 inhibitor effects on renal outcomes, as well as cardiovascular outcomes, by baseline renal function in patients with HFrEF. The first paper comes from Dr. Jhund and colleagues from the University of Glasgow and it is revolving around the DAPA-HF trial.

Dr. Greg Hundley:

Ah Carolyn, tell us a little bit about DAPA-HF.

Dr. Carolyn Lam:

Gladly. In DAPA-HF, the SGLT2 inhibitor, dapagliflozin, reduced the incidence of the primary composite outcome of cardiovascular death or worsening heart failure in patients with HFrEF, with and without diabetes and an estimated GFR of greater or equal to 30. Of more than 4,700 patients with a baseline GFR, 41% had a GFR less than 60. The effect of dapagliflozin on the primary and secondary outcomes did not differ by GFR category or examining GFR as a continuous variable. The pre-specified composite renal outcomes, which in DAPA-HF was a more than 50% sustained decline in GFR, end stage renal disease or renal death. Now this composite renal outcome was not reduced by dapagliflozin, but the rate of decline of GFR between days 14 and 720 was less with dapagliflozin.

Dr. Greg Hundley:

Carolyn, what's the take home message here?

Dr. Carolyn Lam:

Dapagliflozin slowed the rate of decline in GFR in patients with HFrEF, both in patients with and without diabetes. There was no difference in the efficacy of dapagliflozin by baseline renal function in preventing the risk of cardiovascular death or worsening heart failure.

Dr. Greg Hundley:

Okay, well now how about the EMPEROR-Reduced trial?

Dr. Carolyn Lam:

All right. Well, let me remind you first that in EMPEROR-Reduced the SGLT2 inhibitor empagliflozin also reduced cardiovascular death or heart failure hospitalization and total heart failure hospitalization and slowed the progressive decline in kidney function in patients with heart failure with reduced ejection fraction with and without diabetes. Now, more than 3,700 patients were randomized, of whom 53% had chronic kidney disease, defined as a GFR less than 60 or a urinary albumin to creatinine ratio above 300 milligrams per gram. Empagliflozin reduced the primary outcome and total heart failure hospitalizations in patients with and without chronic kidney disease. Empagliflozin also slowed the slope of GFR decline and the risk of the pre-specified composite kidney outcome, now defined as a sustained, profound decline in GFR, chronic dialysis or transplant, was reduced similarly in patients with and without chronic kidney disease.

Dr. Carolyn Lam:

The effect of empagliflozin on the primary composite outcome of cardiovascular death and heart failure hospitalization, as well as the key secondary outcomes of total heart failure hospitalization and GFR slope, were consistent across the broad range of baseline kidney function measured by clinically relevant GFR subgroups or by albuminuria and including patients with a GFR as low as 20. Above all, empagliflozin was well tolerated in these patients with chronic kidney disease. All of this is discussed in a beautiful editorial by doctors Carnicelli and Robert Mintz.

Dr. Carolyn Lam:

Now, can I tell you about yet another paper with the SGLT2 inhibitors? This time a pre-specified comparison of the effect of empagliflozin in patients with and without diabetes.

Dr. Greg Hundley:

Ah, great Carolyn. What did this study find?

Dr. Carolyn Lam:

Well, this is from Dr. Stefan Anker from Berlin and colleagues, including myself and of the more than 3,700 patients enrolled in EMPEROR-Reduced, 50% had diabetes, 34% had pre-diabetes and 16% had normal glycemia. Empagliflozin reduced the risk of the primary outcome similarly in patients with and without diabetes. Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total heart failure hospitalizations, on the decline in EGFR over time or on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with pre-diabetes or normal glycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome. Empagliflozin also did not lower HbA1c in patients with pre-diabetes or normal glycemia and was not associated therefore with an increased risk of hypoglycemia.

Dr. Greg Hundley:

Carolyn what's the take home message here?

Dr. Carolyn Lam:

Well, empagliflozin significantly improved cardiovascular and renal outcomes in patients with HFrEF, independent of baseline diabetes status and across the continuum of HbA1c.

Dr. Greg Hundley:

Very nice Carolyn. Well, my paper comes from professor Wai Ho Tang and it's a basic science paper. Carolyn, aberrant expression of circular RNA or CircRNA, contributes to human diseases. CircRNAs regulate gene expression by sequestering specific microRNAs. In this study, the authors investigated whether CircMAP3K5 could act as a competing endogenous microRNA-22-3p sponge and regulate neointimal hyperplasia.

Dr. Carolyn Lam:

Wow, that's interesting. And what were the results?

Dr. Greg Hundley:

Carolyn, the authors identified that CircMAP3K5 is a master regulator of TET2-mediated, vascular smooth muscle differentiation. Targeting CircMAP3K5, microRNA-22-3p and the TET2 axis, may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis as well as atherosclerosis.

Dr. Carolyn Lam:

Oh, nicely summarized. Thanks Greg. Well, we've got other papers in today's issue. There's an ECG challenge by Dr. Frész on acute coronary syndrome with tall R waves and inverted T waves in the precordial leads, an ignored entity. We have an exchange of letters between Drs. Vandecasteele and Zhao regarding the article, Cardiac Over Expression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.

Dr. Greg Hundley:

Thanks Carolyn. I have some Research Letters. The first Research Letter is entitled, “Cardiovascular Toxicities Associated with Loperamide: An Analysis of the World Health Organization Pharmacovigilance Database,” and the corresponding author is Dr. Pierre Ollitrault. The second Research Letter is entitled, “Incessant Pericarditis as a Risk Factor for Complicated Pericarditis and Hospital Admission,” and it comes from Professor Massimo Imazio. And then finally, there's a White Paper (Frontiers) for atrial fibrillation screening research priorities from the NHLBI workshop with the corresponding author being Dr. Emelia Benjamin from Boston University School of Medicine. Well Carolyn, how about we jump in to more SGLT2 and another feature discussion?

Dr. Carolyn Lam:

Yes, can't wait. Thanks Greg.

Dr. Greg Hundley:

Well listeners, we're now to our feature discussion and we have with us today, Dr. Milton Packer from Baylor University Heart Vascular Center in Dallas and also our own associate editor, Dr. Justin Ezekowitz from Edmonton. Milton, welcome and wanted to ask you first off, tell us a little bit about the background that got you to want to perform this study. And what hypothesis did you want to address?

Dr. Milton Packer:

Greg, first of all, I'm delighted to be here with you and Justin. And as everyone knows, SGLT2 inhibitors have had a remarkable track record in trials of type II diabetes, trials of chronic kidney disease and now trials of patients with heart failure and a reduced ejection fraction. And in these trials, SGLT2 inhibitors have had two important benefits. The first benefit has been a reduction in serious heart failure events, primarily a reduction in heart failure hospitalizations. And the second has been a reduction in serious adverse renal outcomes. And that has been now shown consistently in trial after trial in diverse populations.

Dr. Milton Packer:

Now we carried out a trial called EMPEROR-Reduced with was the trial in patients with heart failure and a reduced ejection fraction. It was a sister study, so to speak, with a very parallel trial called DAPA-HF, which was carried out with dapagliflozin. And both DAPA-HF and EMPEROR-Reduced were studies, were trials of SGLT2 inhibitors, dapagliflozin and empagliflozin in people with heart failure and a reduced ejection fraction. And they produced remarkably consistent results. And specifically a reduction in serious heart failure events and serious adverse renal events.

Dr. Milton Packer:

But the trial studied complimentary patient populations. We studied patients that were a bit sicker than patients in DAPA-HF. And Greg, what's really fun is that each trial designed its own case report forms so that we collected information that the investigators were really interested in and they were not necessarily the same types of information across the two trials. One of the things that was really interesting about EMPEROR-Reduced was we were really interested in these heart failure events. We wanted to understand them. We wanted to understand whether they occurred as outpatients, inpatients. If they occurred as inpatients, what kind of hospitalizations were these? Were these serious hospitalizations? Were these short term, very mild hospitalizations? This paper, the hypothesis in this paper was to take a look at what empagliflozin did in patients with heart failure and reduced ejection fraction, specifically with respect to outpatient and inpatient worsening heart failure events.

Dr. Greg Hundley:

Very nice. How many patients did you include? What were the characteristics of the study population? And what was the design?

Dr. Milton Packer:

We enrolled, randomized 3,730 patients. All patients had heart failure with a reduced ejection fraction. All were receiving all appropriate treatments for heart failure. Interestingly, 20% were receiving nephrolysin inhibitors, which is really a very high percentage, but they were also receiving inhibitors, renin-angiotensin system beta blockers, mineralocorticoid receptor antagonists and they were patients who had an average ejection fraction of about 27%, which is much lower than most heart failure trials recently. They also had meaningfully elevated levels of natriuretic peptides. These were sicker patients and they had a much higher placebo event rate. They were randomized double-blind, one to one ratio to either placebo or empagliflozin. Dose was 10 milligrams once daily. And this was added to all previously existing therapy and patients were followed for double-blind therapy for an average duration of 16 months and we recorded prospectively information on outpatient and inpatient heart failure events.

Dr. Greg Hundley:

Very nice. What did you find, Milton?

Dr. Milton Packer:

We originally reported that in this trial, there was a reduction with empagliflozin on heart failure hospitalizations and that reduction was about 30%. We wanted to know, well, what else was going on with respect to these heart failure events? And so we asked the question, well, did empagliflozin reduce urgent and emergency room visits for heart failure? Did empagliflozin change the types of hospitalizations? We recorded the use of positive inotrophic drugs, vasopressor drugs, vasodilator drugs, cardiac devices, intervention, surgical interventions. And we found out that across the entire spectrum of heart failure outcomes, there was a reduction in serious outcomes with empagliflozin and they all were around a 30% reduction in risk. They varied a little bit from about 28 to 33, but approximately all were in the same ballpark. And what was really interesting was we had a fair number of hospitalizations where patients required IV inotropic drugs, vasopressors, mechanical intervention, they were reduced by 30% with empagliflozin. Hospitalizations associated with intensive care reduced by 30% with empagliflozin.

Dr. Milton Packer:

And then we looked at outpatient events. Outpatient intensification of diuretics reduced by 30, 33% with empagliflozin. We looked at New York heart class. And what was really interesting was that patients treated with empagliflozin had a 20 to 40% greater likelihood of showing improvement in New York heart class and a 20 to 40% lower likelihood of showing worsening in New York heart class. And those benefits, we're seeing within 28 days after randomization. This early effect is really interesting and it's generated a lot of discussion. And so we looked at our Kaplan Meier curves for the composite of cardiovascular death, heart failure hospitalizations, urgent care, emergent care visits, and we found that the two curves separated quite early and reached statistical significance only 12 days after randomization. This is a very early effect. I want to add that this early separation of curves has been reported previously with beta blockers, with mineralocorticoid receptor antagonists, with neprilysin inhibitors and now we can add this early separation with SGLT2 inhibitors.

Dr. Greg Hundley:

Very nice, Milton. Well, I'd like to turn now to our associate editor, Dr. Justin Ezekowitz. and Justin you've seen a lot manuscripts come pass through your hands. What attracted you to this manuscript? And then how do you put the findings that Milton has just described in the context with the other results that we have been witness to regarding SGLT2 inhibitors?

Dr. Justin Ezekowitz:

Thanks Greg. And also, thanks Milton for letting us look at this remarkable manuscript as I do think the clinical implications for a manuscript like this are quite profound. The first thing that really strikes me is we often get worried about looking at a number of different end points. Within a clinical trial, we often don't want to have too many looks at the data because of the risk of finding something that is spurious, is high, but in this case, the way the data was collected and the exploration is quite valuable. We can look at any one of the combinations of clinical end points that actually have direct clinical relevance for a clinician and the patient. And this paper really explored that in a lot of data, in a lot of depth and also helped us by putting the caveats around these findings that this is exploration, but it does anchor it in the SGLT2 world, but also the heart failure world.

Dr. Justin Ezekowitz:

And Milton, I think one of the striking findings that you showed and it's buried in many of the great figures and tables, is that one in two patients had something happen in the next year. In the next 12 months, that patient walking into an office for a routine followup, one in two had something and the reduction was pretty remarkable across the end point. Milton, I wanted to pick your brain on this one, just to understand when you look at the intensification of diuretics, that was anything from adding another 20 milligrams of furosemide, to doubling or tripling that. Do you think these findings are pretty ubiquitous across the patients enrolled? Or do you think they're a niche finding in only some patients at the highest risk?

Dr. Milton Packer:

Well, we actually looked at that. We actually looked at whether baseline variables influenced the effect on intensification of diuretics and it was across the board. Well, let me just say, across the board in the patients that we studied and obviously can't make reference to people we didn't study, but we didn't find any particular subgroup that responded particularly well with respect to either a hospitalizations or diuretic intensification or New York heart class changes. But Justin, there's one thing that you just said that is so important. And that is, our patient population was characterized by their physicians, 70% as having class II heart failure. And a lot of physicians think that class II heart failure represents a stable population, clinically stable population. And as you said, one in two patients in our study during followup had worsening heart failure, either represented as an inpatient or outpatient event. A class II patient with heart failure and reduced ejection fraction, even though they're getting optimal medical therapy, is not a clinically stable patient.

Dr. Greg Hundley:

Very, very interesting finding. Well, just to ask each of you, maybe Milton first and then Justin next, Milton, what do you think is the next study that we need to perform in this patient population using this class of drugs?

Dr. Milton Packer:

We're really excited about a new phase of heart failure research with SGLT2 inhibitors, which is to look at the impact of these drugs in patients with heart failure and a preserved ejection fraction. DAPA-HF and EMPEROR-Reduced were trials of inpatients with hard failure and a reduced ejection fraction. But we really, about half patients with heart failure, have an ejection fraction of greater than 40%. We really need to understand what SGLT2 inhibitors can do for these patients. And here's the good news. And there are two large scale trials that are both nearing completion. And the first of those trials will be reporting out in about nine months from now with the next trial following about six months later. We will in the next 12 to 18 months, have two major large scale trials of these drugs in a population which is highly different and yet complimentary to the patients who have been studied to date.

Dr. Greg Hundley:

Justin, how about you?

Dr. Justin Ezekowitz:

Well, to compliment what Milton is suggesting, I think that's one area. And I think the other area is in implementation science. Now that we have four big classes or groups of drugs, is to how to start these and how to optimize these efficiently in the first month to two months or even three months so the patients can get the benefit for all these medications. And I think what we need to really study is how do we do that? Because we have the drugs but the implementation is where we're not quite there yet. If we get the implementation and testing, randomized strategies and how to do it, I think we may be able to help more patients globally than with the addition of even any new drug that may come out onto the markets soon or in the future, as that remains one of our challenging topics.

Dr. Greg Hundley:

Well listeners, we want to thank Dr. Milton Packer for bringing this study to us at Circulation and also our own associate editor, Dr. Justin Ezekowitz and really highlighting how the initiation of this SGLT2 inhibitor, empagliflozin, at 10 milligrams per day, in a heart failure reduced ejection fraction population with an average left ventricular ejection fraction of 27%, resulted in a 12 day, at 12 days into therapy, a separation of the development of adverse heart failure related events that was then sustained over the next 16 months.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, I want to wish everyone a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation January 19, 2021 Issue

19 januari 2021 | 23 min

In this issue, author Monika Safford and Associate Editor discuss the article “Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the REGARDS Study (Reasons for Geographic and Racial Differences in Stroke).” Then authors Jennifer Ho and Timothy Churchill discuss their Research Letter “Evaluation of 2 Existing Diagnostic Scores for Heart Failure With Preserved Ejection Fraction Against a Comprehensively Phenotyped Cohort.”

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia.

Dr. Carolyn Lam:

Guess what, Greg? We're going to talk to a lovely friend and wonderful colleague Dr. Jennifer Ho soon regarding her research letter on the HFpEF diagnostic scoring criteria.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I've also got another feature discussion in this issue involving the reasons for geographic and racial differences in stroke. It's from the REGARDS study. But first, how about we grab a cup of coffee and jump into the next articles in the issue.

Dr. Carolyn Lam:

I've got my coffee, Greg and I'm ready to tell you about acute infection and endotoxinemia. We know that infections are a well-established risk factor for cardiovascular inflammation, increasing the risk for a cardiovascular complication within the first weeks after that infection. However, what is the mechanism underlying such an association? Well here, Dr. Soehnlein from Germany and colleagues utilized a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation. Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice.

Dr. Greg Hundley:

So, Carolyn, what did they find?

Dr. Carolyn Lam:

Well they found that neutrophils and specifically neutrophil extracellular traps controlled accelerated atherosclerosis during endotoxinemia. These neutrophil extracellular traps or NET-resident histone H2a, heightened arterial monocyte recruitment in endotoxinemia in a mechanism involving electrostatic charge interaction. The clinical implications are that therapeutic neutralization of NET-resident cationic molecules, including histone H2a by use of antibodies or peptides may protect patients at cardiovascular risk during an acute infection from secondary events.

Dr. Greg Hundley:

Wow, Carolyn. Really interesting. Well, my paper comes from Dr. David Park from New York University School of Medicine. Carolyn, elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling in the left atrium that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The authors sought in this study to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.

Dr. Carolyn Lam:

Nice. And so what did they find, Greg?

Dr. Greg Hundley:

Well Carolyn, using the Cleveland Clinic Biobank of human left atrial specimens and their mouse models, these authors found that ETV1 is down regulated in the left atrium during cardiac pressure overload, thereby contributing to both electrical and structural remodeling of the left atrium.

Dr. Carolyn Lam:

Nice. Well Greg, let's talk about what else is in today's issue. There's a Perspective piece from Dr. Delgado on “Changing the Paradigm in the Management of Valvular Heart Disease: In Addition to Left Ventricular Ejection Fraction, Focus on the Myocardium. There's a Research Letter from Dr. Lurz on closure of iatrogenic atrial septal defect following transcatheter mitral valve repair, the randomized MITHRAS trial. There's an exchange of letters between Dr. McAvoy and Dr. Kim regarding the article, Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults. And an ECG challenge by Dr. Avila on complete AV block cured by atrial pacing.

Dr. Greg Hundley:

Very nice, Carolyn. Dr. David Saadoun has an In Depth review on medium and large vessel vasculitis and Dr. Christy Avery has a Research Letter reporting on the trends in US cancer and heart disease mortality from the period of 1999 through 2018. Well, Carolyn, how about now we jump into those feature discussions?

Dr. Carolyn Lam:

Yep, double features. Here we go.

Dr. Greg Hundley:

Well listeners, this is the first of our double feature on this January 19th and we're so fortunate today to have Monika Safford from Weill Cornell in New York and our own associate editor, Mercedes Carnethon from Northwestern University in Chicago. Monika, we'll start with you. Could you tell us a little of the background information pertaining to this study and what hypothesis did you want to address?

Dr. Monika Safford:

Sure. Well, thank you first of all, for the opportunity. We've been studying social determinants of health. I think there's a lot of attention that has come on social determinants of health from health system perspectives in recent years but I think there's less of a recognition of individual practicing physicians of what they can do. What's happened is that there are population managers at most health systems and it seems like it's a fairly distant undertaking compared to day to day clinical care. We wondered whether there was a way to begin to integrate social determinants of health more in the day to day management of patients. And that was really the major motivation here was to take this fairly late recognition, I think, compared to the sociology world of the importance and the relative importance of social determinants to see if we could help clinicians actually use this information to inform their clinical management.

Dr. Greg Hundley:

Very nice. And so what was the study population that you worked with? And what was your study design?

Dr. Monika Safford:

Sure. The REGARDS study, REGARDS stands for reasons for geographic and racial differences in stroke, is a large national cohort, more than 30,000 people who live all over the 48 contiguous United States. About 44% of them are African-Americans and the rest are whites. Everybody was 45 and older at the time of their recruitment between 2003 and 2007. And we're now following them longitudinally for outcomes and among the outcomes are coronary heart disease and a causes of death. It's a terrific cohort to study racial disparities, if you're interested in differences between African-Americans and whites.

Dr. Greg Hundley:

And what did you find?

Dr. Monika Safford:

We did find, which was our initial hypothesis, that the greater the burden of social determinants that an individual is exposed to, the greater the independent risk. There's a definite graded risk. If you just simply count up social determinants, that should really be part of the social history that we're all taught to take in medical school. The greater the number, the higher the risk. And what was really quite concerning was that once you adjusted for all of the things that are available in a typical cohort study, physiologic measures, past medical history, health behaviors. There still was this massive, independent effect, 50% greater after accounting for all of those wonderful phenotypic markers that we have available in a cohort study.

Dr. Greg Hundley:

And what were some examples of these social determinants that we should all be thinking about?

Dr. Monika Safford:

Sure. Educational level. We all ask our patients, what was their educational attainment? Income has come a little bit under scrutiny. We don't typically ask our patients what's your annual household income? But there are lots of proxy markers so we are aware of what our patients can afford and can't afford when we prescribe medications. We have to know whether or not this is something that is within the realm of possible for individual patients. We should get a very good sense of what their financial situation is. Their social circumstances. Are they isolated? Do they live alone? Are we living in a state that is one of those states that doesn't really have a robust public health infrastructure? Are we living in a rural area? Are we in a health professional shortage area? Most physicians are aware of these types of variables.

Dr. Greg Hundley:

Very nice. Well, Mercy, let's turn to you. Can you help us put these findings that Monika is sharing with us today in the context with other studies that have performed really related to this topic?

Dr. Mercedes Carnethon:

Certainly. I'd love to summarize that as well as ask the question. We've known for some time that social determinants of health are associated with many different health outcomes, primarily cardiovascular diseases. We know that the access that individuals have to resources to promote their health and protect themselves really do influence what happens to them in the long run. I was extremely pleased to read this paper prepared by Monika and her group in the REGARDS study because it had many strengths that exceed those of prior studies, namely the large sample size, the significant representation of both Blacks and whites, as well as the ability to study both fatal and non-fatal outcomes. And I think that the summary provided by Monika was excellent and I would love to follow with a few questions if I might. Namely, were the social determinants similarly associated with outcomes in Blacks and whites? We know certainly in this country that the two are correlated. And I just wondered whether or not you saw similar patterns of association whereby those who had adverse social determinants of health also had higher rates of mortality in both Blacks and whites?

Dr. Monika Safford:

Yeah. Wow, what a great question. There's only so much that you can cover in one paper. In this paper, we were really focused on this concept of the burden and a simple count of social determinants of health. And we actually did not stratify by race. We didn't examine this separately by race, but that is exactly what we're doing in another similar study right now. That is a really, really important question because some of these determinants may not be similarly associated for Blacks and whites.

Dr. Mercedes Carnethon:

I'd like to follow as well, so what surprised you about the findings in this study?

Dr. Monika Safford:

Probably the biggest surprise was the difference in the association or the strength of the association between incident fatal CHD. This is primarily sudden death and this is what we all want to try to avoid because this is people who we don't yet recognize having coronary disease. And then when they die at their presentation, it's very frustrating. We sure would love to be able to intervene. We have gotten very good at intervening after people survive a myocardial infarction but the surprising thing was that the strength of this association was really much more pronounced for incident fatal CHD than it was for non-fatal MI. We don't understand the reason for that. That's a puzzling finding that we're definitely diving into as we speak.

Dr. Greg Hundley:

Monika, what do you see is the next study to be performed in this space?

Dr. Monika Safford:

What we're doing right now is we are demonstrating that this is a robust finding across a number of different endpoints. We have a very similar study on stroke, showing large magnitude of exactly the same finding. And we have one that's about to come out on diabetes, hypertension. We are really looking to demonstrate that this approach, this very simple approach of just counting up the number of social determinants, really is a cross cutting observation across a number of different cardio-metabolic outcomes, which would then lend credence to the possibility that physicians could really integrate this into their clinical care management. There's a whole host of studies that need to be done to better understand nuances such as those that Mercedes mentioned. We are really taking a deep dive into how to integrate social determinants of health on the ground into clinical care management, not just for larger health system population managers, but for individual clinicians.

Dr. Greg Hundley:

Mercedes, would you like to add anything?

Dr. Mercedes Carnethon:

I'm very pleased to see this work and I think that I really like the practical nature of it and with the counting of the social determinants of health. I think you're right that we often can go very deep in cohort studies and look at things in very nuanced way. However, I like that this presents an opportunity for clinicians interfacing with patients to have a quick and easy tool to recognize some of the background risks that they face. Thank you for this important work.

Dr. Greg Hundley:

Yes. Well listeners, we really appreciate the opportunity to speak today with Monika Safford from Weill Cornell in New York and our own associate editor, Mercedes Carnethon from Northwestern in Chicago and helping us to understand how social determinants can be used clinically to help identify those at increased risk of adverse cardiovascular events.

Dr. Greg Hundley:

Well, now we're going to turn to our second in our double feature and we'll get to that in just a moment.

Dr. Greg Hundley:

Well listeners, we're now on to our second feature discussion. It's a double feature on this January 19th. And we have with us Dr. Tim Churchill and Dr. Jennifer Ho, both from Massachusetts General Hospital in Boston, Massachusetts. Well Tim, we're going to start with you. Could you describe for us a little bit of the background related to your study? And what hypothesis did you want to address?

Dr. Timothy Churchill:

Absolutely. The background behind this study that we wanted to look at was the recent emergence of the H2PEF score and the HFA-PEFF diagnostic algorithm coming out of the European Society just about a year ago. And we wanted to look at how these two diagnostic tools perform in terms of diagnosis of HFpEF, which as we all know, is a really challenging and complicated, varied and challenging to diagnose condition. And so our specific question, as more than a hypothesis per se, was really to investigate the diagnostic performance of both of these tools against what we consider really a gold standard hemodynamic definition of HFpEF using the patients who were undergoing comprehensive level three cardiopulmonary exercise testing with invasive hemodynamics.

Dr. Greg Hundley:

Very nice. Tell us a little bit, how did you configure your study population? And what was your study design?

Dr. Timothy Churchill:

At our institution, we have a large cardiopulmonary exercise testing program and we took patients coming in from there and who had a preserved ejection fraction, which we defined in line with guidelines as 50% or above and then available transthoracic echocardiography that we could review. And we performed a detailed research over read on the clinical transthoracic echo that had been performed. And we coupled that with the lab data that was drawn on the day of the exercise test, coupled that with the medical history that was previously collated and we tried to look at a population that had all of the necessary score components to assess each of these two scores.

Dr. Timothy Churchill:

And then what we did was we calculated each of the two scores and compared their outputs against, again, as I said, what we consider our gold standard definition of HFpEF, which is a invasively defined definition that accounts for both filling pressures, as well as the relationship of the pulmonary capillary wedge pressure to cardiac output with exercise. Trying to account for the changes in the wedge with increases in flow, increases in cardiac output with exercise.

Dr. Greg Hundley:

Very nice. And just quickly, how many patients did you include in this study? And did you have an equal representation of men and women?

Dr. Timothy Churchill:

We ended up including a 156 patients and there was a female predominant in line with the overarching with both our overarching exercise testing cohort, but also in line with, I would say, the overarching prevalence of HFpEF in many other studies. We ended up with 67% women with an average age of 59 years old.

Dr. Greg Hundley:

Very nice. What did you find?

Dr. Timothy Churchill:

I would say our biggest message, our biggest takeaway was that we found that both of these scores performED quite well overall and performed in a broadly similar fashion. We did note however, that there was a significant under ascertainment of HFpEF at some of the lower scores, which we highlighted as a potential weakness in terms of using these scores for the diagnosis of community HFpEF in that there was a certain number of patients with low scores who would be classified as either not having HFpEF or a low probability HFpEF, who we found to fit our hemodynamic definition. And so we highlighted that as a potential weakness or potential consideration of these. That's one area where these scores might potentially miss people.

Dr. Greg Hundley:

Very nice. Well, let's turn to Jennifer. Jennifer you are spending much of your career helping the world understand more or bringing to light more information really in this field of heart failure and specifically focusing on patients with preserved ejection fractions. How do you put your findings here in the context with some of the other world's literature relative to patients with heart failure preserved ejection fraction?

Dr. Jennifer Ho:

Thank you, Greg. First off, I just want to say that we greatly appreciate the opportunity to participate in this podcast and on behalf of all of our coauthors, we're just thrilled to be here. I guess there are a couple of points that I would take away to try to place our study within the clinical context of HFpEF in general. Number one, we know that HFpEF diagnosis is challenging, which I think is something so fundamental to our field and needs a lot further work. But a lot of other groups have really struggled with trying to define HFpEF and really figuring out who these patients are. There's a lot of work going on there.

Dr. Jennifer Ho:

I would say that our findings really show that these non-invasive tools developed by other groups do help enrich for individuals with HFpEF and that they perform quite well with some potential of misclassification in these lower risk individuals. I'll also say that what's new in our study is that we were able to show a direct relationship of these scores and functional implications that really affect how our patients feel. And so we were able to show that these noninvasive scores really enrich for patients with lower exercise capacity as measured by peak VO2, two worse chronotropic response to exercise, and also worse hemodynamic responses to exercise. And so I think that that's really powerful in taking these noninvasive scores that have been developed by other groups and really showing that there are direct functional consequences for our patients depending on where you're scoring.

Dr. Greg Hundley:

Very nice. Jennifer, where do you think we take these scoring systems next? What do you think is the next research that needs to be performed in this particular space?

Dr. Jennifer Ho:

That's a great question, Greg. I think we do recognize that our sample may be subject to referral bias. These are all patients who were referred for clinical indications for a cardiopulmonary exercise test with invasive hemodynamic monitoring. And so I do think that validation of these scores is necessary across wider samples so we can really affirm generalizability overall. I think on a more fundamental level, so much more work is needed in the HFpEF space in general to better understand disease pathogenesis. We recognize that there's heterogeneity with respect to clinical presentation, with respect to cardiac and extra cardiac organ involvement, with respect to how we even define the disease in the first place. I think a lot of work needs to really focus on potential deep phenotyping approaches and other approaches to tease apart potential subgroups of individuals that have HFpEF that might be more uniform so we can understand all the contributors that really lead to this disease.

Dr. Greg Hundley:

Very nice. Tim, would you like to add anything?

Dr. Timothy Churchill:

I would really echo. I think the biggest immediate question in my mind would be replicating this model and or similar approaches to really using invasive validation in other contexts that may or may not have the same referral population. One of the biggest things that drove this original study originally was that many of the other validation efforts that have formed so far have been based on consensus. And so we think there's a lot of value added by the invasive hemodynamics. And so I think extending that approach, I think can offer a lot of additional value as well in different contexts.

Dr. Greg Hundley:

Very nice. Well listeners, we really want to thank both Dr. Jennifer Ho and Dr. Tim Churchill for bringing us this very informative study and helping us evaluate these new noninvasive scoring methods and comparing them with really well done invasive measures to best characterize patients with HFpEF. And then as Dr. Ho said, perhaps identify groups that further phenotyping may be indicated in other research studies to identify those that are best suited for specific therapies to improve their overall condition.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation January 12, 2021 Issue

11 januari 2021 | 22 min

This week's episode features authors David Kasss and Kavita Sharma as they join Greg to discuss their article "Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run. Your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

I am so excited about today's feature paper. It talks about my favorite topic, heart failure with preserved ejection fraction, or HFpEF, this time giving us really novel myocardial gene expression signatures in human HFpEF. Can't wait to go to that, but I also can't wait to share about some of the really cool papers in today's issue.

Dr. Carolyn Lam:

Now, we know that mitral valve-in-valve and valve-in-ring are alternatives to surgical reoperation in patients with recurrent mitral valve failure after a previous surgical valve repair or replacement. But, what are the outcomes after transcatheter mitral valve-in-valve or valve-in-ring procedures? And what is the clinical significance of post-procedure residual mitral stenosis or regurgitation? Well, we're going to find out in today's paper. Dr. Dvir from Hebrew University in Israel and authors examine the midterm outcomes in the Valve-in-Valve International Data registry, which is a multicenter collaboration and rolling cases performed between March, 2006 and 2020, in 90 centers worldwide.

Dr. Greg Hundley:

Wow, Carolyn. So what did they find?

Dr. Carolyn Lam:

Well, a total of 1079 patients were included with a median follow-up of 492 days. 4-year Kaplan-Meier survival rate was 62.5% in the valve-in-valve, versus 49.5% in valve-in-ring procedures. Significant residual mitral stenosis occurred in 8.2% of the valve-in-valve, and 12% of the valve-in-ring patients. Significant residual mitral regurgitation was more common in valve-in-ring patients. The correlates for residue mitral stenosis were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual mitral regurgitation was a valve-in-ring procedure. Significant residual mitral stenosis and residual mitral regurgitation were both independently associated with repeat mitral valve replacement.

Dr. Carolyn Lam:

So, significant residual mitral stenosis and/or mitral regurgitation were not infrequent after mitral valve-in-valve and valve-in-ring procedures, and we're both associated a need for repeat valve replacement, so strategies to improve post-procedural hemodynamics in mitral valve-in-valve and valve-in-ring should certainly be further explored.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my first paper, it really involves results from the American Heart Association COVID-19 Cardiovascular Disease registry, and it comes from our own associate editor, Dr. Justin Grodin from UT Southwestern Medical Center. So Carolyn, obesity may contribute to adverse outcomes in coronavirus disease, or COVID-19. However, studies of large, broadly-generalizable patient populations are still lacking in the effect of body mass index, or BMI, on COVID-19 outcomes, particularly in younger, adults remains uncertain.

Dr. Carolyn Lam:

Yeah. It is an important question. And so, what did they find?

Dr. Greg Hundley:

Well, Carolyn, obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if they're young. So individuals less than age 50 years. Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals, regardless of age.

Dr. Carolyn Lam:

Wow. An important public health message. Well, my next paper is a basic science one from doctors, Rayner and Karunakaran from University of Ottawa Heart Institute in Canada. For the first time, they investigated the role of RIP kinase 1, a coordinator of NF-kappa B inflammation and cell death, in atherosclerosis.

Dr. Carolyn Lam:

They found that RIP kinase 1 expression was highly expressed in early atherosclerotic lesions in humans and mice. In vitro, both basal and TNF alpha stimulated NF-kappa B activity, and resultant inflammatory gene expression was reduced in macrophages and endothelial cells when RIP kinase 1 was silenced. In vivo therapeutic administration of RIP kinase 1 antisense oligonucleotide markedly reduced atherosclerotic lesion size and macrophage content.

Dr. Carolyn Lam:

Together, these findings suggest that RIP kinase 1 drives inflammation in early atherosclerosis, and targeting RIP kinase 1 therefore provides a novel preventive strategy to treat atherosclerosis.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes from Dr. Kristin Stanford from The Ohio State University. So, Carolyn, brown adipose tissue is an important tissue for thermogenesis, making it a potential target to decrease the risk of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified brown adipose tissue as an endocrine organ.

Dr. Greg Hundley:

While brown adipose tissue has been implicated to be protective in cardiovascular disease to this point, there are no studies that identify a direct role for brown adipose tissue to mediate cardiac function. This study was performed to address this issue.

Dr. Carolyn Lam:

So what did they find?

Dr. Greg Hundley:

Okay, Carolyn. The authors found that transplantation of brown adipose tissue improves cardiac function via the release of the lipokine 12,13di-HOME. Sustained overexpression of 12,13di-HOME using tissue nanotransfection negated the delirious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13di-HOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13di-HOME increase mitochondrial respiration. So, Carolyn, these results identify an endocrine effect of brown fat to enhance cardiac function.

Dr. Carolyn Lam:

So interesting. Well, there are other very interesting types of papers in today's issue. There's an exchange of letters between Drs. Gui and Nahrendorf regarding the article Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes.

Dr. Carolyn Lam:

In cardiology news, Tracy Hampton highlights articles from Nature Biomedical Engineering on AI-based eye movements for cardiovascular risk prediction, from Science on the metabolic profiling of the failing and non-failing heart, and from Science Translational Medicine on the heart healing effects of extracellular vesicles.

Dr. Carolyn Lam:

There's an On My Mind paper by Dr. Pelliccia on gaps in evidence for risk stratification for sudden cardiac death in hypertrophic cardiomyopathy, as well as a Research Letter by Dr. Brown on the association of inducible myocardial ischemia with long-term mortality and benefit from coronary artery bypass graft surgery in ischemic cardiomyopathy, which is a 10-year follow-up of the STICH trial.

Dr. Greg Hundley:

Nice, Carolyn. Well, my articles: Professor Himbert has an In-Depth article on the current indications for transcatheter mitral valve replacement using transcatheter aortic valves, valve-in-valve, valve-in-ring, and valve in mitral annulus calcification. There's a Research Letter from Dr. Martin (Than) regarding the single troponin rule-out of myocardial infarction. And finally, Professor Isser has an ECG challenge involving chest pain with ST-segment elevation in a young woman with a broken heart.

Dr. Greg Hundley:

Well, now how about we proceed to that feature discussion?

Dr. Carolyn Lam:

Yay. Let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we want to bring you to our feature discussion today, and we have with us Dr. David Kass and Dr. Kavita Sharma both from Johns Hopkins University in Baltimore, Maryland. David, could you tell us a little bit about the background related to this study and what hypothesis did you want to test?

Dr. David Kass:

Sure, Greg. My pleasure to be here. We have long had an interest in the syndrome we know as heart failure with preserved ejection fraction, going back, really, decades, and the difficulty in assessing what's really wrong with the heart in this syndrome has been that we get so little information from the tissue itself, that most of the studies that have been done have been done at the macro level and physiology level and epidemiology level.

Dr. David Kass:

But at Johns Hopkins, Kavita Sharma, who now heads up our heart failure transplant group, had established a clinic, a HFpEF clinic, one of the very few in the United States, and the availability of both the patients through the clinic, and then as part of this, right heart catheterizations associated with endomyocardial biopsies being obtained, was really a very extraordinary opportunity to examine tissue at a molecular level, essentially for the first time. There's been no other data set quite like this one.

Dr. David Kass:

So, we had already established both a patient population, very, very well-phenotyped, very much symptomatic, and we had a tissue bank. And as part of a consortium, a network consortium grant that was sponsored by the American Heart Association, called the Go Red for Women Network, we had a project that basically was focused on trying to better understand HFpEF.

Dr. David Kass:

The impetus was really, no one knew anything about what's going on in the heart at the molecular level. Really. There had not been transcriptomic analysis ever done before, and there were plenty of questions that we thought this might be able to answer. Among them, how really different are these hearts from patients who have, what we'll call, garden-variety heart failure, heart failure with a low ejection fraction? That's seemingly not so controversial now, but actually there's still controversy as to exactly what's wrong with these hearts, and so we thought we would be able to tease that out.

Dr. David Kass:

Then it's also been, I think, widely discussed that this is a very heterogeneous disease or syndrome, really, that has a lot of different factors, comorbidities, that are associated with it. So question two was really, how cohesive is the molecular signature that you might see in the myocardium? Is it going to be hopelessly heterogeneous as well, in which case, what does that say about our possibility to develop drug therapies when the underlying biology may be very, very heterogeneous? And if not so heterogeneous, question followup would be, what signatures might be there in subgroups that we could identify, and with subgroup analysis then, help us target in a more personal medicine fashion, ultimately, a therapeutic for the syndrome?

Dr. Greg Hundley:

Very nice. So, David, how did you assemble a study population, and what was your study design?

Dr. David Kass:

In this sense, this was very much an ongoing effort by Dr. Sharma and what was the HFpEF clinic team. Back, probably about 4 years ago, maybe even more, she had started to become interested in this and had amassed a clinic population while she was a resident, and then as a senior resident became more and more interested in this and this became her fellowship project when she was a cardiology fellow at Hopkins.

Dr. David Kass:

And by the time I became more involved with this, basically she had it in operation with study nurses and seeing patients. It was very clinically-oriented. There was some sort of more, I would say, population-level data being collected and studies being done, but nothing like quite what we did here. But that was there.

Dr. David Kass:

So, in terms of a study design, this was almost more a biobank. At this point, there was a cadre of patients she had been following. She had been following this group for some time. Basically, in a freezer we had endomyocardial biopsies under an IRB-approved protocol that had been obtained, and in part we were sort of waiting to get enough tissue together so we had a large enough data population and enough sample, and then really thinking through what might we be able to look at in these pieces, knowing full well that very little had been done. So almost anything we came up with, and we've been doing quite a few other things now as well, was going to be new, so I suppose the simplest study design of all.

Dr. Greg Hundley:

So, what did you find?

Dr. David Kass:

Well, going through those initial questions. Question number one, is there a unique molecular signature? We're looking at using what's called RNA-Seq, which is the newest generation of RNA gene expression analysis, in these myocardial biopsies. The answer was, yes, actually. There was a very unique signature. And this was all done using what we call agnostic bioinformatics approaches, where you just give the data, you give all the genes that are different between HFpEF and a control group, we had a control group, donor hearts. You look at basically the HFrEF group, the people with low ejection fraction, versus control. What are those differentially expressed genes? And of course you have your control.

Dr. David Kass:

So there are three groups and you get a series of little dots in what's called principal component analysis, and it was very clear, right from the beginning, that these groups separated, and this was just purely a statistical approach to say, are they different?

Dr. David Kass:

And then we asked further, are they still different even if we adjust for what are the common comorbidities and the things that differentiated, often, HFpEF from other forms of heart failure, specifically age, sex, having a large body mass index, having diabetes, these were all things that were more prevalent and more severe in the HFpEF group. So we adjusted for these things, again, sort of statistically, and redid this, and it's still absolutely separated. So question one, are they different at the transcript level? Yep. They're different.

Dr. David Kass:

And then, question two is basically, despite the heterogeneity, if you start digging into the genes, what kinds of genes are being differentially regulated? Is there a signature that becomes cohesive and consistent among the patients within the HFpEF group? The answer to that was, yes. And this too was very interesting because we also did an adjustment for the comorbidities, and what we found were the genes that were upregulated in HFpEF, that actually turned out mostly to be down-regulated in the other form of heart failure. Genes specifically associated with the manufacturing of ATP by mitochondria, the ATP synthase genes, those genes were significantly upregulated in HFpEF, but once you adjusted for body mass index, a lot of those pathways disappeared. So, the class of genes that were up regulated was in fact related to comorbidities.

Dr. David Kass:

Then we did the opposite. We looked at those genes that are down-regulated, and found that a large group of genes that were quite different, that are not on the tip of most people's tongues for what goes on in heart failure, mostly associated with protein processing, trafficking, autophagy, the process of protein recycling, endoplasmic reticular stress, which was something that the journal senior editor, Joe Hill, had talked about and published about earlier in the year in a mouse paper where he first came up with this idea that ER stress might be important. Well, looks like it's important in these humans. So, we found some unique signatures.

Dr. David Kass:

And then the last thing I suggested we would look at is whether we could get subsets from the molecular signatures, and the answer to that was, yes. Here we kind of threw the genes at a program and said, "You come up with clusters, purely based on the genes." That's it. No clinical information whatsoever. What it came out with were three groups, and very interestingly, there was a mortality difference between these groups just based on their transcript. One of the groups looked at pretty close, or closer, to HFpEF to reduced EF heart failure, and indeed, the genes that it came up with were typical of hypertrophy and remodeling and matrix remodeling, and that was the one with a group with the highest mortality. And then there was sort of a very different group with small hearts, relatively low levels of natriuretic peptide, an inflammatory pathway signature. Not the kind of thing we're to looking at and say, "Oh yeah, this is obviously heart failure," and yet they were equally symptomatic, tended to be a few more on the female side than male side.

Dr. David Kass:

So, I think, in the end, that study was very successful for all the things we were trying to do, really. That it's distinctive, that there are subgroups that we can identify at the transcriptome level, despite the heterogeneity, and we've got a list of genes now, pathways, really, that look to to be uniquely relevant.

Dr. Greg Hundley:

Very nice summary. Well, let's turn to your colleague, Dr. Kavita Sharma, who is also with us today and helped assemble this wonderful cohort. Kavita, how would you put these findings in the context with some of the other literature that's been published in heart failure preserved ejection fraction?

Dr. Kavita Sharma:

Hi, good morning. Thanks for the opportunity. That's a great question. The idea of trying to phenotype HFpEF has really been around, for now, a couple years, and that's driven by the fact that we have no therapeutic agents to date that have really affected outcomes in this population, in spite of the fact that half of all heart failure is classified as HFpEF and we have many therapies for HFrEF, or low ejection fraction patients.

Dr. Kavita Sharma:

And the thought is that, perhaps, it's a heterogeneous population and we're lumping to many different types of patients together. And so there have been a number of efforts to date to try to phenotype this population, but most of these have been centered around clinical comorbidities, and distinct groups have been identified, but without a clear sense of what is driving mechanistic differences between the groups, and then how to take it to the next step to target therapeutic agents to specific populations within HFpEF.

Dr. Kavita Sharma:

I think this is a big step closer to trying to really understand how we can target therapies. So, we've seen efforts at phenotyping and there are some overlap between the three groups that we identified from our RNA sequencing work, but this is now giving us a clue as to how to target mechanisms of disease.

Dr. Greg Hundley:

Very nice. Well, Kavita what do you see is the next study to perform, really, in this space, to follow your work?

Dr. Kavita Sharma:

Our goal is to really perform a comprehensive, as we call it, omics approach to phenotyping and HFpEF. We are actively looking at metabolomics, both from the blood and the tissue in collaboration with investigators at U Penn, we hope to also look at proteomics, and eventually single cell sequencing, as well as really trying to understand some of the actual myocyte-level contractility issues. And this is work that actually has just come out as well from our group, looking at sarcomere function in HFpEF from the right ventricle. Our hope is that each of these areas is going to further our understanding of myocardial deficits, so to speak, and areas that we could target for therapies.

Dr. Greg Hundley:

Very nice. David, do you have anything to add to that?

Dr. David Kass:

No. I think Kavita said it very, very well, and clearly the goal is to ultimately develop a more mechanistically-driven, personalized approach to the subsets of HFpEF so that hopefully we get a therapy that actually is going to work. These are not tiny subsets of this group. Remember this is half of all heart failure and that's a big number, and even a subgroup that might represent one-quarter of half of all heart failure is still a big number, and so none of this is ever going to be like an orphan disease suddenly where we're dealing with a very small group of people.

Dr. David Kass:

But even if it was, it would still be a major step forward, but it's not going to be that. I think what you're going to hopefully come up with, with a signature that can be targeted and with the therapy that's effective on the basis of that, is going to, I think, help a large population.

Dr. Greg Hundley:

Well, listeners, we want to thank Dr. David Kass and Dr. Kavita Sharma, both from Johns Hopkins University in Baltimore, Maryland for bringing us this new information related to RNA sequencing to really help better phenotype patients with heart failure and preserved ejection fraction, so that in the future, we may have therapies that can help this patient population.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2021.

Circulation on the Run: Discussing Circulation’s Response to COVID-19

5 januari 2021 | 36 min

This week's episode is special: To start 2021, Circulation's Digital Strategies Editor, Amit Khera, hosts a look back at Circulation's response to the Covid-19 pandemic. Circulation's Executive Editor James de Lemos and Senior Associate Editor Biykem Bozkurt discuss the initial days of Covid manuscript submissions to Circulation. Then Amit interviews author Fatima Rodriguez and her findings of racial and ethnic differences of patients suffering from Covid-19. Finally, Amit interviews authors Nicholas (Nick) Hendren and Justin Grodin as they discuss their article, which was one of the first science outputs from this AHA COVID registry.

TRANSCRIPT BELOW:

Dr. Amit Khera:

Well, welcome to Circulation on the Run. This is Amit Khera. I am digital strategies editor for Circulation, and I have the privilege of standing in for Carolyn Lam and Greg Hundley on this very special edition this week. We have no Circulation issue, so we get to use this and we thought we would use it for a really special look at COVID the Circulation response. It's a time to take a pause and reflect on what we've seen so far this year and what science and initiatives have come out of Circulation. And it's a real privilege today to be joined by first senior associate editor of Circulation, Biykem Bozkurt, who's professor of medicine at Baylor College of Medicine, and also James de Lemos. He's executive editor of Circulation and professor of medicine at UT Southwestern Medical Center. Welcome to you both.

Dr. James de Lemos:

Thank you.

Dr. Biykem Bozkurt:

Thank you, Amit.

Dr. Amit Khera:

Well, Biykem, I'm going to start with you. I remember when COVID came out, it was, we were all overwhelmed. The data were coming fast and furious. Most importantly as cardiovascular specialists we wanted to know how to manage these patients and what manifestations we're seeing. Things were coming from all over the world, and you were tasked with the challenge of, well, how do we organize and curate all this? And what can Circulation do to be most helpful in this response? And you came up with some really creative ideas that I really lodge you for. Maybe you can tell us a little bit about what was going through your mind when this was starting and what are some of the initiatives you started around that?

Dr. Biykem Bozkurt:

Thank you, Amit. And I really appreciate your pushing it to reflect. In early March it was clear that COVID was surging and we had to create a platform rapidly to disseminate the insights and the best practices from around the world in a timely fashion, and also inform future research for the fight against COVID. We discussed amongst the senior editors, and it was apparent early on that we would not have large-scale multicenter trials. And most of the information was going to come from site experiences and our cohorts, which were so valuable, and everybody was yearning for that information. With that framework in mind, we thought the best platform would be to do a call for submission of rapid research letters. And also we thought of interviews with experts from the hotspots, and we rapidly assembled a Circulation COVID editorial team, which comprised of me along with my colleagues, Salim Virani, Erin Michos, and then both of whom are the guest editors at Circulation, along with Mark Drazner, Darren McGuire and yourself.

Dr. Biykem Bozkurt:

And we created a call for rapid research letters for COVID and also started doing short video interviews from pandemic hotspots around the globe. We wanted these interviews to be dynamic, informative, conversational, both recognizing the crisis and the human factor as well as the best practices. We were so hungry for information. So we thought of a dyad approach where the interviews would be conducted by early career fellows in training, along with regional experts from the hotspots who were leading the fight formulating solutions. And we are so indebted to these experts and heroes for sharing their stories and experience on the cardiovascular presentations and the practices and how they were managing their patients. And these were called COVID updates from the front lines.

Dr. Biykem Bozkurt:

We had approximately 19 interviews with leaders from Seattle. That was one of the early hotspots. Then we moved on to Singapore because they were having such valuable and successful interventions. Then we went over to Madrid, Spain, where there was a huge hotspot, of course New York City. Then we interviewed with Milan, Italy, Brescia, Italy, Wuhan, China, New Orleans, South Korea, Salt Lake City, Paris, French, Houston, Texas, Atlanta, San Francisco, Delhi, India.

Dr. Biykem Bozkurt:

And we also try to address not only the local expert's approach to how to treat and manage and what they were seeing, but also strategically how the health disparities were being handled, how the emergency room or ICU clinicians were tackling COVID. We also try to provide a nursing perspective and even pandemic modeling. For our call for research letters we had approximately, or more than 1,000 papers submitted, 414 of those were original research letters and about 265 as research letters. So I think it was truly a gratifying experience that we were able to provide a voice for the frontline cardiovascular specialists, providing what they were seeing, what they were doing, and also a perhaps a platform that was quick enough, dynamic enough for us to disseminate information. And also a platform for publications as research letters, which are concise and addressing the issue at hand and creating a portfolio by which all the investigators could voice their observations.

Dr. Amit Khera:

Well, listen, first and foremost, that was a heroic effort and a huge volume of different components, both research components, regional research articles, research letters, and then the videos. And I'll say those videos included fellows. I know I watched many of them before I went on service and taking care of patients to learn what people were doing. And that's so different than what we do in a scientific journal where we peer review and all that. And I can't tell you how helpful that was. And then something else you said was the personal experience. I remember watching a few physicians talking about what it meant personally for them and their families and quarantining and how hard that was and the human toll. And boy, that was really amazing. And I know we'll look back on those years to come and as we think about what COVID was when it first started.

Dr. Amit Khera:

I'll pivot a little to some of the science. I think having seen this from a different vantage point, at first you weren't sure how many papers you'd get. We were all looking for sort of kernels. And then all of a sudden there's a deluge of papers, right? Can you talk to that experience about how you learned how to curate all this when it was sort of started slow and then it was overwhelming?

Dr. Biykem Bozkurt:

We knew we would get a lot of papers. We didn't realize the true magnitude. At the beginning we thought that the assigned group, which we call the COVID editor group would be able to handle this. And thus we were trying to triage and provide a structured approach to this. It was quickly clear with James and Joe's and Darren's help that we needed the remainder of the whole editorial board. I remember initially we started with that small group and immediately expanded it to the larger group for us to be able to tackle.

Dr. Biykem Bozkurt:

I think starting with March, there was a steady rise in the types of papers. The interesting concept was the observations eventually start coming with a certain repeated theme. And of course the ones who provided the initial observations usually had the innovative part of the initial, the first one to recognize it. And there was a lot of debate. For example, when we were first seeing the papers about, or the research letters about the clots we were saying, or asking the questions, "Whether these were higher than the other ICU patients and so forth?"

Dr. Biykem Bozkurt:

But as the numbers increased, it was the summation of the gestalt of I think what the papers were providing was also moving the field. So not only the volume, I think that was a very interesting experience. Of course how to deal with that on an operational level, at a journal level. But also cataloguing and creating these, okay, these appear to be myocarditis, these appear to be potentially the clots. And then recognizing the how the story's evolving about COVID. And of course, intermittently we had the commission request and ask individuals to provide reviews that are with the insights, creating the synthesis from this culmination of this large volume of papers. And I think we try to do that in a timely manner periodically.

Dr. Amit Khera:

Yeah.

Dr. James de Lemos:

Actually just how hard it was to evaluate science in the midst of a pandemic. You know, what these investigators were doing in the midst of their surges was frankly heroic in the beginning. They were terrified, didn't know what was happening in their sites and they were submitting research. But the challenge is that it's not the kind of research we're used to evaluating in Circulation in terms of very well controlled clinical studies with good control groups and clear experiments. We were forced to evaluate research in a war zone basically and decide when something was actionable enough that we thought the clinical community could get ahold of it.

Dr. James de Lemos:

And at the same time we also had to think about our mission to publish durable science that will last beyond a few weeks or few months of the pandemic. And it was a real challenge and credit to Biykem and Augie here, who's running this podcast for the nights and weekends that we're done evaluating these and the many discussions about really what's the bar for research to get published in the midst of a pandemic. None of us and any of the journalists had ever been through this before.

Dr. Amit Khera:

I think those are great points. And I may even add to that just as much as there was the wanting to get things out that would help clinicians on the front lines, also responsibility of not publishing something erroneous where people would do the wrong thing. And we've certainly seen that along the way. So that was an added challenge. James, I'll pivot to you a bit more on this, in reflection, if you think about the papers now that you'd be able to look back, what are some of the ones that you remember the most, or you think were most impactful published in Circulation so far?

Dr. James de Lemos:

Well, some of the ones at the very beginning that were really written with almost a 24 or 36 hour cycle to get information out, there was a research, a review paper rather by Nick Hendren and Les Cooper that really came out almost the first weekend after this group launched. Biykem was involved in that. It was a remarkable effort to summarize really weeks old data on the potential cardiovascular complications. And it was an instant classic. Another one I think that has been tremendously important and durable was the report from Bonnet's group in France on the MIS-C syndrome in children that has been really paradigm changing. I think it was, it won the Willerson award as our top clinical paper of the year because the editors and editorial board felt that this was the most impactful paper we published of all papers in the year. And I think it certainly was amazing work to pull together that kind of series in such a short period of time and define a syndrome really that had never been reported before.

Dr. Amit Khera:

Yeah. You know, I'm looking here out of the maybe near a 1,000 papers or so of different varieties that came through, those are certainly two very memorable ones and several others. Biykem, I'm thinking about some other articles and even some really interesting frame of reference pieces that people, just sort of personal reflections. What are some of the ones that you remember?

Dr. Biykem Bozkurt:

The sequence of how it evolved is truly, left a sort of enduring impact on me. The first one that I remember was Kevin Clarkson's paper that provided the initial review, and we all were reading that, of course. Nick Hendren and of course Mark Drazner's paper also added a larger framework of the whole spectrum of cardiovascular disease or cardiovascular abnormalities with COVID. We, I think, try to provide a right balance in terms of the research papers and have received a large scale of papers on DVT and PE. And we then clustered quite a few of those. One of which was from Wuhan, China and the others were from U.S. And that became a very nice complimentary portfolio of three DVT PE papers, which I thought was very helpful at that juncture, because that came a little bit later in the timeframe. I can't recall, I think it was around June timeframe where we were able to formulate, really, this is truly a pattern.

Dr. Biykem Bozkurt:

The other very interesting paper that I remember is a series of echocardiographic imaging of all hospitalized patients from Israel. This was published in July. This was one of the first structured screening by echocardiography of all comers to the hospital. And it was about a 100 patients and it was by Topilsky. If I remember correctly, it was published in July. And that was the first one stating that a large number of patients had abnormality in the cardiac structure and predominantly RV, which until that time it was anecdotal case reports. We were all hearing about the RV and PE.

Dr. Biykem Bozkurt:

Then I think in July we had Peter Lewis' very nice review. And of course, Damien Bonnet's the multi-system inflammatory syndrome in the pediatrics, especially how to manage it. We also had a HRS partnership on guidance for how to do EP studies during the time of COVID, and a variety of frame of references. Some of which were about certain different approaches. We had one paper about senior woman leaders as to how they were supporting their colleagues. We also had early career faculty members who had provided their frame of references about social consciousness and ethical dilemmas, all of which were a true complimentary portfolio, providing not only the scientific expertise about human factor in managing this.

Dr. Amit Khera:

Well, you certainly have a great perspective on all the articles that came through, Biykem, and listed several of the highlights and James, I'm going to pivot you and ask you, what comes next? As one of the senior editors along with Biykem for Circulation, what do we need to see next in cardiovascular space or literature as it relates to COVID? I appreciate there's also what's happening with COVID in general, but what do we need to know and what's the level and bar of science now?

Dr. James de Lemos:

The bar is back to requiring excellent science, even for COVID cardiovascular disease, really. Because we know enough about the disease that we need the best information that's clinically actionable and meet sort of usual circulation standards. And what I'd say we need next is we need long-term outcome data. So we have a lot of information about short-term cardiovascular complications of the illness, but the next wave, and we're going to get through this, right? The end, the light is on for the end of this thing. But then the next phase is what's the long-term implications of cardiac injury that occurs in the hospital? What are the cardiovascular manifestations of these long haulers? And I think that will be the kind of research that's durable really over the next few years.

Dr. James de Lemos:

I'm very, very hopeful that we won't be talking about hospitalized COVID in 2022, that that will run its course and not be a dominant theme in Circulation. But I do think we're going to need long-term follow-up of cardiovascular issues for these patients. Particularly given the subtle cardiac abnormalities that Biykem was talking about that we've been reporting in the hospital.

Dr. James de Lemos:

The other piece I would just say is that we know almost nothing about cardiovascular manifestations of non-hospitalized COVID. Almost everything that we've published and other journalists have published has been about the minority of patients that get hospitalized. But we do need to know more about the many larger proportion that never get hospitalized.

Dr. Amit Khera:

That's a nice segue when we talk about sort of high quality science and maybe slowing things down just a bit to make sure we're getting the best answers. And that's a pivot to the AHA COVID-19 Cardiovascular Disease Registry, something which you have co-chaired and spearheaded. And we recently had a milestone at DHA scientific sessions. We had the first output just in a few months to already have some high-quality research coming out, we're going to hear in just a bit from two of our featured articles that were leg breaking science out of that registry in shortly. Tell us a little bit about the inception of that registry, what led to it and sort of how did it form?

Dr. James de Lemos:

Well, the impetus was really the same as what Biykem was talking about with her nights and weekends trying to generate information for practitioners. It was that feeling of powerlessness that we all had early on, knowing that this surge was coming, developing in other parts of the country and realizing that we knew nothing and all of us felt the need to fight back. And as you know, Amit, this really grew out of work of our young people that we developed, or I should say we, meaning our fellows developed a program to teach us about COVID and to study COVID in the patients at our two teaching hospitals. And that really led us to realize that the field needed generalizable knowledge that was beyond single center experiences and their work really directly led to the idea to approach the American Heart Association about a multicenter registry and then Sandeep Das, one of our associate editors and a faculty member at UT Southwestern and I pitched this to the AHA and then we put together a great steering committee and launched this.

Dr. James de Lemos:

And I think the unique thing about this that we tried to do was in the same, we recognized that the window for discovery was short and the usual way of registry research wouldn't work. And so what we did is we democratized the process. So we allowed multiple teams of investigators to be doing science simultaneously on a secure platform at the AHA, the precision medicine platform. And that's allowed dozens of projects to forward in parallel so that within this six month timeframe we have these two papers published, but we've got a lot of other, what we hope will be important work that can still make a difference in the pandemic.

Dr. Amit Khera:

Well, thank you for that. And I won't steal this under the upcoming articles to talk more, but congratulations to you on seeing this come to fruition, all the fruits of your labor in a very short amount of time. So we look forward to seeing many, many more papers coming out of it. I want to wrap up by just saying, I know we are certainly not done with the COVID pandemic, but it is a new year by the time this podcast comes out. And so we want to make sure we have time to reflect on what lessons were learned. What we learned about scientific publishing in these really trying times. And I want to congratulate you both on coming up with some very creative strategies to be as contributory as possible to what the field needed at the time. And I think you achieved that and we look forward to continuing to learn from Circulation and from the work coming in about this pandemic and many more things to come. So thank you both for your time today.

Dr. James de Lemos:

Thank you.

Dr. Biykem Bozkurt:

Thank you.

Dr. Amit Khera:

So now we're moving on to the featured article. This is the first of two, and I'm fortunate to be joined by my colleague here, Dr. Fatima Rodriguez, who's an assistant professor at Stanford in the division of cardiology. Welcome, Fatima.

Dr. Fatima Rodriguez:

Thank you so much, Amit for the invitation.

Dr. Amit Khera:

Well, you had this really important article on racial and ethnic differences in presentations and outcomes in those hospitalized with COVID and certainly there's been a lot about racial and ethnic differences. Tell me a little bit about the genesis of this particular article. What made you decide to use the registry early on as one of the first studies to evaluate this registry?

Dr. Fatima Rodriguez:

So as you heard from Dr. James de Lemos and Sandeep Das, the American Heart Association very rapidly created this registry to democratize and accelerate the way we do research during the pandemic. And this topic of racial ethnic disparities was right off the bat selected as a priority area because of the inequities that we're seeing, and that have been magnified by the COVID-19 pandemic.

Dr. Amit Khera:

Well, there's so much that you found and when it came to who was affected and who ended up in hospital with COVID and then obviously exploring some outcomes, maybe tell us a little bit about what are some of the main findings of this work?

Dr. Fatima Rodriguez:

We had a lot of significant findings, but I would say that some of the most important findings is that black and Hispanic patients really accounted for over half of the hospitalizations and the deaths in the registry during this first data cut. A third of the patients that were hospitalized were Hispanic and a quarter were black. Asian patients that we also studied had more severe presentations when they were admitted to the hospital. We were also surprised that race and ethnicity itself was not independently associated with worse in-hospital outcomes or other adverse cardiovascular outcomes. But again, this suggests that we really need to move upstream from hospitalizations to deal with the factors that result in the higher rates of hospitalizations for these underserved communities.

Dr. Amit Khera:

You know, I think you just summarized it so well. And I think for many of us that saw this paper, we saw that there was no difference in in-hospital outcomes in general and after adjustment, which I think that was a little surprising. Maybe we shouldn't have been surprised. Or do you think that perhaps looking at all the sort of media and the press about adverse outcomes we should have thought differently, or do you think this is the actual finding that one can expect?

Dr. Fatima Rodriguez:

Yes, we were surprised as well. And our hypothesis was that race and ethnicity would be independently associated with worse in-hospital death, but also mace. But it actually turns out there have been many publications across many different sites in the United States that have documented similar findings. Again, the caveat being here is that these patients were hospitalized and as a clinician you and I know that once people get in the hospital, at least for a disease like COVID-19, the care is fairly protocolized. And more of the variation mortality has to do with where these individual patients are hospitalized. And again, not surprising with the new disease that there's a lot of in-hospital variation. So not to say that there aren't disparities, but at least the hospital itself does not seem to be a cause of disparities and outcomes by race and ethnicity.

Dr. Amit Khera:

I mean, that's an incredible important finding to your point about once you get to the hospital people seem to do comparably well. So I think you said this in your conclusion as well. We really need to work upstream and is also profound that 58% were Hispanic or non-Hispanic black that were hospitalized with COVID. What are some of the upstream things we could be doing?

Dr. Fatima Rodriguez:

Yes, and this finding has been consistent across many studies. And I think that this reflects the over representation of these communities and the essential workforce, right? People that are not able to isolate. People that need to show up to work every day. People that live in multi-generational households and therefore exposed to the virus and higher rates of transmissions. So first I would say we need to try to do things to prevent the transmission in the first place in the communities. For essential workers they need to be provided the protective gear to again prevent them from the transmission. And now things are different then when we did this study. Now we have a vaccine that's about to be rolled out that we were discussing before, and we really should prioritize these communities in the vaccine rollout as well.

Dr. Amit Khera:

All great points. And as we drill down a little deeper into some of your findings, I think one that really stuck out to me was how much younger the Hispanics and non-Hispanic blacks were. I think average age of 57 and 60 versus 69 in non-Hispanic whites. Tell me a little bit about your thoughts on what is driving that younger age as well?

Dr. Fatima Rodriguez:

Yes, I agree that that was a fairly striking finding, especially Hispanic patients were on average 57-years-old compared to non-Hispanic whites who were 69-years-old when they were hospitalized. So more than 10 year difference. Again, I think a lot of this reflects the nature of the workforce and help individuals are higher rates of getting exposed, but also likely reflect some of the underlying co-morbidities. Remember, these are patients that are sick enough to require hospitalization. And again, we know that individuals that have higher rates of diabetes, obesity, and other risk factors have a higher tendency to be hospitalized.

Dr. Amit Khera:

You know, you also looked a bit at Asians, I should mention that. I think some of the findings were increased respiratory complications and perhaps some issues related to delayed some of the observations around Asian patients.

Dr. Fatima Rodriguez:

So the Asian patients did comprise a smaller portion of our registry, but again, still a notable finding that they tended to be sicker at time of presentation. We developed a cardio-respiratory disease severity scale specific to COVID, modified from the WHO scale. And again, found that patients even after adjusting for all other factors did tend to have a higher disease severity when they came in. One of the hypothesis of why this was the case is that they tended to have longer delays from symptom onset to both hospital arrival and to the diagnosis of COVID-19. And our study didn't look up why, but there have been some other studies that have suggested perhaps that there's been some hesitation in the Asian community to seek medical care for a variety of factors.

Dr. Amit Khera:

You know, and I think as we try to think about what are some implications of this work and what are next steps that could be one is to how do we enhance understanding of the need for prompt care in the Asian community, that could be one take home. One other tantalizing finding was this observation of less Remdesivir use amongst non-Hispanic blacks in this study, you made a point of that. What do you make from that, and what are some of the reasons you think are for that?

Dr. Fatima Rodriguez:

Absolutely. And we were interested in looking at how COVID-19 specific therapies varied by race ethnicity. And of course, things have changed dramatically in this area. As an example, Hydroxychloroquine was the most frequently used drug, and we know we don't use that right now in practice because it's not recommended. However, and Remdesivir is one of those drugs that does have fairly good evidence to use. And we saw that less than 10% of patients in our registry were on Remdesivir during the study period, with black patients being the least likely to be on this drug. Part of this may be explained by the lower rates of clinical trial participation among these patients, and then the other may be just higher rates of comorbidities. But again, might preclude the use of this drug. And we actually have a paper coming out from our registry, exactly looking at the differences in clinical trial participation by race and ethnicity.

Dr. Amit Khera:

Well, certainly look forward to seeing that. I think that would be an important followup to this. So I guess, leaving you the last word. This was I think a really important finding, helping us understand where the problem is, if you will. Actually there's numerous problems, but your point about upstream focus. So what's next? What do we do next in this field in terms of helping eliminate these disparities that we're seeing in COVID-19?

Dr. Fatima Rodriguez:

Yes, our hope when we started this registry is that we would have nothing to say at this point, this far along in the pandemic. I will also say one point that we didn't discuss is that mortality was high, and it was high among all groups. So we still have work to do in the inpatient setting to lower mortality, especially as the pandemic continues. But again, our work really suggests that we need to move upstream and focus specifically on vulnerable and marginalized communities, such as racial ethnic minorities to try to prevent the high rates of COVID-19 infection, and in particular high rates of severe COVID-19 infection.

Dr. Amit Khera:

Well, that was a fantastic review. And congratulations again on this leg-breaking science at the AHA sessions and one of the first early manuscripts coming out of the AHA COVID-19 registry. So thank you again, Dr. Rodriguez. It was a true pleasure to have you on today.

Dr. Fatima Rodriguez:

Thank you so much, Amit.

Dr. Amit Khera:

And now for our second featured article, we have Dr. Nicholas Hendren, who's chief cardiology fellow at UT Southwestern Medical Center and Dr. Justin Grodin, who is an assistant professor in the heart failure transplant section at UT Southwestern Medical Center. Their articles entitled Association of Body Mass Index and Age With Morbidity and Mortality in Patients Hospitalized With COVID-19, also from the AHA registry and also a late breaker at the AHA scientific sessions. Welcome gentlemen, and congratulations to you both.

Dr. Justin Grodin:

Thank you.

Dr. Nicholas Hendren:

Thank you.

Dr. Amit Khera:

Well, I'm going to jump right in, this obviously was a really exciting article. One, because of course it's timely with COVID. Secondly because it's one of the first science outputs from this AHA COVID registry, so we're all very excited about it. And importantly, really impactful findings I felt. So maybe I'll start with you, Justin. Tell us out of all the different questions and people were working on this registry, how did this sort of move to the top? What was the impetus behind this question?

Dr. Justin Grodin:

Well, I mean, I think the answer really lies from clinical experience. I think as you know, Amit, and as Nick knows, we quickly understood as the pandemic evolved that in addition to what we would call more traditional risk factors like cardiovascular disease, diabetes, hypertension, et cetera, and old age, we noticed that the young individuals that were hospitalized with this disease were actually more likely to be overweight or obese in comparison with their older counterparts. So really based on those empiric clinical observations we hypothesized that that would certainly influence outcomes for those that are in the hospital or ill enough to be in the hospital with this disease. As most COVID research has gone, we're basing kind of a hypothesis based on pure clinical assertion. So that was really, the origin was very organic and really based at observations made at the bedside.

Dr. Amit Khera:

I think that makes a lot of sense, and as you pointed out, with COVID drinking from the fire hose initially and hearing a lot of reports about interplay of obesity. But I think the value here of the registry was which was systematic curation and acquisition of patient data. So definitely makes a lot of sense why you pursued this. And I think what you found first and foremost was that the prevalence of obesity was higher in your patients hospitalized with COVID than those from exchange of the U.S. population. And then I'll turn to you, Nick. Tell us a little about what you all discovered, what happened with these folks with obesity? What was the course? What were some of the findings?

Dr. Nicholas Hendren:

You know, as Dr. Grodin mentioned, we were really interested at the intersection between the obesity epidemic and the COVID-19 pandemic. And they're major questions focused on two parts initially, which is, are people who are obese at increased risk of dying in the hospital? And the second part being, if you're hospitalized and obese, are you more likely to be intubated? And the answer to both of those after adjusting for the traditional risk factors like age, renal function, et cetera, were yes. And so what we observed was that people who are younger than 50 and severely obese, that means a BMI greater than 40, were at increased risk of dying. And that includes young people who otherwise might not think that they were high risk of dying. And then we observed that your body mass index, if you're obese, again a BMI greater than 30, puts you at increased risk of ending up on the ventilator unfortunately.

Dr. Amit Khera:

So really I'm going to dig deeper here as you all did in this paper. At first, obviously the prevalence of obesity was higher. Secondly, as you pointed out certain complications like being on the ventilator and I think VTE and other complications, and then some really interesting finding was this interaction with age. Maybe, Nick, tell us a little bit more about that age interaction.

Dr. Nicholas Hendren:

I think a lot of people are familiar with that age is one of the strongest, if not the strongest risk factor for dying from COVID-19. And what we were interested in was, if you adjust for age and try and take away the association between age, what is the risk of obesity in and of itself? And so we looked at patients that were less than or equal to 50 years old, kind of 51 to 70 and older than 70 years old. And really wanted to look at for those individuals that are obese in those age groups, what are their outcomes? What is their risk? And what we observed was that if you're older than 70 and obese, your risk of dying is probably not all that different by BMI. But if you're younger than 50 and obese, your risk is significantly higher if you're obese than if you were normal weight for that age group.

Dr. Amit Khera:

It's pretty fascinating this age interaction, that obesity seem to be more of a bad actor, if you will, in young people than it was an older people. And Justin, why do you think you find that? What was the rationale or biology there?

Dr. Justin Grodin:

You know, Amit, I think that's a great question. And that's a question that we were asking ourselves. As with other diseases, individuals that are more obese tend to be younger in general. So it's very unusual to see somebody that's older that is otherwise obese. So we do see a little bit of an imbalance in the age distribution, favoring higher obese groups in those that are younger. And that certainly could have influenced some of the observations that we saw. And then I think what's perhaps more interesting is, really what makes these young people that we would otherwise think would be low risk, high risk? What is it about obesity that portends a higher risk with COVID-19?

Dr. Justin Grodin:

And Nick and I, we speculated in the manuscript and really the reasons are threefold. At least we think, obviously it could be more than that. But number one is that we all know that obesity can be associated with metabolic diseases, diabetes, and whether or not there's some subclinical or undiagnosed form of that that is also contributing to risk in these people mediated by obesity could be one possibility.

Dr. Justin Grodin:

The second is actually directly related to the SARS-CoV-2 virus itself in that the ACE2 receptor is actually abundantly expressed in adipocytes. And so we know that obese individuals have more adiposity perhaps putting them at higher risk. And then the third reason is that individuals that are more obese actually have just more mass on their thorax and that might influence some of their pulmonary dynamics and might put them at increased risk for adverse events.

Dr. Amit Khera:

All certainly great hypotheses, and obviously further things to test. I'm looking at your conclusions and essentially you reminded us that preventive strategies in obese people regardless of age is something we need to focus on. So I think that's a really important take home point. Last question. Do you, Nick, I want to first congratulate you. I know way back when we were just thinking about the problem of COVID and begin to collect our own data and that germ of an idea really snowballed into this idea of the AHA COVID registry, and you had a critical role in that. I remember talking to you and you were putting in data on nights and weekends. How does it feel now to see the output of your work really so quickly and so such impactful work after doing all this labor and working so hard to get this up and running?

Dr. Nicholas Hendren:

Well, I think anytime you're able to have at least a small amount of success or something that's felt to be valuable to the contributions, it's always a nice thing. And it was such a team effort all the way through and from the American Heart Association to our attendings, Dr. de Lemos who spoke earlier and Dr. Grodin and all of our team members. And so it's really impressive how the entire field of medicine and cardiology has come together and try and battle COVID across all lines. And so to contribute to that in even a small way is hopefully helpful. And hopefully people will read our information and make choices that will help keep them safe and keep people out of the hospital and doing well off the ventilators.

Dr. Amit Khera:

Well, thank you. And congratulations to you both on a really fantastic work and impactful paper. And that's it for me, I'm Amit Khera, digital strategies editor for Circulation covering for Carolyn Lam and Greg Hundley, who you'll hear from next week. Thank you all for enjoying our podcast today.

Dr. Amit Khera:

This program is copyright of the American Heart Association 2021.

Circulation January 5, 2021 Issue

30 december 2020 | 30 min

New in 2021, we will feature 2 Feature Discussions every other week. For this week, we start with author Michael Gold and editorialist Sana Al-Khatib as they discuss the article "Primary Results from the Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low Ejection Fraction (UNTOUCHED) Trial." Then, we switch to an important discussion about children and COVID-19 as author Israel Valverde and Associate Editor Gerald Greil discuss "Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley:

And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we have two features in this issue.

Dr. Carolyn Lam:

I know.

Greg Hundley:

Yeah. And I've got the first one. It's going to be evaluating the acute cardiovascular manifestations in 286 children with multi-system inflammatory syndrome.

Dr. Carolyn Lam:

Wow. That is so important in the current pandemic. Well, the other is also so important. It's really, really critical results from the subcutaneous ICD trial called UNTOUCHED. I think that one might change clinical practice. So, do you want to tell us about other papers first?

Greg Hundley:

Yes. Carolyn, I'm going to grab my cup of coffee and we'll get started and my first paper comes from China. Professor Junbo Ge. So Carolyn PCSK9, mainly secreted by the liver and released into the blood elevates plasma load density lipoprotein cholesterol by degrading LDL receptors. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, as well as the underlying mechanisms still remain unclear.

Greg Hundley:

So this group detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin a2b beta-3 activation, alpha granule release, spreading and clot retraction. They also investigated the underlying mechanisms. Using myocardial infarct models, they explored the effects of PCSK9 on microvascular obstruction and infarct expansion, post myocardial infarction.

Dr. Carolyn Lam:

Oh, nice. And what did they find?

Greg Hundley:

Well, Carolyn, PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, as well as myocardial infarct expansion post MI by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors, or aspirin, abolished the enhancing effects of PCSK9 supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.

Dr. Carolyn Lam:

Wow. Very interesting. Indeed, the pleiotropic effects. Well guess what? My paper talks about the first non-LDL lowering treatment that has been shown to reduce CABG in a blinded randomized trial. Greg, can you guess what that treatment was? Well, here's a hint, here's a hint. It's the REDUCE-IT trial.

Greg Hundley:

Well, Carolyn, thanks for the hint. It must be icosapent ethyl.

Dr. Carolyn Lam:

Indeed, indeed. As a reminder, REDUCE-IT was a multicenter double-blind placebo controlled trial, which randomized statin treated patients with elevated triglycerides, controlled LDL and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl at four grams daily or placebo. The primary and secondary composite end points were significantly reduced. The current paper examined all coronary revascularizations, recurrent revascularizations and revascularization subtypes. First revascularizations were reduced by icosapent ethyl versus placebo with a hazard ratio of 0.66, which is a number needed to treat of only 24. Similar reductions were observed in total revascularizations and across elective, urgent and emergent revascularizations. Icosapent ethyl significantly reduced PCI and CABG with a hazard ratio of 0.61. So, icosapent ethyl reduce first and total coronary revascularization, including PCI and CABG in patients with elevated triglycerides and high cardiovascular risk despite well controlled LDL. Isn't that cool?

Greg Hundley:

Very nice Carolyn. Well, my next paper comes from Professor Kari Alitalo, from the University of Helsinki. So Carolyn recent discoveries have indicated that in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. The author set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B or VEGF-B in the heart and the effect of VEGF-B on recovery from myocardial infarction.

Dr. Carolyn Lam:

So what were their results?

Greg Hundley:

Well Carolyn, the myocardial VEGF-B trans-gene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in sub-endocardial myocardium in adult mice and structural and functional rescue of cardiac tissue after myocardial infarction. So VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue. Well, Carolyn that's all of the main articles. How about we turn to some of the other articles and letters in the issue?

Dr. Carolyn Lam:

Yeah. Why not? And Greg, let me start by talking about an exchange of letters between Dr. Wei and Dr. Fox on interpreting the net clinical benefit from rivaroxaban plus aspirin versus aspirin for chronic vascular disease. There's also an ECG challenge by Dr. Patel elusively entitled, A Rainy Day. Here's a hint, it's about hypothermia. In cardiology news by Bridget Kuhn. She talks about how the pandemic throws cardiovascular trials off course, there is an On My Mind paper by Dr. Most entitled, The Striking Similarities of Multi-system Inflammatory Syndrome in Children and a Myocarditis-like Syndrome in Adults: The overlapping manifestations of COVID-19. As a couple of Research Letters, one by Dr. Malhotra on Defining the Normal Spectrum of Electrocardiographic and Left Ventricular Adaptations in Mixed Race, Male, Adolescent Soccer Players, as well as by Dr. Qi on adherence to a healthy sleep pattern and incident heart failure, a prospective study of more than 400,000 UK Biobank participants.

Dr. Greg Hundley:

Very nice Carolyn. Well, I've got a primmer review of Cardiac Involvement in Multi-system Inflammatory Syndrome in Children with the corresponding author being Dr. Kevin Freedman. Well, how about we get off quickly to those next two feature discussions?

Dr. Carolyn Lam:

Yay! Let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we are to the first of our double feature for the new year 2021. And with me is Israel Valverde from King's College in London and our own associate editor, Dr. Gerald Greil from UT Southwestern in Dallas. Welcome gentlemen. And as we get started Israel, could you tell us a little bit about the background that framed this study and the hypothesis that you wanted to address?

Dr. Israel Valverde:

Thank you. I mean, the main problem we had in Europe around April 2020, was that both the Center for Disease Control and Prevention in the U.S. simulated a clinical ALIT about a newly described immune disease and inflammatory syndrome in children associated with a COVID infection. And there were similarities with all the well-known syndromes, such as viral myocarditis, Kawasaki disease, Kawasaki shock syndrome, and toxic shock syndrome, that we were a bit of confused, because of the overlap in clinical presentation, because it was a true diagnostics challenge. So the hypothesis in this study is we wanted to describe the cardiovascular implications in this newly described sinus syndrome.

Dr. Greg Hundley:

Very nice. So tell us a little bit about your study design and what study population did you assemble to address this question?

Dr. Israel Valverde:

I think that was the most difficult thing in the study, because thanks to the Association For European Pediatric Cardiology, the APC, we coordinated a multicenter study involving all they would appear on centers that we were 55 centers from 17 countries all over Europe. And we were able to recruit 286 children with this new newly described syndrome and cardiovascular manifestations.

Dr. Greg Hundley:

And tell us, what did you find?

Dr. Israel Valverde:

I think we can summarize that in three main findings. First is that cardiac involvement is very common in children with multi-system inflammatory syndrome associated with coronavirus disease, 2019 infection. Second, that inflammatory markers were significantly raised in most children, particularly their C-reactive protein, ferritin, pro-calcitonin, N-terminal pro BNP natriuretic peptide, interleukin 6, and D-dimer level. And finally, that 65% of patient with MIS-C had evidence of previous infection with severe acute respiratory syndrome coronavirus too, either by PCR, immunoglobulin M or immunoglobulin G.

Dr. Greg Hundley:

Were there any particular aspects of your results that may have segregated to the boys versus the girls?

Dr. Israel Valverde:

Not really. We couldn't find any differences between boys and girls, because our study population was quite similar, but we couldn't find any differences between them. What we found is that there is a huge difference between children and adults.

Dr. Greg Hundley:

And what was the age range of these children?

Dr. Israel Valverde:

From a couple of weeks, until 18 years old.

Dr. Greg Hundley:

And no differences in the scope of the syndrome that they experienced in the younger children versus the-

Dr. Israel Valverde:

Initially we found two peaks. Similarly to the peaks of viral myocarditises, which is affecting more of the children below two years, and also adolescence.

Dr. Greg Hundley:

Well Gerald, multi-system inflammatory syndrome in children. How to results from this study compare with perhaps other inflammatory disease processes that have been observed in children, such as Kawasaki disease, et cetera.

Dr. Gerald Greil:

So we and Circulation were very lucky to get a bunch of submissions regarding a MIS-C and also have a radio article regarding this and I would like to point our readers towards that. I think the key issue is it's a new disease entity. The community is pretty clear about it, that other diseases like Kawasaki disease have similarities, but it's not the same thing. And we wanted to be very clear about this. Obviously, more things need to be investigated, but the key findings where Dr. Valverde pointed out in other study groups within the U.S. and within Europe, all point to the same direction, that is a new entity, we need to further investigate.

Dr. Greg Hundley:

How about the cardiovascular aspects, what differences in cardiovascular disease with this syndrome, again, relative to other perhaps inflammatory diseases that might affect the heart in children?

Dr. Gerald Greil:

As far as we know. And once again, when we're talking about a very preliminary data, is that the outcome in children having MIS-C usually good. Dr. Valverde pointed out in his study series of more of 286 children, there was only one death and recovery was pretty high rate. We have similar findings from U.S. groups, other findings from a group in Paris and Europe. So, I would like to point our readers to other summaries where it's pretty clear that it's a new disease entity. Overall, it's actually rare in children. So we want to make a pretty clear point that it's a rare disease, which at this point in time seems to have a good outcome.

Dr. Greg Hundley:

Well Israel, I'm going to come back to you. What do you see is the next study that should be performed perhaps in this general area of cardiovascular disease for children?

Dr. Israel Valverde:

So I think what we have learned is that the way to move forward is the collaboration between centers. So now that we have a large study multicenter group, our idea is continue describing the long-term outcomes of the study population, because most of them recovered, but a few of them keep, for example, coronary artery dilatation. So do they recovering when you have time until you have time, do they do the ejection fraction, the function of the heart go back to normality soon? Or do we have to wait? So I think that's the next step forward to probably the long-term outcome of the study population.

Dr. Greg Hundley:

Longitudinal follow-up. And Gerald, do you have anything to add to that?

Dr. Gerald Greil:

I would just like to reiterate what Israel said, that we need to focus on multicenter studies. I hope Circulation can be a platform to reunite different groups around the world. Because as I mentioned before, I think we have a new disease entity in front of us. We don't know the long-term outcomes. And in the interest of our children confronted with new disease, we need to be very, very careful to learn how we need to follow up these children and how we potentially need to treat them in the long-term.

Dr. Greg Hundley:

Well, listeners, this has been a fantastic discussion with Dr. Israel Valverde from King's College in London and our own Dr. Gerald Greil from UT Southwestern, revealing some aspects of this multi-system inflammatory syndrome that's associated with COVID-19 in children. And so, on behalf of Carolyn and myself, well, we've got to get to the next feature. So, I'm not going to let you go just yet. Well, listeners, we are in the double feature year 2021. In our second feature discussion today, we have Dr. Michael Gold from Medical University of South Carolina and our own associate editor, Dr. Sana Al-Khatib, who has written an editorial on this paper. And she is from Duke University. Welcome to you both. Michael, we'll start with you. Could you describe for us a little bit about the background related to this paper and what hypothesis did you want to address?

Dr. Michael Gold:

Well, thank you. And thank you for this opportunity. The implantable defibrillator is a fundamental aspect of the treatment and prevention of sudden cardiac death. It's been around for almost 40 years now and is commonly used in the system has evolved from being a surgical procedure, requiring a thoracotomy to a transvenous procedure in which leads could be placed into the heart. While it's very effective, the major limitation of this in many people's minds were, major limitations were both of complications associated with the transvenous lead. Those include infections and lead failures, as well as unnecessary or inappropriate shock to patients. And based on that, the subcutaneous ICD was developed as the latest iteration of this technology in which a lead is placed under the skin and tunneled up along the sternum, so that one could sense and shock the heart when necessary without being subjected to an intravascular lead.

Dr. Michael Gold:

And the device has been around for 10 years or so. It's proven to be effective, but primarily used in niche populations of younger patients, patients with poor vascular access and those considered at relatively low risk with few comorbidities, such as patients with Brugada syndrome or long QT syndrome or possibly hypertrophic cardiomyopathy. We felt it was important both to establish the role of the subcutaneous ICD in a more typical group of defibrillator patients, as well as with the multiple evolutions now of programming, as well as technology within the device of seeing if the more modern contemporary devices were as effective in these sicker populations, and also could reduce some of the issues seen earlier in terms of higher rates of inappropriate shock therapy.

Dr. Greg Hundley:

So Michael we're working with subcutaneous ICDs. What was your study population and how did you design this study to really test the efficacy of the subcutaneous ICDs relative to the more conventional transvenous lead systems in these high-risk patients?

Dr. Michael Gold:

So what we did was to first identify a population and the most common population price of the implantation in the United States have for sure, in many of the countries is primary prevention patients and low ejection fraction. So we restricted the study to patients with an ejection fraction less than 35% and primary prevention, meaning have never had an episode of sustained ventricular tachycardia or cardiac arrest. So starting with that population, this was a prospective large registry. The bandwidth was out there to do a very large randomized trial, which was just done, although not as in a sicker patient population that study called PRAETORIAN was going on simultaneously. And what we decided was to be aggressive if you will. And we defined our endpoints for the study by looking at identified studies previously with transvenous ICDs that have the most contemporary programming and the lowest risk of inappropriate shock.

Dr. Michael Gold:

So we used the MADEIT-RIT study, which most people probably would consider it to be the ultimate, if not one of the two contemporary studies for that. And we wanted to essentially compare head-to-head results with that, obviously without those specific patients, but using that as in some ways a historical control or benchmark. So, we set what we wanted to use as our performance goal based on the MADEIT-RNT study for inappropriate shocks, as well as looked at complication rates, using performance goals that have been well-established by the FDA. And we use an 18-month time window, because that's a time when most inappropriate shocks as well as most complications will show up with this device.

Dr. Greg Hundley:

So what did you find?

Dr. Michael Gold:

So, what we found was first that we accomplished the goal of having patients who were had much more comorbidities or sicker, if you will. A majority of patients of the over 1,000 patients in the study had ischemic heart disease. I mean, ejection fraction, it was down 26%. In perspective, the early studies of the S-ICD, I mean, ejection fractions are 40% higher, almost 90% of patients have heart failure rather than a third of patients in previous studies and the incidents of diabetes, kidney disease, hypertension and other things with two to three times higher than what would have been done or shown in any early registries of the S-ICD. So we're very pleased about that. Again, there were over 1,100 patients in this study. And what we showed was that at 18 months, the inappropriate shock rate for the whole population was only 4%, hopefully 2.7% annually, which is quite low compared to any other S-ICD study and was very favorably compared with the MADEIT-RIT study easily met the performance goal for that.

Dr. Michael Gold:

And if we looked at that subgroup of patients who had generation three of the most modern of the S-ICD devices that have a newer discrimination algorithm, that number even became lower than that. So again, very, very reassuring to see what we found there and for the generation three device, it was only 2.9% of patients in 18 months had any inappropriate shock for that. And if we then looked at the other aspects of it, the all shock rate for appropriate and inappropriate shock was only 10% of 18 months, which meant the performance goal for that as well. And what's important about the all shock rate is that it's nice to show that the device can defibrillate a patient in the lab when you're testing them. And this was successful in 98, 99% of the time, which is typical for transvenous or subcutaneous devices. But when we looked at spontaneous arrhythmic events, it was highly effective, 100% of VT storms, and all but one case of a VTVF episode was converted with defibrillator, that one case actually spontaneously converted, but was officially listed as a failure, because it didn't convert right away.

Dr. Michael Gold:

But no patients had a cardiac due to ventricular fibrillation that could not be successfully treated or ended up requiring external defibrillation. And finally, despite a much sicker population, again, if you will, we showed that at 18 months, the overall complication rate from the device was only about 7% in total, which again is very low compared to what we'd expect to see with other devices. And no patient developed a bloodborne infection or a true lead failure, which is one of the major complications that, and dreaded complications of transvenous devices.

Dr. Greg Hundley:

Well, Sana as our editorialist, what stood out to you as being really important findings in this study?

Dr. Sana Al-Khatib:

First of all, I want to start by congratulating Michael and his team on the completion of this important study. And I agree that this has been a really important addition to the armamentarium of studies related to subQ-ICDs. We have had registries in the past. In fact, Michael alluded to the publication of the PRAETORIAN trial, which was really the first trial to compare the S-ICD with the transvenous ICD in a randomized control trial design. However, despite the important contributions of the PRAETORIAN trial, there were several things that remain unaddressed or unanswered in terms of the rate of the end points, especially in appropriate shocks with the newer S-ICD models. So where we had an abundance of those in the UNTOUCHED study, and then really the important question of do the results of that trial, which was largely not done in the United States, apply to the average patient, seen in the United States.

Dr. Sana Al-Khatib:

And then could those results be extrapolated to sicker patients, because as Michael very nicely highlighted that those patients were not as sick as patients that we see in routine clinical practice. So from my perspective, those are the findings of the UNTOUCHED study are really important, because we now have confirmation that the S-ICD is actually effective and safe in a patient population representative of the average patient seen in clinical practice in the U.S. with a primary prevention indication for the ICD, no really sicker patients, good representation of women, black patients. So overall, I think this trial really gives me a reassurance that the subcutaneous ICD is safe and effective, that the rate of inappropriate shocks with the newer generation of ICDs is really low. That said, I just wanted to highlight a couple of points that I'm hoping to see more data on as we go forward.

Dr. Sana Al-Khatib:

The study was only 18 months long. It would be good really to have a longer studies. Again, the average age of patients enrolled in the trial was on the younger side in the 50s, and I would love really to see more data on the S-ICD in older patients. And also as Michael said that these results were obtained in patients who had a primary prevention indication for the ICD on the basis of systolic heart failure. Well, we have other patient populations. And especially with, for example, patients with hypertrophic cardiomyopathy, where the rate of inappropriate shocks might be higher, and it would be great to see even more data as we go forward on that patient population and other subgroups of patients that were not included or not well-represented in the trial, but overall a really important trial.

Dr. Greg Hundley:

Very nice Sana. And Michael, just swinging back to you, what do you think are some of the next studies that might be performed in this space?

Dr. Michael Gold:

No, I think that Sana made some nice points. I should point out that, in its, I think appropriate vision, the FDA require as long-term evaluation of devices and studies. So the S-ICD post-approval study, which I'm fortunate enough to be involved with as well, is a five-year followup study. We've already published a little bit on two and three-year data, but we will have five-year data on this device in a patient that is closer to the S-ICD than the early registries. It was not restricted to just low EF patients, but it was a U.S.-only study of over 1,500 patients. So, a larger study that has the typical distribution of patients that we see in a U.S. practice who would be eligible for the S-ICD, those without pacing indications and both primary and secondary prevention patients. So I think that will be very important.

Dr. Michael Gold:

Where the technology is going is largely, there will still be iterations of longer battery life, smaller devices and those things, but there's been a real push to be able to also provide pacing therapy without the need for intravenous leads. So there are several models and systems approaches being used, including adding a lead-less pacemaker that will communicate with a subcutaneous ICD or placing a lead under the sternum, still extra vascular with the capabilities of pacing. So I think the next sort of group of trials will likely be seeing on this device other than simply looking at other populations in a little more depth will be further expansion of the technology to allow for a greater use of a device for those patients who may require a pacing.

Dr. Greg Hundley:

Well listeners, we want to thank Dr. Michael Gold from Medical University of South Carolina and Dr. Sana Al-Khatib from Duke University, our editorialists for describing this study. And in regards to those, or in regards to subcutaneous ICDs, providing confirmation that these devices are both effective and safe, particularly in a U.S. population for primary prevention of sudden death and really a high-risk patient population with low ejection fraction. On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run. This program is copyright of the American Heart Association, 2021.

Circulation December 22/29, 2020 Issue

21 december 2020 | 28 min

This week's episode features author Peter Schwartz and Associate Editor Sami Viskin as they discuss the article "Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to learn a little bit more about long QT syndrome and whether or not those that are athletes should continue exercise training. Maybe some can and before, we thought that they couldn't. But before we get to that, how about we take a look at some of the other papers in this issue.

Dr. Carolyn Lam:

Wow, that was a good hook, Greg. But yes, I want to tell you about this first paper, which is all about weight loss and changes in body composition. So, we know that intentional weight loss is associated with a lower risk of heart failure and atherosclerotic cardiovascular disease, especially among patients with type 2 diabetes. However, what is the contribution of baseline measures and longitudinal changes in fat mass versus lean mass and waist circumference to that risk of heart failure and myocardial infarction in patients with diabetes?

Dr. Carolyn Lam:

Well, investigators led by Dr. Pandey from UT Southwestern and colleagues evaluated more than 5,000 adults from the Look AHEAD Trial without prevalent heart failure. Fat mass and lean mass were predicted using validated equations and compared with DEXA measurements in a subgroup. Adjusted Cox models were then used to evaluate associations of baseline and longitudinal changes in fat mass, lean mass, and waist conference over one and four years follow up with the risk of overall heart failure, HFpEF, and HFrEF and myocardial infarction.

Dr. Greg Hundley:

Interesting, Carolyn. So, what did they find?

Dr. Carolyn Lam:

So, among patients with type 2 diabetes and who were overweight or obese, fat mass and lean mass could be estimated using anthropometric equations with good overall agreement compared with DEXA, so that's the first finding. Next, a decline in fat mass and waist conference, but not lean mass, were each significantly associated with a lower risk of heart failure, but not myocardial infarction.

Dr. Carolyn Lam:

Furthermore, a decline in waist circumference was significantly associated with a lower risk of HFpEF, but not HFrEF. Fatness and waist circumference may represent key modifiable targets for lifestyle interventions to reduce the risk of heart failure with preserved ejection fraction in type 2 diabetes. Cool, huh?

Dr. Greg Hundley:

Yeah. Very nice, Carolyn. Well, my first paper comes from Professor Davide Capodanno, and it's examining self-expanding bioprostheses for TAVR. So, Carolyn, there are few randomized trials comparing these bioprostheses for transcatheter aortic valve replacement or TAVR, and no trials have compared TAVR bioprostheses with the supra-annular design. So, this SCOPE 2 trial was designed to compare the clinical outcomes of the ACCURATE neo and the CoreValve Evolut valves.

Dr. Greg Hundley:

Now, it's a randomized trial performed at 23 centers in six countries between April 2017 and April 2019. And patients greater than 75 years with an indication for transfemoral TAVR as agreed by the heart team were randomly assigned to receive treatment with either the ACCURATE neo, so there are 398 of those patients, or the CoreValve Evolut bioprostheses, also 398 patients. The primary endpoint powered for non-inferiority of the ACCURATE neo valve was all-cause death or stroke at one year. The key secondary endpoint powered for superiority of the ACCURATE neo valve was new permanent pacemaker implantation at 30 days.

Dr. Carolyn Lam:

Okay. So, what were their results?

Dr. Greg Hundley:

Well, Carolyn, the transfemoral TAVR with the self-expanding ACCURATE neo did not meet non-inferiority compared to the self-expanding CoreValve Evolut in terms of all-cause death or stroke at one year. And was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACCURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and one year. Cardiac death at 30 days was 2.8% versus only 0.8% with the CoreValve Evolut. And moderate or severe aortic regurgitation at 30 days was 10% versus only 3% and they were significantly increased again in that ACCURATE neo group.

Dr. Carolyn Lam:

Wow. Okay. Thanks for that, Greg. Well, my next paper is from the basic science world. Dr. Colucci from Boston University Medical Center and colleagues tested the hypothesis that sarco/endoplasmic reticulum, calcium ATPase or SERCA, which is a major regulator of calcium homeostasis in the heart, whether or not it plays a critical role in mediating mitochondrial calcium and mitochondria-dependent apoptosis in response to reactive oxygen species.

Dr. Carolyn Lam:

So, in adult rat ventricular myocytes expressing an oxidation-resistant mutant of SERCA in which the cysteine-674 was replaced by serine. Mitochondrial calcium and the rise in mitochondrial calcium to exposure to an oxidant were decreased as was apoptotic myocyte death by mitochondrial pathways. Mice with the same SERCA mutation were protected from adverse cardiac remodeling, apoptosis, and progression to heart failure following chronic aortic constriction.

Dr. Greg Hundley:

Mm-hmm (affirmative) Carolyn, so this is another one where I get to ask you, what were the take home messages and what were the clinical implications?

Dr. Carolyn Lam:

I thought you'd ask that, Greg. So, these findings indicate that by contributing to sarcoplasmic reticulum calcium load, the chronic oxidative activation of SERCA may play a critical role in promoting the adverse effects of hemodynamic overload leading to pathologic remodeling. These findings illustrate the importance of post-translational modifications of SERCA and raise the possibility that the expression of a redox-insensitive form of SERCA may be of value in the treatment of heart failure.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper also comes from the world of basic science and looks into the mediators of atrial fibrillation. So, as some background, Carolyn, ibrutinib is a Bruton's tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. But it also increases the risk of atrial fibrillation, which remains poorly understood.

Dr. Greg Hundley:

So, the investigators performed electrophysiologic studies on mice treated with ibrutinib to assess the inducibility of atrial fibrillation. In human subjects, again, one of the strengths of some of these basic science papers in Circulation, the pharmacovigilance database or VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of atrial fibrillation.

Dr. Carolyn Lam:

Oh, that's really interesting, Greg. So, it seems like these authors were working toward understanding the mechanism of atrial fibrillation in those receiving ibrutinib. So, what did they find?

Dr. Greg Hundley:

Right, Carolyn. So, the authors found that using chemoproteomic profiling they were able to identify a short list of candidate kinases that was narrowed by additional experimentation, leaving C-terminal Src kinase or CSK, as the strongest candidate for ibrutinib-induced atrial fibrillation. Cardiac-specific CSK knockouts in mice led to increased AFib, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AFib associated with kinase inhibitors blocking CSK versus non-CSK inhibitors with reporting odds ratio of eight. So, Carolyn, perhaps CSK inhibition is the mechanism by which ibrutinib leads to atrial fibrillation.

Dr. Carolyn Lam:

Wow. That is convincing. Well, there are other really nice papers in today's issue. First, there's a research letter by Dr. Iglesias on the effects of fentanyl versus morphine on ticagrelor-induced platelet inhibition in patients with STEMI, the PERSEUS randomized trial. There's also a research letter by Dr. Young entitled the characteristics and outcome of COAPT eligible patients in the MITRA-FR trial. Another research letter by Dr. Zhang on specific modified mRNA translation system.

Dr. Greg Hundley:

Very nice, Carolyn. Well, I've got an exchange of letters by Dr. Spal, Whitlock, and Kebabs regarding the article, Impact of Left Atrial Appendage Exclusion on Short-Term Outcomes in Isolated Coronary Artery Bypass Graft Surgery. And then our own Mark Link discusses changes for practicing physicians regarding the new AFib guidelines.

Dr. Greg Hundley:

And finally, Dr. Vera Bittner has a perspective piece on the new 2019 ACC/AHA Guidelines on the primary prevention of cardiovascular disease. So, this new primary prevention guideline two fills a critical gap by pulling together and updating, as appropriate, guidance on nine topic areas of risk assessment, diet, exercise and physical activity, obesity, type 2 diabetes mellitus, blood cholesterol, hypertension, smoking cessation, and aspirin use.

Dr. Carolyn Lam:

Nice. Well, Greg, guess what? That brings us to the last issue in 2020. Can you believe it, Greg? It's been just so great working with you. It's been such a privilege working with Circulation. And, drum roll, new for 2021, Circulation on the Run is returning with a new format. Watch out for it. Let me give you a hint, it's going to come with a double feature per issue. Isn't that great, Greg?

Dr. Greg Hundley:

Absolutely. Some of the things that you hear folks really enjoy those opportunities we have with authors to review their papers. Well now, with many of the issues next year, we'll have two feature discussions.

Dr. Carolyn Lam:

Exactly. So, you've been listening to Circulation on the Run, but we've been listening to you, too. So, join us again in 2021 for our new features and new format. Thanks.

Dr. Greg Hundley:

And yes, Carolyn, but first, we've got to go and listen to this issue's feature discussion and talk about that long QT syndrome, exercise training-induced repolarization abnormalities. They can masquerade, perhaps, as long QT syndrome.

Dr. Carolyn Lam:

Cool.

Dr. Greg Hundley:

Welcome, listeners, to our feature discussion today. And we're very fortunate, we have Prof. Peter Schwartz from Istituto Auxologico Italiano in Milan and our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center. And we're going to be reviewing exercise training induced repolarization abnormalities, masquerading as congenital long QT syndrome. Well, first Peter, we'd like to start with you. And could you tell us, or provide us with some of the background information of why you wanted to perform this study and what hypothesis did you want to address?

Prof. Peter Schwartz:

The background is a very simple and I've been involved in the long QT syndrome since exactly 50 years. And as a partial result of that, I developed the idea that usually I... despite my making many errors in many areas, usually I don't miss the diagnosis of long QT syndrome. As a matter of fact, the study that you're publishing now is the result of a complete serendipity. It was not planned. We had to no hypothesis. It simply started because at one point I entered the impression that we might've made a diagnostic error and this bothered me very much.

Prof. Peter Schwartz:

It all started about eight, 10 years ago. When in some cases of our patients in whom we had made a clear diagnosis of long QT syndrome. At their yearly controls, we found that the LQT had been completely normalized. So I was pretty upset about it because I couldn't understand it. And my first reaction a natural reaction was to blame my associates, "We have made a mistake. You've did an error. There was an error in measurement." But as a matter of fact, there were no errors.

Prof. Peter Schwartz:

So I start thinking, "What the hell is going on here?" Now we are in a fortunate position because due to my long standing activity in the long QT syndrome, we are a referral center for all cases or most cases in Italy where people are suspected have the long QT syndrome. In Italy by law, anyone who wants to practice any type of sport at an amateur level or pro-competitive level, needs to have an eligibility certificate. So they have to go to sport doctors and it eases when the problems arise because not infrequently these doctors with somewhat limited experience in diagnosing prolongation and abnormalities in the QT intervals, are worried to make a mistake because a mistake can be a fatal one if the subject allow them to practice pause or die suddenly on to field. So they tend to refer them to us.

Prof. Peter Schwartz:

And so the advantage in my position was that we had a large number of these kids or young people coming to us. When I started to realize that it was not one accident, but another accident, another situation where these young people who clearly had to stop training in an intensive way, because they will no longer allowed by the sport doctors to practice sport. And the normalization of the T-wave abnormalities of the QT interval. I said, "Well, I mean, there must be something here."

Prof. Peter Schwartz:

So we start collecting the data, increasing the numbers, and I think it should be evident there was no design. I mean, it was a clinical observation that was evolving with time, but with adequate numbers. And then of course at one point we start following it more carefully, everything. And these led to the actual numbers that, in my opinion, were sufficiently strong to junior agents in need to publish it and to give a message because essentially this situation in one in which is very possible that even good and experienced doctors make a mistake. And the mistake could be a very bad thing, because if you miss the long QT syndrome and there is, of course, the patient is at risk of dying. But if you leave it, someone is affected and he is not affected, you are affecting his or her quality of life because they cannot practice sport, you generate anxiety. So a proper diagnosis is important. This was the basis of our study.

Dr. Greg Hundley:

Very good. So, it sounds like you're going to be performing a cohort study. Can you describe for us a little more specifically, how many subjects did you include? And who did you include in this cohort? And what measurements did you address?

Prof. Peter Schwartz:

So essentially we looked at the consecutive cases, sent to us by sport doctors with a suspicion of long QT syndrome. They were, if I remember, correctly 310 such individuals about 100 were found not to have the long QT syndrome. And these doctors were concerned they made the wrong measurement and measurement error. All the things that happened that are very well-known. About the remaining 200 in, I think about 120, we had a genetic confirmation of the long QT syndrome. We found disease causing mutation. So, that was pretty clear.

Prof. Peter Schwartz:

Then we had a group of individuals who are genotype-negative. We know very well. I mean, I proposed this thing in 1979, 1980, confirmed it in 1999, that there are some individuals affected by the long QT syndrome. But whoever I did a normal QT interval and that's a possibility, who are genotype-negative.

Prof. Peter Schwartz:

So, it's not surprising that in some cases we have genotype-negative individuals, but with a pattern so clear in terms of long QT syndrome that will make it to diagnosis. Within this group of genotype negative, there was another, let's call it a subgroup. I think it was about 15, 18% of the entire group who were genotype-negative, no family, sorry, neither had an event, a typical, absolutely typical electrocardiographic pattern with a fairly long QT interval QTc in the range of 490. So clearly prolonged significant repolarization abnormalities.

Prof. Peter Schwartz:

But when they were stopped in terms of exercise within three, four or five months, their pattern normalized completely, the QTc went back to normal, repolarization abnormalities disappeared. So this is the group on which we did focus and focusing for the next studies. And in some of them, when we told them, "You don't have the long QT syndrome, is a reaction that we interpret is due to the mechanical stretch of your heart because of very intense exercise training."

Prof. Peter Schwartz:

Some of them did return to practice sport in a very intensive way and all these patterns reappeared again, proving, I think this was the most important point. I mean, shows that you can go back and forth if you stretch the heart in this way, the abnormalities reappear.

Prof. Peter Schwartz:

So this is the essence of the study that carries in my opinion, a number of practical implications, because I think that now, when we are dealing with these youngsters, where we would be making a complete diagnosis. In some cases, I actually started even beta blockers, which is... I mean, afterwards it turns out to be an error and it bothers me, because I don't like to make an error with these patients. But they were so clear. I mean, I could have bet anything that they are affected by the long QT syndrome. But within four or five, six months, they were completely back to normal.

Prof. Peter Schwartz:

So the essence of the studies that we think the youngsters who practice intensely sport, some of them react to these physiological similar situation in an abnormal way. In analogies like with the food allergy. I mean, if you take something that bothers you and the point is, then you just avoid it. With exercise, of course is more difficult for other reasons, but probably it's the quantity of exercise.

Prof. Peter Schwartz:

Now, one change I've observed in recent years is that for youngsters practicing sports, a lot of things have changed. I've done a lot in sports myself soccer, tennis before moving toward golf. But in our days we were just playing, yes, we were playing a lot. But what has changed now is that all these kids have a trainer. They are sent for regular exercise two hours a day, five days a week. And that is probably too much for some of them.

Prof. Peter Schwartz:

So we need to recognize that there are certain individuals who, for whatever reason, I suppose that there is a genetic predisposition tend to react to these excessive amount of exercise training with abnormalities in their electrocardiogram. And for them, probably the logical thing is to reduce the amount of exercise. I would not stop it completely, they should reduce the dose and then have probably a normal life.

Prof. Peter Schwartz:

This is also raises the analogy with drug-induced long QT syndrome. When you have a parent in normal individuals who take any drug that contains an IKr blocker and they could develop to a certain point and the long QT syndrome. Now the situation with exercise is probably not so severe. I don't think the risk is so high, but clearly it is people have a tendency to react to possibly a variety of stimuli with QT prolongation. so they should be more careful about it.

Dr. Greg Hundley:

You know, I'll tell you, I think the world thanks you for your just observational skills and working through that whole situation that you observed in a very precise, organized fashion to bring us this interesting result. Well, Sami, can you help... Obviously this caught your eye as an associate editor at Circulation. What else attracted you to this study? And how would you like to comment on what Dr. Schwartz has just provided to us?

Dr. Sami Viskin:

Well, in Circulation, we were immediately attracted to this study, especially coming from Peter. Peter has been a pioneer in the entire area for long QT for many, many years. We call him Mr. QT because of his contributions to the field. So we're immediately interested in the paper, which is fascinating. It came a few months after we had reviewed a different paper that deals with patients who have the positive-phenotype, for long QT syndrome and have negative-genotype.

Dr. Sami Viskin:

That was a paper published in the July issue of Circulation with senior author Connie Bezzina. They performed a genome-wide association study to 1,800 patients with long QT, and they compared them with 10,000 healthy individuals. And what they found in these patients who represented 11% of the entire long QT syndrome population was that even though they do not have mutations, they tend to have several genetic variance together. None of them is severe enough to cause the disease but present by itself when they were in their group together in a single individual, then they create the phenotype of long QT syndrome, which is as severe as the phenotype of those who have bona fide mutations.

Dr. Sami Viskin:

So, that article was like the background for this one. And in fact, one of the arguments one could do is that the athlete's described by Peter could just have phenotype-positive, genotype-negative long QT, but what Peter would make sure to stress is that they do have electrocardiogram, but not only they do not have symptoms, they have a low pre-test probability of having the disease because they were discovered by screening and also they have a negative family history. So it's a different group of individuals what Peter is describing here. And time will tell. I mean, I'm sure we will be seeing more publications on this, and I will tell you, it's probably that we just looking at a new form of acquired long QT syndrome. Time will tell.

Dr. Greg Hundley:

Very nice. Just briefly, both gentlemen, maybe in 20 seconds or so, what do you think is the next study that needs to be performed in this new group that's been discovered?

Prof. Peter Schwartz:

Greg, we have already started the next study. We are going to compare 700 relatively younger athletes who have intensive exercise and who have a completely normal QTc and completely normal T wave to all our subjects that have defined these phases in our study that performing a similar level of exercise show these changes. And then we are collecting their DNA, and we're going to have an whole exome study for the possibility of identifying some genetic markets that might predispose to something like this.

Prof. Peter Schwartz:

One possibility that I'm interested in is the possibility that the underlying mechanism, maybe something related to the so-called sex activated trainers, which might lead to an increase in intracellular calcium and produces alterations. There are other possibilities, but this is one. And in doing this study, we are also going to begin to look at echocardiography and imaging to see if there are different patterns in terms of mechanics that might contribute to explain.

Prof. Peter Schwartz:

So the point is that on the one hand we wanted and we did confirm the clinical data. So, we know that we are dealing with a factor and we think that's a fact as practical implications for management. Now, the next questions, which I wish to attack as well is why is it, what is the underlying mechanisms?

Dr. Greg Hundley:

Very good, Sami.

Dr. Sami Viskin:

That exactly the direction we were expecting to see if they have a similar polygenic risk score factor as in the study by Bezzina.

Dr. Greg Hundley:

Very nice, well listeners, this has been a wonderful discussion. And we also want to thank Dr. Peter Schwartz for all of his efforts for many years in this area of long QT syndrome and bringing this new finding to light that there is now an observation that not necessarily are all long QTs. Number one of the 300 subjects, 100 actually didn't have it. And then there are some that are phenotype-positive, but not genotype-positive. And we have more to learn about the variance that swings with the presence of the long QT after strenuous exercise. Well, on behalf of Carolyn and myself, we want to thank Peter, thank Sami Viskin and wish all of you a great week. And we will catch you next week on the Run.

This program is copyright the American Heart Association, 2020.

Circulation December 15, 2020 Issue

14 december 2020 | 24 min

This week's episode features author Adnan Kastrati and Associate Editor Dharam Kumbhani as they discuss ticagrelor or prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature Ticagrelor Prasmul in patients with ST segment elevation myocardial infarction undergoing primary PCI. More on that story later, though. How about we grab a cup of coffee and look at some of the other papers in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would. And actually, I'm going to talk about two papers and they're all about BET, BET or promo domain, an extra terminal epigenetic reta proteins. And in particular, this one called BRD4. Now these proteins have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecular BET protein inhibitors, such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet genetic studies elucidating the biology of BET proteins in the heart have not been conducted. Well, at least until this week's issue where we have not one, but two papers, both elegantly using mouse genetic studies.

Dr. Carolyn Lam:

In the first from Dr. Srivastava from Gladstone Institute of Cardiovascular Disease in San Francisco and Dr. Jain from Perlman School of Medicine in Philadelphia and their colleagues, they found that BRD4, that particular BET epigenetic reader protein, forms a transcriptional regulatory module with GATA4, a lineage determining transcription factor in cardiomyocytes. This BRD4 GATA4 module was a critical orchestrator of mitochondrial bioenergetics in the adult heart.

Dr. Greg Hundley:

Well Carolyn, that is a wonderful summary. What are the clinical implications?

Dr. Carolyn Lam:

Identification of this new BRD4 interaction partner, such as GATA4 could provide new insights into developing epigenetic based therapies for heart failure. And the second paper is from Dr. Joseph Hill and Thomas Gillette from University of Texas Southwestern Medical Center and their colleagues. And what they found was that BRD4 was essential to the maintenance of mitochondrial electron transport chain function via transcriptional regulation of a nuclear mitochondrial gene network. BRD4 heterozygous deletion resulted in delayed heart failure, whereas pharmacological BRD4 inhibition using JQ1 induced modest changes in mitochondrial genes suggesting potential cardiac toxicity in targeting BRD4 at baseline.

Dr. Greg Hundley:

So what does this mean for us clinically, Carolyn?

Dr. Carolyn Lam:

As more potent and specific inhibitors are developed targeting BRD4 for clinical settings in oncology and other diseases, we must carefully monitor bezel cardiac performance for functional and mitochondrial deterioration. Important clinical message there.

Dr. Greg Hundley:

Great job, Carolyn. Well, my first paper is entitled "An Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaques" And it comes to us from Dr. Tomas Neilan and his colleagues at the Mass General Hospital. The study was situated in a single academic medical center. And Carolyn in this paper, there are actually three studies described. First, there's a primary analysis that evaluated whether exposure to an immune checkpoint inhibitor during treatment for cancer was associated with atherosclerotic cardiovascular events among 2,842 patients versus 2,842 controls that were matched by age, a history of cardiovascular events and cancer type.

Dr. Greg Hundley:

In the second study, a case crossover analysis was performed with an at risk period defined as the two year period after, and the control period as the two year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events including myocardial infarction, coronary revascularization, and ischemic stroke. And secondary outcomes included the individual components of that primary outcome.

Dr. Greg Hundley:

Finally, in the third study in this paper, there's an imaging stub study of 40 individuals, and it looked at the rate of atherosclerotic plaque progression compared from before and after starting the immune checkpoint inhibitor. All study measures and outcomes were blindly adjudicated in this third study.

Dr. Carolyn Lam:

Wow, a three in one. That really sounds novel. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. In the matched cohort study, there was a three-fold higher risk for cardiovascular events after starting an immune checkpoint inhibitor. There was a similar increase in each of the individual components of the primary outcome. In the case crossover study, there was also an increase in cardiovascular events from 1.37 to 6.55 per hundred person years at the two year time point.

Dr. Greg Hundley:

And then lastly, Carolyn, in the imaging study, the rate of progression of total aortic plaque volume was three fold higher after immune checkpoint inhibitors from 2.1% per year to 6.7% per year after receiving these agents. The association between immune checkpoint inhibitor use and increased atherosclerotic plaque progression was attenuated with the concomitant use of statins or corticosteroids.

Dr. Carolyn Lam:

Wow, Greg. So I suppose what all this shows is that we need to be aware of the cardiovascular risk prior to, during and after treatment with immune checkpoint inhibitors and perhaps, you know, optimize these cardiovascular risk factors. Thank you, Greg.

Dr. Greg Hundley:

You bet. Well, Carolyn, my next paper is from Dr. George Vlachojannis from University Medical Center at Utrecht. These authors conducted a randomized control multi-center trial in the Netherlands enrolling STEMI patients planned to undergo primary PCI. Now patients were randomly allocated to receive in the ambulance before transfer a 60 milligram loading dose of Prasugrel, either being crushed or as integral tablets. The independent primary end points were thrombolysis in myocardial infarction, TIMI three flow in the infarct related artery at initial coronary angiography, and complete greater than they go to 70% ST segment resolution one hour post primary PCI. The safety end points were TIMI major and bleeding academic research consortium, or BARC, greater than three bleedings and secondary end points included platelet reactivity and ischemic outcomes.

Dr. Carolyn Lam:

Nice trial design. So what did they find?

Dr. Greg Hundley:

Well, Carolyn, a total of 727 patients were assigned to either crushed or integral tablets of Prasugrel. The median time from study treatment to wire crossing during primary PCI was 57 minutes, and the primary end point of TIMI three flow in the infarct related pre primary PCI artery occurred in 31% in the crushed group versus 32.7% in the integral group. No difference, P .064. Complete ST segment resolution one hour post primary PCI was present in 59.9% in the crush group and 57.3% in the integral group. Again, no difference, P equals .055. Platelet reactivity at the beginning of primary PCI measured as the P2Y12 reactivity unit, differed significantly between the groups. Crushed was 192 versus integral was 227 and the P value was less than 0.01. TIMI major and BARC greater than three bleeding occurred in 0% in the crushed group and 0.8% in the integral group and in 0.3% in the crushed group versus 1.1% in the integral group respectively. So there were no differences observed between groups regarding ischemic events at 30 days.

Dr. Greg Hundley:

So Carolyn, in conclusion, prehospital administration of crushed Prasugrel tablets does not improve TIMI three flow in the infarct related artery, pre primary PCI or complete SD segment resolution one hour post primary PCI in patients presenting with STEMI planned for primary PCI.

Dr. Carolyn Lam:

Interesting and interesting stuff with platelet reactivity and bleeding. Thank you, Greg. Well, there are other papers in today's issue. There's an in-depth paper by Dr. Katsanos on stroke prevention in atrial fibrillation, looking forward. There's a research letter by Dr. Berger on myocardial injury in adults hospitalized with COVID-19 and another by Dr. Hacker on again, immune checkpoint inhibitor therapy and how that induces inflammatory activity in large arteries.

Dr. Greg Hundley:

Well, Carolyn, I've got a couple other papers to talk about in this issue. There's a On My Mind piece from Dr. deFilippi entitled "Navigating Testing for COVID-19." There's a Perspective from Dr. Ridker entitled "Equipoise Trust and the Need for Cardiologists to Randomize Patients into Anticoagulation Trials in the Time of COVID." There's an ECG challenge from Dr. Arias entitled, "A Paced Tachycardia." And then finally, there's an exchange of letters from Drs. Liu regarding a prior publication entitled "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets." Well, Carolyn, how about we get to the world of anti-platelet therapy, ticagrelor prasugrel in patients with ST segment elevation myocardial infarction, shall we?

Dr. Carolyn Lam:

Yes, let's go Greg.

Dr. Greg Hundley:

Well welcome, listeners, to our featured discussion today on this December 15, and we are going to learn and discuss a little more, a paper pertaining to ticagrelor versus prasugrel in patients with ST segment elevation myocardial infarction. And our lead author today is Adnan Kastrati from Deutsches Heart center in Munich. And we also have our own Associate Editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas. Welcome, gentlemen. Adnan, maybe I'll start with you. Could you tell us a little bit about the background related to this article and what was the hypothesis that you wanted to address?

Dr. Adnan Kastrati:

First of all, thank you very much for having me here to share with you some thoughts. Thank you, Dharam, for handling our paper in Circulation. We are very honored to have it published there. About these are the ISAR REACT-5 series of studies dedicated to optimizing the antiplatelet therapy in patients and anticoagulant therapy in patients with acute and chronic coronary syndromes, mostly who are undergoing a PCI procedure. We started to think about that study immediately after the publication of the platelet trial. We showed the superiority of prasugrel in patients with acute coronary syndromes. These were the two new ADP receptor antagonists at the time. And so as a physician, we are interested to know which of them was better because there was no direct comparison. And so that's why we decided to have an open-label trial randomized. Most of the centers were situated in Germany. Two centers were situated in Italy. The private end point was adopted to the private end point of the trials in this skill. Only one difference was there, instead of cardiovascular death, we put all cause death in the primary end point. Why? Because all cause death may also reflect the gradient end bleeding between the two drugs. We wanted to have a more integrative endpoint in this sense. So it was a combination of all cause death, myocardial infarction, and stroke.

Dr. Adnan Kastrati:

It was a one year followup study. The study had two groups of steady patients, which was about 40% of the patients, included in the multicentral trial. And what we found in this trial, it was the same results as it was found in the whole trial. The advantages seen for prasugrel was present here also. Although we lost the significance in the evaluation of the primary endpoint. It was a 31% increase or 24% decrease with prasugrel in that sense. But otherwise everything was in the same direction as in the whole trial. And if you look also in the components of the primary end point…, you have the chance to see that numerically, it was the same trend for all components. Although the trial was not powered for going to evaluate the component of the prime end point. This was the main result.

Dr. Greg Hundley:

It sounds like you had 1,653 patients with STEMI randomized to receive ticagrelor or prasugrel and 10% experienced the primary end point in the ticagrelor group, but only 7.9% in the prasugrel group. But the P value was only .10. We saw trends toward favoring prasugrel rather than sort of a definitive difference. Is that a correct summary?

Dr. Adnan Kastrati:

Yes, it is a correct summary. I would say this group of patients is the most interesting subgroup of patients in ISAR 5 trial. Why? Because the pretreatment strategy is the same. Because there have been a lot of discussions about non-S-segment segment elevation acute myocardial infarction due to the difference in pretreatment. Although it was intentional, some people felt it's different and they said you have two different strategies there. In the STEMI subgroup, the pretreatment strategy was the same, so it was a head to head comparison of two drugs, even according to the same strategy. This is one.

Dr. Adnan Kastrati:

Second, you have to look back at the trials in the same field…Both these trials, if you look closely to the results of for STEMI patients, both of these trials haven't shown a significant result for the STEMI subgroup. For plateau it was a P value of 007 and for tritan it was a P value of 0014 only. Why? Because in the tritan it was very specific. They included also patients after fever analyzes and the significance came only from the comparison of tritan in this group, not in the primary PCI group. In the plateau and ISAR-5 we excluded these patients.

Dr. Greg Hundley:

Dharam, we're going to turn to you now. Adnan's really framed this study nicely, but can you help us from your perspective, put this study in perspective with others that have been published in this space?

Dr. Dharam Kumbhani:

Yeah, thanks, Greg. And I want to congratulate Adnan and his group for providing the field with another really well conducted study in a very important field. The center has done some very, very landmark trials, and I think this is another one of those. It sort of helps us understand potentially the best treatment mechanism or protocol for patients undergoing primary PCI for STEMI in this case. As you nicely outlined sort of the background for this, the only other trial that I'm aware of in this space is directly comparing pasugrel and ticagrelor head to head was the Prague 18 trial, which was smaller. I think it was about under 1100 patients. So even the STEMI cohort here was larger than that trial. But that trial ended up being terribly underpowered and unfortunately, also discontinued prematurely. So there wasn't really any significant difference that was noted in that trial and there was also a high crossover to clopidogrel in that other trials.

Dr. Dharam Kumbhani:

So I think that trial, in fact, we had published a trial in circulation as well. And I think this study sort of helps to advance the field a little bit by providing a head to head comparison between the two drugs. If I may extend some of the discussion points that were brought up earlier, I think, again, there is a couple of things that jumped out to me. One is, as you mentioned, the semi cohort is very interesting and very important. The p-value for interaction between the STEMI and the non-STEMI population was not significant for the primary end point. So that is certainly important when considering these results.

Dr. Dharam Kumbhani:

And the second thing is the differences that were noted in the rates of reinfarction, both spontaneous as well as PCI related. And although that is very interesting, we certainly have to keep that first point in mind when considering that. I think it becomes more hypothesis generating that MI rates ended up being higher with ticagrelor compared with prasugrel, and then sort of trying to tease that out in terms of, was that just a play of chance? Do we end up seeing that, is there a real biological reason for that? All of the trials was extremely well done. There were about 29 patients that did not have one-year follow-up and there were about 67 or so MI events. I think it's very interesting, and I think for at least for me, when I review this trial, I think it brings up some very interesting hypotheses that I think we would need to test further. Those anyway, my sort of high-level thoughts on this excellent trial.

Dr. Greg Hundley:

Very good. Well, I'd like to ask you just in 20 seconds, each of you, what's the next study that needs to be performed in this field? Adnan, start with you.

Dr. Adnan Kastrati:

I don't expect trials doing the same thing that we have done in ISAR-X5. We are planning now that ISAR-X6 trial. They are finalizing the protocol, and it will be a large trial of 9,000 patients with acute coronary syndromes in which will test the need for aspirin after discharge. That means all the spaces will be with the potent P2I12 inhibitors. And one group, it will be a placebo controlled trial. One group will have aspirin after discharge, the other placebo. And this is now, for us, the most important thing in this area.

Dr. Adnan Kastrati:

If I have the chance to respond to Dharam about the mechanistic insights of this effect, I would say that we have shown aggressive cardiology, our data about platelet function. It is the biggest platelet function studies in this area, 600 patients. We have tested in patients after PCI. We tested ADP in used aggregation after ticagrelor and prasugrel. And prasugrel was associated with a 30% reduction in platelet aggregation in these patients. And I think that this offers the mechanistic basis also for our results. And the results will be published shortly.

Dr. Greg Hundley:

Very nice, and Dharam.

Dr. Dharam:

Thank you for that response, Adnan. And Greg, to your question, I agree. I think it would be hard, although the field would really benefit from having a head to head comparison between these two drugs again in a larger study. I do think a lot of the interest and excitement in the ACS field is on de-escalation strategies as the outline. And so I suppose that that's sort of where we'll see a lot more in terms of clinical trials.

Dr. Greg Hundley:

Very good. Well listeners, this has been a wonderful discussion and we appreciate the input from the primary author, Dr. Adnan Kastrati, from the Deutsches Heart Center in Munich and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern. Really reviewing prasugrel versus ticagrelor for primary PCI in patients with STEMI only, and showing really no difference in their primary endpoint of death, myocardial infarction, and stroke, with however an increased risk of reinfection in the patients receiving ticagrelor only.

Dr. Greg Hundley:

So on behalf of Carolyn and myself, we wish you a great week and look forward to catching you next week On the Run. This program is copyright the American Heart Association, 2020.

Circulation December 8, 2020 Issue

7 december 2020 | 25 min

Dr. Carolyn Lam :

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley :

And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam :

Greg, today's feature paper is a research letter, but, oh my gosh, it is so interesting. It's about surgical explantation of transcatheter aortic bioprosthesis. TAVRs we know is on the rise and so is the rise of surgical explantation cases and we really need to understand it better. Hang on, we're coming to that, but maybe, let's start with some other papers in the issue first, shall we? Let me go first, you go grab your coffee and listen because we're going to talk about the efficacy of ertugliflozin on heart failure related events in patients with type II diabetes and established atherosclerotic cardiovascular disease in the results of the VERTIS CV trial.

Dr. Greg Hundley :

Carolyn, tell us a little bit about the VERTIS CV trial.

Dr. Carolyn Lam :

Sure. The primary results of the VERTIS CV trial have already been published. This cardiovascular safety trial was actually performed to satisfy the 2008 guidance from regulatory agencies for new antihyperglycemic agents. It found that patients with type II diabetes and atherosclerotic cardiovascular disease randomized to ertugliflozin achieved the primary objective of non-inferiority to placebo in time to first major adverse cardiovascular event or MACE, a composite endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke. The first secondary outcome in the hierarchal testing sequence was superiority for the time to composite of cardiovascular death or heart failure hospitalization, which was not met and therefore formal hypothesis testing ended with this endpoint. Now in today's paper, the authors led by Dr. Cosentino from Karolinska Institute and Karolinska University Hospital in Stockholm, Sweden, present the results from pre-specified analyses of the effect of ertugliflozin versus placebo on a series of heart failure related outcomes from this VERTIS CV trial.

Dr. Greg Hundley :

Ah, Carolyn. Tell us what were the results of this new study.

Dr. Carolyn Lam :

Of more than 8,200 randomized patients, almost 24% had a history of heart failure and almost 61% had a pre-trial ejection fraction available, including 959 patients with an injection fraction less than or equal to 45%. While ertugliflozin did not significantly reduce first heart failure hospitalization or cardiovascular death, it did reduce first and total hospitalization for heart failure events with a relative risk for first heart failure events being similarly beneficial number one, in those with versus without a history of heart failure and number two, in those with a history of heart failure with reduced ejection fraction or preserved ejection fraction. However, the risk reduction tended to be greater for those with an ejection fraction less than or equal to 45%. Although, the test for interaction by injection fraction was not significant. The effect of ertugliflozin on risk for first heart failure hospitalization was consistent across most baseline subgroups with a greater effect in three populations, including those with impaired kidney function and those taking diuretics. Now, this is discussed an editorial by Doctors Faiez Zannad and Martin Cowie. You must pick it up and read it.

Dr. Greg Hundley :

That's great, Carolyn. What a fantastic another piece of information on the SGLT2 inhibitors.

Dr. Greg Hundley :

Well, my first paper comes to us from Dr. Peter Liu from the University of Ottawa Heart Institute and his colleagues. Carolyn, this article focuses on cardiac hypertrophy, which as you know, is a key biological response to injurious stresses such as pressure overload. Also as you know, when cardiac hypertrophy is excessive, it can lead to heart failure. Innate immune activation by danger signals through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain-containing protein 1, or NOD1 and its adaptor receptor interacting protein, RIP2, may play a major role in cardiac remodeling and progression to heart failure. These authors hypothesized that NOD1 and RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone.

Dr. Carolyn Lam :

I like that, NOD1 and RIP2. What did they find?

Dr. Greg Hundley :

These authors found that innate immune NOD1/RIP2 signaling was a major contributor to cardiac remodeling following stress. This process was critically joined by and regulated through the mitochondrial danger signal protein adapter MAVS. The authors found that this novel complex coordinates remodeling, inflammatory response and mitochondrial energy metabolism in stressed cardiomyocytes, thus NOD1/RIP2 MAVS signaling complex may represent an attractive new therapeutic approach toward modulating LV hypertrophy mediated heart failure.

Dr. Carolyn Lam :

Very nice, Greg. Now in the next paper, do you remember the VOYAGER PAD trial? Well, it was the trial that demonstrated superiority of rivaroxaban plus aspirin versus aspirin alone to reduce major cardiac and ischemic limb events following lower extremity revascularization. Now clopidogrel is commonly used as a short term adjunct to aspirin after endovascular revascularization. However, does clopidogrel modify the efficacy and safety of rivaroxaban in this setting? Well, that's the question that today's paper is addressing and it is led by corresponding author, Dr. Hiatt from University of Colorado School of Medicine.

Dr. Greg Hundley :

What did they find, Carolyn?

Dr. Carolyn Lam :

Well in the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia, regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use as well, but with a trend for more ISTH major bleeding with clopidogrel use more than 30 days than a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization, regardless of concomitant clopidogrel with a short course of less than 30 days associated with less bleeding.

Dr. Greg Hundley :

Very nice, Carolyn. Well, my next paper comes to us from Dr. Hinson from the Jackson Laboratory for Genomic Medicine. Carolyn this paper focuses on a particularly challenging heart failure associated sarcomere gene, cardiac troponin T, that is encoded by TNNT2. Remember Carolyn, this is a thin filament protein that functions in the tripartite troponin complex, where calcium binds and triggers twitch force. Relative to other sarcomere genes, pathogenic TNNT2 variants are associated with poor prognosis as they carry an increased risk of sudden cardiac death that is disproportional to myocardial remodeling. The investigators used human pluripotent stem cell derived cardiomyocytes in cardiac microtissue and single cell assays and functionally interrogated 51 TNNT2 variants, including 30 pathogenic likely pathogenic variants and 21 variants of unknown significance called VUSs. They utilized RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants.

Dr. Carolyn Lam :

Wow. And so what were those consequences, Greg?

Dr. Greg Hundley :

They found that hypertrophic cardiomyopathy associated TNNT2 variants increased cardiac microtissue contraction while dilated cardiomyopathy associated variants caused decreased contraction. Both of which parallel changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and could be utilized to predict TNNT2 variant pathogenicity. In summary Carolyn, this research found that number one, inheritance of pathogenic TNNT2 variance is a leading cause of cardiomyopathy and number two, the majority of TNNT2 variants identified in the human population are classified as those VUSs or variants of unknown significance, which limits their clinical utility in genetic testing. As such, reclassification of TNNT2 variants would improve cardiomyopathy risk determination and treatment responses for individuals harboring these variants.

Dr. Carolyn Lam :

Nice. Thank you, Greg. Well, in this next paper, I think the title summarizes it all: “Is There a Sex Gap in Surviving an Acute Coronary Syndrome or Subsequent Development of Heart Failure?” Well, Dr. Justin Ezekowitz from Vigor Center, University of Alberta in Canada and his colleagues used a large population based cohort of more than 45,000 patients with MI between April 2002 and March 2016, to examine the incidence and geographic findings, treatment and clinical outcomes of patients with a first time and MI. To elucidate the difference between sexes, a series of multi-variable models were created to explore all MI and non-ST elevation MI versus ST elevation MI over time.

Dr. Greg Hundley :

What did they find Carolyn?

Dr. Carolyn Lam :

Well, some attenuation of differences in clinical outcomes over time had occurred. Women maintained a higher risk than men of dying or developing heart failure in the subsequent five years post both STEMI or non-STEMI, even after accounting for differences in angiographic findings, revascularization and other confounders.

Dr. Greg Hundley :

Well, Carolyn, how about we get to some of the other articles in the issue. And I've got a really nice Research Letter from Professor Damien Bonnet entitled, “Addition of Corticosteroids to Immune Globulins is Associated with Recovery of Cardiac Function in Multi-inflammatory Syndrome in Children.” There's also a Research Letter from Professor Peter van der Meer entitled, “Human Pluripotent Stem Cell Derived Cardiomyocytes of Peripartum Cardiomyopathy Patients Reveal at Aberrant Regulation in Lipid Metabolism.” And Carolyn, finally I have an ECG Challenge entitled, “Wide QRS Complex Tachycardia in a Young Pregnant Woman, is it SVT or VT?” The age old question from Dr. Gunaseelan.

Dr. Carolyn Lam :

Nice. Well, there's also an exchange of letters between Drs. Ross and Loupy regarding the article, “Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy after Heart Transplantation: a Population Based Study,” and a beautiful Perspective piece by Dr. Verma entitled, “Two Tales, One Story and that is talking about the EMPEROR-reduced and DAPA-HF trials.” A beautiful summary there. Let's get on now though to that feature discussion. Shall we, Greg?

Dr. Greg Hundley :

You bet looking forward to it.

Dr. Carolyn Lam :

Transcatheter aortic valve replacement or TAVR has indeed become an established alternative to surgical aortic valve replacement for patients with severe aortic stenosis. Now, while the TAVR usage has increased, so has surgical TAVR valve explantation. However, that's not been really well described its clinical impact or outcomes well until today's research letter in Circulation, which represents the largest series of TAVR explants from a national database. And I'm so pleased to have with us the first and corresponding author, Dr. Shinichi Fukuhara from University of Michigan to describe the study as well as our associate editor, Dr. Tim Gardner from University of Pennsylvania. Welcome, gentlemen. Shinichi, if you don't mind for non-interventionists and non-surgeons like myself, why would you need to explant TAVR in the first place? Maybe you could start with that and then tell us about your study.

Dr. Shinichi Fukuhara:

First of all, thank you so much for the kind invitation. It's a great honor to be with you and Dr. Gardener. That's a very good question and a very timely question actually. When we started implanting TAVR valves probably about nine years ago or so, that was when the TAVR valve was FDA approved, we were not thinking about second TAVR procedure after the initial TAVR valve fails. And then as time goes on, we started to recognizing, some patients' TAVR valves started failing and these failure patterns can be paravalvular leak, can be structural valve degeneration, can be endocarditis. Not all patients with a failing TAVR valve can be treated with a second TAVR valve procedure and the most common driving factor at least in my program at the University of Michigan is unsuitable anatomy for a second TAVR valve and the most common anatomy pattern is a risk of a coronary artery obstruction by the second TAVR valve. These are the common scenarios where patients need TAVR valve explantation scenarios.

Dr. Carolyn Lam :

Thank you so much for that as a background. And as you nicely set up in your paper, as we do more TAVR, obviously there are going to be more situations like this. Please tell us what you found.

Dr. Shinichi Fukuhara:

First of all, what we found from this project, first, surgical TAVR valve explant procedure is not as simple as people thought it would be. I remember back in 2014, 2015 when I was still a trainee, people were talking about, which is better TAVR SAVR TAVR or SAVR TAVR SAVR? However, based on what we are just starting to see, TAVR SAVR sequence may not be a good option for younger people based on the present study data. The fact that more than 50% of patients who require the major simultaneous procedures such as aortic repair and the mitral procedures is a something TAVR implanters in our community should be more aware.

Tim Gardner:

I think it's very important for Shinichi to tell us to emphasize the mortality rate that you saw with the SAVRs following TAVR because that's really, I think the sobering information here. This is not comparable to doing a redo aortic valve or redo SAVR. Just tell us about that, Shinichi.

Dr. Shinichi Fukuhara:

First of all, these STS database. We have a STS predicted risk of a mortality, which is available for patients undergoing isolated SAVR procedure. And then based on the even isolated the SAVR procedure, the OE ratio of observed to expected mortality ratio was actually higher than 1.5 for isolated SAVR procedure in patients requiring TAVR explant. More importantly, patients who are requiring TAVR explanted SAVR, as well as a concomitant cardiac procedure are demonstrating almost close to 20% mortality rate, which is to me very striking after we analyze that data set. And this is something our community, the TAVR implanters in our community should keep in mind.

Dr. Timothy Gardner:

Yeah. Obviously not only is the surgery, the removal of the TAVR device and replacement with a surgical valve, not only is that complex anatomically and technically, but the associated mortality seen in this series of patients that they reported is higher than expected and actually quite high in terms of absolute operative or hospital mortality. I take this important research letter as a sort of a warning message to all of us, in particular, the cardiology community, to realize that once a TAVR valve is placed, it is more difficult and riskier to remove that and replace it with a surgical aortic valve replacement, if for some reasons such as endocarditis or valve failure or whatever comes to play.

Dr. Timothy Gardner:

And obviously as Shinichi has already said, when you're looking at a younger patient, patient under 60 for example, who needs an aortic valve procedure, you need to keep in mind whether as he said earlier, it's might be safer to do a SAVR first. And then if there's another procedure required, that could be because of valve failure, a TAVR could be done rather than just assuming that the TAVR is going to be there and that it can be easily replaced or taken care of. At any rate, I think that's the very important point of this paper. And I think this is really the first report and not only by the way, does it show that this is happening, but in the most recent year of your report, Shinichi, how many SAVRs after TAVR were reported, number of cases?

Dr. Shinichi Fukuhara:

The 2018, the last year of this study period was actually the highest obviously and it was a close to 300 cases reported. And then the number of case is a steeply increasing as I demonstrated in the figure one in the paper.

Dr. Timothy Gardner:

That really emphasizes obviously TAVR volume is increasing. TAVR is now being placed in younger patients who have perhaps a greater chance of requiring a second procedure. And if it has to be explantation of the TAVR because of the complexity and the inability to use another TAVR to fix the valve, the technical challenges and the operative risks are much higher.

Dr. Timothy Gardner:

Well, I just think that this is a warning call that we have to be realistic about the secondary requirements for patients that have TAVR and we don't yet even have a much more than a 10 year experience with TAVRs and we're seeing an increasing number of patients just in the STS database who are having to come back for TAVR explant and it's a difficult, challenging procedure. One point that Shinichi made in his article is that this technical challenge of TAVR explant may be something patients requiring this procedure may need to be referred to surgeons and hospitals with high aortic surgery volume. This is not necessarily a procedure that a surgeon can get experienced with and comfortable with doing two or three a year. That's another bit of the message here.

Dr. Carolyn Lam :

Thanks, Tim. And Shinichi, what would be your take home message to the clinical community listening in?

Dr. Shinichi Fukuhara:

Thank you so much. Yeah, this is a little bit redundant statement, but I think that another important message from this paper is that these low risk younger patients choosing to have a TAVR procedure as the initial valve therapy should be informed of the future procedure risks of a TAVR explant which frequently requires more of device explanating and the possible unplanned concurrent procedures and for these reasons careful assessment of aortic root anatomy and the feasibility of a repeat TAVR procedure should be part of with the initial TAVR workup. If we decide to proceed with TAVR for younger patients and then therefore heart team approach remains extremely important in the TAVR practice, that's my take home message.

Dr. Timothy Gardner:

And I'd like to reinforce that. This is, as we know, the heart team concept has been so important in providing optimal care for patients with aortic valve disease and this is a reminder of part of the discussion that should be happening at the heart team level.

Dr. Carolyn Lam :

Thank you so much. Clear take home messages that you've got right here on Circulation on the Run.

Dr. Greg Hundley :

This program is copyright the American Heart Association, 2020.

Circulation December 1, 2020 Issue

30 november 2020 | 25 min

This week's episode features author Torbjørn Omland and Senior Guest Editor Vera Bittner as they discuss the artile "Growth Differentiation Factor-15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized with COVID-19."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn our feature this week gets into inflammatory biomarkers in patients that have been hospitalized with COVID-19, but before we get to that, how about we grab a cup of coffee and work through some of the papers in the issue. Would you like to go first?

Dr. Carolyn Lam:

Absolutely. With both the coffee and the papers. So great, for this first paper, have you thought about concentric versus eccentric cardiac hypertrophy? We traditionally associate them with pressure versus volume overload respectively in cardiovascular disease, both though conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetric growth of the cardiac myocytes in mainly width or length respectively. However, the molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood.

Dr. Carolyn Lam:

That is until today's paper, and it is from Dr. Kapiloff from Stanford University, and Dr. Rosenfeld from UCSD, School of Medicine and their colleagues, and what they did was used primary adult rat ventricular myocytes, as well as Adeno associated virus mediated gene delivery in mice, to define a regulatory pathway controlling pathological myocyte hypertrophy, and they found that asymmetric cardiac myocyte hypertrophy is modulated by serum response factor phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes In vitro, and In vivo.

Dr. Carolyn Lam:

Serum response factor phosphorylation was bi-directionally regulated at signalosomes organized by the scaffold protein muscle, A kinase anchoring protein beta. This newly identified molecular switch controlled a transcriptional program responsible for modulating changes in cardiomyocyte morphology that occurs secondary to pathological stressors.

Dr. Greg Hundley:

Very nice, Carolyn. So switches controlling this transcriptional program. Tell us a little bit, and bring us back to the clinical relevance of this and starting with that concentric versus eccentric hypertrophy?

Dr. Carolyn Lam:

I thought you may ask. The identification of a molecular mechanism regulating that asymmetric cardiomyocyte growth, really provides a new target for the inhibition of pathological cardiac hypertrophy. Studies in mice using these Adeno associated virus based gene therapies to modulate that signalosome, really provided proof of concept for translational potential in the treatment of pathological cardiac remodeling and prevention of heart failure.

Dr. Greg Hundley:

Oh, wow. Very nice, Carolyn. Well, my first paper comes to us from Professor Dirk Westermann from Hamburg, and focuses on cardiogenic shock patients, and veno-arterial ECMO, the results from the international multicenter cohort study. So Carolyn this study evaluated data from 686 consecutive patients with cardiogenic shock treated with VA ECMO with or without left ventricular unloading using an Impella, and they conducted this at 16 tertiary care centers across four countries. They examined the association between left ventricular unloading and 30 day mortality.

Dr. Carolyn Lam:

Huh, so what did they find?

Dr. Greg Hundley:

Okay. Carolyn. Well, left ventricular unloading was used in 337 of the 686 patients enrolled, and after propensity matching 255 patients with left ventricular unloading were compared with the 255 patients without left ventricular unloading. In the match cohort, left ventricular unloading was associated with lower 30 day mortality without differences in the various subgroups. However, complications occurred more frequently in patients with left ventricular unloading, like severe bleeding, which happened in 38.4% versus only 17.9% in those without unloading. There was also access-related ischemia and renal replacement therapy.

Dr. Greg Hundley:

So Carolyn, the take-home message from this International multi-center cohort study, is that left ventricular unloading is associated with lower mortality, and cardiogenic shock patients treated with VA ECMO, despite higher complication rates. In the absence of randomized trial data these findings support the use of left ventricular unloading and cardiogenic shock patients treated with VA ECMO, and call for further validation, ideally in a randomized controlled trial.

Dr. Carolyn Lam:

Very nice. Well for my next paper, Greg, it's all about desmin. Now we know that mutations in the human desmin gene caused myopathies and cardiomyopathies. Well, today's authors, Dr. Hermann and Schroeder from University Hospital Erlangen in Germany and Dr. Lilienbaum from University of Paris and France and their colleagues, report an adolescent patient who underwent cardiac transplantation, due to restrictive cardiomyopathy caused by a heterozygous R406W desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin, and to intercalated disc proteins. Effects of this mutation on the molecular properties of desmin were then addressed by cell transfection and In vitro assembly experiments. They further generated these desmin mutation knock-in mice haboring the orthologous form of the human, R406W-desmin.

Dr. Greg Hundley:

So Carolyn, what did they find?

Dr. Carolyn Lam:

Well, they demonstrated a novel pathomechanism in which cardiotoxic R406W-desmin, could adapt dual functional status with the abilities to integrate into the indogenous intermediate filament network, and to cause formation a protein aggregates. This R406W-desmin modified the extra sarcomeric cytoskeleton, such that desmin filaments were not anchored to desmosomes anymore. Thereby destroying the structural, and functional integrity of intercalated discs.

Dr. Greg Hundley:

What are the clinical implications?

Dr. Carolyn Lam:

Well, since these cardiotoxic desmin mutations could affect the integrity of intercalated discs, thereby inducing conduction defects and malignant arrhythmias, they suggest early implantation of pacemaker, or cardioverter defibrillator devices, may be considered to prevent certain cardiac death in patients with these mutations. Furthermore, state-of-the-art basic molecular risk stratification of desmin mutations may encompass a multidisciplinary experimental approach as exemplified by the approach taken here, which comprises assessment of the tissue pathology in conjunction with genome analysis and desmin assembly studies as well as patient mimicking cell and animal models for the In vivo validation of these mutations.

Dr. Greg Hundley:

Well, fantastic, Carolyn. Well, my next paper comes to us from Dr. Ravi Shah from the Massachusetts General Hospital. This study evaluated 2,330 white and black young adults, average age of 32 years, in the Coronary Artery Risk Development in Young Adults, or the cardiac study, to identify metabolite profiles associated with an adverse cardiovascular disease phenom that included, myocardial structure and function, fitness, vascular calcification, and then also mechanisms, and other cardiovascular outcomes that would occur over the next two decades. Statistical learning methods, including elastic nets and principal component analysis, and Cox regression generated parsimonious metabolite based risk scores, validated in over 1800 individuals in the Framingham Heart Study.

Dr. Carolyn Lam:

Wow. What did they show, Greg? Wow, that's a lot of work.

Dr. Greg Hundley:

Yeah. So Carolyn, the authors found two multiparametric metabolite-based scores linked independently to vascular, and myocardial health. With metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and finally collagen metabolism. Over nearly 25 year median follow-up, and cardia, this metabolite based vascular score, and the myocardial score, and the third and fourth decade of life were associated with clinical cardiovascular disease. Importantly, the authors replicated these findings in 1,898 individuals in the Framingham Heart Study followed over two decades, such that young adults with poor metabolite based health scores had higher hazard ratios of future cardiovascular disease related events.

Dr. Carolyn Lam:

Oh wow. Greg, what an elegant study with both development and validation cohort evaluating the metabolome.

Dr. Greg Hundley:

Yes. Carolyn. So metabolic signatures of myocardial, and vascular health in young adulthood specify known novel pathways of metabolic dysfunction, relevant to cardiovascular disease associated with outcomes in two independent cohorts. So these data suggests that efforts to include precision measures of metabolic health in risk stratification to interrupt cardiovascular disease at an early at stage, are warranted.

Dr. Carolyn Lam:

Wow. So interesting. Other very interesting articles in today's issue, there's an In Depth article by Dr. Angiolillo entitled, “The Antithrombotic Therapy for Atherosclerotic Cardiovascular Disease Risk Mitigation in Patients with Coronary Artery Disease and Diabetes.” There's also Research Letters, one by Dr. Sultan on, “The Longterm Outcomes of Primary Cardiac Lymphoma” and one by Dr. Wang on, “Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair Following Myocardial Infarction.”

Dr. Greg Hundley:

Great, Carolyn. Well, I've got a couple other articles in this issue as well. One is by Professor Ganesan Karthikeyan who has an On My Mind piece entitled an “Alternative Hypothesis to explain Disease Progression in Rheumatic Heart Disease.” Dr. Stuart Chen has an ECG challenge entitled, “Alternating QRS Duration and a Normal T-waves. What is the mechanism?” Then finally, Carolyn, a series of Letters to the Editor, one by Dr. Peterzan and the other by Dr. Mehmood regarding the prior published article, entitled “Cardiac Energetics in Patients with Aortic Stenosis and Preserved Ejection Fraction.” Well, Carolyn, how about we get onto that feature article and learn more about inflammatory biomarkers in hospitalized patients with COVID-19?

Dr. Carolyn Lam:

Yes. Let's go. Greg.

Biomarkers are really playing an increasingly important role in cardiovascular disease, and even in the current COVID 19 pandemic, there's been a lot of news about how biomarkers such as traponin may be prognostic, and in fact, we're all wondering about maybe even newer biomarkers. In fact, today's feature discussion does bring to light one of the newest, and in fact, this is the first publication on the role of Growth Differentiation Factor 15 or GDF-15 in COVID-19. We're so pleased to be discussing this with the corresponding author, Dr. Torbjørn Omland from University of Oslo, in Norway, as well as our senior guest editor, Dr. Vera Bittner from University of Alabama at Birmingham. So welcome both. Tobjorn, could you tell us a little bit about GDF-15 and what made you look at it, and what did you find?

Dr. Torbjørn Omland:

Yeah, so GDF-15, that's a very interesting biomarker. It's considered a biomarker of biological aging cellular stress, and perhaps also the inflammation, and tests being studied within the cardiovascular field for some years now, and it has been shown to be a strong prognostic indicator across the cardiovascular spectrum, actually. So it is a new biomarker in one sense, but there are some data already in the cardiovascular field.

Dr. Carolyn Lam:

Not in COVID. So this is the first study to really look at its prognostic value in COVID 19. So congratulations Torbjorn, and if I may also to the first author, Dr. Peter Meer, a good friend as well, but please, could you tell us about your study and what you found?

Dr. Torbjørn Omland:

Yes. So when the COVID pandemic hit Norway in the spring, we thought that we should plan a prospective biomarker study. So we had to really fast track approval by the IRB and so forth, and we're able to actually cover most of the patients that were hospitalized in our hospital, Akershus University hospital, which is right outside of Oslo, and it's a pretty large hospital by Norwegian standards. It covers about 11% of the Norwegian population.

Dr. Torbjørn Omland:

So in that period, when we were including, we had 136 patients hospitalized with confirmed COVID 19, and we have biobank bank samples from 123 of these, and then there have been reports from retrospective studies, first from China, that seemed to suggest that markers like cardiac troponin, Anti-Troponin T, and Ferritin were associated with outcome, but those studies were prone to selection bias in that the measurements were performed in the most sick patients. So in this study we included all patients and then we thought we should examine a broad panel of biomarkers, and that included Interleukin 6, CRP, Procalcitonin, Ferritin, and the D-dimer Cardiac troponin, and N-terminal pro B, and GDF-15.

Dr. Carolyn Lam:

Wow. Thank you, Torbjorn. Even before you carry on with the results, can I just say having visited your hospital in pre-COVID days, I can only imagine what a work of love this was to do it prospectively. Any particular experiences to talk about, to get a fast-track even in the midst of to perform a well done prospective study, that must have taken a lot.

Dr. Torbjørn Omland:

Yes. But it's also interesting in that the whole sort of ablation on Norway was very much into this from the highest political level. Also, the decision that the older research on COVID should be prepared to retire, then the IRB had an eight hour and deadline for them to approve or not approve the study. So that's went surprisingly smoothly, I must say.

Dr. Carolyn Lam:

Wow, that's great. So what did you find?

Dr. Torbjørn Omland:

Yeah, so we found that among these biomarkers, several seem to predict outcome, and the primary end point of this study was to combined end-point of the hospitalization in the ICU, or death. We found that also markers like cardio traponin, BNP, ferritin, and the D-dimer and so forth, in univariable analysis, were very associated with outcome, but when we perform a more comprehensive, mostly variable modeling, then the prognostic value of some of these markers disappeared. In contrast, for GDF-15, it seemed to perform very strongly, both on the baseline sample, and interestingly also it increased in those reaching the primary end-point during the hospitalization. So it provided a very strong and independent information also when we adjusted for clinical risk scores, like the NEWS score. So that was a very pleasant surprise to see that there was one marker that's actually performed so well. The other marker that's also performed well was Ferritin.

Dr. Carolyn Lam:

Very interesting, and so the new score being the National Early Warning Score. Thank you. Verra, I really love to bring in your thoughts. I mean, could you take us behind the scenes with the editors? What did you think when you saw this paper?

Dr. Vera Bittner:

As you know, I mean, a lot of journals have been inundated by COVID papers, and so this one stuck out to us, because it's the first time that we had seen that anybody linked GDF-15 to a COVID population, even though it has been out in the literature for ACS, and in my prognostication, and in a healthy populations, and in chronic coronary disease populations, heart failure, and so on. So this is the first time that we've seen it applied there.

Dr. Vera Bittner:

Then I would echo some of the things that Torbjorn said, that we were also impressed, that it was prospective, because when you look at some of the other biomarker studies, what was prognostic in one with then not shake out the other one, because either different variables were included in the models, because the population's differed. So to have something that was representative of the population that was actually admitted to this, Norwegian Academic Hospital, stood out to us. So we're excited to get this paper basically for circulation, and hope that it also will be impetus for future research.

Dr. Carolyn Lam:

Thank you so much for sharing that end for helping us publish such a beautiful paper. Did you have some questions for two of your own?

Dr. Vera Bittner:

Yeah. So what stuck out to me is that you had this a whole crew of biomarkers, and then when you looked ultimately at the final model, there were two that were standing out, that was ferritin, and it was the GDF-15, and then when I looked at your graph, it looks like not only did these biomarkers measure different contrasts, but their time-course also seemed to be different, and so I was just wondering whether you had thought about, maybe using these to joint the model outcome, and whether we might even be able to get more information that way.

Dr. Torbjørn Omland:

I think that's an excellent suggestion, and as you correctly pointed out, they do have different sort of profiles and ferritin being an acute phase reactant, having various sort of dramatic early rise whereas we see that GDF-15 increased progressively during the course of hospitalization in the most severe patients. I think when combining them, is actually a great IMT that we should look further into.

Dr. Carolyn Lam:

Very nice. Torbjorn, if I could, I've got a couple of questions too. So 123 patients, 35 of whom had the primary outcome, right? So that may be sort of seen as, is this too small? and they're all hospitalized patients. So could I ask, what do you predict maybe seen in a larger population or outside of Norway or in a non-hospitalized population?

Dr. Torbjørn Omland:

So as you say, we were early with this report, but since it was submitted, there has been a couple of smaller studies that seemed to confirm our results. So that is reassuring, but of course we would like to have studied this in logical patients. We are in touch with the other biobank samples that could possibly confirm the data. So that's one obvious step. Then it's very interesting, as you say, could we sort of expand this to also apply to non-hospitalized patients? I think that it would be a very interesting hypothesis to test, and I think there's still a pretty good rationale for this.

Dr. Torbjørn Omland:

It's interesting that the insoluble group actually showed a correlation that when the soluble ST2 concentrations and GDF-15. So there might be that those with more susceptibility to COVID infections, actually, I thought that, that is actually reflected by GDF-15 concentrations, but the challenge is how to sort of get a representative non-hospitalized population, but interestingly, I was approached by some of the hospital staff that actually are in contact with general practitioners, and wanted sort of implement this test also for this group.

Dr. Carolyn Lam:

So Verra, we're really grateful that Allan Jaffe was working with you in managing this beautiful paper, and if you don't mind me cheekily paraphrasing that you said you might channel him, if you could, what would the channeled Allan Jaffe perhaps say about what's needed in this whole biomarkers fear in COVID-19?

Dr. Vera Bittner:

Hopefully, many. A channeling element is obviously difficult, because he is such an incredible expert on biomarkers that I can't even pretend to be able to see, that you might be thinking, but it seems to me that one thing that we could all agree on is that it would be really exciting if something like the: get with the guidelines COVID registry, could decide to measure this marker perspectively in the participating hospitals, for example.

Dr. Vera Bittner:

Then be able to look at this in a much, much larger population. I mean, especially with different ethnic backgrounds as well. I mean, I noticed actually to my surprise that, this Norwegian study how to fairly high proportion of Asians in the sample, but that may not be the ethnic distribution that we might see in different regions of the US, or different regions of the world. So it would be really nice to incorporate the measurement of this biomarker in much larger datasets. So things can be explored a bit further.

Dr. Carolyn Lam:

That's excellent, and Torbjorn, if you could channel Allan. What would you say?

Dr. Torbjørn Omland:

That's a difficult path, but absolutely just to me what Verra said. Then I think the importance of prospective studies in the COVID biomarker field, I think is our at most importance.

Dr. Carolyn Lam:

I think on behalf of both Torbjorn and I, and in fact everyone in circulation. Thank you, Verra for the amazing work that you and your team do for circulation as well. Thank you so much for making the time to share your thoughts today and thank you for that beautiful, beautiful paper both of you. Thank you. (singing). Listeners you've been listening to Circulation on the Run. Thank you for joining us from Greg and I. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright, the American Heart Association 2020.

Circulation November 24, 2020 Issue

23 november 2020 | 27 min

This week’s episode features author Emma Birks and Associate Editor Hesham Sadek as they discuss the article " Prospective Multicentre Study of Myocardial Recovery Using Left Ventricular Assist Devices (REmission from Stage D Heart Failure: RESTAGE-HF): Medium Term and Primary Endpoint Results."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center of VCU Health in Richmond, Virginia. Carolyn, our feature article this week, we're going to examine myocardial recovery using left ventricular assist devices, getting some early results from the RESTAGE-HF study. But before we jump to the feature discussion, how about we discuss some of the papers in the issue? Would you like to go first?

Dr. Carolyn Lam:

Yes I would. Have you thought about what's the benefit of emergent coronary angiography after resuscitation from out of hospital cardiac arrest for patients without ST elevation? It's an important question. Well, the portal study was reported by Dr. Kern from University of Arizona and colleagues, and this was designed to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated out of hospital cardiac arrest in patients without ST elevation. So adult comatose survivors without ST elevation after resuscitation, were prospectively randomized to early coronary angiography versus no early coronary angiography, where early was defined as less than 120 minutes from arrival at the PCI capable facility. The primary endpoint was a composite of efficacy and safety measures, including efficacy parameters of survival to discharge favorable neurological status at discharge echo measures of left ventricular ejection fraction, more than 50% and a normal regional wall motion score within 24 hours of admission.

Dr. Greg Hundley:

So, lots of data here. What did they find?

Dr. Carolyn Lam:

So, unfortunately the study was prematurely terminated before enrolling the target numbers of patients. A total of 99 patients were enrolled from 2015 to 2018 and 49 were randomized to early coronary angiography. The primary endpoint of efficacy and safety was not different between the two groups. Early coronary angiography was not associated with any significant increase in survival or adverse events. And early coronary angiography revealed a culprit vessel in 47% with a total of 14% of patients undergoing early coronary angiography, having an acutely occluded culprit coronary artery. So while this was an underpowered study, when considered together with previous clinical trials, it does not support early coronary angiography, comatose survivors of cardiac arrest without ST elevation, whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes does require additional study. And this is discussed in an editorial by Dr. Lemkes from Amsterdam university medical center.

Dr. Greg Hundley:

Very nice Carolyn. So at least the study that points us toward the next study that has to be performed and also does with other studies provide a little more clarity. Well, my next paper is from Professor Sanjiv Shah and--oh, wait a minute! And also from you as a co-author. Well, Carolyn, how about we have a little mini feature discussion where I can ask you some questions and then you can tell us all about your paper.

Dr. Carolyn Lam:

Happy to.

Dr. Greg Hundley:

Great. So Carolyn, what hypotheses were you testing and what was your study design and who was included in your study population?

Dr. Carolyn Lam:

Okay. So the question was we wanted to answer was thus a systemic pro-inflammatory state as indicated by proteomic profiling. Does that mediate the association between comorbidities and normal cardiac structure and function in HFpEF. To answer that we studied 228 patients with HFpEF from our multicenter promis HFpEF study. And these patients had 248 unique circulating proteins quantified using the old link multiplex immunoassay. Now I'm going to describe a complex analysis, but we basically had to first perform principal component analysis. And we did this to summarize 47 proteins known a priori to be involved in inflammation, and then used unbiased network analysis of all the 248 proteins to identify clusters of proteins that over-represented inflammatory pathways. We then used a mediation analysis to determine whether and to what extent inflammation mediates the association of comorbidity burdens with abnormal cardiac structure and function. And finally, we externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HFpEF.

Dr. Greg Hundley:

Wow Carolyn, such a great design and an app machine learning mediation analyses, and then validation in an independent cohort. So tell us, what did you find?

Dr. Carolyn Lam:

So first, comorbidity burden was associated with abnormal cardiac function and structure and with these principle components of clusters of inflammation proteins. Second, systemic inflammation was associated with echo indicators of worse hemodynamics, like higher EDE' ratio and worse, right ventricular function. And third, inflammation indeed mediated the association between comorbidity burden and many of these echo parameters with, and I'm going to name a couple of routines. So TNF-R1, uPAR, IGFBP-7 and GDF-15 being the top individual mediating proteins. In the validation cohort inflammation was up-regulated in HFpEF compared to controls and the most prominent inflammation protein cluster identified was also the same one as in PROMIS-HFpEF.

Dr. Greg Hundley:

Beautiful Carolyn. So with these new proteins identified, what's the take home message here?

Dr. Carolyn Lam:

Here it is. Proteins involved in inflammation form a conserved network in HFpEF. And this was found across two independent cohorts. This may mediate the association between comorbidity burden and echo indicators of worst hemodynamics and right ventricular dysfunction. In totality, these findings support the comorbidity inflammation paradigm in HFpEF.

Dr. Greg Hundley:

Great job Carolyn, I liked the mini feature. That was so nice having one of the authors of the study here to explain kind of a two for one here, because we're going to get a feature and a mini feature. Have you got another paper you want to tell us about?

Dr. Carolyn Lam:

Thanks Greg and that works both ways. This next paper provides insights into the identity origin and function of many cells that make up late stage atherosclerotic lesions. It also identifies the mechanisms by which these control plucks stability. So corresponding author, Dr. Owens from Virginia School of Medicine and colleagues conducted a comprehensive single cell RNA sequencing of advanced human carotid endarterectomy samples, and compared these with murine micro dissected advanced atherosclerotic lesions with smooth muscle cell and endothelial lineage tracing to survey all plaque cell types and to rigorously determine their origins.

Dr. Greg Hundley:

Carolyn you know, this is another great study where we have both human subjects research and small animals. What were their results?

Dr. Carolyn Lam:

They provided evidence that smooth muscle cell specific knockout of transcription factors, KLF4 versus Oct-4 showed virtually opposite genomic signatures and their putative target genes played an important role, regulating smooth muscle cells phenotypic changes. They also provided evidence that smooth muscle cell derived cells within advanced mouse and human atherosclerotic lesions exhibited far greater phenotypic plasticity than generally believed, with KLF4 regulating the transition to multiple phenotypes, including LGALS 3 plus osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis. So in summary, smooth cell phenotypic switching produces cells that can be beneficial or detrimental to lesion stability and may be an important mechanism controlling the risk of unstable atherosclerotic plaque and myocardial infarction or stroke.

Dr. Greg Hundley:

Oh, great job, Carolyn. Well, the next paper I have is from Professor Muredach Reilly from Columbia University. And Carolyn smooth muscle cells play significant roles in atherosclerosis via phenotypic switching, a pathological process and with smooth muscle cell D differentiation, migration and trans differentiation into other cell types yet how smooth muscle cells contribute completely to the pathophysiology of atherosclerosis remain somewhat illicit. So the authors sought to reveal the trajectories of smooth muscle cell trans differentiation during atherosclerosis, and to identify molecular targets for disease therapy by combining smooth muscle cell fate mapping and single cell RNA sequencing of both mouse and human atherosclerotic plaques.

Dr. Carolyn Lam:

Echoing what you said earlier, Greg, both animal and human data. Terrific. So what were the results?

Dr. Greg Hundley:

The authors found that smooth muscle cells transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. Smooth muscle cell derived intermediate cells termed stem cells were multiphoton and could differentiate into macrophage like and fibro chondrocyte like cells as well as returned towards the smooth muscle cell phenotype. Retinoic acid signaling was identified as a regulator of the transition of smooth muscle cells to stem cells and RA signaling was dysregulated in symptomatic human atherosclerosis. Finally Carolyn, human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene low PSI and correlated between coronary artery disease risk levels and repressed expression of these genes. Now, activation of RA signaling by all trans retinoic acid and the anticancer drug for acute promyelocytic leukemia blocked the smooth muscle cell transition to stem cells, and that also reduced atherosclerotic burden and then promoted fibrous cap stability. So a lot of clarification of the role of smooth muscle cells, trans differentiation and the development of atherosclerotic disease

Dr. Carolyn Lam:

Indeed and translational implications. Interesting. Now let's review some of the other papers in this issue. Shall we? First as an, on my mind paper by Dr. Kullo on familial hypercholesterolemia, a reportable disorder. There's an exchange of letters between doctors Lazzerini and Li regarding the article autoantibody signature in cardiac arrest.

Dr. Greg Hundley:

Thanks Carolyn. Well, I've got a couple other papers to tell you about really a series of research letters from the mailbag. So first Daniel Modin has a Research Letter entitled “Acute COVID-19 and the Incidents of Ischemic Stroke and Acute Myocardial Infarction.” Dr. Christian Mueller has a Research Letter entitled “Effect of a Proposed Modification of the Type 1 and Type 2 Myocardial Infarction Definitions on Incidents and Prognosis.” And finally Carolyn a Research letter from Dr. Jizheng Wang involving an East Asian-specific common variant in TNNI3 that appears to predispose to hypertrophic cardiomyopathy. Well, Carolyn, what a great issue and thank you for that many feature, but how about we proceed on next to our feature discussion?

Dr. Carolyn Lam:

Let's go, Greg.

Today's feature paper is one of those that I think is going to change clinical practice. So please listen up. It's about the RESTAGE-HF study. So pleased to have with us the first and corresponding author, Dr. Emma Birks from University of Kentucky Gill Heart and Vascular Institute, as well as our associate editor, Dr. Hesham Sadek from UT Southwestern to discuss this very important paper. Emma, could you please describe the RESTAGE heart failure study?

Dr. Emma Birks:

Let's say prospective study of patients getting left ventricular assist devices. So patients with very advanced heart failure are receiving left ventricular assist devices as either a bridge to transplant or as destination therapy. And they're seeing them for chronic heart failure because really all other medical therapy has failed and we use the pump to try and recover their own heart. So when the pump's implanted, we optimize the LVAD unloading, the maximum loading, and we give them a very aggressive medical therapy regime, unless they may not have tolerated these medications before because of poor blood pressure and renal dysfunction, we find they do tolerate them. So we give them in very aggressive doses and then we monitor their underlying function at regular intervals and try and promote recovery. So with that, we had done this in England in the past, in a single center study, but it had not yet been reproduced, which was obviously essential to have a bigger impact.

Dr. Emma Birks:

So we did a prospective study of six big US centers. We found that we've created a primary endpoint that was statistically powered in advance. And the primary endpoint was the number of patients that recovered within an 18 month period, that were explanted and remained off the pump and alive without transplant over for one year. So overall we found that of the 40 patients we recruited in the centers with chronic heart failure, we were able to explore 19. Of those that satisfied the primary endpoint, that was actually 40% of patients, with 52.3% being explanted overall. And importantly, patients were explanted in all six centers, so we found that the protocol was reproducible under the how much higher rate of recovery that you would otherwise see. Normally there is a database in the US that tracks outcomes from bad patients. And generally only 1-2% seemed to recover enough to be explanted generally. So this was a much bigger percentage.

Dr. Carolyn Lam:

Emma, first of all, congratulations, what an important trial and what stunning results. More than half of patients receiving that protocol were explanted. That's just remarkable. Now, could I just ask, what is it that you did that was different? I noticed you spent a lot of time saying this was an aggressive pharmacological protocol that was along with the LVAD unloading. Could you maybe elaborate on that a little bit more?

Dr. Emma Birks:

Yeah, I think that was a very important part of it. So generally I think when the LVAD goes in most centers, the patients are very sick, so most of those patients wouldn't then try and recover them or look at underlying functions. I think that was the first thing that was different was to try very hard. And then we had centers, the experience, I had done this before, it was also very helpful, all agreeing to do the same thing. We use a very aggressive regime of ACE inhibitors, Beta blockers, auto serotonin antagonists and ARBs. And that was also an unusual thing. We use the fact that they're supported with the pump to use both an ACE and an ARB together, but the idea that they have better blood flow in the cranial is way more tolerant and we give very high doses. So we use Lisinopril with the target dose of 40 milligrams, Coreg with a target dose of 50 BID, Aldactone 25 milligrams daily.

Dr. Emma Birks:

And then we add in losartan if they tolerate it and actually aim for 150 milligrams daily, so those doses are very high. And I think not normally given to people on LVADs. So you must've had the LVAD that don't tolerate the medical therapy and stop it. They might just have blood pressure control, etc. There is now also another INTERMACS trial, a sort of big study that's come out that actually shows benefit of neurohormonal antagonists in general. So that goes together with our study to show that they should already be given and then the regular testing. So we had quite thorough testing. So first of all, we do echos on the pump and then we do echos with the LVAD turned down to a speed at which is not contributing. So we do that and we do an echo at five minutes with it down 15 minutes, and then we walk the patient, distress them. Once we show that the hearts come down in size and improved function, then we do an exercise test, right heart cath on an off pump to look at the hemodynamics.

Dr. Carolyn Lam:

Wow. So tremendous effort and really the protocol is unique in and of itself, not just the pharmacological therapy, also the way this is monitored and decisions are made really, really amazing. Just one last question for me, because it's a humbling reminder of the importance of neurohormonal blockade in these patients. Do you continue that after they're explanted?

Dr. Emma Birks:

Yes, we do. And we continue aggressively and that's slightly different as well in that normally you wouldn't give a patient a nascent an up of course, but given that they've already tolerated it on the pump in that same patient. So we restart the same drug regime afterwards, and we actually like to get them to quite along that dosage before we discharge them from the XPLAN, we don't want to do that slowly. We get them back on it quite quickly. And then we follow them very carefully because we don't really know the long-term durability.

Dr. Carolyn Lam:

Wow, thank you. Hesham. I would love your thoughts on this paper. I mean, it really, really is remarkable results.

Dr. Hesham Sadek:

Yeah. I mean, I was very happy that we received this paper to review, frankly I've been following that work for a long time since the first new England paper that came out and I'd like to congratulate you for an amazing work. I think this will change the field. First, how was this trial different from the first trial, other than the fact that it's multicenter, what would you say are the major changes that you made to the protocol and what you've learned since the first trial?

Dr. Emma Birks:

Yes, you're absolutely right. We did make some changes. So first of all, it was six sites instead of one site. I think it was very important to reproduce it in the US but we changed the protocol itself as well. The first trial had optimization of the LVAD speed, really just by echo looking at the reduction in the ventricle size. It had the aggressive medical regime was very similar except this time we increased the Losartan dose from 100 to 150 after the Hill's trial came out. The testing was very frequent in the original English Sheffield study, probably a little bit too frequent to be able to be adopted on a wide scale. So we tried to reduce it down a little bit. So we decrease the frequency of the low-speed echos. I think we had them at six weeks, four months, six months, nine months in a year.

Dr. Emma Birks:

And after that, we saw if they were already improving and started and only did them at a year to 18 months, if they were improving. And then we also cut down the number of exercise tests. So we didn't do the exercise test until the echo was already showing significant improvement. For two reasons, one, we didn't find it very reliable and two, it was just too much testing for the patient. So it was more of a confirmatory test. In fact, it wasn't a requisite for a pump explantation. We didn't do a left heart catheter, which we did before. Previously we tried to measure LVEDP, this time we decided which was enough. So we just did a right heart cath on and off pump. And we did that once the echo was improved as well. So we rationalized that a little bit. And then the other important thing was before in hayfield study, once we saw the ventricular size come down and injection fraction start to improve, we actually added in Clenbuterol, which was a Beta-2 agonist.

Dr. Emma Birks:

And the idea with that was to cause a kind of physiological hypertrophy so that when you took the pump out, the heart didn't just dilate. We were worried about atrophy at the heart on the pump long-term. So we did that to try and improve the durability of recovery. So the reason we left off this time was really the previous protocol was very good, but was very complicated. So we wanted to see what rate of recovery we could get just with the aggressive reverse remodeling, neurohormonal drugs, plus the aggressive testing and the optimum loading with the idea that later on, we could add on either Clenbuterol or something later to improve the durability of recovery, if the ability of recovery is not good enough, but actually so far it's proven to be pretty good because the study itself takes quite a long time. It was sort of to recruit them. We had an 18 month period than the follow-ups. It was already a multi-year study. So we wanted to establish a regime that many centers could use to try and promote recovery.

Dr. Hesham Sadek:

I want to follow up on that last point, because as you know, I've looked at some of these Heights as well in our center, and we looked at the results with you and Stavros and others. So the myocytes size is expected to change, decrease with unloading, right with sufficient unloading. So how would you prepare the Myocardium to take on the normal afterload if you are not going to induce by a beta agonist, for example,

Dr. Emma Birks:

What I would like to do in the future is try using the pump itself actually. Sometimes there's heart recovers, the heart shrinks and actually start opening their own valve and working in the heart. Of course, when you have the HeartMate one, actually, sometimes wasn't synchronous with the heart. So sometimes the heart will beat against the pump anyway. Once you go to the continuous flow pumps, you've got continuous unloading. So I think it'd be very interesting to intermittently turn down the pump speed and load the heart to work it before you take the pump out. So I would really like to do that. I think that might be the next interesting phase of the study to improve your ability to.. So I guess once you've got maximum reverse remodeling and improvement in function, you could just turn the pump speed down to let the valve open.

Dr. Hesham Sadek:

Do you think perhaps if you do that, you will increase the percentage of patients that can be explanted? Do you think that could be a factor in the percentage of patient that can be explained?

Dr. Emma Birks:

I think it might be, it might more improve the, to your ability to make sure we have for a long, good echo function afterwards.

Dr. Hesham Sadek:

That's great. So another question this was limited to not ischemic cardiomyopathy patients. Can you elaborate a bit on why not include, for example, revascularized ischemic cardiomyopathy patients.

Dr. Emma Birks:

Yeah, so we did that really just because we didn't want to change too much from the original protocol. We also stuck with one device because we thought if you have multiple pumps, multiple diagnosis, it does get hard to analyze in a multicenter trial. So we did that on purpose and we were always trying to simulate the bridge to transplant population in the age group too. But actually interestingly, most of the patients recruited in the trial were destination therapy patients in the end.

Dr. Emma Birks:

I think this could be done with ischemic cardiomyopathy. I think we don't have enough data on ischemic cardiomyopathy to know whether it does or it doesn't recover. So I don't think our results say that it's only known as ischemics. I think it just means we haven't studied ischemics sufficiently. Logically they might have more scarred. It might be harder to get such a good percentage to recover. I think all of us in our individual centers have seen a few and we've sort of seen the on pump echo improved, and we've tested them and then taken some out. But most of these cases are anecdotal. So I think that is another important study that needs to be done, obviously a large group of patients.

Dr. Hesham Sadek:

I agree. So given that they're not ischemic cardiomyopathy, do you know how many of them had genetic testing or what is the percentage of monogenic cardiomyopathys or how do you think these patients would respond to this protocol?

Dr. Emma Birks:

But if you had a familiar history and actually found it didn't make any difference, whether they recovered or not. I think some of us have personally seen actually those were the familial cardiomyopathy tend to recover more actually again, anecdotally. We published a people before looking at the Titin gene saying that that did recover. I think actually only five of these patients, 12% of them had a family history, but some of them recovered

Dr. Hesham Sadek:

One final question, as you know, I'm a basic scientist. So ultimately the question I'm going to ask, what do you think the mechanism is? Is it that these hearts are just in a vicious cycle of remodeling and validation, increased pressure, and you were sort of giving it a chance for actual structural reverse remodeling where you changed the geometry of the myocardium and perhaps rest of myocardium, allow for improvement of calcium cycling dynamics, or do you think, is something more exciting? Like three-generation for example.

Dr. Emma Birks:

Yeah, that's very interesting because I think the LVAD doesn't unload, so it shrinks the ventricles. I think it does improve the geometry and the dynamics. And then you use the drugs where they may have felt before you almost put them from class four, heart failure into class three with the bad to give that chance to work again. And then I think various cellular and fibrotic factors have been looked at and it's hard because there was so many factors have been looked at that. You were going to find some that go up and some that go down and what's important. But the impression I get overall is that you do get improvement, the matrix limits, the recovery on the fibrosis and the matrix. Whereas you do get improvements of myocardial function and cellular function. The cells will tend to reverse the dysfunction and it's really whether that happens or not. It's probably limited a lot by the matrix

Dr. Carolyn Lam:

That is amazing here. Hesham, I'm going to put you on the spot. Do you have your own hypothesis about this

Dr. Hesham Sadek:

Based on the work that they did initially in the new England paper, we did actually a small pathology study looking at cell cycle of cardiomyocytes from the core samples and from the explanted hearts post-transplant and we saw evidence of increased cardiomyocytes cell cycle in these patients along with decreased DNA damage and some metabolic remodeling as well with mitochondria. So, you can't really tell much from tissue whether you regenerated it or not, but as you know myocytes don't divide and this is the basis for the lack of spontaneous regeneration of the myocardium. So if this in fact removes the block to cardiomyocyte cell cycle, then this might be a regenerative therapy mechanism.

Dr. Carolyn Lam:

Well, this is amazing. I wish we had all day to discuss this more. I mean, this is the only place you can get a discussion that goes from clinical to basic signs and back to clinical. Thank you so much, Emma and Hesham for sharing today. Thank you audience for joining us today. You've been listening to circulation on the run on behalf of Greg as well. Don't forget to tune in again next week.

Speaker 1:

Program is copyright the American heart association, 2020.

Circulation November 17, 2020 Issue

16 november 2020 | 25 min

This week’s episode features author Jaime Layland and Associate Editor Dharam Kumbhani as they discuss the ariticle "Colchicine in Patients with Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial."

TRANSCRIPT BELOW:

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health, in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, for our feature discussion we're talking about a very hot topic these days, the role of colchicine, this time in patients with acute coronary syndrome, with Australian data. I cannot wait to get to that, but I'm going to make you wait because I want to tell you about a whole lot of other really cool papers in today's issue.

Dr. Carolyn Lam:

First, have you ever wondered what is the association between risk factor control and cardiovascular disease risk in type 2 diabetes? Well, today's paper answers that. It's from Dr. Wright from University of Manchester and her colleagues who looked at a retrospective cohort using data from the English practices from Clinical Practice Research Datalink, or CPRD, and the Scottish Care Information diabetes dataset. They also linked to hospital and mortality data and identified more than 101,000 patients with type 2 diabetes in CPRD matched with almost 379,000 controls without diabetes and almost 331,000 patients with type 2 diabetes in the Scottish Care Information diabetes database between 2006 and 2015. The main exposure was a number of optimized risk factors, and these are: (1) Nonsmoker; (2) total cholesterol less than 4 mmol/L; (3) triglycerides less than or equal to 1.7 mmol/L; (4) HB A1c less than 7%; and (4) systolic blood pressure less than 140 or less than 130 mmHg of high risk.

Dr. Greg Hundley:

Carolyn, I am very curious. Lots of data here. What did they find?

Dr. Carolyn Lam:

So the key findings were:

Dr. Carolyn Lam:

First, even with optimally managed risk factors, people with type 2 diabetes still had a 21% higher risk for all cardiovascular disease events and non-fatal coronary heart disease, and a 31% higher risk of heart failure hospitalization compared to patients without diabetes.

Dr. Carolyn Lam:

2. Only 6% of people with type 2 diabetes had optimal risk factor controls, so a very low percent.

Dr. Carolyn Lam:

3. The association between the number of elevated risk factors and cardiovascular disease events and mortality was much stronger in patients with type 2 diabetes but without cardiorenal disease compared to those with established cardiorenal disease. People without cardiorenal disease were also younger and more likely to have suboptimal risk factor control and fewer prescriptions for risk-factor-modifying medication.

Dr. Carolyn Lam:

So take-home message: Greater use of guideline-driven care, clinical decision support, drug intervention, and self-management support should be encouraged for risk factor control, and people with type 2 diabetes and without cardiorenal disease may especially benefit greatly from cardiovascular disease risk factor intervention.

Dr. Greg Hundley:

Very nice, Carolyn.

Dr. Greg Hundley:

Well, my first study comes from Dr. Gregory Lewis from Mass General Hospital in Boston, Massachusetts. Carolyn, another quiz: Have you wondered about differences in metabolism in those who exercise versus those that do not?

Dr. Carolyn Lam:

Greg, I wonder about that all the time when I'm running out there.

Dr. Greg Hundley:

In this study, cardiopulmonary exercise testing, or CPET, and metabolite profiling was performed on Framingham heart study participants aged about 54 years with 63% of them being women with blood drawn at rest in 471 subjects and then again at peak exercise in 411.

Dr. Carolyn Lam:

Nice, and kudos for the majority women. So what were the results?

Dr. Greg Hundley:

The authors observed changes including reductions in metabolites implicated in insulin resistance and increases in metabolites associated with lipolysis, nitric oxide bioavailability, and adipose browning. Exercise-induced metabolite changes were variably related to the amount of exercise performed, peak workload, sex, and body mass index. There was attenuation of favorable exercise excursions in some metabolites in individuals with higher BMI and greater excursions in select cardioprotective metabolites in women despite less exercise being performed. Four metabolite signatures of exercise response patterns were analyzed in a separate cohort. The Framingham offspring study of 2,045 were about age 55 years and 51% were women, two of which were associated with overall mortality over a median follow-up at 23 years.

Dr. Greg Hundley:

So Carolyn, in conclusion, the authors found acute exercise elicits widespread changes in the circulating metabolome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise that could be useful in future studies.

Dr. Carolyn Lam:

Beautiful. I'm going to keep exercising and I bet you will, too, Greg.

Dr. Carolyn Lam:

So this next paper is a mechanistic study that revealed a special population of tissue regulatory T-cells in the heart with a unique phenotype and pro-repair function. So this comes from corresponding author Dr. Cheng from Tongji Medical College of Huazhong University of Science and Wuhan Hubei, China. He and his colleagues studied the dynamic accumulation of regulatory T-cells in the injured myocardium in mouse models of myocardial infarction, myocardial ischemia re-perfusion injury, or cardiac cryo injury, and using state-of-the-art methods such as bulk RNA sequencing, photo conversion, parabiosis, single-cell TCR sequencing, adoptive transfer, and functional assays.

Dr. Greg Hundley:

Carolyn, interesting. What did they find?

Dr. Carolyn Lam:

They showed that regulatory T-cells that accumulate in the injured myocardium after myocardial infarction or myocardial ischemia re-perfusion injuries had a distinct transcriptome which differs from lymphoid organ regulatory T-cells and other non-lymphoid tissue, and this represents a novel population of tissue regulatory T-cells in the heart. These heart regulatory T-cells were mainly thymus driven and recruited from the circulation showed active local proliferation with the IL-33/ST2 axis promoting their expansion. With the phenotype of promoting tissue repair, heart regulatory T-cells over-expressing spark contributed to elevated collagen content and enhanced maturation in infarct scars to prevent cardiac rupture and improve survival after myocardial infarction.

Dr. Carolyn Lam:

So in summary, this paper identified and characterized a phenotypically and functionally unique population of heart regulatory T-cells, which may lay the foundation to harness these cells for cardiac protection in myocardial infarction or other cardiac diseases.

Dr. Greg Hundley:

Wow, Carolyn. Very interesting.

Dr. Greg Hundley:

Well, my next paper comes from Dr. Michael Rubart from Indiana University School of Medicine, and as some background it's going to discuss calmodulin. So calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a P.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying this N98S mutation knocked into CALM1 replicate the human arrhythmia phenotype and then to examine some of the arrhythmia mechanisms.

Dr. Carolyn Lam:

Okay. So what did they find?

Dr. Greg Hundley:

Carolyn, several techniques were used in this study. Mouse lines heterozygous for the CALM1 N98S allele generated using CRISPR and caspase 9 technology. Also, adult mutant mice and their wild-type litter mates underwent electrocardiographic monitoring. Ventricular D and re-polarization was assessed in isolated hearts using optical voltage mapping, and action potentials in wholesale currents as well as calcium influx were measured in single ventricular myocytes using patch-clamp techniques and fluorescence microscopy, respectively. Microelectrode techniques were employed for in situ membrane voltage monitoring of ventricular conduction fibers. Carolyn, it was really a comprehensive study.

Dr. Greg Hundley:

So what did the authors find? Heterozygosity for the CALM1 N9S mutation was causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTC interval prolongation, and bidirectional ventricular tachycardia. Second, beta adrenergically induced calcium influx L dysregulation contributed to the long QT phenotype. And finally third, they found that pause dependent early after depolarizations and tachycardia induced delayed after depolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constituted potential sources of arrhythmia in the CALM1 N98S positive hearts.

Dr. Carolyn Lam:

Wow. Sounds like a really comprehensive study. Thanks, Greg.

Dr. Carolyn Lam:

Let's talk about some other papers in this issue, shall we? There is a Perspective piece by Dr. Klassen on the COVID-19 pandemic, a massive threat for those living with cardiovascular disease among the poorest billion. There's an ECG challenge by Dr. Littman on a malignant electrocardiogram. Here's a hint: It's a pseudo-infarct pattern with important learnings. They're in an exchange of letters between Drs. Packard and Schwartz regarding the role of lipoprotein A and modification by alirocumab, a pre-specified analysis of ODYSSEY Outcomes randomized clinical trial.

Dr. Greg Hundley:

Oh thanks, Carolyn. I've got a couple other papers. Dr. Venkateswaran Subramanian has a Research Letter entitled Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice. Professor Jan Cornell has another research letter entitled Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease. The LoDoCo2 proteomic substudy. And then finally, Dr. Sanjay Kaul from Cedars-Sinai Medical Center has a white paper reviewing the benefit/risk trade-offs in assessment of new drugs and devices.

Dr. Greg Hundley:

Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and acute coronary syndromes.

Dr. Carolyn Lam:

Yeah. Let's go, Greg. Today's feature discussion is all about colchicine, that commonly used treatment for gout that has recently emerged as a novel therapeutic option in cardiovascular medicine. I am so pleased to have with us the corresponding author of today's paper, Dr. Jamie Layland from Monash University, as well as our associate editor, Dharam Kumbhani, from UT Southwestern to discuss this very important trial data from Australia. Jamie, could you start us off by telling us all about this Australian COPS trial?

Dr. Jamie Layland:

We performed the Australian COPS trial back in 2015, and it finished recruiting in 2018. Essentially the trial was a trial to look at the safety and efficacy of colchicine being used in acute coronary syndromes, and this was prior to the release of important trial COLCOT. So essentially we randomized patients who presented to the hospital with an acute coronary syndrome to receive colchicine twice daily for one month followed by colchicine once a day for 11 months, and we followed these patients up for a minimum of 12 months. This was performed across 17 sites across Australia, and we looked at a composite endpoint of total death, acute coronary syndromes, unplanned urgent revascularization, and stroke.

Dr. Carolyn Lam:

Nice. So Jamie, could I first clarify that this was an investigator-led trial, I'll bet, and man, first of all, applause for doing this. I can only imagine how much work this took and maybe then tell us about the results.

Dr. Jamie Layland:

Yeah. So this was an investigator-initiated trial through a network of academic investigators across Australia on limited research funding, so through philanthropic and institutional support. So it was a huge effort over a number of years, and I'm very thankful to the support of Circulation and Dharam in supporting the paper, which I think was a great success.

Dr. Jamie Layland:

So the results of this trial were a surprise to us all, but essentially this was a negative trial in the sense that colchicine did not improve the primary outcome, so there was no improvement in the rate of the COLCOT outcome. And interestingly, there was an increase in total mortality, in particular non-cardiovascular deaths were higher at five compared to the placebo at one. That was over a 12-month follow-up period.

Dr. Carolyn Lam:

Interesting. So Jamie, I'm going to ask the question that's on everyone's mind then: What's the difference between your trial and COLCOT?

Dr. Jamie Layland:

That's a great question. Obviously, COLCOT was a much larger trial. COLCOT was an international trial of over 4,000 patients. Similar patient demographics, similar patient subgroup of acute coronary syndromes. However, importantly, COPS was a trial of inpatient initiation of colchicine. So patients when they had their STEMI, or non-STEMI most commonly, they were given colchicine usually within 72 hours of their index hospitalization and sometimes sooner, and this was given prior to discharge. With COLCOT, the median time of administration of colchicine was around 14 days, so slightly different groupings there. However, in COLCOT you were allowed to administer colchicine as an inpatient. You can see obviously from the European side of cardiology the impressive data when colchicine was given earlier in COLCOT how this translated to improved outcomes. So clearly, there is a potential benefit there for early administration of colchicine when you look at these two trials.

Dr. Jamie Layland:

But we administered colchicine acutely when patients presented in their index hospitalization. We also importantly used a different dosing schedule to COLCOT. So COLCOT was 0.5 mg daily and we used 0.5 twice daily. This was for the first 30 days, and this was based on early data from the group from western Australia who showed that when colchicine was given to patients at a BD dosing in those patients who were already on aspirin and high-potency statins, there was a significant reduction in hsCRP, obviously a commonly used marker of inflammation at four weeks, and also based on data showing that there was a heightened inflammatory response in the early days following an acute coronary syndrome. So we felt that using this twice-daily dose would be advantageous and potentially helpful for our patients. So they're the two main differences between the studies.

Dr. Carolyn Lam:

Thanks for explaining that so clearly. Dharam, could I have your thoughts? This was, of course, discussed heavily, right, by the editors. Could you give us a sneak peek of what else was discussed?

Dr. Dharam Kumbhani:

The trial is very important, although it is smaller perhaps in sample size and kind of done with less resources than COLCOT. I do think this adds to the body of literature on colchicine for secondary prevention of CAD. And one of the interesting things is that we see we also have the LoDoCo2 trial, which was a slightly different population, Jamie, which was the chronic coronary artery disease patients, but also still looking at secondary prevention. What is really striking to me is that a very similar signal in non-CV death was noted in that trial as well. Again, it was not seen in COLCOT and LoDoCo1, but it was very interesting that a similar finding was there. So I do think this is something that the field will need to investigate more and really try to understand is this just noise and by chance alone, or is this something that that's a real signal for.

Dr. Carolyn Lam:

Jamie, what are your thoughts about that and in LoDoCo differences with your trial?

Dr. Jamie Layland:

Good question, and a very important topic that obviously is currently under discussion amongst the colchicine community. As I said, it was a surprising result. We weren't anticipating this non-CV death signal, but as Dharam said when LoDoCo2 came out, a fantastic trial again, but this signal of non-CV death. I don't know whether it's merely just a noise as you say or whether it's a significant finding, but clearly we need to do more research in this field to understand the mechanism and whether this is a real signal or not. It seems a little bit discordant with previously published work. So if you look at the literature in patients with gout from across the world, there's no real signal of increased non-CV death in those patients. However, with patients with acute coronary syndrome as we are administering the colchicine on a daily basis and then commonly this isn't used for gout, so that is a slight difference. But certainly, there was no signal in the non-CV literature to support the findings that we had and the signal in LoDoCo2.

Dr. Jamie Layland:

The other thing to note is in a cohort of five non-CV deaths, three out of those five patients were actually not taking colchicine at the time of their death. They stopped the drug prematurely. So I think we just need to take a step back and really await the results. Obviously, we've got two-year and five-year data coming out from the COPS trial which will be interesting to look at, but also the Clear Synergy trial from the McMaster team, that would be a very important trial providing more data on this potential signal. But reassuringly, and I feel more reassured knowing the COLCOT data, which is a slightly similar cohort to ours, showing that there was no trend towards increased non-CV deaths. So I think it's something that we have to be aware of and there will be lots of metro-analysis I'm sure being published in the coming months looking at this specifically. But yeah, I think we shouldn't cast any aspersions on colchicine yet. I think that's too early, but I do think we need more data.

Dr. Carolyn Lam:

Thanks, Jamie. Speaking of looking deeper in your data and looking at those who died and were they taking the medication and so on, you did some other post-hoc analysis, right? And maybe you could just describe briefly, for example, the 400-day followup.

Dr. Jamie Layland:

Yes. So the interesting thing with our data, and I had mentioned this before, is that we had limited resources, so we really wanted to do this trial, and obviously competitive funding is tricky at the best of times, but we were really committed to doing this trial and we had a group of investigators who were all committed to doing this trial. But for this to work, we had a single research nurse and a fellow performing the follow-up. So at times, there was a little lag between the timing of the follow-up. So we ended up getting follow-up which was slightly prolonged over the 12-month window. On average, it was around 400 days. When we looked at the 400-day data, we saw that there was an increasing separation of the biomarkers after 365 days.

Dr. Jamie Layland:

The results, this was obviously not the primary outcome, this was a sensitivity analysis, but there was a suggestion or a significance out to 400 days with an improvement with colchicine. However, this is the primary composite outcome, so revascularization, acute coronary syndrome, stroke, and total death notwithstanding this positive outcome, there was still this trend to high rate of mortality, so that has to be taken into consideration. But there was a suggestion that the longer the duration of colchicine was given for, it culminated into these lights affect. And we see from CT data that colchicine actually has some plaque-modulating effects and reduces high-risk or low-attenuation plaque. So you could hypothesize that as the majority of the benefits seen in colchicine in LoDoCo2, in COLCOT, and in COPS was the reductions in urgent revascularization, stroke, and acute coronary syndromes.

Dr. Jamie Layland:

So perhaps there is this effect that colchicine is having on plaque stabilization so we're seeing less longer-term events, but this is just hypothesis generated and we need more data to support that. But it is a very interesting finding nonetheless.

Dr. Carolyn Lam:

Thank you. Dharam, could I hand you the last word on where you think this field is going or where you think it should go?

Dr. Dharam Kumbhani:

I think Jamie put it really nicely. I think he outlined the study nicely with its strengths and its limitations, and I think this is obviously a debate between perhaps the colchicine believers and the ones that are still perhaps trying to understand a little bit more about its true role, because as was mentioned I think there's really a benefit in ischemia-driven revasc. I think we've seen that in almost all the colchicine trials. There is no reduction in mortality, and as we saw in the COPS data maybe it goes the other way. So I think from a pathophysiological standpoint it makes sense. I think there's good translational data to suggest that it would be beneficial in this patient population, but I think that's the beauty of having clinical trials and the ones that are done by different investigators and perhaps in different settings, because they help us answer the truth. And whether colchicine becomes a stable part of our armamentarium for secondary prevention of CAD going forward, I think the jury is still out and as was mentioned I think Clear Synergy would probably be very helpful in hopefully tying all this together.

Dr. Dharam Kumbhani:

So again, I want to congratulate Jamie and his team for really providing us with a very interesting trial done in a very pragmatic setting, and I think the field is very thankful to them for providing us with this information.

Dr. Carolyn Lam:

Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to join me and Greg again next week.

Dr. Greg Hundley:

This program is copyright the American Heart Association 2020.

Circulation November 10, 2020 Issue

9 november 2020 | 23 min

This week’s episode features author Kazuomi Kario and Associate Editor Wanpen Vongpatanasin as they discuss the article "Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis: Practitioner-Based Nationwide JAMP (Japan Ambulatory Blood Pressure Monitoring Prospective) Study."

TRANSCRIPT BELOW:

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, when is the best time to check your blood pressure if you have a home monitoring device? Morning? Afternoon? Nighttime? And what do those nighttime fluctuations infer? Well, we'll hear a lot more in our feature discussion today, but first let's grab a cup of coffee and jump into some of the other papers in the issue. I'm going to start first this week, and my first paper comes from Dr Joe Wu at Stanford University. Carolyn, a quiz. Are all endothelial cells alike?

Dr Carolyn Lam: Jeez, Greg. Okay, I'm going to hedge. I bet a lot of them share similarities, but there may be some differences.

Dr Greg Hundley: Yes, Carolyn. Dr Wu and his associates perform a series of elegant experiments involving mice, and they found that certain tissue-specific endothelial cells cluster strongly by tissue, like those in the liver or the brain, whereas others from, for example, adipose tissue or the heart have considerable transcriptomic overlap with endothelial cells from other tissues. They identified novel markers of tissue-specific endothelial cells and signaling pathways that may be involved in maintaining their identity, and sex was a considerable source of heterogeneity in the endothelial transcriptome. In addition, they found that markers of heart and lung endothelial cells in mice were conserved in human fetal heart and lung endothelial cells and identified potential angiocrine interactions between tissue-specific endothelial cells and other cell types by analyzing ligand and receptor expression patterns.

Dr Carolyn Lam: So interesting, Greg. You especially had me at sex differences. So, what's the take home message?

Dr Greg Hundley: Right, Carolyn. So this group discovered a series of transcriptional networks that maintain endothelial cell heterogeneity, and that angiocrine and functional relationships exist between tissue-specific endothelial cells. These findings open the door for future studies that can manipulate these pathways and perhaps modify processes, like atherosclerosis, that impact the endothelium.

Dr Carolyn Lam: Wow, that's cool, Greg. Well, from your paper, I'm going to a mechanistic paper too, and the next study really aimed to define cardiac fibroblasts' heterogeneity during ventricular remodeling, as well as the underlying mechanisms that regulate their function, so important questions here. And co-corresponding authors, Drs Prósper and Lara-Astiaso from Clinica Universidad de Navarra in Pamplona in Spain, as well as Dr Lindner from Maine Medical Center Research Institute in Scarborough, Maine in the U.S., and their co-authors, basically characterized cardiac fibroblasts after myocardial infarction using a whole host of very novel techniques like single-cell and bulk RNA sequencing, ATAC sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing.

Dr Greg Hundley: Very intriguing. What did they find?

Dr Carolyn Lam: They identified and characterized a unique cardiac fibroblast subpopulation that emerged after myocardial infarction in mice. These activated fibroblasts exhibited a clear profibrotic signature expressing high levels of collagen triple helix repeat containing 1 and localized into the scar. Moreover, the absence of this regulator resulted in pronounced lethality due to ventricular rupture. Finally, a population of cardiac fibroblasts with a similar transcriptome was identified in a swine model of myocardial infarction, as well as in heart tissues from patients with myocardial infarction and dilated cardiomyopathy.

Dr Greg Hundley: Ah, so important information on how fibroblasts start the scar formation after infarction. So, Carolyn what's the take home message here for this research?

Dr Carolyn Lam: Well, this paper really provides important information on cardiac fibroblast heterogeneity, their dynamics during the course of myocardial infarction, and the authors also redefine the cardiac fibroblasts that respond to cardiac injury and participate in myocardial remodeling. This study identifies collagen triple helix repeat containing 1 as a novel regulator of the healing scar process, and as a target for future translational studies.

Dr Greg Hundley: Great, Carolyn. You're doing such a great job. This is an issue for double quiz. Have you ever heard of treatments for hypertension incorporating Chinese herbal formula gastrodia-uncaria granules?

Dr Carolyn Lam: What? Are you trying to speak Chinese, Greg?

Dr Greg Hundley: Yeah (affirmative) Okay.

Dr Carolyn Lam: I'm sure you're going to tell us about it.

Dr Greg Hundley: Right. So this study is from Professor Yan Li from Ruijin Hospital in Shanghai, Jiao Tong University School of Medicine. Gastrodia-uncaria granules Carolyn, is a mixture of Chinese herbs that dates back many years, I think thousands, and in this study was used in patients with masked hypertension. So in the study, patients with an office blood pressure of less than 140/90 millimeters of mercury, but a daytime ambulatory blood pressure of 135 to 150 millimeters of mercury systolic or 85 to 95 millimeters of mercury diastolic, were randomized one-to-one to receive the treatment of, and I'm going to abbreviate it, GUG versus placebo, 5 to 10 grams twice daily for four weeks. The primary efficacy variable was the change in daytime ambulatory blood pressure.

Dr Carolyn Lam: Ah. (affirmative), so did it work?

Dr Greg Hundley: Well, in their intention-to-treat analysis, daytime systolic-diastolic blood pressure was reduced by 5 and 3 millimeters of mercury in the GUG group, and 3 and 1.6 millimeters of mercury in the placebo group, respectively. The between group difference in blood pressure reductions was significant, 2.5 and 1.7 millimeters of mercury, and 24-hour blood pressure by 2 and 1.5 millimeters of mercury, but not for the clinic and nighttime blood pressures. The per protocol analysis in 229 patients produced similar results. Only one adverse event, sleepiness during the day was reported and no serious adverse events occurred. So Carolyn, a potentially inexpensive regimen found useful in China for patients with masked hypertension. To learn more of the results of this interesting study, listeners are suggested to review the article in this particular issue.

Dr Carolyn Lam: Wow, interesting Greg. Okay. So from hypertension to CABG. Now we know that approximately 15% of saphenous vein grafts occlude during the first year after coronary artery bypass graft surgery, or CABG, despite aspirin use. So can ticagrelor added to standard aspirin improve saphenous venous graft patency at one year after CABG? Now this is the question that Dr ten Berg from St. Antonius Hospital from Nieuwegein in Netherlands, and colleagues sought to answer in the popular CABG trial, which was an investigator-initiated randomized double-blind placebo-controlled multicenter trial of 499 patients with one or more saphenous vein grafts, who were randomly assigned after CABG to ticagrelor or placebo added to standard aspirin. The primary outcome was saphenous vein graft occlusion at one year assessed with coronary CT angiography occurred in 10.5% of the ticagrelor group, versus 9.1% in the placebo group, so that's an odds ratio of 1.29, and it was not significant. The secondary outcome of one year saphenous vein graft failure, which was a composite of vein graft occlusion, revascularization, myocardial infarction in the myocardial territory supplied by the vein graft, or sudden death, well, that occurred in 14.2% of patients in the ticagrelor group, versus 11.6% in patients in the placebo group. Again, not a significant difference.

Dr Greg Hundley: So Carolyn, a negative study? What's our take home here?

Dr Carolyn Lam: In this randomized double-blind placebo-controlled trial, the addition of ticagrelor to standard aspirin after CABG did not reduce the rate of saphenous vein graft occlusions at one year. Now, this conclusion differs from some other studies that investigated this research question, and this is discussed in this editorial that you got to pick up. It's by Dr Goldman from the University of Arizona.

Dr Greg Hundley: Wow, Carolyn. Great job. Well, we've got a couple more articles in this issue, and I'll start by describing a research letter by Dr Daviet regarding heparin-induced thrombocytopenia in COVID-19, and then Carolyn there's a second research letter from our own Torbjørn Omland regarding established cardiovascular biomarkers provide limited prognostic information in unselected patients hospitalized with COVID-19. And then finally, from Dr Chonyang Albert, a case series entitled, The Enemy Within: Sudden Onset of Reversible Cardiogenic Shock with Biopsy-Proven Cardiomyocyte Infection by SARS-CoV2.

Dr Carolyn Lam: We've also got an ECG challenge by Dr Sreenivasan entitled, A Red Flag ECG, also known as, and have you heard of this, South African flag pattern. Okay, here's a hint. It's an important, but subtle ischemic ECG change. You got to look it up. There's an On My Mind paper by Dr Alexander on at risk of depriving patients’ life-saving cardiac surgery, and those are the implications of the ischemia trial for CABG. A Research Letter shared by Dr Susen entitled, Endotheliopathy is Induced by Plasma from Critically-ill Patients and Associated with Organ Failure in Severe COVID-19. And finally, in Cardiology News, Tracy Hampton reviews the most recent literature in top journals like Nature, Metabolism, Cell, Stem Cell, and Circulation Research. Wow. Bonanza issue. So cool, but I really want to hear about the different blood pressure patterns now. Let's go to our feature discussion, shall we?

Dr Greg Hundley: Absolutely. Here we go. Well, listeners we are excited to get to this feature discussion to learn more about the use of ambulatory blood pressure measures, particularly those that are collected 24 hours and during the nighttime. We have with us, Dr Kazuomi Kario from the Jichi Medical University in Japan, and our own Associate Editor, Dr Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas. Welcome to you both. And Kazuomi, could you start us off please and just describe some of the background that led you to perform this study? And what hypothesis did you want to address?

Dr Kazuomi Kario: The old guidelines management of the hypertension and now recommend instead of the office blood pressure, now the ambulatory blood pressure management. So for example, the ABPN and also home blood pressure monitoring, but the 24-hour blood pressure reduction is very much important, all prefer the values, but also our hypothesis took on the 24-hour blood pressure quantity reduction, but also, we should normalize our circadian rhythm. Usually blood pressure reduced by 10 to 20% at night during the sleep compared to the daytime. But the other group, is exhibited and predicated known six bars and also is either higher at night during the nighttime period compared to the daytime. And also home blood pressure variability, that hurts blood pressure in the morning. So circadian rhythm normalization and also, I recreate blood pressure variability especially is more precise. It's important for the quality control over for the hypertension management. So my hypothesis is that blood pressure reduction, the other most blood pressure, and the normalized circadian rhythm, under agitate, to keep agitate among as such. All the three components I did try to optimize 24-hour blood pressure control, so I want to confirm our hypothesis. To optimize 24-hour blood pressure control consists of these three components, 24-hour pressure reduction, and the normalize circadian rhythm and the keeping the other keep such, it shouldn't be; I have, have you left your prevention or not? That's my hypothesis and background.

Dr Greg Hundley: So with our 24-hour ambulatory monitoring evaluating in this study, do we have the normal dip during the evening? Do we have a rise associated with the circadian rhythm? What is the variability of the blood pressure over time? Tell us what study population, and how did you design this study to address your hypothesis?

Dr Kazuomi Kario: This population is the hypertension patients, 90% or more on the out-patients who keep the adequate, the active daily readings, and they are medicated, or usually conventional hypertension medication is the effective to reducing the office blood pressure and they can. But the other hypotension treatment may not be sustained to be reducing the nocturnal blood pressure and next morning people are taking pills. So it may be that the picture of the nighttime blood pressure and the morning blood pressure. So our hypothesis targets is already mitigated hypotension patient, but we should find out control for the current hypotension treatment. It should be the nighttime and next morning.

Dr Greg Hundley: So we're addressing whether the efficacy of or any hypertensive medications are maintaining low blood pressures at night and avoiding a surreptitious rise in blood pressure when we wake up. So how many patients did you enroll and what were your study results?

Dr Kazuomi Kario: The total study population number is 6,359 patients or enrolls. And we find out, compared to the daytime. Daytime also where the risk of the nighttime blood pressure other age, was more the precise this predictor of cardiovascular events. So, cardiovascular events consist of the atherosclerosis cardiac events consists of stroke and coronary artery disease. And also the nighttime blood pressure associated with the risk of the heart failure. And very interestingly, disrupted circadian rhythm, it rises at night higher during the nighttime compared to the daytime, it was independent of risks for the cardiovascular event, especially for the heart failure. So even after controlling for the daytime, even on the nighttime blood pressure, this pattern nighttime riser was an independent risk, so very interesting results.

Dr Greg Hundley: So elevations of systolic blood pressure during nighttime, during sleep were associated with future atherosclerotic cardiovascular disease, as well as heart failure. And one more quick point, was there a particular magnitude of rise of that systolic blood pressure at night was important. And did you find similar results for men and for women?

Dr Kazuomi Kario: Yes, similar results for men and the women. Theo other factor was age was increased. The almost the higher during the nighttime or other age of the rising pattern was 10 allowed during the nighttime compared to the daytime.

Dr Greg Hundley: So even a 10% increase in systolic blood pressure at night relative to daytime was important for forecasting these adverse cardiovascular events. So Juan pen, can you help us take these results from this elegant ambulatory monitoring study and put those in the context of other study results that have evaluated 24 ambulatory monitoring of blood pressure?

Dr Wanpen Vongpatanasin: I think the notion of nighttime blood pressure as the independent predictor of cardiovascular outcome has been shown in other cohort, but usually not this large magnitude, that is an international registry. I had call that in different countries around the world that demonstrate this. But again, like I said, it compiled from a smaller dataset, there's even fewer data sets in the United States. There's a cohort from Jackson Heart, but again, it's less than a thousand and most of other cohorts have looked at mostly a target organ level, not at the heart CV outcome. So I think this add to an important observation, and I think that the results from the nighttime it's similar, but extended from previously that look at individual outcome using a adjudicated data committee that also a very distinctive feature of the study that is a committee that look at this and look at a specific outcome rather than just a retrospective using the death index from different countries. The other part is slightly different perhaps, and they learn from reading it is the extreme dipping, also dropped a lot. Initially people think that it might be associated with the worst outcome, but even to me I wasn't sure what this mean, but in this study the most extreme dip, maybe not, not as much that shouldn't be worried as much compared to the actual nighttime blood pressure itself or not dipping itself.

Dr Greg Hundley: Kazuomi what do you see as the next study that needs to be performed in this area of research?

Dr Kazuomi Kario: Oh, it's the observational study of the current medical situations maybe kind of situations. So next step, we should focus on that nighttime blood pressure; regardless of the office and the daytime, so even there are controls, if we should target the nighttime blood pressure and the toxicity controls, organ damage should be decreased and the subsequent cardiovascular events should be decreased. So observational study targeting the nighttime blood pressure is the next topic.

Dr Greg Hundley: And Wanpen do you have anything to add to that?

Dr Wanpen Vongpatanasin:I'd like to see more large observational study from the US with the diverse population, because the salt consumption in Asia, particularly in Japan, are probably among the highest. So perhaps the nighttime blood pressure, it's confounded by high sodium and something, and we're not too far behind obviously, but it'd be nice to know what it means in the US. And obviously they're targeting nighttime blood pressure, it's the hot topic and that's by itself is probably another 30 minutes to an hour of discussion. But I think that that's very important area of research.

Dr Greg Hundley: Listeners, what a really wonderful discussion. And in this study from Japan of over 6,000 individuals treated for high blood pressure, those with 24-hour monitoring and exhibiting a rise in systolic blood pressure during the nighttime was associated with future cardiovascular events and an increase in the risk of heart failure. Moving forward from these experts, performing additional observational studies to confirm these findings and other populations, and perhaps a randomized trial, trying to target therapeutic interventions that would lower nighttime blood pressure may be warranted. Thank you Dr Kario and Dr Vongpatanasin. We wish you a great week and we look forward to catching you on the run next week. This program is copyright The American Heart Association, 2020.

Circulation November 03, 2020 Issue

2 november 2020 | 22 min

This week’s episode features author Karolina Szummer and Associate Editor Emmanouil Brilakis as they discuss the article "Comparison Between Ticagrelor and Clopidogrel in Elderly Patients with an Acute Coronary Syndrome: Insights from the SWEDEHEART Registry."

TRANSCRIPT BELOW

Dr Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature article, we're going to investigate antiplatelet therapy use, but in older patients, as opposed to those that are middle-aged, and have sustained a prior acute myocardial infarction. But, before we get to that, how about we grab a cup of coffee and jump into the other papers in the issue?

Dr Carolyn Lam: Absolutely, Greg. I've got my coffee right here, and I really want to start with a paper that adds to our understanding of, guess what, the sodium=glucose cotransporter 2 inhibitors, SGLT2 inhibitors, and their diuretic and natriuretic effects in combination with loop diuretics. Of course, a clinically really important question since now we know that SGLT2 inhibitors improve outcomes in patients with heart failure in whom they are likely to be co-prescribed with a loop diuretic. So, Professor Chim Lang from University of Dundee and his colleagues performed the RECEDE-CHF trial, which was a randomized double-blind placebo-controlled crossover trial of 23 patients with type 2 diabetes and HF REF taking regular loop diuretics who were randomized to the SGLT2 inhibitor empagliflozin 25 milligrams once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urine volume from baseline at week 6.

Dr Greg Hundley: So, empa versus placebo. What did they find?

Dr Carolyn Lam: In patients with heart failure and type 2 diabetes taking a regular loop diuretic, empagliflozin caused a significant increase in urine volume at both day 3 and week 6, compared to placebo, as well as empa also caused a significant increase in electrolyte-free water clearance. Though there was a small non-significant increase in natural uresis with empagliflozin at day 3, this was absent by week 6. These results suggest that empagliflozin may have an advantageous diabetic profile in patients with type 2 diabetes and heart failure in addition to loop diuretics, with only a short transient natriuresis.

Dr Greg Hundley: Very nice, Carolyn. Great information. Diuretics, heart failure reduced ejection fraction, and empagliflozin. Well, my clinical paper comes from Dr Renato Lopes from Duke University Medical Center, and this is a sub study from the ISCHEMIA trial that evaluates whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in patients with a history of heart failure or left ventricular dysfunction when the EF is greater than 35%, but less than 45%.

Dr Carolyn Lam: Aw, that mid-range ejection fraction. Favorite topic. So, Greg, what did they find?

Dr Greg Hundley: Those with heart failure and left ventricular dysfunction randomized to the invasive versus the conservative strategy had a lower rate of the primary outcome, 17% versus 29%. Whereas those without heart failure and left ventricular dysfunction did not, 13% versus 14%. A similar differential effect was seen for the primary outcome, all-cause mortality and cardiovascular mortality, when invasive versus conservative strategy associated outcomes were analyzed with LVF as a continuous variable for those with and without prior heart failure.

Dr Carolyn Lam: Wow, that is clinically important, Greg. So, can you summarize our take home message?

Dr Greg Hundley: Well, Carolyn, ischemia trial participants with stable ischemic heart disease and at least moderate ischemia with a history of heart failure or LV dysfunction, were at increased risk for the primary outcome. And in this small high-risk subgroup with heart failure and an ETF between 35% and 45%, an initial invasive approach was associated with a better event free survival. This result should really be considered for hypothesis generation and future studies.

Dr Carolyn Lam: Greg, for the next paper, do you remember hydrogen sulfide? The stuff we learned about in school. It's the gas with that characteristic foul odor of rotten eggs. Well, guess what? This whole paper is about hydrogen sulfide, and in the body, it actually has antihypertensive and anti-inflammatory effects, and its endogenous generation key enzyme is cystathionine gamma lyase, or CSE, and that's expressed in CD4+ T cells. So today's paper provides insights into how all of these players work together in the development of hypertension. To investigate the pathophysiological relevance of this CSE hydrogen sulfide system, co-corresponding authors, Doctors Geng and Cai from Fuwai hospital and Chinese Academy of Medical Sciences, Peking University Medical College, as well as Dr Xu from Peking University Health Science Center in Beijing. Well, they and their coauthors performed elegant experiments involving peripheral blood lymphocytes, isolated from hypertensive patients or spontaneously hypertensive rats. They also looked at mice with CSE-specific knockout in T cells, and CD4 null mice.

Dr Greg Hundley: Well, Carolyn, what did they find?

Dr Carolyn Lam: Well, they found that endogenous cystathionine gamma lyase, or CSE, and hydrogen sulfide, but not cystathionine beta-synthase, in lymphocytes, responded to blood pressure changes. Deleting CSE in CD4+ T cells exacerbated angiotensin II-induced hypertension by reducing circulatory and renal T regulatory numbers. Hydrogen sulfide from CSE self-hydrates, liver kinase 1, thereby activating the AMP kinase energy pathway to promote TReg differentiation and proliferation, which then attenuates the vascular and renal immune inflammation, and thus, prevents hypertension.

Dr Greg Hundley: Carolyn, this sounds like a very thorough study. What are the clinical implications?

Dr Carolyn Lam: Endogenous CSE hydrogen sulfide in lymphocytes may be both a potential biomarker of hypertension, or its complications, or hydrogen sulfide donor may be a therapeutic approach to lower hypertension.

Dr Greg Hundley: Great, Carolyn. Well, my next paper comes from Professor Goo Taeg Oh from Ewha Women's University, and it really involves the world of inflammation. So Carolyn, as you know, macrophages produce many inflammation-associated molecules released by matrix metalloproteinases, such as adhesion molecules, as well as cytokines, which play a crucial role in atherosclerosis. In this paper, the authors investigated the relationship between Ninjurin-1, or nerve injury-induced protein 1, a novel MMP9 substrate expression, and atherosclerosis progression.

Dr Carolyn Lam: Ninjurin-1? Interesting. So, what were the results?

Dr Greg Hundley: Well, Carolyn, Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls, as well as athero-prone, apolipoprotein E-deficient, or APOE -/- wild type mice. Two important findings, Carolyn. First, the authors in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted pro-inflammatory gene expression by activating mitogene-activated protein kinase, or MAP kinase, and inhibiting the phosphoinositide 3-kinase signaling pathway. Whole-body and BM-specific Ninj1 deficiencies significantly increase monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Now, in addition and secondly, macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessed both in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of the disorder in mice, regardless of the presence of Ninj1. So in summary, Carolyn, Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis.

Dr Carolyn Lam: Wow, Greg, that was incredibly summarized. Thank you. Let's go through what else there is in today's issue. In cardiology news, Bridget Kuhn talks about how the pandemic intensifies the push for home-based cardiac rehabilitation options. There's a white paper by Dr Ho and colleagues, including me, describing the diagnostic dilemma of HFpEF. There's a Research Letter by Dr Gill talking about the cardiometabolic trait sepsis and severe COVID-19, a Mendelian randomization investigation. There's also a Research Letter by Dr Wu on the atlas of exosomes microRNAs secreted from human iPSC-derived cardiac cell type.

Dr Greg Hundley: Carolyn, this issue is just packed with articles, because I've got five more to tell our listeners about. First, it's a research letter from Professor G. Hovingh, entitled, Inclisiran Durably Lowers LDLC and PCSK9 Expression in Homozygous Familial Hypercholesterolemia, The ORION-2 Pilot Study. Next, there's an ECG challenge from Dr Jason Gilge relating to AV conduction during atrial flutter. Next, Dr Keith Churchwell has a nice piece related to the importance of those involved in cardiovascular care and participating in their civic duties, including voting. Next, Professor Karthikeyan has nice On My Mind related to overestimation of stroke risk and rheumatic mitral stenosis and the implications for oral anticoagulation. And finally, Carolyn, another research letter, from Dr Pieter van Paassen, entitled, Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19. Well, Carolyn, how about we get on to our feature discussion and review in older patients, which antiplatelet therapy may be safest?

Dr Carolyn Lam: Let's go!

Dr Greg Hundley: Well, listeners, now we're turning to our feature discussion, and today we'll talk about antiplatelet therapy. And then we have with us, Dr Karolina Szummer from Karolinska Institutet, and our own Associate Editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Welcome to you both, and Karolina, let's start with you. Could you describe for us your hypothesis and some of the background information that led you to perform this study?

Dr Karolina Szummer: Thank you so much for having me here and for sharing the ideas behind our study. Current recommendations recommend that we use high-potent antiplatelet agents for treating myocardial infarctions, and in particular, elderly patients are not included. So we decided to do an observational study to look at patients in our Swedish registries treated for myocardial infarctions who were 80 years and older. Dr Greg Hundley: Very nice. Can you tell us a little bit more about your study design? And also the study population?

Dr Karolina Szummer: The startup populations are all patients who were admitted to an acute coronary care unit for treatment of myocardial infarctions, and they were all 80 years and older, and they were included from 2010 to 2017. So this encompasses the period during which treatment with ticagrelor was introduced. So we are comparing to ticagrelor versus clopidogrel for the outcomes during the year, following the myocardial infarction.

Dr Greg Hundley: And how many patients did you enroll in the study? And what were your study results?

Dr Karolina Szummer: We enrolled, in total, 14,000 patients, and these consisted of non-STEMI and of STEMI patients. The majority, about two thirds, were non-STEMI patients. We show, in this study, elderly patients have a lower risk of readmission for myocardial infarction or stroke, but they have a higher risk of having readmission for bleeding and death. So the risk-benefit ratio seems to be skewed towards having, probably, more harm with ticagrelor being more risky than clopidogrel in this study population of elderly.

Dr Greg Hundley: And was this true for both men and for women?

Dr Karolina Szummer: Yes. So this was true for both men and women. And we did a sensitivity analysis. We looked closer at those who are younger than 80 years old, and in this patient population, the results selected in the same way as for our cohort of elderly, they actually did have the same benefit with a low risk of MI, stroke, and death, and high risk of bleeding. But in the elderly, we noticed a signal towards harm with an increased risk of death.

Dr Greg Hundley: It sounds like with ticagrelor, did we have a lower risk of death and a slightly lower risk of myocardial infarction and stroke, but a higher risk of bleeding? Was that the findings?

Dr Karolina Szummer: So for the elderly, there was a high-risk of death and bleeding with ticagrelor compared to clopidogrel, but a lower risk of ischemic component of MI and stroke.

Dr Greg Hundley: And then with those under 80, those were the ones that had the lower risk of death, lower risk of MI and stroke, but the higher risk of bleeding?

Dr Karolina Szummer: Yes, that's correct. So really the end point that differs most is that there is sustainment towards higher mortality in the elderly, because in both younger and elderly, the risk of readmission for bleeding was elevated in both.

Dr Greg Hundley: Now, let's turn to our own Associate Editor, Manos Brilakis. Manos, can you help us put these results into perspective, relative to other studies that evaluate the efficacy of antiplatelet therapy, post myocardial infarction?

Dr Emmanouil (Manos) Brilakis: I would like to start by congratulating Dr Szummer. It's a wonderful paper, and, I think, provide some new insights on how to use the medications in the ACS patients. And going on the background, if we look at the guidelines, both the European guidelines, as well as the American guidelines, what they say is that both ticagrelor, as well as prasugrel, are preferred and recommended for patients with ACS, both non-ST elevation ACS, as well as ST segment elevation myocardial infarction. And actually, European guidelines say that clopidogrel should only be used when prasugrel or ticagrelor are not available or are contraindicated. And this is based on two trials. One is the PLATO trial, and the other is the TRITON-TIMI 38, that both showed, actually, more benefit with the more intensive P2Y12 inhibitors. And this is what is extrapolated to all patient populations. But as you've heard before, there was only a minority of elderly patients that were included in those trials, about 13% to 15%, and that is why the present study is important, because it suggests that maybe we should look more carefully into the patient's age and potentially other characteristics like frailty or other comorbidities, that might actually alter the risk-benefit ratio. And maybe those medications should not be routinely given to all patients, but perhaps, elderly patients, or at least some of them, might not require, and actually be better off with clopidogrel.

Dr Greg Hundley: Let's turn back to Karolina. Karolina, the study was observational. What do you see as, perhaps, a next study to follow up the results that you've brought to us with this study? Dr Karolina Szummer: So the next step would definitely be to do a randomized control trial in the elderly to explore this topic further, to really know for sure what the safety and efficacy is, and what's the best treatment would be for these patients.

Dr Greg Hundley: Very good. And Manos, do you have anything to add?

Dr Emmanouil (Manos) Brilakis: One more thing. So, there was actually a trial that compared ticagrelor as well as prasugrel with clopidogrel in elderly patients that was called the POPUlar AGE trial that was published last year. And actually this one, published earlier this year, and actually this trial randomized a thousand patients who were more than 70 years old, to either more-intensive or less-intensive. And the results were actually very similar to the findings from Dr Szummer's study from SWEDEHEART, showing that there was more bleeding without any ischemic benefit. And didn't show actually higher mortality but didn't show any significant benefit. So that actually adds to the data that maybe the elderly patients, the selection of antiplatelet agent should be taken into account. And I think for me, this also extrapolates the high bleed risk, higher risk of bleeding, based on criteria, which we currently use mainly for duration. We say, for example, if you're precise DAPT score, which is a score for determining risk of bleeding, is high, you should consider shorter duration of DAPT, but it doesn't say anything about the type of DAPT. And for me, this makes sense that the high bleeding risk, and age is one of the main risk factors for high bleeding risk, should be taken into account also for determining the type of P2Y12 inhibitor.

Dr Greg Hundley: Well listeners, we've had a great discussion with Karolina Szummer from Karolinska Institutet, and our own Manos Brilakis from the Minneapolis Heart Institute, really reviewing the utility of ticagrelor versus clopidogrel in older individuals, above the age of 80, that have sustained myocardial infarction, and identifying that ticagrelor is associated with a higher risk of death and bleeding, as opposed to clopidogrel, opening the question up as to whether further studies in older individuals need to be performed to examine the efficacy of antiplatelet therapy. So, on behalf of Carolyn and myself, we wish you a great week and look forward to catching you On the Run next week. This program is copyright the American Heart Association, 2020.

Circulation October 27, 2020 Issue

26 oktober 2020 | 26 min

This week’s episode includes author John McMurray and Associate Editor Brendan Everett as they discuss the effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction.

TRANSCRIPT BELOW:

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, I hear you might have an interesting feature paper?

Dr Carolyn Lam: Oh, yes. I think everyone's going to look forward to this one, because we cannot get enough of the DAPA-HF study. This is another very important prespecified analysis, looking at the effect of dapagliflozin on outpatient worsening of patients with heart failure with reduced ejection fraction. Very important stuff coming right up, but first, I've got two papers looking at congenital heart disease that I'd like to share with you, Greg. Have you got your coffee?

Dr Greg Hundley: Yeah, I do. Let's get going.

Dr Carolyn Lam: Well, as you know, the mechanisms of congenital heart disease associated right ventricular dysfunction are not well-understood. And so, in this first paper, Dr Reddy from Stanford University and colleagues assessed lipid peroxidation, a potent form of oxidative stress, as well as mitochondrial function and structure, in right ventricular myocardium, collected from patients with and without right ventricular failure. And what they found, was that right ventricular failure was characterized by increased oxidation of membrane phospholipids, known as lipid peroxidation and its products, such as 4-hydroxynonenal, or 4-HNE. Now, 4-HNE binds to metabolic and mitochondrial proteins, and was associated with decreased myocardial energy generation and mitochondrial structural disruption with increasing severity of right ventricular hypertrophy and right ventricular failure. Mechanistically, the authors showed that 4-HNE was sufficient to decrease energy generation by inhibiting electron transport chain complex activities and mitochondrial dynamics.

Dr Greg Hundley: Dr Carolyn, a lot of mechanism here. So clinically, what are the implications?

Dr Carolyn Lam: I thought you'd ask. Well, since standard heart failure therapies, such as ACE inhibitors and beta blockers, are ineffective in the treatment of right ventricular failure, developing therapies focusing on new targets, such as what we talked about, the lipid peroxidation, could improve right ventricular function in congenital heart diseases by improving mitochondrial energy generation and cardiomyocyte survival.

Dr Greg Hundley: Ah, very interesting, Carolyn.

Dr Carolyn Lam: Thank you. The next paper, also very interesting, this time focusing on Tetralogy of Fallot, the most common cyanotic congenital heart disease. Now, this is from Dr Marijon from Hôpital Européen Georges-Pompidou in France and colleagues who highlighted, first, that sudden cardiac death represents an important mode of death in these patients with Tetralogy of Fallot, yet data evaluating the ICDs in these patient population, really, has remained scarce. And so, they use the nationwide French registry to include 165 patients with Tetralogy of Fallot with an ICD initiated in 2010 by the French Institute of Health and Medical Research. 63%, by the way, of these ICDs, were used for secondary prevention.

Dr Greg Hundley: Ah, Carolyn, I can't wait to see. What did they find?

Dr Carolyn Lam: So during a median follow-up of 6.8 years, 47% of patients received at least one appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% overall, 7.1% in the primary prevention, and 12.5% in the secondary prevention cohorts, respectively. 43% of patients presented with at least one ICD complication, and, importantly, QRS fragmentation was the only predictor of appropriate ICD therapies. So, even before you asked me, Greg, the take home message is, patients with Tetralogy of Fallot and an ICD, experience high rates of appropriate therapies, including those implanted for primary prevention. The considerable long-term burden of ICD-related complication, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria, including QRS fragmentation, might improve our risk prediction.

Dr Greg Hundley: Oh, very nice summary, Carolyn. Learned a lot there. Well, I'm going to steer us to two other papers in the issue, and the first one is from the world of basic science, and it's from Dr John Cooke from the Houston Methodist Research Institute. So Carolyn, the angiogenic response to ischemia restores perfusion, so as to preserve tissue. Something we all know. A role for mesenchymal to endothelial transition in the angiogenic response is controversial, and this study utilized a murine model of hindlimb ischemia and an in vivo Matrigel plug assay, together with lineage tracing studies and single-cell RNA sequencing, to examine the transcriptional and functional changes in fibroblasts in response to ischemia, to determine if resident fibroblasts contribute to angiogenesis.

Dr Carolyn Lam: Ah, it's so interesting. Do fibroblasts contribute to angiogenesis? What did they find, can't wait?

Dr Greg Hundley: Yeah, Carolyn. So, in both mice and human-isolated fibroblasts, these author studies indicated the presence of subsets of tissue fibroblasts, which seemed poised to contribute to the angiogenic response. And the expansion of these subsets with ischemia was dependent upon activation of innate immune signaling, and this signaling contributed to recovery of perfusion and preservation of ischemic tissue. Really interesting findings. Didn't suspect the fibroblasts as being the contributors here.

Dr Carolyn Lam: Very nice, Greg. Thank you. You've got another one.

Dr Greg Hundley: Yes. So the next study is from Professor Phillips Tsao from Stanford University School of Medicine. Well, Carolyn, this is a genome-wide association study, and it's from the Million Veteran Program, testing 18 million DNA sequence variants in patients with abdominal aortic aneurysms. In the study, they identified 7,642 cases and 172,172 controls in veterans of European ancestry, with independent replication and another study in 4,009 72 cases and 99,858 controls.

Dr Carolyn Lam: Wow.

Dr Greg Hundley: So it's nice, they have a replication study. The authors then use Mendelian randomization to examine the causal effects of blood pressure on abdominal aortic aneurysms. And they examine the association of abdominal aortic aneurysm risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and lastly, derived a genome-wide polygenic risk score to identify a subset of the population at greater risk for disease.

Dr Carolyn Lam: Wow. So a GWA study with replication to identify those at risk for abdominal aortic aneurysms in huge cohorts. What did they find?

Dr Greg Hundley: Well, Carolyn, this study was managed by one of our experts in GWA studies, Dr Wendy Post, and through GWAs, the authors identified 14 novel loci, and there were already 10, so it brings the total number of significant abdominal aortic aneurysm loci to 24. So a new finding there. And in their Mendelian randomization analysis, they demonstrated that a genetic increase of 10 millimeters of mercury in diastolic blood pressure, as opposed to systolic blood pressure, likely had a causal relationship with the future development of abdominal aortic aneurysms. They observed that 19 of those 24 aortic aneurysm risk variants associate with aneurysms in at least one other vascular territory. And then lastly, a 29 variant polygenic risk score was strongly associated with abdominal aortic aneurysms, independent of family history and smoking risk factors. So Carolyn, in conclusion, the authors in this study identify novel abdominal aortic aneurysm genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of abdominal aortic aneurysms, independent of their family history. And their data suggests that perhaps extending current screening guidelines to include testing for those with high polygenic abdominal aortic aneurysm risk, would significantly increase the yield of many of our current screening algorithms, as you know, that predominate based on smoking and age.

Dr Carolyn Lam: Wow. Very, very impressive and convincing data. Thanks, Greg. Let me tell you about other papers in today's issues. There's a research letter by Dr Tiburcy on inhibition of prolyl-hydroxylase domain enzymes, and how that protects from reoxygenation injury in the engineered human myocardium. There's another research letter from Dr Ohbe, entitled, The Risk of Cardiovascular Events after a Spouse's ICU Admission. And, one more from Dr Ganatra, on chimeric antigen receptor T cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma.

Dr Greg Hundley: You know, Carolyn, our research letters, they really pack a punch. Such very interesting research, in a nice concise format. I've got some other publications. So first, there's an On My Mind piece from our own Charlie Loewenstein, and also Dr Solomon from Boston, Massachusetts, involving, Severe COVID-19 as a Microvascular Disease, does endothelial exocytosis drive COVID-19? And next, there's a case series entitled, ECMO Therapy for Cardiac Lymphoma, and it's from Dr Oscar Cingolani. And then finally, Carolyn, a very nice ECG challenge from Dr Bansal, related to identifying the location of an AV block. Well, Carolyn, I'm really excited to get onto your feature discussion.

Dr Carolyn Lam: Let's go, Greg. Today's feature discussion looks at a prespecified analysis of DAPA-HF. My goodness, I don't think we can get enough of the data from DAPA-HF, and we have none other than be corresponding author, Dr John McMurray from University of Glasgow, to discuss this exciting paper, as well as our associate editor, Dr Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts. So John, today's feature paper, all about outpatient worsening of heart failure. Could you please start by defining what we meant by that, and why is it so important?

Dr John McMurray: Our interest in this actually started back when we did PARADIGM and we had collected, in a not very systematic way, information about episodes of outpatient worsening, so by that, I mean episodes of worsening symptoms and signs, not leading the patient to go to the emergency department or be admitted to hospital. The sort of worsening that a patient might tell you about in your outpatient clinic, say they're a bit more breathless or they've got a bit more ankle swelling, and you do something about it. And that's the critical part. You decide to increase their dose of diuretic, add another drug. And in PARADIGM, we find that those episodes, first of all, were quite common, and secondly, and most importantly, we're actually prognostically very significant. They were associated with worse outcomes. So in that HF, we decided that we would collect these more systematically, we would try and define them a little bit more robustly, so we would require the investigator to report worsening signs and symptoms, and we also wanted evidence that additional treatment had been given and then that had been sustained for at least a month, because, as you know, diuretic dose can increase and decrease. Then we prespecified, as you said, Carolyn, that we would then incorporate those manifestations of worsening, as an additional component to our primary composite endpoint, which was cardiovascular death, heart failure hospitalization, worsening of heart failure requiring intravenous therapy, so an urgent visit for that, that would often be in an emergency department, and then in addition to that, this further manifestation of worsening as the extra component to this broader composite outcome that we hoped would encompass the whole range of worsening of heart failure that a patient might experience.

Dr Carolyn Lam: Thanks so much, John, and you actually preempted my question of how it differed from the original primary outcome that included urgent heart failure visits, intravenous diuretic use, but not these nuance outpatient intensification of heart failure therapy that I really salute you for prospectively collecting information on. So could you summarize what you found, please?

Dr John McMurray: Well, first comment to make, Carolyn, is that we included those urgent visits requiring intravenous therapy, because, as you know, in the U.S., I think there is a move to try and avoid admission and to treat patients in the ambulatory care setting or non-ward setting. Although, I have to say, as it turned out, those episodes of worsening were very infrequent. There was, I think, 33 in total in DAPA-HF, compared to almost 600 of the other episodes of worsening. The ones that we almost feel at a brainstem reflex level when we see patients in our clinics. So what did we find? Well, we find that when you add those episodes of worsening, then, of course, you considerably increase the proportion of patients who have, from what you might call, the most trivial manifestation, worsening the events we just talked about, all the way through to the very worst, in other words, death, from cardiovascular causes, in fact, so much so, that by about two years of follow-up, the Kaplan-Meier rate for that expanded composite endpoint was about 33%. And, as you know, Carolyn, we're talking about a trial that enrolled patients who were very well-treated by conventional standards and who, by and large, had mild symptoms, but 70% were NYHA class II. And yet, within two years, if you take into account all of these different manifestations of worsening, we had about one-in-three people in the placebo group that deteriorates, and we reduced the risk of deterioration with dapagliflozin, we reduced the instance of that expanded composite endpoint by 27%, and that was a highly statistically significant result. And if you like numbers needed to treat, then for that expanded very broad composite endpoint, the number needed to treat over the median follow-up of 18.2 months, was only 16. And by the way, we did confirm that those outpatient worsening events were prognostically significant as well.

Dr Carolyn Lam: Very good. Brendan, could I bring you in on this? It's got such great implications, maybe you could share a little bit about what the editors thought when we saw this paper?

Dr Brendan Everett: One of the key things that the editors thought when they reviewed this, was the fact that, as you pointed out, you collected these outpatient worsening episodes prospectively across the trial and did so in a very rigorous and systematic way. And I think for those of us who take care of patients with heart failure, which of course is most cardiologists, these kinds of episodes where your patient calls you and their weight's gone up, or where they've gotten a little more short of breath, then you, over the phone, intensify their diuretic regimen, are incredibly common, and, of course, bothersome to the patient and challenging for the clinician who's caring for the patients too. So I think, in that sense, it's a really important paper. That was the other aspect, I think, that the editors were interested in. But the impact, the clinical impact on day-to-day care of patients with heart failure, was substantial. The other part that I found intriguing, because of course, when you're caring for individual patients, you don't have a sense, necessarily, of what these episodes mean in a broader population for those patients' overall risk of bad outcomes. So you mentioned it right at the end when you were speaking a moment ago, about the association of these outpatient intensifications of oral diuretic therapy and their association with future bad outcomes within the trial. Could you tell us a little bit about what those were and why they ended up seeming so important, both to patients and to you as the trialist?

Dr John McMurray: We write about these being common, in fact, in the placebo group in DAPA-HF. I think it was 14% of patients had one of those episodes of outpatient worsening. And again, as you correctly identified, in the majority of cases, the therapeutic intervention by the physician, was simply to increase the dose of diuretic, although, actually about 40% of people also, at some point, had the addition of another drug. So, in terms of the significance of those events, in PARADIGM, we find that they appeared to be associated with almost the same impact on mortality as being admitted to hospital with worsening heart failure. But in fact, in DAPA-HF, where we collected more of these events, so maybe we collected, perhaps, the more severe cases in DAPA where we collected them systematically, we find that the prognostic impact wasn't quite as large. So for example, if you were admitted to hospital with heart failure during DAPA-HF, then you were six-times more likely, subsequently, to die in that rather short follow-up period, than if you had no manifestation of worsening. On the other hand, if you had an outpatient episode of worsening, then it was around a three-fold higher risk of death than if you had no manifestation of worsening. So, my take home from this was that these episodes really do matter to patients. Not only, of course, do they matter because it means the patient doesn't feel so good, but they matter because that patient suddenly is on a different prognostic trajectory, and you can change that by intervening. So these events are common, they're prognostically bad news, and fortunately, we can reduce them. And maybe the last thing to say, which I also didn't mention, I apologize, was that, of course, if you look at that expanded endpoint, as you can imagine, because there's so many events now, you see the effect of treatment very, very quickly. So by day 27 after randomization, in other words, by day 27 after starting dapagliflozin, we had a statistically significant reduction in the occurrence of that comp standpoint, that then remained significant thereafter.

Dr Brendan Everett: Thanks, John. I had one other question that I hope doesn't take us too far into the weeds, but I think as a clinician, when you care for these patients, you try to intensify their outpatient therapy, and when that seems to fail, the patient then becomes admitted to the hospital. And I thought it was very interesting and thoughtful the way that you approach that problem, in other words, you have potentially, of this composite endpoint, you have the outpatient worsening that comes first, and then it's followed, in many cases, by a hospitalization for heart failure. How did you tease those two apart? And what analyses did you do to make sure that what you were really measuring was the effect of the outpatient intensification, rather than really just a prelude to a hospital?

Dr John McMurray: Very good question, Brendan. So, obviously, we were concerned about the possibility of double counting, so we did a primary analysis in which we built in a blanking window. So, for example, if you had an episode about outpatient and you or I increased the patient's oral therapy, but within 30 days, they were admitted to the hospital, then in our analysis, that patient only counted once, and the event that counted was the hospital admission, not the outpatient episode of worsening. And then, as I said, we did a number of sensitivity analyses where we adjusted the length of that blanking period, because we recognized, obviously, that some people, that episode of outpatient worsening that you intervene for, your intervention may not work and they may still get hospitalized. So we try to, as you obviously identified when you read our manuscript, we tried to counter that by not double counting episodes of outpatient worsening that were closely adjacent to the hospital admission.

Dr Carolyn Lam: Could I end with just one quick question? You've published many times with us at Circulation, and I'd like to think that that's from a very good experience with us, with working with us, and I've noticed even in this discussion, it's just so interesting the exchange. And so, John, could you say a few words about publishing in Circulation, and why do it?

Dr John McMurray: Well, obviously it's our leading cardiovascular journal. As I was being trained as a fellow, it was every fellow's aspiration to publish a paper in Circulation. So reputationally, obviously, it's very, very important. But why do I like Circulation other than that? Well, first of all, you handle papers quickly and efficiently. I think you're very fair. I really like the reviews. So I would say one of the greatest frustrations most authors, and certainly I know that from my own experience, is when you get poor reviews. I don't think I get those from Circulation, so you obviously have a much higher quality review. I like the way the editors give you guidance about the manuscript and how to respond to the reviewers. That's really, really helpful, because sometimes you think, "Well, that reviewer’s comment doesn't make sense. Do I have to really do that?" But often, your replies to me, come with guidance about how to handle the different reviewers’ comments. So, all in all, it's fair. I would say that's always important. Everybody will not get every paper accepted, but I think you get a very fair response from Circulation. It's good. It's thoughtful. So, that's fine.

Dr Carolyn Lam: Thank you so much, John. I'm sure I'm speaking on behalf of Brendan as well, and kudos to him because obviously he managed this paper so well. Thank you, audience, for joining us today on Circulation on the Run. So don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association.

Circulation October 20, 2020 Issue

19 oktober 2020 | 25 min

This week's episode includes author Daniel Lackland and Associate Editor Mercedes Carnethon as they discuss the article "Forty-year Shifting Distribution of Systolic Blood Pressure with Population Hypertension Treatment and Control."

TRANSCRIPT BELOW

Dr Greg Hundley: And I'm Greg Hundley associate editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature is good news. What do I mean by good news? It's going to be a tale of how hypertension has evolved in the Southeastern United States. And it's going to review how that's progressed its treatment efficacy in both those of white, and men and women of black race. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in this issue.

Dr Carolyn Lam: Man, you got my attention, Greg. You definitely got my attention.

Dr Greg Hundley: Very good. Well, Carolyn, my first paper is from the world of basic science, and it's from Dr Maya Kumar from Stanford University School of Medicine. This group maps the step wise remodeling of pulmonary arteries in a robust chronic inflammatory mouse model of pulmonary hypertension. A model that demonstrates pathologic features of human disease, including right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation and perivascular inflammation, all of those combined. And the author sought to define the cell behaviors underlying each stage of vascular remodeling, and identified a pathway required for neointima formation with the premise being that this understanding could be pivotal in modulating progression of disease in pulmonary hypertension.

Dr Carolyn Lam: Nice. So what did they find?

Dr Greg Hundley: Well, Carolyn, they found surprisingly. The neointima arises from smooth muscle cells and not the endothelium. Medial smooth muscle cells proliferate broadly too thick in the media, after which a small number of smooth muscle cells are selected to establish the neointima. These neointimal founder cells subsequently undergo massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery smooth muscle cell population is heterogeneous, and the authors identify a Notch3-marked minority subset of smooth muscle cells as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension, thus perhaps providing a new mechanism from which to test therapies to thwart the progression of disease in those with pulmonary hypertension. Very interesting basic science work.

Dr Carolyn Lam: Yeah. And very important too. Thanks Greg. Well, I've gotten another basic science paper too. First, let me ask you, do you think of DNA methylation much?

Dr Greg Hundley: We hear a lot about that, Carolyn. Methylation and changing DNA and how it might be transcribed. Tell us more.

Dr Carolyn Lam: DNA methylation is indeed a mechanism of gene transcription regulation. It's recently gained a lot of attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, the authors Dr Stenzig from University Medical Center, Hamburg-Eppendorf and colleagues knocked out the main de novo DNA methyltransferase in cardiomyocytes. Also, called DNMT3A in human induced pluripotent stem cells. They then assess the functional consequences of DNA methylation deficiency under control and stress conditions in human engineered heart tissue from these knockout derived cardiomyocytes.

Dr Greg Hundley: Wow, Carolyn. So what did they find here?

Dr Carolyn Lam: Three main consequences of DNMT3A knockout. Number one, there were gene expression changes of contractile proteins, such as higher atrial gene expression. Number two, there was ever an activation of the glucose lipid metabolic regulator PPAR gamma, which was associated with accumulation of lipid vacuoles in these knockout cardiomyocytes. And number three, HIF-1 alpha protein instability occurred, which was associated with impaired glucose metabolism and lower glycolytic enzyme expression rendering the knockout engineered heart tissues sensitive to metabolic stress such as serum withdrawal and restrictive feeding. So in conclusion, these results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.

Dr Greg Hundley: Wow, Carolyn. That was really fascinating, especially helping us understand how DNA methylation is operative, great summary there, and it's just organized so well. Learned a lot from that. I'm going to switch back and move into the world of clinical science on this next article. And it really fascinating, projecting outcomes using some biomarkers that I hadn't heard of previously. This paper is from Dr Alan Maisel from University of California, San Diego School of Medicine, and it evaluated the utility of advanced biomarkers for discriminating type one versus type two MI in patients presenting to the emergency room. In the study, two cardiologists adjudicated type one and type two MIs and six biomarkers were analyzed cardiac troponin I, copeptin, mid-regional pro-atrial natriuretic peptide, C-terminal proendothelin-1, mid-regional pro-adrenal Mendelian, and finally procalcitonin. And the prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular events or mace included the composite of acute MI, unstable engine of petrous, re-infection, heart failure, and stroke at 180 days of follow-up.

Dr Carolyn Lam: So what did they find with these very interesting biomarkers, Greg? Were they able to distinguish type one from type two MI?

Dr Greg Hundley: Great question, Carolyn. So among 2,071 patients type one MI and type two MI were adjudicated in 94 and 176 participants, respectively. Patients with type one MI had higher levels of cardiac troponin I while those with type two MI had higher baseline levels of all of the other biomarkers. Next, combining all the biomarkers resulted in a similar accuracy to a model using clinical variables and cardiac troponin I, and the addition of the biomarkers to the clinical model yielded the highest AUC, under the curve. Next, other biomarkers, but not cardiac proponent was associated with mortality and mace at 180 days among all the patients with no interaction between the diagnosis of type one or type two MI. Then conclusion, Carolyn, the assessment of these new biomarkers, reflecting pathophysiologic processes occurring with type two MI may help differentiate it from type one MI. Additionally, all the biomarkers measures except cardiac troponin I were significant predictors of prognosis regardless of the type of MI, both type one and type two.

Dr Carolyn Lam: That's really cool, Greg. Thanks. I'm going to end with a clinical paper too, and maybe ask you, Greg, you know so much about AI playing a role in cardiac MRI. Do you think it could do that in echo too?

Dr Greg Hundley: Leading question, Carolyn. Now, you have expertise in this area as well. I bet it could be helpful. Tell us what you've got in this paper.

Dr Carolyn Lam: Well, automated interpretation of echocardiography with deep neural networks and AI could support clinical recording and improve efficiency. Now while prior studies evaluated spatial relationships using still frame images and echo these authors who were led by Dr Tsai from National Cheng Kung University Hospital and college of medicine in Taiwan, these author's aim was to train and test a deep neural network for video analysis by combining spatial and temporal information to automate the recognition of left ventricular regional wall motion abnormalities on echo. So they collected a series of transthoracic echocardiogram examinations performed between July 2017 and 2018 in two tertiary care hospitals. Regional wall abnormalities were defined by experienced physiologists and confirmed by train cardiologists. First, the authors developed a 3D convolutional neural network or CNN model for view selection to ensure stringent image quality control. Second, a unit model segmented the images to annotate the location of each left ventricular wall, and third, a final 3D CNN model evaluated echo videos from four standard views before and after segmentation and calculated a wall motion, abnormality confidence level for each segment.

Dr Greg Hundley: Very nice, Carolyn. So a lot going on to identifying the wall and then performing analysis on those walls' segments. So what did they find?

Dr Carolyn Lam: So when a series of more than 10,600 echoes, their view selection model identified 6,454 or 61% of exams with sufficient image quality. The external validation was performed in 1,756 exams from an independent hospital. The final model recognizes regional wall motion abnormalities, and the cross validation and external validation datasets with an area under receiver operating characteristic curve of impressive now 0.91 and 0.89 respectively. In the external validation dataset, the sensitivity was almost 82% and specificity also almost 82%. And so in echo exams of sufficient image quality, it is feasible from this work for deep neural networks to automate the recognition of regional wall motion abnormalities using temporal and spatial information from moving images, further investigation is required to optimize the model performance and evaluate clinical application.

Dr Greg Hundley: Sounds very exciting. Helping facilitate the identification of regional wall motion abnormalities. Well, how about if we jump into some of the other articles in the issue, would you like to go first?

Dr Carolyn Lam: I'd love to Greg. There's Research Letter from Dr Wu on patient-specific induced pluripotent stem cells and how they implicate intrinsic impaired contractility in the hypoplastic left heart syndrome. There's an In-Depth paper by Dr McEvoy on lifelong aspirin for all in secondary prevention of chronic coronary syndrome. Is this still sacrosanct or is reappraisal warranted? In our Cardiovascular Case Series, Dr Grodin talks about an uncommon disease in a rare location, the mystery of the rapidly progressive cardiomyopathy. A very interesting one. You have to read it. We have a Research Letter from Dr Golbus on changes in type of temporary mechanical support device use under the new heart allocation policy. There's an ECG challenge by Dr Choxi entitled entitle, 􀍞􀁞how me the P wave.􀍟 Very interesting title. You got to pick it up. And there's an On My Mind paper by Dr Thibodeau on telehealth for uptight titration of guideline directed medical therapy and heart failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got a couple of letters. First, there's an exchange of Letters to the Editor regarding the article 􀍞􀀾ow Attenuation Noncalcified Plaque to Predict Myocardial Infarction: Are We There Yet?􀍟 And it's from Dr Alfonso and then a response from Dr Williams, and finally, a Research Letter entitled The Effectiveness of Deep Sedation for Patients with Intractable Electrical Storm Refractory to Antiarrhythmic Drugs. And it comes from Dr Raphaël Martins. Well, Carolyn, how about we move on to that feature article and learn more about hypertension in the Southeastern United States?

Dr Carolyn Lam: You had me waiting right from the start, Greg. Let's go.

Dr Greg Hundley: Well, listeners, welcome to our feature discussion today. And we're going to be reviewing a paper regarding hypertension and with us, we have Dr Daniel Lackland from Medical University of South Carolina and our own associate editor, Mercedes Carnethon from Northwestern University. Welcome to you both. Well, Dan let's get started with you. Can you tell us a little bit about the background information pertaining to your paper? And then what was the hypothesis that you wanted to test?

Dr Daniel Lackland: For decades, we've known that the Southeastern portion of the United States is a disadvantaged area, but a great geographic diversity where you had these great rates of disease. In 1960, there was NIH-supported the Charleston Heart Study and the Evans County Georgia Heart Study. And these were two databases that were trying to actually look for some type of a factor that was in this population that was leading to the great risk, we became the custodians of this database. And then the regard study focused in or structured around 2000 began to also look at areas of the Southeast. And so the question that we had was using these cohorts, looking at 40 years, have we seen a difference in blood pressure? We did see a difference in outcomes, but have we seen also the difference in blood pressure in this high-risk group?

Dr Greg Hundley: It sounds like your hypothesis was to determine whether blood pressure had diminished. And you've told us a little bit about your study design, but perhaps can you describe a little more of the study population.

Dr Daniel Lackland: In the Charleston Heart study, Charleston, South Carolina, it was basically the County and there was a random sample SLED it in that area and Evans County, Georgia Friday it was just everybody that was in the County. Curtis Hames was the individual at that time and put together these two nice cohorts. These were individuals, obviously in 1960 a time before we were treating blood pressure and recognizing pressure. So there was a blood pressure measurement, there was a cholesterol measurement and basically, a general overall assessment that was having in both of these cohorts in 1960. These individuals again were followed, and then when the regard study was started in the late 1990s, it did also again, blood pressure measurements, but with a focus in the Southeastern portion of the United States. And so you were able to see this population. So it was an opportunity to look at some cohorts that were readily available and using them for a unique way to consider it in this particular high-risk area.

Dr Greg Hundley: Very good. And so how many total subjects did you have?

Dr Daniel Lackland: In the Charleston Heart Study and Evans County, Heart Study you were looking at several thousand and you were comparing it to a slightly higher group from the regards where you're looking at 5,000 or so.

Dr Greg Hundley: So what did you find, Dan?

Dr Daniel Lackland: We found some wonderful things. Certainly, the blood pressures had come down just like national studies have shown. The top of the list was these excessive blood pressures, these severe blood pressures of where 10% of the African-American men and women in 1960 had systolic blood pressures greater than 2000. These were virtually eliminated. We didn't see this later on 40 years later, I think a wonderful accomplishment. The other piece is that while all the blood pressures came down, blood pressures came down significantly greater for African-American men and women and all facets. So those blood pressures that we would have considered high 140, whatever, those all came down there, and they came down greater than we saw among white men and women. We were seeing the gap that was so huge in 1960. The racial gap, starting to come together with a very positive type of sign. The other piece excitingly, we saw the blood pressures in the lower percentiles coming down suggesting that maybe some of the lifestyle that we've been implementing around the country were also being implemented successfully in this high-risk Southeastern population.

Dr Greg Hundley: Very good. So Dan, in 1960, 10% of the men and women had systolic blood pressures greater than 200 millimeters of mercury. And you saw mark declines after the year 2000, and then also you saw declines for those that had mild elevations in blood pressure, systolic blood pressures in the 140-millimeter mercury range. And one quick question, was this true for both men and women?

Dr Daniel Lackland: Yes, indeed. Both men and women, everybody's blood pressure came down.

Dr Greg Hundley: So Mercedes, let's turn to you help us put this paper in the context with other manuscripts that we review at circulation, but also the world's literature.

Mercedes Carnethon: I'm really excited about the opportunity to feature these findings and circulation, because I think they provide a very unique contribution to the literature about the population trends and levels in blood pressure, in the United States and around the world. And one thing that's really important is we don't often talk about our population level successes. And as we know, hypertension is one of the leading drivers of cardiovascular disease. And particularly when we think about reasons for disparities in some of the diseases that Dan mentioned earlier, heart failure, renal disease, hypertension as a primary driver of this, as well as stroke. I certainly can't leave that out. And so to hear that over time a population levels of blood pressure are shifting downward or are certainly shifted downward is really heartening news. It does back certain questions. We certainly still see disparities in blood pressure levels between blacks and whites in this country, but are most likely a primary driver of the disparities that we see in stroke, in renal failure, in certain cardiovascular diseases, and as well as heart failure. And so it's wonderful to see this. And I asked Dan and his colleagues, this particular study data was from the baseline of the regard's cohort and extremely well-designed study that's captured individuals from across the United States. I have two questions, Dan. One is, were you able to tease out any differences in blood pressure between those in rural versus more urban areas in the Southeast and the second, because this ended in 2005, what do you project would happen today? Do you think these trends are holding? Have we gotten better? Where do we stand?

Dr Daniel Lackland: That's wonderful questions. As far as the rural urban, in one sense or certainly Evans County, Georgia is all rural. And if you compared a little bit teasing out, as you've suggested, the Evans County rates were just exceptionally higher than the of the urban sides. If you will allow me for a moment to call Charleston, South Carolina is somewhat urban community. You did see some differences, but they were relatively subtle. Where we are today, if we look at the clinical data, it looks like the top of the list, those excessive, severe blood pressures that particularly we saw in black men and women in 1960 are gone. Now we're working on the moderate blood pressures that Greg had referred to. And I think that, that's fun on that. Those are also coming down. The exciting piece though, although also those lower blood pressures that you refer to, so that in that prevention side of it, those blood pressures are coming down. And that lifestyle, maybe our messages are gradually getting there to all of the population. Dr Greg Hundley: Very good. Let me ask you here in closing, maybe 30 seconds for each of you, what do you think is the next study that needs to be performed in this particular area? Dan, we'll start with you.

Dr Daniel Lackland: I think we know that the interventions work for everybody. So I think we're one of the pieces. Again, is to look at the groups that we've been referring to now with the new guidelines and the new classifications of hypertension, looking at those people that we used to call prehypertension and now have become stage one hypertension, and also elevated blood pressure. Can we implement lifestyle interventions and get down a lower blood pressure? The other piece on the global side that we have mentioned, I think there are global populations around the world that actually unfortunately were similar to what 1960 South Eastern populations are. And I think this is a good model to make sure that we can take what we've done here and take it to other populations around the world.

Dr Greg Hundley: Very good, Mercedes?

Mercedes Carnethon: What I'm most curious about going forward is what proportion of this decline is due to pharma-cotherapies and what proportion is due to shifts in lifestyle behavior? As a data type of person, I would be very interested in teasing this out because there are multiple contributions to high blood pressure, some of which need to involve interventions at the individual level and others that can be implemented on a population scale. And those population scale interventions, for example, reducing sodium and certain foods have the potential to reach all populations, including vulnerable populations, and are less dependent on one's ability to adopt lifestyle changes individually. And so I would be most curious about trying to tease that out so that we can appropriately target resources that will reach the largest and most vulnerable populations.

Dr Greg Hundley: Well, listeners we're most appreciative to have this opportunity to speak with Dan Lackland from Medical University of South Carolina and Mercedes Carnethon from Northwestern University. And listen to them describe these very encouraging results from the regard study, showing that there have been detriments in both severe and mild to moderate hypertension over the last 40 years in the Southeastern United States. So on behalf of both Carolyn and myself, we wish you a great week, and we'll catch you next week on the run. This program is copyright the American Heart Association, 2020.

Circulation October 13, 2020 Issue

12 oktober 2020 | 23 min

This week’s episode includes author Mark Chan, editorialist Thomas Wang, and Associate Editor Wendy Post as they discuss the prioritization of candidates of post-myocardial infarction heart failure using plasma proteomics and single-cell transcriptomics.

TRANSCRIPT BELOW:

Dr Greg Hundley: And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, really interesting, involving proteomics and single-cell transcriptomics, trying to identify how we could prioritize individuals after they've sustained myocardial infarction as to whether or not they'll develop heart failure. Lots to go over in that feature. But before we get to that, how about we grab a cup of coffee and start in with some of the other interesting papers in this issue?

Dr Carolyn Lam: Absolutely. I've got my coffee and I have to tell you though, I am so excited about this feature, it comes from Singapore, but my first paper too is about transcriptomic profiling. But Greg, I have to ask you first, have you heard of the cardiac cellulome?

Dr Greg Hundley: Oh my goodness, Carolyn. So you're starting the reverse-quiz strategy to help me. I have not heard of the cellulome. Help enlighten me.

Dr Carolyn Lam: I just love that word. We've heard of all kinds of other omes, but this cellulome is something I've learned through today's paper. So the authors today who are Alexander Pinto from Baker Heart and Diabetes Institute and colleagues, they developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome. And that refers to the network of cells that forms the heart. The method was utilized to profile the cardiac cellular ecosystem in response to two weeks of angiotensin II as a pro-fibrotic stimulus. So what did they find? Well, they identified two previously undescribed cardiac fibroblasts populations that are the key drivers of fibrosis. Their names were Fibroblast-Cilp and Fibroblast-THBS4. Now, these do not correspond to smooth muscle actin-expressing myofibroblasts, which have been widely viewed as the primary drivers of fibrosis. So this is really novel. The cardiac cellular landscape was sexually dimorphic at the cell abundance and gene expression level, including cellular responses to angiotensin II induced tissue remodeling. So these data really provide insights into the cellular and molecular mechanisms that promote pathologic remodeling in the mammalian heart, and really highlight that early transcriptional changes precede chronic cardiac fibrosis.

Dr Greg Hundley: Very nice, Carolyn. Well, let me switch to the clinical realm. And my first paper comes from Professor Holger Thiele from the Heart Center Leipzig at the University of Leipzig, and it's involving general versus local anesthesia with conscious sedation for patients undergoing TAVI procedures. So the study comes from the SOLVE-TAVI study, and it's a multi-center open-label 2x2 factorial randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVR, comparing conscious sedation versus general anesthesia. And the primary efficacy endpoint was powered for equivalence, and consisted of the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatments, and acute kidney injury at 30 days.

Dr Carolyn Lam: Wow, Greg, as I understand it, about half of patients today receive TAVI or TAVR with conscious sedation. So it's really an important question. So what did they find? Dr Greg Hundley: You're exactly right. So the composite end point occurred in 27% of the conscious sedation patients and 26% of the general anesthesia patients. Really equivalent. And this held true for each of those composite endpoints. In addition, there was a lower need for inotropes or vasopressors with conscious sedation, versus general anesthesia. Thus, these findings suggest that conscious sedation can safely be used for patients undergoing TAVR procedures.

Dr Carolyn Lam: Very important clinical one, Greg. Well, I've got a clinical paper for you too. And this one, trying to answer the question, what's the optimal duration of dual anti-platelet therapy, or DAPT, after PCI with drug-eluting stents. A very familiar, perhaps, an important question. So these authors, led by Dr Deepak Bhatt from Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, performed a systematic review and network meta-analysis of 24 randomized controlled trials comparing short-term DAPT, or less than six months, followed by aspirin or P2Y12 inhibitor monotherapy, versus mid-term DAPT, which was six months, versus 12 months DAPT, as well as an extended-term DAPT, which was more than a year after PCI with a drug-eluting stent.

Dr Greg Hundley: So Dr Carolyn, three groups, what did they find? Dr Carolyn Lam: Compared to 12 months DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduced major bleeding after PCI with a drug-eluting stent, whereas extended-term DAPT reduce myocardial infarction at the expense of more bleeding events. Overall, the extended-term DAPT was associated with a higher risk of major bleeding compared with all other DAPT groups, except in patients with acute coronary syndrome.

Dr Greg Hundley: So extended, more bleeding complications. So take me home on this, Carolyn, what is the final message here?

Dr Carolyn Lam: Here's the message. Compared with 12-month DAPT, the net clinical benefit appears to favor short-term DAPT followed by P2Y12 inhibitor monotherapy instead of aspirin in select patients. Although, extended term DAPT has a role for patients who have a low bleeding risk, but a higher ischemic risk, such as those with acute coronary syndrome, thus a personalized approach appears to be warranted.

Dr Greg Hundley: Very good. Well, I'm going to turn back to the world of basic science and discuss a paper related to pulmonary hypertension. And it comes from Dr Sébastien Bonnet from the University Laval. So Carolyn, the subcellular mechanisms that govern the transition from a compensated to a de-compensated right ventricle in patients with pulmonary hypertension remain poorly understood, and as a consequence, there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. So this study investigated the long non-encoding RNAs, powerful regulators of cardiac development disease, in relation to adverse RV remodeling in pulmonary artery hypertension.

Dr Carolyn Lam: So these LNK RNAs, I think that's what they're called, right? Long non-coding RNAs, what did they find?

Dr Greg Hundley: This was another one of our really nice translational articles, because they combined results from both animals and human subjects. The authors demonstrated that the long non-coding RNA H19 is upregulated in decompensated right ventricles due to pulmonary hypertension, and the finding correlated with RV hypertrophy and fibrosis. Now, similar findings were observed in monocrotaline and pulmonary artery banded rats. The authors found that silencing H19 limits pathological RV hypertrophy, fibrosis, and capillary rarefaction, thus preserving RV function in those two models of pulmonary hypertension, both the monocrotaline and the pulmonary artery banded rats, without effecting pulmonary vascular remodeling. And finally, Carolyn, the authors found that circulating H19 levels in plasma of patients, discriminate pulmonary arterial hypertension patients from controls correlated with RV function and predicted long-term survival in two independent idiopathic pulmonary artery hypertension cohorts. Moreover, H19 levels delineated subgroups of patients with differential prognosis, when combined with NT-proBNP levels or the risk score proposed by both the Reveal and the 2015 European Pulmonary Hypertension Guidelines. So, in summary, these authors findings identify H19 as a potentially new therapeutic target to impede the development of maladaptive RV remodeling, and thus a promising biomarker as well of pulmonary arterial hypertension severity and prognosis.

Dr Carolyn Lam: Oh, Greg, I love that. Not just the paper, but the way you explained it. Thanks so much. Well, let's dip into what else there is in today's issue, shall we? First, there's Global Rounds by Dr Yacoub entitled, Towards Meeting the Challenges of Improving Cardiovascular Health in Egypt. There's a research letter by Dr Cheng on imaging the sarcoplasmic reticulum calcium signaling in intact cardiac myocytes. There's another Research Letter by Dr Angiolillo on the pharmacodynamic and pharmacokinetic effects of a low maintenance dose ticagrelor regimen, versus standard dose clopidogrel, in patients with diabetes without prior major cardiovascular events, undergoing elective PCI. And this is the OPTIMUS-6 study. There's an On my Mind paper by Dr Santos on coronary artery calcification and familial hypercholesterolemia, and an ECG Challenge by Dr Liu, which is not your uncommon electrocardiographic findings, and really looking at Q waves with post-QRS deflections. I'll let you take a look.

Dr Greg Hundley: Oh, wow, Carolyn. This issue is just jammed with really nice articles. I've got a research letter entitled, Long-Term Outcomes After Infective Endocarditis, Following Transcatheter Aortic Valve Replacement, and it's from Dr Josep Rodés-Cabau from Quebec Heart and Lung Institute. And then finally, a nice exchange of letters by Drs Rozenbaum, Kemner, and Parasuraman regarding the article Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy, and there's a very nice response by Dr Kazi. Now we get to proceed on to that feature article.

Dr Carolyn Lam: Yay! Let's go, Greg.

Dr Greg Hundley: Well listeners, we are to our feature discussion. And today we have Dr Mark Chan from the National University of Singapore, our own associate editor, Dr Wendy Post from Johns Hopkins, and Dr Thomas Wang from the University of Texas Southwestern Medical Center. Well, Mark, we'll start with you. Could you explain to us some of your thinking behind how you formulated this study and what was the hypothesis that you wanted to address?

Dr Mark Chan: The background, really, was to try to prioritize protein candidates in post myocardial infarction heart failure. We do know that there are several hundred candidates out there in the literature, but really, what we wanted to do was to try to enrich and select out what we thought would be the most biologically relevant proteins. And really, the hypothesis was that, by combining two very powerful unbiased discovery tools that have been developed in the last few years, we would be able to achieve this goal. The two tools, I think, Tommy would be very familiar with, because he's used plasma proteomics as well in a lot of his work. That's one of the unbiased discovery tools that we used. Measuring 1300 proteins in blast mine. Second two was a single-cell transcriptomics where we're able to look at RNA sequences, genome RNA sequences, at the individual cell level. So we first started off with cohorts of patients with acute myocardial infarction that were followed up for about five years for heart failure events, and we obtained plasma from these patients at about 30 days after myocardial infarction. So with the initial plasma proteomics, and found more than 200 candidates, actually very similar to what we actually see in the literature in terms of protein candidates predicting heart failure, in particular, post-MI heart failure. We then thought that what we really want to do is prioritize the most important proteins, and that's when we went onto single-cell transcriptomics. And we found a total of 83 protein candidates, which were directionally similar across the human plasma proteomics and the single-cell transcriptomic data across different models of ischemic heart failure. And six candidates are the ones that we are hoping to discuss a bit more about, the top six candidates, today, which I'm sure you'll ask me about very soon.

Dr Greg Hundley: You've really led us into the next question. Tell us a little bit about the six candidates.

Dr Mark Chan: The top six candidates to all of us are really familiar with NT-proB natriuretic peptide that's been around for decades, cardiac troponin, that's the second well-known, well-established candidate, and four other candidates that seem to be really emerging as potential targets in heart failure and ischemic cardiomyopathy. Angiopoietin-2, thrombospondin-2, latent-transforming growth factor binding protein 4, and a less commonly investigated protein, FSLT3, or follistatin-like related protein 2. The two candidates that are particularly interesting to me are angiopoietin-2 and thrombospondin-2 , and looking at a lot of Tommy Wang's work as well, we can see that these two candidates looking to be important future targets for biomarker discovery, validation, and maybe, potentially, druggable candidates to manage patients with post-MI heart failure and ischemic cardiomyopathy.

Dr Greg Hundley: Wendy, coming to you as an associate editor and really an expert in genetic epidemiology, what intrigued you about this article? Especially I heard Mark discuss differentially expressed genetics and transcriptomics. What brought you to this article and what increased its relevance to you?

Dr Wendy Post: We were very intrigued by both the importance of the problem that was being addressed, in that ischemic cardiomyopathy is a very common and major challenge that we all encounter as cardiologists, but also the unique approach that was used to handle a large amount of data. So with the plasma proteomic approach, which Mark described as the first step, you take thousands of data points and try to narrow it down, which he did, but still needed to narrow it down even more. And then use a complimentary, but different, approach to try to understand which of these hits, so to speak, maybe the ones that are important. And so using the single-cell transcriptomic approach, was able to narrow down to these six candidates. And then it was very reassuring that two of the six were what we would have hypothesized. So if you didn't find those, we'd worry that maybe something was wrong with your approach. So on the one hand, you'd say, "Well, we already knew that. So what are you telling us?" But it actually was proof, so to speak, that your approach was working, and that these other four novel candidates might turn out to be the next BNP. So that was really a few of the things that intrigued us about this paper.

Dr Greg Hundley: So Tommy, as a practicing clinical cardiologist, and then also, really, as a clinician researcher, what do you see as relevant with Mark's work and also Wendy's description here for all of us that are seeing patients that has sustained myocardial infarction?

Dr Thomas Wang: I think as Mark and Wendy have both nicely summarized, but I'll revisit, they're really two areas in which knowledge of these biomarkers could impact patient care down the road. One is an informative set of biomarkers to tell us which among the large number of patients with myocardial infarction might be destined to develop heart failure so that we can, as clinicians, ramp up our therapies, increase our vigilance, increase our monitoring, so that we might be able to intervene on that at a very early stage, or even before the heart failures develop. The second, which is potentially even more exciting, is the possibility that some of these biomarkers might be so informative of pathways leading to heart failure, that we could actually directly intervene on the pathways that are reflected by these biomarkers. So in other words, biomarkers would tell us not just biology, but about therapeutically effective strategies. And I think, as Mark has nicely emphasized, there are scores, if not hundreds, of biomarkers that have been looked at in this context, and there's no amount of resource in the world that allows investigators to pursue, in prospective clinical studies or experimental studies, all of these biomarkers. And so the real value of their study is to illustrate an approach for winnowing down this large number of biomarkers down to a smaller set, a much smaller set, that seem really worth pursuing in further study.

Dr Greg Hundley: Well, with that lead in, Tommy and Mark and Wendy, maybe start with you, Mark, what do you see as the next step and this area of research moving forward?

Dr Mark Chan: I think I need to sound a word of caution first with respect to the study itself. It is, at the end of the day, still a very descriptive study. Heavy in bioinformatic elucidation of targets. So careful mechanistic validation and further understanding of these highly prioritized targets will still be important. In terms of how we can potentially get these results closer to the post-MI heart failure patients, closer to the bedside, one concept that I think it's becoming increasingly apparent is that a lot of these bioactive proteins in circulating plasma are likely a part of the secretome. Part of what we call exosomes or micro-bubbles that are secreted by cells. And we do see the origin big cells in the single-cell studies as part of this paper. We do get an idea. A lot of these cells really are within the extracellular matrix, which is the substrate in which your cardiomyocytes are embedded. We think that enriching the plasma for the exosome fraction, which one of my colleagues is now working on, could be the best way to derive a more powerful tool for prognostication. To really determine with a high level of specificity, not just sensitivity, but highly specific to determine which patients end up with post-myocardial infarction heart failure. So enriching plasma for exosomes and potentially looking at the proteins within these exosomes, we've already started work on that. And so far, the results, compared to the proteins just measured in free plasma, seem to predict heart failure events a lot better when we come down to the exosome fraction. The other project, this is using exosomes to treat post-MI large animal models. So we have injected mesenchymal cell stem cell derived exosomes, and we've shown that they can reduce infarct size in large animal models, and also prevent some of the hemodynamic complications that result in heart failure. But really, trying to find which are the proteins actually are meaningfully preventing heart failure and reducing infarct size, I think that is also going to be part of the next steps.

Dr Greg Hundley: Mark, thank you for that summary. Tommy, do you have anything to add to that?

Dr Thomas Wang: I certainly agree with all that's been said. I would also emphasize that understanding the biology of some of these newer biomarkers and how they might link heart failure or active MI is going to be really important when we consider potential clinical applications. And so, further along the experimental line, I think animal models, mouse models, and other types of models, being which the biology and pathways we would manipulate it so that we can see whether these biomarkers truly do reflect etiologic pathways in heart failure would be valuable.

Dr Greg Hundley: Thank you, Tommy. Well, listeners, we've had a great presentation from Dr Mark Chan, an excellent review by both Wendy Post and Tommy Wang, emphasizing how we are discovering new protein biomarkers using plasma proteomics for identification of those that may develop heart failure after myocardial infarction. And more to come in this area. We feel very privileged to have the opportunity to work with bright young investigators like this and present this work in Circulation For both Carolyn and myself, we wish you a great week and look forward to catching you next week on the Run. This program is copyright American Heart Association, 2020.

Circulation October 06, 2020 Issue

5 oktober 2020 | 26 min

Dr James de Lemos: Hello, my name is James de Lemos. I'm the executive editor for Circulation, and I'm delighted to be joined here by Tim Gardner professor of surgery at University of Pennsylvania and our long-term associate editor in charge of cardiac surgical content at Circulation; and Marc Ruel, who is professor of cardiac surgery at University of Ottawa and the chair of the department there and who for many years has led the cardiac surgery supplement issue. Mark, Tim, welcome. Marc, please introduce this issue for our listeners.

Dr Marc Ruel: Thanks so much, James. It's a very exciting year academically for cardiac surgery. We've had a lot of great developments from new data on long-term patency and outcomes with radial artery graphs through the results of the ischemia trial. And I think the 2020 themed issue around cardiovascular surgery is exactly in that framework. I think it will garner wide interest. It has a number of original papers, six original research articles, two more translational papers included in those six. We have two research letters. We have two frame of reference papers as well. And one state-of-the-art piece on exynos transplantation. We always keep in mind to have those issues very relevant to surgeons and to gather the very best cardiovascular surgery science. But in the same token we also want to make sure that they are relevant to the wider cardiovascular community. So I think, and I hope that everyone will enjoy this issue as the very best that's happened in cardiovascular surgery over the year.

Dr James de Lemos: Well, thank you, Mark. Let's get started with discussion of the first paper and one that I'm actually quite excited about. This is long-term results of the radial artery CABG in clinical outcomes trials. What did the investigators look at in the study?

Dr Marc Ruel: I think this is a very important paper, which adds to the increasing data around long-term benefits of arterial grafts, multi arterial grafts, and more specifically the radial artery. So here's a paper mostly from Australia. First author being Professor Buxton, who is a very well-known senior surgeon who has been really a grandfather in this field. And the last author is David Hare who is a cardiologist, also professor in Australia. And essentially there were two radial artery comparative trials that have been undertaken many years ago, well over a decade ago, when we now have 10-year data on those two trials. One of the trials compared the radial artery to the right internal thoracic artery. And the second trial a little bit smaller to the saphenous is vein grafts. So it holds 400 patients in the first randomized comparison and around 225 in the second, i.e. the radial versus saphenous vein. So it's wonderful that this is very long-term data. We have 10 year patency data, not on all patients. There was a distribution as to when the angiogram or the CT scan would be performed for patency over the course of the 10 years of the study. But the follow up is excellent and there are actually patency as well as clinical differences between the groups. And maybe I can say a couple of things around those. So, in the radial versus right internal thoracic artery cohort, there's both a patency and a mortality as well as a major adverse cardiac events benefit for the radial artery over the right internal thoracic artery. And yes, you've heard right, the comparator is the right internal thoracic artery. Now a couple of chatty it's all the Redis in there had to be done as a free graph. So they are connected. This is an art technique that everyone is very comfortable with and you have to use a six or seven Oh one friable internal thoracic ultra. So it may not really provide or present the call the way at its best advantage. If you will, there may be some benefits or a loss for not having it as a pedicle, but nevertheless, and in the second comparison, looking at the radio versus 225 patients, there was a patiency advantage for the radio Herceptin in Spain. But partly because the comparison was less power than the first, there was no major adverse cardiac event or even mortality difference. So I think again, aligns with the data that we know the arc trial, as we all know, 10 years was neutral. There was no benefit to internal thoracic arteries versus small one, which regards to anything repeat revascularization based mortality. And we know have 10-year data recently published that shows that the radial artery in pooling patient level data from many randomized clinical trials leased their survival benefits. So I think it's fair to say based on available data now with this team issue in 2020 in the fall, that the best second RGO is very likely or radio RV and too many people surprised.

Dr Timothy Gardner: Yeah. If I could just add my perspective, there's an editorial by Steve brings on this. This really does solidify the data about long-term radial, artery patency. And that was when I came away with, it's not so much the comparison of the radial on the right internal thoracic, but the fact that the radial artery would be like held up very well.

Dr James de Lemos: If you're referring a young patient or considering a young non-diabetic patient for cabbage at this point, was you select a radial artery or right internal memory?

Dr Timothy Gardner: Well, I probably would favorite as a second graph the right internal thoracic artery rather than. As a free graph, but I certainly wouldn't hesitate to use the radial artery as the second graph there as a third grade. My competence in the radial artery continues to grow in this report reinforces that.

Dr James de Lemos: Excellent really important study for both the cardiac surgeons and the cardiologists that read our journal. Let's switch gears and talk about bowel surgery, Tim, the camera Cardiolite study drills deep into different strategies for repairing the mitral valve. What did we learn there?

Dr Timothy Gardner: Well, first of all, this study, which comes from Mark Raul's unit Benson Chan being the first author and address the issue that repair with resection of the mitral valve made me to functional stenosis of the valve. And that has been a concern among surgeons and that has led some surgeons to prefer non-lethal the resections repair. And this study was very carefully done and actually demonstrated that the data did not support the fact that resection versus preservation is this okay with the riff? So I think that, you know, there are various ways to repair the valve. And if you go back to the original descriptions of mitral valve repair resection was a major component for many people in many studies. And this is a reassuring study that either approach appears to be effective without badly under sizing the annulus that there should not be residual mitral stenosis.

Dr James de Lemos: Tim is one of these materially easier to do in the operating room. So then it would emerge as the preferred therapy or is it really going to be surgeon dependent.

Dr Timothy Gardner: I think it’s fairly surgeons dependent. I mean, we have technical variations for a lot of operations, and I think it's when the surgeon is comfortable with Mark. You might want to comment on that point.

Dr Marc Ruel: Yeah, I agree with both of you. I think it's very reassuring because there's the orientation of where the last issue is. Small. The patient's exposure is not knowing that you can use theater technique and in some cases not have to go on to the pathway. We Muscle is a reassuring avenue. So I think every surgeon has her or his preference, but it's nice to know that both these can be used interchangeably without any drawback to the patient.

Dr Timothy Gardner: Let's switch gears and talk about a paper that I think has pretty profound implications for both of our specialties. And this is an observational analysis from the RS trial, evaluating the association of postoperative atrial fibrillation in the long-term risk of stroke. Mark, what did you think of this paper and its implications?

Dr Marc Ruel: This is a very interesting piece that comes incidentally from the heart trials. So non related to what we were Just discussing before the 3000 patients or so of the art trial were followed at 10 years. Mostly with regards to major adverse cardiac events, et cetera, anything that's related to the question at stake at the time, which was single internal for us, incidentally, the authors have ready data regarding the incidence of stroke at 10 years. And they were able to use those and go back to those stations who have postoperative atrial fibrillation and see if there was a correlation, even when accounting for other factors in the patient profile. So interestingly about 24% of patients have had post-op and post-op you, is defined in variety of ways for this particular study, it was defined as 30 seconds at least of atrial fibrillation or atrial flutter during the index hospitalization after the operation. So I think this is a very fair and square type of definition and those patients and those who have the CBA incidents by 10 years was 6.3% versus those who did not have postoperative 3.7%. So this is obviously a significant numerical and also statistically significant higher risk for those patients who have post-operative a-fib. So there's a number of caveats around that. All the risks for post-doc are often the same ones that may lead to the risk of stroke over the long-term. So I think we should see this not as probation. But that should be not even as an association. But certainly as a correlation, but it is really unique data that has not been produced before. Like postoperative is so common after cardiac surgery. It affects many of the patients that both the cardiology and cardiac surgery individuals have to treat. And I think the more information on it, the better, there were a number of interesting observations warfarin, for instance, even though the incidence of post-op 24% was used in only about 8% of the overall trial. So one may debate, have these patients being anticoagulated enough also, would there be a way to provide enhanced surveillance to patients who have post-op in order to maybe catch them prior to them having a cerebral aspir event? So I think it's really very interesting data. I would like to briefly provide one last tidbit of information, which I thought was very, very fasting. So the authors used the CHADS two score in order to kind of ascertain your overall risk attributed to which regards to stroke in those patients. So this is probably the latest and best iteration of the Chad score if you will. And they found that in patients with a score of less than four, so it was zero to three. There was no difference with regards to the incidents of CVA or in signers versus those who have post-op after the operation. However, when the score rich four or higher. This is rare to you where the risk was concentrated. So that particular cohort of patients seemed to be the one where I think the efforts with subsequent studies should be concentrated in order to intervene and hopefully catch these patients who may have atrial fibrillation without having it.

Dr James de Lemos: Does this change your practice at all? Do you think, I mean, I guess it's interesting for me because obviously I see a lot of these patients back from surgery and I've tended to candidly ignore short episodes of peri-operative atrial fibrillation. And this really raises questions as to whether that approach is wise and needs to be revisited.

Dr Timothy Gardner: I agree completely on the other hand, I think that targeting patients, I mean, I think the last point that Mark made about the patients that ended up with problems with higher AFib and with consequences had other risk factors associated with their risk of stroke. So this continues to be a really tough group to manage. I think that one question that we all have is do the, the, the new novel oral anticoagulant agents provide better long-term protection. As a topic for another important study that should be coming down the pipe pretty soon.

Dr James de Lemos: And I'll just point out to our listeners that at the American heart association meeting in November, that late breaking trial will be presented called search AI cardio length that will evaluate extended monitoring creature fibrillation after surgery. And I think that will build off, of this theme that perhaps atrial fibrillation after cardiac surgery is a more important tissue than many of us considered. Let's move to the next paper, Tim, this is really right in your wheelhouse in terms of surgical. So specialization. And this is an interesting paper. I thought evaluating variation and congenital heart surgery outcomes across centers in the U.S. and this group really evaluated a large proportion of dissenters doing congenital heart surgery in the U S.

Dr Timothy Gardner: Yeah, absolutely. And they made use of the STS database. They've got good data and it is a multi-institutional review group, really looking at how to optimize outcomes. And I think that, the assumption is that regionalization with more attention to high volume centers, especially for the most high risk say neonatal heart surgery is the way to go. But this study actually while demonstrating significant hospital variations also demonstrated that and reading their conclusion. Now a substantial portion of potential improvements that could be realized on a national scale are related to variability among lower risk patients. And this makes me think back to Dr John Kirkland, who was maybe the first one in our field to actually develop a checklist of important steps and management strategies during the surgical procedure in the early post-operative period. He worked with IBM on that. And I think that lesson here that I take away from it is that volume may be important, but not just for the high risk neonatal population, but for all congenital heart surgery patients. And it really is an important specialty. And there may be some opportunities for improvement just by standardizing sort of management of even the lower risk patients. This is one of several reports from this multi-institutional group that is focused on data from the STS database in congenital heart surgery. Good job demonstrating these variations in outcome.

Dr James de Lemos: Yeah. And I think tremendously important, right? Because these lower risk in general procedures may be more like other procedures that cardiac surgeons do. And I think you make a great point that these systems based approaches to minimizing variation do seem to matter. And I wouldn't have thought that the, this is another one of the theme really here in the issue where we have a lot of studies that are challenging the way we thought about, common medical and surgical problems, really a fascinating piece. Let me take a moment here to introduce a new member of our team for the themed issue. Mike Fischbein, who's a surgeon scientist at Stanford, a practicing cardiac surgeon on the faculty there, but also runs a large and very successful basic science laboratory. And he has joined the surgical team for the themed issue to add his particular expertise in the evaluation of the basic science papers. Mike, welcome to the team. I think our readers and listeners will really benefit from having your perspective. And I'd like to have you now please talk about the basic science papers here in the issue.

Dr Michael Fischbein: Thank you very much, James. It's really a pleasure to be part of a team. The paper that I'd like to discuss today is a feature of basic science paper entitled a Single cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns and Control and Aneurysm Human Aortic Tissue. This is from Scott LeMarie group from the Department of Surgery at Baylor College of Medicine. I think this study is very important. It's focusing on the ascending, thoracic aortic aneurysm, as you know, ACE and aortic aneurysms are the second most common aneurysm after abdominal aortic aneurysms. One of the risk factors of ascending aortic aneurysms is that as they grow, they can tear dissect or rupture. Both of which are life-threatening currently the only treatment option is prophylactic surgery. And this is really based on size criteria alone. Now, while over time, we've established that smooth muscle cell loss and exhale and matrix breakdown are important during this process, really the molecular mechanisms or pathophysiology is poorly understood. Therefore, limiting development is novel drug regimen, and this manuscript, the authors use single RNA sequencing to compare the aneurysm wall to normal control. Aorta is taken from transplant recipients. One of the benefits of single cell RNA sequencing is that allows one to identify the cellular components or heterogeneity within the aortic wall. And it also allows us to see the aneurysm relevant transcriptome changes in the major vascular cell types within the aorta. The authors identified 11 major cell types in the aorta, including a number of different smooth muscle cell subtypes and to Celia's cells, fibroblasts and inflammatory cells, including T-cells and macrophages. They found over 500 altered genes comparing the aortic wall to normal control. Mitochondrial dysfunction seemed to be altered in several gene types and they identified a transcripted factor ERG, which stands for Erythroblast Transformative, specific Related Genes to be important in maintaining the normal aortic wall function. And this was reduced specifically in smooth muscle cells, fibroblasts and endothelial cells. This is really an exciting target that may lead to drug development in the future. So thank you very much, James, for allowing me to participate in the group. And I think this will be an exciting paper for the readers.

Dr James de Lemos: So Mike, thanks so much. Really appreciate your perspectives here. Another really interesting area that is quite forward-thinking Mark is this idea of 3D printing. Theotic roots and conduits. Tell us about this paper from Joe Woo’s group.

Dr Marc Ruel: This is another great contribution from Joe's lab. Looking at the issue around bell spring, and many would call it bear hair because essentially they preserve and surgeons go to great pain and great strides to try to recreate if you will be normal slash nets, these geology and aortic root sinuses. And many of us, when we do this operation are taking great minutia and creating those. And there's a number of things that happen. And all of these techniques vary from the more approach of just taking a straight to, and essentially reinventing the native aortic valve and connecting the coronary buttons. So Joe's lab wanted to study this with regards to the translationally relevant outcome of opening velocity and closing gossip with regards to the RP pal. And they've done this 3D printed biomechanical study, aware they have used for signing LT. Val, that'd be put into these different configurations, some including Neil, if you will, some including what we call a bell solver type of breath and using the natives or signing as a control in the same 3d biomechanical model. And essentially the conclusions of the study, which is free, elegant be performed and Bree compelling from a data point of view is that a simpler appears to be better too many. I'm sure the investigators I'm sure what will be many readers price. These trade routes' configuration without Neil sinuses seem to have the lowest coast opening and closing velocity. So it would suggest that this may translate into longer term durability of the valve. Now, there are other reasons why someone, for instance, the one I do this operation, I like to use Valsalva graft. It's not because I so strongly believe that Neo sinus type should be there is because it also gives enhance an easier reach to the corny about adding a vertical followed by a horizontal type of pattern I find is a bit more reliable and it may not really matter what the opening and closing philosophies are because those files are not intrinsically abnormal. So they may last for many decades going forward. But nevertheless, I think this is a very important study and series of experiments, and we're very happy to include it in the theme this year.

Dr Timothy Gardner: Yeah. And if I could just add the thing that I admire most about this study is that not just how they come up with this innovative, 3D printing way to model, but the team included mechanical engineers and bioengineers at Stanford, and that's adding real substantial science to what some surgeons have theorized about. So this is a small study, but the results are quite interesting. Let's talk now.

Dr James de Lemos: It's about this remarkable Primer that we've had on critics, transplantation. This is something I wouldn't have imagined five years ago would be something we'd have even considered close enough to clinical application to publish in circulation. But what's different about this now and what should our readers look to in the future with this technique.

Dr Timothy Gardner: This paper comes from a group at the Mass General [Hospital]. They've continued to work on Xenotransplantation as a possible solution to the need for new donor organs. And I think the most remarkable thing is after almost silence for 10 years, they have outlined the possibility much more realistically now of coming up with Xenotransplantation as a usable alternative, based on some very important basic science work that others have done in baboons and that they have model into additional experiments. This is what was a very informative article for me. And it's still some ground to cover, but they've really worked away at the science and think that they believe that they're nearing the point where they know transplantation or for cardiac replacement is a possibility. Again, amazed I sort of thought Xenotransplantation was an impossible dream 10 years ago. And here we are, perhaps at the point where it is more of a realistic possibility.

Dr James de Lemos: Really remarkable. When you think about these technologic advances that are getting so much closer to clinical application. Well.

Dr Timothy Gardner: Thank you both. I'd like to take just a moment to recognize Sara O'Brien in [the] Circulation Editorial Offices in Boston for her remarkable contributions yet again, to pulling this issue together and keeping Mark and Tim and Mike and myself on task to bring this issue home. And thank Mark Tim and Mike for pulling together. What I really believe is far and away, our finest issue. We're talking here in my opinion about multiple studies that changed the way we think about cardiovascular surgery and its complications, including atrial fibrillation that affects all of us in cardiovascular medicine.

Dr James de Lemos: Marc, would you like to make some final comments as we wrap up today?

Dr Marc Ruel: Absolutely. I could not agree more with your statement, James. I think this is a team effort and I want to be cognizant to the leadership of Circulation for as the premier cardiovascular journal, recognizing the importance of cardiovascular surgery in the field and dedicating an issue through what is best that's happened over the last academic year or so. We want this issue to continue for all time. And I think it's very well started and it's growing nicely. And thanks to the efforts of many, including of people on this call today. I hope that our readers will like it and I foresee it will garner interest even beyond the strict fields of cardiovascular surgery but to the entire cardiovascular community.

Dr Greg Hundley: This program is copyright American Heart Association, 2020.

Circulation September 29, 2020 Issue

28 september 2020 | 20 min

This week’s episode includes author Finnian Mc Causland and Associate Editor Justin Ezekowitz as they discuss angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction.

TRANSCRIPT BELOW

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we're going to be talking about RNEs and renal outcomes in HFpEF. Oh, you got to hold me back this is going to be such an interesting discussion. But maybe let's grab our coffees. Are you ready to talk about some of the papers in today's issue? Dr Greg Hundley: You bet. Dr Carolyn Lam: Well the first paper I have really represents a novel gene therapy approach to atrial fibrillation. So doctors led by Dr Arora from Northwestern University Feinberg School of Medicine and colleagues used a novel gene therapy approach in a canine rapid atrial pacing model of atrial fibrillation to demonstrate that NADPH oxidase-2 or NOX2 generated oxidative injury by causing upregulation of a constitutively active form of acetylcholine-dependent potassium current, or IKH is an important mechanism underlying electrical remodeling in the fibrillating atrium.

Dr Greg Hundley: Wow, Carolyn, very interesting. Tell us a little bit more about this gene therapy approach.

Dr Carolyn Lam: They performed targeted expression of anti-NOX2 short hairpin RNA in the intact atria of the dogs, and then subjected those animals to rapid atrial pacing for a period of several weeks to months. The novel atrial gene therapy approach prevented the development of electrical remodeling and sustained atrial fibrillation thus demonstrating for the first time a clearer causative role for NOX2 generated oxidative injury in the creation, as well as the maintenance of electrical remodeling in atrial fibrillation. Furthermore, they demonstrate that a likely cellular and molecular mechanism by which oxidative injury created a vulnerable substrate for atrial fibrillation, the results of this study yield therefore valuable mechanistic insights into the pathogenesis of atrial fibrillation and have important therapeutic implications for this clinical management.

Dr Greg Hundley: Very nice, Carolyn. We need more therapies for AFib. Boy, that's so informative. Well, the next paper that I have sort of merges the world of electrophysiology with the world of imaging and it comes to us from Dr Michela Casella from Centro Cardiologico Monzino. Among 162 consecutive patients, this study evaluated the combined utility of electroanatomic voltage mapping coupled with cardiovascular magnetic resonance imaging to guide endomyocardial biopsies.

Dr Carolyn Lam: Oh, so interesting. A combined noninvasive and invasive electrical guide to perform cardiac biopsies, wow. So what did they find Greg?

Dr Greg Hundley: So they found that the sensitivity of pooled electroanatomic voltage mapping and cardiovascular magnetic resonance was as high as 95%. EVM and CMR together conferred an endomyocardial biopsy positive predictive value of 89%. Endomyocardial biopsy analysis allowed to reach a new diagnosis different from the suspected diagnosis in 39% of patients, complication rates were low, mostly vascular access related, with no patients requiring urgent management. Most impressive for this manuscript are the illustrative figures that are provided. It's really a great article for those performing biopsies, doing imaging, or the EP procedures that guide the biopsy process.

Dr Carolyn Lam: Really nice, Greg, thanks. Now for the last paper, have you ever thought about atherosclerosis as an autoimmune disease?

Dr Greg Hundley: Well, I wonder, we're learning so much about our immune systems these days, perhaps.

Dr Carolyn Lam: Indeed, throughout the inflammatory response that accompanies atherosclerosis auto-reactive CD4 positive T helper cells do accumulate in the atherosclerotic plaque. Apolipoprotein B-100 or Apo B is the core protein of LDL really serves as the auto antigen that drives the generation of pathogenic T helper one cells with pro inflammatory cytokine secretion. Yet there may also exist Apo B specific CD4 positive T cells with an athero protective regulatory T cell phenotype in healthy individuals. And that relationship between the protective Apo B reactive T regulatory cells and the pathogenic T helper one cells really has remained unknown until today's paper. And this is from Dr Ley from the La Jolla Institute for Immunology and colleagues is really the first report to characterize CD4 positive T cells recognizing Apo B in the mouse with a combination of a novel MHC II tetramer and single cell transcriptomics immuno receptor sequencing and functional evaluation, and their results demonstrated an unexpected mixed phenotype of Apo B reactive auto-immune T cells in atherosclerosis and suggest an initially protective auto immune response against Apo B with a progressive derangement in clinical disease. These findings really identify Apo B auto-reactive T regulatory cells as a novel cellular target in atherosclerosis.

Dr Greg Hundley: Very nice Carolyn, boy that was a beautiful summary. I've got in the mail bag just a couple of things to talk about before you get to the discussion of some research letters. There's an ECG challenge from Dr Gunaseelan involving a young patient with chest pain. And then Theresa Wang has a very nice case series involving pulmonary hypertension, entitled Pressures at an All Time High.

Dr Carolyn Lam: There's also an On My Mind piece by Dr Perman on overcoming fears to save lives. So COVID-19 and the threat to bystanders CPR in out-of-hospital cardiac arrest. There's a research letter by Dr Myhre on cardiovascular hospitalizations, influenza activity, and COVID-19 measures, another by Dr Gurbel on the first inhuman experience with inhaled acetylsalicylic acid for immediate platelet inhibition, the comparison with chewed and swallowed acetylsalicylic acid. A final research letter by Dr Zurek rounds us up regarding neuregulin one inducing cardiac hypertrophy and impaired cardiac performance in post myocardial infarction rats, very surprising because we thought this was protected. So there you have it for this issue, Greg, shall we go on to our future discussion?

Dr Greg Hundley: Absolutely.

Dr Carolyn Lam: In patients with heart failure, chronic kidney disease is really common and associated with a higher risk of renal events than in patients without chronic kidney disease. In fact, these renal events are really increasing in prominence in the heart failure literature. And so I'm really welcoming the discussion of today's feature paper, which looks at the renal effects of angiotensin neprilysin inhibition in patients with heart failure with preserved ejection fraction in the PARAGON trial. I'm so pleased to have with us the first and corresponding author of this paper, Dr Finnian Mc Causland from Brigham and Women's hospital, as well as our associate editor Dr Justin Ezekowitz from University of Alberta. Finnian, congratulations on this beautiful paper. Could you please tell us a little bit about the overview? What motivated it, what you found?

Dr Finnian Mc Causland: It's long been a passion of mine to look at this interaction or intersection between cardiology and renal events. And if the truth be told, I had a moment in my life where I thought about being a cardiologist but I was swayed in other directions during my training in Ireland. Well, I've always been very much interested in this intersection, like I said, and so I've had the opportunity to work very closely with Scott Solomon and others at the Brigham who lead many of the heart failure trials that you are all aware of much more than I have been. And this particular subset of patients with heart failure with preserved ejection fraction is a very unique population that were studied in the PARAGON-HF trial. And we thought it was a unique opportunity to look at some of the pre-specified secondary end points, which were the renal outcomes in terms of trying to figure out what the effect of this was compared to valsartan therapy in this patient population. So I think looking at this intersection between heart failure and preserved ejection fraction and the deterioration of kidney function was the primary driver to look at this in the PARAGON heart failure trial, and to really look at the comparison between sacubitril-valsartan with valsartan in this patient population.

Dr Carolyn Lam: Indeed, thanks so much Finnian, and here's a confession too. I really liked nephrology during my training. (laughs) I thought it was really cool and with all the interventions, and so I really admire the many things you think about, especially in these patients, who've got multisystem disease, but okay. Moving on with PARAGON, I know that the secondary outcomes were reported and it was really a striking effect on the renal events. And so glad that you're shedding more light in it. Could you tell us what this paper added?

Dr Finnian Mc Causland: Yeah, so here we really got into I suppose the depths of the renal composite outcome and just to remind everybody that was a composite of a 50% or greater decline in eGFR, the development of end stage renal disease, or death from renal causes, so this was the composite outcome that was examined. We really evaluated this in a lot more detailed breaking our composite down into its individual components, as well as looking at it in totality. And I think the big take away point was that we found there was an almost 50% reduction in this primary renal composite outcome for patients on sacubitril-valsartan compared with valsartan.

Dr Carolyn Lam: And what about the components and the sort of further analyses?

Dr Finnian Mc Causland: Yeah, so getting into the, I suppose the details in a little bit more granularity, the major driver of those events will be 50% or greater decline in eGFR. And that's where the majority of these events really came from over the follow-up of PARAGON. And so this was assessed that various study business throughout the course of the few years that the patients followed up with PARAGON. And I think if we look at this slope and this was clarified in terms of the overall slope analyses of the eGFR. And we thought this relatively early separation in favor of sacubitril-valsartan so that there was less decline in eGFR over time compared with valsartan. So I think this was a supportive finding from the slope analysis that really got to this 50% threshold and that many people have examined in greater detail than they had the cardiovascular literature. So it takes a fair degree of kidney function decline to really reach that threshold of 50%. And so I think this was a very repulsed finding supported by the slope analyses.

Dr Carolyn Lam: Yeah, and to the audience that's listening, you have to grab hold of figure three of this paper, and that shows the eGFR slopes, which is something that's I think really important in current heart failure literature, the concept of the eGFR decline. So really nice work. Congratulations again, Finnian. Justin, could you put these findings in context for us?

Dr Justin Ezekowitz: Finnian once again, congratulations on getting this analysis. Pretty complex area to try to analyze and analyze properly, given that there's an expansive renal literature out there about looking at eGFR and how you look at it. So I think there's a couple of questions that come to mind when we think about the PARAGON trial overall. When we think about the protection of the kidneys over three, four, five years, my sense was from your analysis and perhaps you could expand on it is there seems to be very few events in those people with pretty preserved eGFR, but a greater number of events in those less than 60 mils per minute, and I'm wondering if you think that there's more of a unique place for medications such as sacubitril-valsartan and that cohort and if so is it really, that's where all the action is, but there's no real difference? Or do you think there's an interaction there that we should explore?

Dr Finnian Mc Causland: Thinking back to the entry criteria for PARAGON-HF, one had to have an eGFR more than 30 mils per minute at baseline. And you had to go through this kind of complex running period where you didn't have elevations of creatinine or potassium that went inside the pre-specified ranges. So after you took that element of what many people would consider hemodynamic changes, acute hemodynamic changes out of it, you were left with participants who entered the double blind randomized period. And there, I think that's where again, we started to kind of see most of the end points in terms of follow-up, which again were mostly the eGFR decline. If you go to table two of the paper, you'll see the composite, the components of the renal composite broken out into those with eGFRs of less than 60 or 60 or greater at baseline. And even in both groups, I think you'll find that again they were both driven by the 50% decline, but you only really saw the end stage renal disease events or very few deaths from renal causes in those with eGFR of less than 60 mils per minute of baseline. And I think really what that speaks to is that these are the patients with quote unquote, chronic kidney disease at baseline are the ones who have that detrimenting kidney function to begin with. And so we're more likely to progress as we know than those with more preserved kidney function. And so if you followed patients both for really good kidney function over time, it's going to take a long time before they get that really severe decline due to the compensating mechanisms that the kidney has to preserve eGFR in the face of decline. So I think once you get into the more advanced disease, you really start to see the deterioration where there's very little renal functional reserve to cope with any additional damage or hemodynamic changes. So to me, it wasn't particularly surprising that that's where the action was. To answer your second point of should we be focusing therapy here? If you look at the median eGFR in the PARAGON heart failure study was around 63 mils per minute. So about half of these patients I suppose could be classified as having impaired kidney function. If you look at it by CKD criteria it's eGFR of less than 60. And so I think there's a huge opportunity there to really think about this population in terms of trying to look for interventional studies and potentially protect patients as we've seen with this molecule, and but also with others such as SGLT-2 inhibitors, what I'm really intrigued about is if this was persistent at eGFRs below 30, because of course, one of the most devastating icons for patients with kidney disease that we deal with is the development of end stage renal disease and those who go on to hemodialysis. So if there was some mechanism to prevent those even higher risk patients from progressing, I think that would be a huge opportunity for further research in this area.

Dr Justin Ezekowitz: Thanks for that very complete and thorough answer Finnian, and that actually maybe leads to putting this in context for the majority of people who will read Circulation and the audience will most likely be cardiovascular specialists and understand a lot of what you said, but could you put this in context with other studies that really are nearby to this trial, such as CREDENCE where the eGFR slope might be slightly different, or even the UK HARP-III trial where the same molecule was used, but in a different population, I wonder if you could give us some context for these findings.

Dr Finnian Mc Causland: Sure, yeah. I mean, I think the UK HARP-III trial maybe is the first one to discuss since this was a comparison of sacubitril-valsartan versus irbesartan. This was a study performed in the United Kingdom and they recruited patients with chronic kidney disease, a small proportion of those patients had heart failure, but this was not any of the pre-specified entry criteria for this study. And their primary outcome was the change in measured glomerular filtration rate after 12 months. And really they found that there was no significant difference at the 12 month mark between sacubitril-valsartan versus irbesartan. And so we were asked a similar question when we presented this study in abstract form at the American Society of Nephrology meeting in Washington last year. And I think a lot of the differences potentially relate to the difference in entry criteria for the patients. But also one might argue that 12 months of follow-up may not have been enough to see these differences in eGFR slope, which tend to occur, I suppose, rather later in the course of progressive kidney disease and heart failure. And so that may be part of the reason that we didn't see the differences with UK HARP-III. In terms of CREDENCE, obviously it's a different molecule. And if you look at our main eGFR decline over time in PARAGON-HF, it was around 0.7 mils per minute, per 1.7, three meters squared per year. And so this compares with the about 1.5 mils per minute in CREDENCE, remember CREDENCE recruited patients with chronic kidney disease. PARAGON-HF recruited patients with heart failure and preserved ejection fraction. So differences in terms of the inclusion criteria right off the bat. I think other big differences where the CREDENCE compared, and it kind of flows in versus placebo, there was an active comparator in PARAGON-HF in terms of it was sacubitril-valsartan versus valsartan. So we saw differences in eGFR slope, despite an active comparator, I think was also quite telling and that there appears to be some additional renal benefit in the additional sacubitril versus blast inhibition alone. And so I think the mechanisms is a whole other area, right? For research, I don't think we're entirely clear of the underlying mechanisms of this potential renal benefit, but I think we're pretty excited in the kidney community. Where now we have several molecules that may have potential to slow kidney functional decline, SGLT-2 inhibitors being one class potentially sacubitril-valsartan in another, and the top line results from their number are just out as well. And so there's ongoing trials that are looking at kidney function outcomes there. So we're getting pretty excited and we're not quite as jealous of the cardiology community as we used to be.

Dr Carolyn Lam: I couldn't think of a better way to summarize those findings and to put it into context of other very hopeful medications for the cardio renal outcomes. Thank you so much Finnian for joining us today and for publishing such a great paper with us at Circulation. And thank you, Justin, for your perspectives.

Dr Justin Ezekowitz: Thanks Carolyn, and Finnian congrats to your team as well. This has been a terrific paper to be able to handle and read and look at figure three, and it tells a lot of the story of what you saw.

Dr Finnian Mc Causland: Thank you very much again for the opportunity and a big shout out to everybody that worked in PARAGON-HF and especially to the support from Scott Solomon and John McMurray for getting me involved. It's a pleasure to be part of this.

Dr Carolyn Lam: Thank you so much from Greg and I for joining us today, tune in again, next week.

Dr Greg Hundley: This program is copyright of the American Heart Association 2020.

Circulation September 22, 2020 Issue

21 september 2020 | 28 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, our feature paper today talks about the risks of sudden cardiac death, something that we still grapple with, and do you know what, really highlights the important emerging role of biomarkers of myocardial stress, myocardial injury, or even subclinical inflammation in predicting this risk. A really important discussion coming right up.

But before we do that, let me tell you about a paper in today's issue that really provides novel mechanistic insights into atrial fibrillation pathogenesis. In fact, this is the first paper to demonstrate that decreased expression of a striated muscle preferentially expressed protein kinase, or SPEG in atria, is causally linked to altered diastolic calcium handling and human paroxysmal atrial fibrillation.

This is from corresponding author, Dr Wehrens and colleagues from Baylor College of Medicine. And they used phosphoproteomic studies to identify S2367 on ryanodine receptor type-2 as a novel kinase substrate of SPEG. Through the study of novel ryanodine receptor type-2 phospho-mutant mouse models, they revealed that in contrast to previously characterized phosphorylation sites on this receptor, S2367 phosphorylation inhibited diastolic calcium release from the receptor, while loss of phosphorylation of the site increased atrial fibrillation susceptibility.

Dr Greg Hundley: Wow, Carolyn. So the clinical implication is that normalizing S2367 phosphorylation in SPEG activity may provide novel therapeutic opportunities for the treatment of atrial fibrillation, right?

Dr Carolyn Lam: You bet, Greg. Too smart. And this is discussed in an accompanying editorial by Drs Knollmann and Blackwell from Vanderbilt University Medical Center.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got a paper pertaining to COVID-19, and it comes to us from Dr Leo Nicolai from the Klinik der Universität München in Germany. Carolyn, I really enjoyed this article about COVID-19. I found it very intriguing, and the study addresses the mechanisms by which the SARS-CoV-2 infection, associated pneumonia or COVID-19, leads to subsequent respiratory failure, complicating renal and myocardial involvement, and the prothrombotic phenotype found in some patients with COVID-19.

62 subjects were included in the study, 38 patients with RT-PCR confirmed COVID-19 and 24 non-COVID-19 controls. The investigative team performed histopathological assessments of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet-neutrophil functions and coagulation tests.

Dr Carolyn Lam: Wow, that sounds like really sort of in-depth testing. And what did they find?

Dr Greg Hundley: Several things, Carolyn. First, the authors found evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. They found that in COVID-19 patients, inflammatory microvascular thrombi are present in the lung, kidney and heart, containing neutrophil extracellular traps associated with platelets and fibrin.

Second, they observed that COVID-19 patients also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood which changes with disease severity, whereas cases of intermediate severity show an exhausted platelet and hyperreactive neutrophil phenotype. This finding differs for severely affected individuals. Among severely affected COVID-19 patients, there is excessive platelet and neutrophil activation compared to healthy controls and non-COVID-19 pneumonia.

Finally, dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability. So in conclusion, taken together, this team's data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19, and further work is suggested to identify methods to disrupt immunothrombosis in patients with COVID-19.

Dr Carolyn Lam: Wow. That makes a lot of sense and is important information. Thanks, Greg. Well, this next study really aimed to assess the current trends in US mortality related to congenital heart disease from infancy to adulthood over the last 19 years, and to determine if there were differences by sex and ethnicity.

This is from Dr Lopez from Texas Children's Hospital and Baylor College of Medicine and colleagues who conducted an analysis of death certificates from 1999 to 2017, and also used data from the National Center for Health Statistics' live birth data and US Census Bureau bridged-race estimates as denominators for these population estimates.

Dr Greg Hundley: Wow, Carolyn. Really interesting article. So what did they find here?

Dr Carolyn Lam: So overall, US mortality due to congenital heart disease throughout the lifespan has decreased over the last 19 years, with the greatest mortality rate in infants. Disparities in mortality due to congenital heart disease persists for males compared to females, with men having higher mortality than women, and for non-Hispanic blacks compared to non-Hispanic whites.

For those less than 50 years old with congenital heart disease as a contributing cause of death, associated genetic abnormalities are the leading underlying cause of death, whereas myocardial infarction was the leading cause of death in those 50 years and older.

And so, the authors also concluded that determining factors that contribute to these disparities, such as access to quality care, timely diagnosis and maintenance of insurance, will be very important moving into the next decade.

Dr Greg Hundley: Boy, that is such a timely topic. Beautiful presentation.

Dr Carolyn Lam: Thanks, Greg. And now for my last paper. We've heard a lot recently about angiotensin-converting enzyme 2, or ACE2, that’s that membrane protein that enables COVID-19 infectivity and which also converts angiotensin II, which is a potent vasoconstrictor, to angiotensin 1-7.

Now, today we've got a paper that provides novel insights into the contribution of ACE2 to the development of pulmonary arterial hypertension. And this is from Dr Shyy and Yuan as co-corresponding authors from the University of California, San Diego, as well as Dr Yuan 00:08:06 from First Affiliated Hospital of Xi'an Jiaotong University in China.

The authors used cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension to investigate the post-translational modification of ACE2 in terms of, firstly, phosphorylation by AMP-activated protein kinase, which enhances ACE2's stability, and two, ubiquitination of oncoprotein murine double minute 2, or MDM2, which is involved in ACE2 degradation.

Dr Greg Hundley: So what did they find here?

Dr Carolyn Lam: MDM2 expression was increased in lung tissues from patients with idiopathic pulmonary arterial hypertension and animals with experimental pulmonary hypertension.

On the other hand, N-kinase phosphorylates ACE2 at S680 and inhibits MDM2- mediated ubiquitination of ACE2 at K788. Functionally, ACE2 phosphorylation and deubiquitylation increases eNOS-mediated nitric oxide bioavailability in the endothelial cells.

Dr Greg Hundley: Okay, Carolyn. What are the clinical implications here?

Dr Carolyn Lam: So post-translational modification of ACE2 is a novel strategy to develop new therapies for pulmonary arterial hypertension. On the other hand, inhibition of MDM2 has great potential for pulmonary arterial hypertension by stabilizing ACE2.

Dr Greg Hundley: Wow, beautiful summary there. Let me describe some of the other articles in the issue. First, Dr Jawad Butt has a research letter regarding the impact of COVID-19 on first-time acute stroke and transient ischemic attack admission rates and prognosis in Denmark. It's from a nationwide cohort study.

Next, there's an exchange of letters regarding the article, preventive or deferred ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and an implantable defibrillator, the Berlin VT multicenter randomized trial. And that comes to us from Drs Krisai and Kuck.

Next, there's a very nice ECG challenge from Dr Arrey-Mbi wide complex QRS rhythm in a 52-year-old male with an altered mental status.

And then finally, a nice case series from Dr Oscar Cingolani, entitled, ECMO therapy for cardiac lymphoma.

Dr Carolyn Lam: Well, I've also got a research letter by Dr Verdonschot on distinct cardiac transcriptomic clustering in titin and lamin-associated dilated cardiomyopathy patients.

There's also a white paper by Dr Butler on glucagon-like peptide-1 receptor agonists and heart failure, highlighting the need for further evidence generation and practice guidelines optimization.

And finally, an On My Mind piece by myself and Dr Butler entitled, “Victims of Success and Failure,” where we really describe how, with so many effective therapies for HFrEF these days, have we become victims of our own success?

Dr Greg Hundley: Very nice, Carolyn. Well, how about we get on to that feature and hear a little bit more about myocardial stress injury and the association with sudden death?

Dr Carolyn Lam: Yes. Let's go, Greg. Sudden cardiac death is the most common cause of death in the United States but identifying individuals at risk before they suffer a fatal event remains really challenging. In fact, it's the sad truth that the majority of sudden cardiac deaths occur in low-risk populations, often as the first manifestation of cardiovascular disease.

Now, can biomarkers help us identify those at risk of sudden cardiac death? Well, you have to listen to our discussion of today's feature paper, a beautiful paper that I'm so pleased to be welcoming the first and corresponding author, who's also our associate editor, Dr Brendan Everett from Brigham and Women's Hospital, who will talk about it, as well as our guest editor, Professor Harvey White, who is director of research at the Green Lane Cardiovascular Service in Auckland, New Zealand.

So welcome, gentlemen. And Brendan, could I get you to start by telling us what you did in this study and what you found?

Dr Brendan Everett: We were interested in exploring this problem. Dr Albert, Christine Albert, who is the senior author on the paper, has years of experience looking at sudden cardiac death as an important outcome amongst patients who may not have yet been diagnosed with cardiovascular disease.

And of course, as you mentioned in your introduction, it can be the first manifestation of cardiovascular disease. And because we, as physicians, don't get a chance to then help patients recover and treat them for their cardiovascular disease, we often feel like we've missed the opportunity to help people live longer and more productive lives.

The problem, of course, with this is that there's a huge population of people who are at risk, but actually identifying tests that will work well enough and can be used in a broad population, who, in aggregate, are actually at low individual absolute risk, is very challenging.

The markers that we selected to study for this paper included measures of lipids, in this case, total cholesterol, the HDL cholesterol, NT-proBNP, a marker of myocardial stress, which is, I'm sure, familiar to many people on the podcast, high-sensitivity cardiac troponin I, which again, is increasingly used throughout the world, including here in the United States, and hsCRP, a marker of subclinical inflammation.

I think the advantage that we had is that, over the years, Dr Albert has compiled a number of cases of sudden cardiac deaths in cohorts that have been followed prospectively for a long period of time. These are NIH-funded cohorts and include studies that may be familiar to your listeners, like the Nurses' Health Study, the Physician's Health Study I and II, the Women's Health Study.

These are cohorts that have been following patients for, in some cases, decades, and of course, when you have a lot of patients or participants and you follow them over many years, some of them die suddenly. Not very many, fortunately, but enough so that if you aggregate all six cohorts together, you can have a total of, in our case, 565 cases, which is more, I think, as far as I know, anyways, than other cohorts that are out there that have studied this question.

We were able to match those two-to-one with 1090 controls, and then measure the biomarkers I mentioned earlier in all of those patients, and then look at the association between those common, relatively accessible biomarkers and the risk of sudden death.

Dr Carolyn Lam: Congratulations. I do think this is the largest collection of sudden cardiac death cases, as well as with prospectively collected blood samples. And I do believe yours is the first to really have a multi-marker approach. So now, could you tell us what you found?

Dr Brendan Everett: We first assessed each of these four markers individually and found that their risk of sudden cardiac death was relatively strong and was independent of other traditional cardiovascular risk factors, such as cigarette smoking or body mass index and those sorts of things. It appeared, at least in our analysis, that NT-proBNP and cardiac troponin might have been slightly more powerful correlates of the risk of sudden cardiac death in total to HDL cholesterol ratio in hsCRP.

But nonetheless, when we put them all together in a comprehensive model, we found that the risk estimates for each individual marker were maintained. In other words, they were independent of one another and they all remained statistically significant. So this tells me, as a cardiologist and an epidemiologist, that we're getting a sense of somebody's risk from multiple different perspectives. We're integrating that information, and then potentially, when we combine those markers together, have the opportunity to have an improved ability to identify individuals at risk.

And so, that's actually what we did, and I think this is what you're asking about. We decided to create a very simple biomarker score where we gave each participant one point if their concentration of a given biomarker was in the top core tile of that biomarker's range, so the top 25%. So just by way of example, if somebody had all normal biomarkers except for a high total cholesterol, the HDL ratio, they would get one point.

The total number of points, of course, could range from zero to four, and then we looked at what the risk of sudden cardiac death was across that scale. And what we found is that it went up in a relatively linear fashion. The odds ratio increased by about 1.6 per individual point of score increase, such that, for example, compared to those individuals with a score of zero, who of course, had normal concentrations of these four biomarkers, if you had all four be elevated, your odds ratio of sudden cardiac death was actually seven. If you just had three out of the four being abnormal, it was approximately four. So those participants with at least three or four abnormal concentrations of these biomarkers seemed to be at a high relative risk or odds ratio for sudden cardiac deaths.

Dr Carolyn Lam: Ah. Love it, Brendan. And for all of you who are listening, you have to pick up the paper and look at the figures. The story is all there, the individual biomarkers and that score. I love the simplicity and the clarity of the message.

Harvey, could you summarize for us and perhaps give us a sneak peek of the discussions that occurred behind the scenes when this paper landed on your desk?

Dr Harvey White: When I saw this paper, it was terrific. And I had to decide whether to get reviewers who are experts in sudden death, or are experts in cholesterol, or troponin, or each of the four biomarkers, and I chose to get people who are interested in sudden death. And I had three reviewers, and they all said it was absolutely terrific, elegant study, robust data.

They focused on the cut points, for example, NT-proBNP. Initially, Brendan, you looked at the median for your study, and the reviewers said, "Well, can we look at clinically relevant?" So they requested that you consider that, and I must say, your responses were just terrific. And so, you went to a cut point of 125, which is clinically relevant. I think this is extraordinarily important. The reviewers stressed that you should be careful with your conclusions. And you carefully said, "This represents only the first step in testing whether these biomarkers may serve as valuable clinical tools."

I would go further than that. I think these four tests are inexpensive, they're clinically available. I don't do them on all patients, but I do them on some. I always do lipids, and I do NT-BNP in somebody with heart failure or decreased ejection fraction. And I always do troponin, which I think is extremely important. Even in the normal range, it trebles its risk.

So a question to Brendan. I think if I found a high troponin, I want to look at CRP, look at NT-proBNP, and I'd have the cholesterol HDL ratio. So what would you think about cascade screening and the implications of that on cost effectiveness?

Dr Brendan Everett: I think that's a really excellent suggestion. We hadn't thought of that, as you know, and it doesn't come up as an idea in the discussion. I think, at least here in the United States, the standard test would be a total cholesterol to HDL ratio, and of course, with that, oftentimes in LDL cholesterol, because that's where we focus our preventative efforts with statins, as you mentioned. And we typically would not do a troponin in otherwise healthy and ambulatory patients.

I think that's a creative suggestion, the idea that if you had an abnormal cholesterol, and then an abnormal NT-proBNP, and then would you move to a CRP and a troponin as well? I think in the type of patient that we're talking about, a primary prevention patient who may have occult cardiovascular disease, CRP is probably the best validated, epidemiologically, as a marker of risk and to guide therapy.

But I think one thing that we struggled with, and I'd be interested in your view on this because you're such an expert on cardiac troponin, is, what are the therapeutic interventions that you would use for somebody with an elevated biomarkers for... And we addressed this a little bit in the discussion, and I think it's just common sense preventive therapy, but I don't know if that struck you as the right thing to do, or if you had other ideas about how to address somebody who might have, theoretically, an elevated risk of sudden cardiac death.

Dr Harvey White: I think it's challenging common sense. Do people use them? So I think the stress should be that preventive therapy should be used in these patients. So blood pressure and history of hypertension is related to sudden death. In your study, sudden death was more common in individuals who didn't exercise. Obviously, they're higher cholesterol, so you got to promote weight loss, blood pressure, nonpharmacological means diabetes is associated with, and a higher HbA1c, so you really want to get the HbA1c down.

Whenever you find an abnormal troponin, you need to go back to the patient and get an echocardiogram. Have they got left ventricular hypertrophy? Have they got underlying LV dysfunction, and so forth? And to get the patient on board, one of the things that you would challenge with doing is the drug use during follow up. And I was particularly interested in beta blockers, which of course, may reduce sudden death.

But I'm also interested in, about 30% of patients with sudden death have taken cocaine or alcohol. And so, addressing drug use is important, addressing alcohol is important. And just as an add-on in this age of COVID, don't take hydroxychloroquine, because that might cause sudden death.

Dr Carolyn Lam: Harvey and Brendan, those were just really excellent points. In fact, I was sort of thinking along the same lines of, what are the therapeutic implications of this? And I think one of the management implications addresses one of the limitations, perhaps though, because this study did not include electrocardiographic or imaging information, like left ventricular ejection fraction. I just wanted to double-check if that's the case, Brendan. And if you could, how has this impacted your own practice, or what's the next steps, you think?

Dr Brendan Everett: You are absolutely correct, that as a routine, none of the studies that we included in this research work actually had baseline electrocardiograms or echocardiograms. I think when you take the perspective of wanting to screen or thinking about screening a broad population for the risk of sudden cardiac death, an echocardiogram is probably not a feasible study. Although, to Harvey's earlier point and to your own point, using that as a subsequent test, along the lines of the cascade screening approach, when you have an abnormal cardiac troponin or an abnormal NT-proBNP, perhaps an echocardiogram is a very good study to order at that point.

The lack of electrocardiograms, I think, is another limitation of our work. Those are more commonly used, at least I think, as a screening tool, at least in the United States, when somebody has a history of hypertension, for example.

I think, with respect to your last question, "How has it changed my own practice?", I think the key thing that I wanted to emphasize, which is an important limitation of the study, is that this is a case control study. So what we're able to do is, we're able to estimate relative risks. And relative risks of seven are high. They're impressive, right?

The problem is that we can't actually estimate what the absolute population risk is of sudden death based on the patients or the participants in these studies. So it's hard to take the group of participants that we were able to look at and watch carefully prospectively, and then back-calculate what the absolute risk of sudden cardiac death would be in a broader population.

So in order to take a research finding like this, where there's a high relative risk, and start to think about population-wide screening, you have to know how that will implicate or affect the absolute risk. If your absolute risk is tremendously low, seven times tremendously low is still tremendously low.

However, if you can find a population where a relative increase of seven in your absolute risk actually becomes clinically important, then you begin to have an argument about population screening and whether or not it's worthwhile and effective, or potentially how it can reduce the occurrence of sudden death, which is our goal, after all, with a study like this.

Dr Carolyn Lam: What a balanced discussion. So thank you, Brendan. That was a very important point. Finally, are you planning next studies, or what's the next step then, you think?

Dr Brendan Everett: Well, I think the next step would be to try and figure out how to translate the data that we have here into a real sense of how this would affect absolute risk. This would then have implications for cascade screening, as Harvey mentioned earlier, potentially broader use of these biomarkers as screening tools in otherwise healthy populations, and of course, implications, both about the testing characteristics and false positives and those sorts of important issues, and then the cost and the cost effectiveness, how much it would cost to screen such and such a population to prevent one sudden cardiac death. Those would all be the next steps, I think, in terms of determining whether or not this approach could be implemented more broadly.

Dr Carolyn Lam: Thanks, Brendan, and thank you so much for this paper. It's just so beautifully and elegantly put. It's something I'm going to remember and already taken my clinical practice to recognize persons at risk and whom I want to do further work of.

Thank you so much for joining us today, Brendan. Thank you so much, Harvey. And thank you, audience, for listening today. Please tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation September 15, 2020 Issue

14 september 2020 | 28 min

This week’s episode includes author Jeffrey Testani and Associate Editor Justin Grodin as they discuss empagliflozin heart failure, including diuretic and cardio-renal effects.

TRANSCRIPT:

Dr Greg Hundley: And I'm Greg. I'm the director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, the SGLT-2 inhibitors have really revolutionized heart failure treatment, but we still need to understand a bit better how they work. And today's feature paper is so important, talking about diuretic and cardio-renal effects of Empagliflozin. That's all I'm going to tell you though, because I want to talk about another paper in the issue very related. And it's from John McMurray from the University of Glasgow with insights from DAPA-HF. But maybe a question for you first. Have you ever wondered what to do about loop diuretics doses in patients with heart failure and whom you're thinking of initiating an SGLT-2 inhibitor, Greg?

Dr Greg Hundley: Absolutely, Carolyn. That comes up all the time and how do you make that transition.

Dr Carolyn Lam: Exactly. And so this paper is just so important, and Dr McMurray and his colleagues showed that in the DAPA-HF trial, the SGLT-2 inhibitor, dapagliflozin, first, just as a reminder, reduce the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. And in the current paper, they examined the efficacy and tolerability that dapagliflozin falls in relation to background diuretic treatment and change in diuretic therapy, following randomization to dapagliflozin or placebo. They found that 84% of patients randomized were treated with a conventional diuretic, such as the loop or thiazides diuretic. The majority of patients did not change their diuretic dose throughout follow-up. And the mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization. Although a decrease in diuretic dose was more frequent with dapagliflozin than with placebo, the between-group differences were small. So treatment with dapagliflozin is safe and effective regardless of diuretic dose or diuretic use.

Dr Greg Hundley: Very nice, Carolyn. That's such a nice practical article. I really enjoyed your presentation of that. My next article comes from Professor Karlheinz Peter, and it's investigating the reduction of shear stress and how that might impact monocyte activation in patients that undergo TAVI. So this group hypothesized that the large shear forces exerted on circulating cells, particularly in the largest circulating cells, monocytes, while passing through stenotic aortic valves results in pro-inflammatory effects that could be resolved with TAVI. So to address this, the investigative team implemented functional essays, calcium imaging, RNA gene silencing and pharmacologic agonist and antagonist to identify the key mechanical- receptor mediating the shear stress sensitivity of the monocytes. In addition, they stained for monocytes in explanted, stenotic, aortic human valves.

Dr Carolyn Lam: Lots of work done in a very translational study. So what did they find Greg?

Dr Greg Hundley: They found monocyte accumulation at the aortic side of the leaflets in the explanted aortic valves. That was the human subject study. In addition, they demonstrated that high shear stress activates multiple monocyte functions and identify PZ1 as the main responsible mechanoreceptors representing, therefore, a potentially druggable target. So reducing the shear stress from a stenotic valve promotes an anti-inflammatory effect and, therefore, could serve as a novel therapeutic benefit of those undergoing TAVI procedures.

Dr Carolyn Lam: Really nice, Greg. Thanks. We're going to switch tracks a bit, Greg. What do you remember about Noonan's syndrome?

Dr Greg Hundley: Oh boy. Impactful, congenital disease for both the probands, as well as the family.

Dr Carolyn Lam: That's truly beautifully put and you're right. Noonan syndrome is a multisystemic developmental disorder characterized by common clinically variable symptoms, such as typical facial dysmorphism, short stature, developmental delay, intellectual disability, as well as cardiac hypertrophy. Now the underlying mechanism is a gain of function of the RAs MAPK signaling pathway, kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, really remains limited. So today's paper contributes significantly to our understanding and is also notable for the methods that these authors use to uncover this novel potential therapeutic approaches. The paper is from Dr Cyganek and Wollnik as co-corresponding authors from the University Medical Center Göttingen in Germany. And they presented a family with two siblings, displaying an autosomal recessive form of Noonan syndrome with massive hypertrophic cardiomyopathy. As the clinically most prevalent symptom caused by allelic mutations within the leucine zipper like transcription regulator 1. They generated induced pluripotent STEM cell derived cardiomyocytes of the effected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level.

Dr Greg Hundley: Carolyn, is such a thorough investigative initiative. So what did they find?

Dr Carolyn Lam: They found that the patients induced, pluripotent STEM cell cardiomyocytes recapitulated the hypertrophic phenotype and uncovered, a so far not described, causal link between this leucine zipper like transcription regulator 1 dysfunction and ras map, kinase signaling hyperactivity, as well as, the hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics providing a molecular underpinning for the clinical use of these drugs in patients with Noonan syndrome. In a proof of concept approach, they further explored a clinically translatable intronic CRISPR repair and demonstrated a rescue of the hypertrophic phenotype. Massive amount of work in a beautiful paper.

Dr Greg Hundley: You bet, Carolyn, and boy giving hope to address some of that adverse phenotype in the heart. What an outstanding job.

Dr Carolyn Lam: You're right, Greg. But now switching tracks a yet again. What do you know about ischemic preconditioning? Ischemic preconditioning refers to the process in which non-lethal ischemic stress of the heart prevents subsequent lethal ischemia reperfusion injury and provides important intrinsic protection against ischemia reperfusion injury of the heart, as well as other organs. So in this paper co-corresponding authors, Doctors, Zhang, Xiao and Cao from Peking University and colleagues provided multiple lines of evidence that a multifunctional TRIM family protein, the Mitsugumin-53 or MG53 is secreted from the heart in rodents in response to ischemic, preconditioning or oxidative stress. Now this secreted MG53 protected the heart against ischemia reperfusion injury. In the human heart, MG53 was expressed at a level about 1/10th of its skeletal muscle counterpart. And MG53 secretion was triggered by oxidative stress and human embryonic STEM cell derived cardiomyocytes, while deficiency exacerbated oxidative injury in these cells.

Dr Greg Hundley: Very nice, Caroline. Tell me the take home message. How do I incorporate this information, maybe even clinically?

Dr Carolyn Lam: Well, these results really defines secreted MG53 as an essential factor, conveying ischemic preconditioning induced cardioprotection. Now, since systemic delivery of MG53 protein restored ischemic preconditioning mediated cardioprotection in deficient mice, recombinant human MG53 protein could perhaps, or potentially be developed, into a novel treatment for various diseases of the human heart in which indigenous MG53 may be low.

Dr Greg Hundley: All right, Carolyn. I'm going to tell you about a couple of letters in the mailbag. First, there's a research letter from Richard Vander Heide regarding unexpected feathers in cardiac pathology in COVID-19. And then, there's a large exchange of letters between Dr Yuji MIura, Chuanli Ren and Laurent Azoulay regarding a prior publication, entitled "Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer, A Population-Based Cohort Study." And then finally, Carolyn, there's another research letter from professor, Nilesh Samani, entitled "Genetic Associations with Plasma ACE2 Concentration: Potential Relevance to COVID-19 Risk."

Dr Carolyn Lam: Wow, interesting. There's also an "On My Mind" paper by Dr Kimura on "contextual imaging, a requisite concept for the emergence of point-of-care ultrasound." There's an ECG challenge, by Dr Dewland, with a case of an intermittent -wide QRS complexes. There's a cardiovascular case series presentation by Dr Nijjar on "a solitary left ventricular septal mass and amaurosis fugax."

Dr Greg Hundley: That's great, Carolyn. How about we move on to the feature discussion.

Dr Carolyn Lam: Let's do that.

Dr Greg Hundley: Well listeners, we are here to discuss again, another important paper related to SGLT-2 inhibition. And we have with us, Dr Jeff Testani from Yale New Haven and our own associate editor, Dr Justin Grodin from University of Texas Southwestern Medical Center. Welcome gentlemen. Jeff let's start with you. Can you describe for us some of the background behind this study, and then also the hypothesis that you wanted to address?

Dr Jeffrey Testani: Our lab is very interested in understanding volume overload and heart failure, why does the kidney retain sodium and why it stops responding to loop diuretics. Several years ago, when the SGLT-2 first came out, we saw them as a diuretic with the side effect of glucosuria. Back when they were still being thought of as primarily diabetes medications. But as the story unfolded and we saw that the SGLT-2 seemed to be doing something much more than just control blood glucose in diabetics and was demonstrating, particularly, a pronounced effect on heart failure outcomes, we got very interested in, better understanding this.

We know that loop diuretics, they're really a double-edged sword. Loop diuretics are our mainstay of therapy to relieve congestion and heart failure patients, but they do so at the expense of quite a bit of toxicity. And we know that the loop diuretics directly cause neuronal activation, elaboration of rennin, norepinephrine, etc. through their effects directly on the kidney. In addition to causing normal moral activation through the volume depletion they cause. And as we all know, blocking the neurohormonal activation is one of the primary therapies we use in heart failure. So even though it helps our patients keep the fluid off, it does that at an expense of potentially some very negative effects.

The interesting thing with the SGLT-2 inhibitors is, we've seen that in the diabetic populations, that they seem to actually improve volume status in diabetics, more so than one would really expect by the week diuretics that they are. And by and large, they were doing that without a pronounced activation of the neurohormonal system. So this led us to the conclusion that we really need to rigorously study this in heart theory and see what exactly are these effects of diuretics volume status and how much negative impact will any of those effects bring towards normal activation, kidney dysfunction, etc.

Dr Greg Hundley: Very clever, Jeff. How did you go about addressing this question? What was your study design and what was your study population? Who did you enroll?

Dr Jeffrey Testani: We wanted to have a pretty clean mechanistic study here. We weren't looking at ethnicity. We were really trying to understand a mechanism here and what are these agents doing to sodium handling in the kidney, etc.

We enrolled diabetic patients that were stable. Per their advanced heart failure position, they were at added at a stable volume status. They hadn't had recent changes in medications diuretics, and we use the crossover design where we brought the patient in for about an eight-hour rigorous GCRT type study where we administered empagliflozin in 10 milligrams and then did some pretty rigorous characterization of them. As far as body fluids spaces, renal function, normal activation, your sodium excretion. Then they would continue that therapy for two weeks, come in for a terminal visit, that was a very similar protocol. Then we'd wash them out for two weeks and cross them over to the alternative therapy. And they were randomized whether they had placebo or epilobium first in order.

Dr Greg Hundley: Very good. So a crossover design. And what were your study results, Jeff?

Dr Jeffrey Testani: We were quite interested in the overall effects and it was actually quite surprising. We know the loop diuretic resistance is common and when physicians and patients are not responding well enough, oftentimes we add thiazides. And thiazides waste potassium. They waste magnesium. They increase uric acid. They usually cause renal dysfunction and significant normal activation. That was the default hypothesis that we would see that. And to the contrary, we pretty much saw the opposite of what a thiazide did. We saw a modest, but clinically significant natriuresis. So as a monotherapy, these drugs are quite weak. Although we saw a doubling of a baseline level of sodium excretion, that's sort of a clinically irrelevant amount as an acute diarrheic. However, when we added the eplerenone to a loop diuretic, we got a 30, 40% increase in sodium excretion. And just to benchmark that, if you look at the dose trial where they compared low dose to high dose Lasix, which were one X versus two and a half X, their home loop diuretic, they got a similar increase in sodium excretion.

So even though 30, 40% increase in sodium excretion doesn't sound like a lot, it's all of our normal interventions. It's actually a pretty significant increase. We found that happened acutely. And to our surprise, that natriuretic effect had not completely gone away by two weeks. So the patient was still in a negative sodium balance at the two-week time point. And they actually had a reduction in their blood volume, in their total body water, in their weight, as a result of that kind of slow persistent, natriuresis that had happened over those two weeks.

We were unable to detect any signs of normal MAL activation with this. There was actually a statistically significant better change in norepinephrine during the dapagliflozin period versus placebo. And there's some evidence that, that might be an actual finding of saccharolytic effect of these drugs. As in many of the other trials we've seen no, despite a reduction of blood pressure and probably volume status, heart rate stays the same or even goes down. And we saw an improvement in uric acid. We saw no additional potassium wasting. We saw an improvement in serum magnesium levels. So really kind of like I started this way is the opposite, in many ways of what we see, side effect wise, with the diuretic is what we saw with addition of an SGLT-2 inhibitor.

Dr Greg Hundley: Listeners, we're going to turn now to Dr Justin Grodin, who's one of our associate editors and is also an editorialist for this paper. And Justin, we've heard some really exciting results here. The addition of a dapagliflozin to a loop diuretic enhancing the neurohormonal access and receiving some unexpected benefits on the electrolyte portfolio. Can you tell us a little bit about how you put this work in the context of everything else that we have been reading about this exciting new class of drug therapy?

Dr Justin Grodin: This certainly is exciting because with the release of the DAPA-HF clinical trial, just about a year ago, we've really come to recognize that there really are substantial, long-term beneficial effects with SGLT-2 inhibition in patients with heart failure, and as Jeff alluded to, a lot of these effects, we saw that they were beneficial in individuals that are high risk or who already had heart disease and diabetes. And we weren't sure if that was going to translate to individuals with heart failure. We really saw beneficial effects in both, individuals with heart failure, with or without diabetes. So this is an interesting paradigm because, although we saw dramatic effects in long-term survival quality of life, the mechanism was actually somewhat murky. And a lot of this was transitive based on prior works. We obviously had a strong hypothesis that they would work through reducing incident heart failure and diabetics, but then we were left questioning what is the mechanism? And I think Jeff highlighted it quite well.

There was the early thought that this was perhaps just a weak diuretic and that it was additive, and these patients were just getting long-term natiurer recess. And then others thought that there might've been, perhaps, some positive influence by some very low level, blood pressure reduction with these therapies.

So in that sense, I think Jeff's paper really is put in context and when we reviewed it, we thought it was quite fascinating because I think as Jeff showed in his paper quite elegantly and actually in a very, very careful study, which the reviewers and your editorial staff appreciated, we really saw that there was a probably more robust response to natriuresis than we had anticipated. And importantly, this was independent of glycosuria, which is a very important observation. And if I might take a 10,000-foot view of at least this therapy and how we might think about it as an incremental therapy in heart failure, it's really doing something else. So we thought that with SGLT-2 inhibition, you get a little sodium and a little natriuresis, maybe perhaps a little bit extra, as it complexes with glucose.

I think if you look at what the potential physiology would be with this therapy is that it's doing far more than that. And I think Jeff's study at least supports some of the speculation. And again, I'm going to perhaps look beyond SGLP-2 inhibitor, and then more so focus on the physiology of the proximal convoluted tubule. And given the location of the blockade, this is really priming the kidney, or at least Jeff's manuscript, and Jeff's analysis, supports the hypothesis that SGLT-2 inhibitors influence the proximal tubule environment, such that the kidney is ready to reset in natriuresis. And I think Jeff's data it at. least supports that because if we look at the proximal tubule physiology, there's really a lot more going on, then SGLT-2 inhibition.

There are other receptors that it can influence that might also promote natriuresis. It can also promote increased distal sodium delivery to other areas of the nephron. And in essence, this almost, and in Jeff has put it this way before, which I totally agree. This gives the opportunity for the kidney to taste the salt, as opposed to the more common state that we have in somebody with heart failure and congestion, where, and I talk about this on rounds all the time, the kidney's response to a failing heart is to retain salt and water. So this kidney is in this perpetual state of dehydration. And I think the idea that Jeff's analysis is at least supporting, is that somehow, we were influencing the physiology in the proximal convoluted tubule, we are actually priming the kidney and readying it. We're almost hitting reset, where the kidneys may lose this physiology, thinking that the body is dehydrated and in essence, really readying it to assist with decongestion.

Dr Greg Hundley: I love the way you explained that. It's almost as if I'm on ward rounds with you that just knocks home a lot of the message here, and the importance of Jeff's work. Understanding the physiology of the proximal tubule and then readying the kidney, instead of moving into a mode of retaining salt and water, actually allowing that to flow and facilitating a diaresis. I'll start with you, Jeff, and then come back to Justin. You might have unlocked a really special key here. What do you see as the next steps in research in this particular field?

Dr Jeffrey Testani: I think Justin really, really captured the essence of what excites us so much about this is, most diuretics are a brute force sort of approach to getting salt out of the body. They are a stick, not a carrot and SGLT-2 inhibitors, when you look at them as how they would work as a brute force diarrheic, they are really wimpy and there is every opportunity for the kidney to defeat the of a SGLT-2 inhibitor, if it wanted to buy where they work and what they block. But the reality is, is that they really seem to be the carrot almost. if you think of resetting the sodium set point of the kidney, kind of quenching some of that salt first or sodium humidity that Justin was referring to.

And the thing that's really interesting is when we look at trials like DAPA-HF. So despite the fact that they do seem to have this natural effect in blood pressure lowering effect and these different effects, they don't tend to cause hypertension, over diaresis, it's a much more of a natural, where the kidneys regulatory mechanisms are still operative. we have this duality of not causing over diaresis but causing diaresis. So it's really when the body needs to get rid of salt, it helps it do that. And so I think the next steps, at least for our research program is, we want to understand taking these drugs out of the context of stable, relatively euvolemic chronic heart failure patients. And when we put them into the acute setting of actual volume overload, do we see more robust diathesis and that natriuresis in that setting.

The second thing is we want to dig into what is the internal mechanisms that are allowing the kidney to do these things. How is it that it's able to dump out salt when it's beneficial, but not leaked over to uresis. Since we're digging into those mechanisms, I think will give us some additional insight into this class.

Dr Greg Hundley: Justin.

Dr Justin Grodin: I think Jeff really encapsulated, or at least certainly highlighted some very important points, that are largely in parallel with where I foresee this. Because really, if you look at just study, a lot of these patients were quite stable. So the questions that come along are whether or not that this synergistic effect number one, is sustained long-term. Because there are some data, at least in diabetic individuals, that this might not be the case. So Jeff's paper elegantly highlights the influence of these therapies in two weeks. Now, whether that's sustained is certainly unclear. I think the logical next step is, "Okay. We show that we have a therapy that might prime the kidney for increased natriuresis" what are its effects and individuals that might need the natriuresis even more. So as Jeff highlighted individuals with more decompensated heart failure, that are more congested and more hypervolemic.

And then obviously individuals that might be quite diarrheic resistant. This is something that I think Jeff and I have given talks on. And Jeff is clearly one of the world's experts in this space, but it's obviously a very attractive possibility that this might influence individuals whose kidneys are teased or trained into just holding onto sodium, no matter what. Or really no matter what therapies we give the kidney. I don't know if Jeff mentioned this, but at least in his analysis, they also showed through indicator dilution methods that there was a reduction in plasma volume in these individuals. And I think that's really important because we at least hypothesize that in many heart failure phenotypes, plasma volume is certainly a component of decompensation. So whether these kidneys have a more pleiotropic effect on the fluid balance from your status between the interstitium and the vascular space, long-term is really unknown.

Dr Greg Hundley: I want to thank both Jeff and Justin. What an incredible, exciting discussion. And this paper, Jeff, were so thrilled to have the opportunity to publish it in circulation. And the clarity, helping us understand some of the mechanism of the efficacy of SGLT-2 inhibition. And then this unique combination of SGLT-2 with loop diuretics, potentiating, dieresis natriuresis without some of the harmful effects on serum electrolytes. And then I really appreciate both of you giving us an insight into the future where more work is needed to understand, is this a sustainable beyond two-week effect? And then, can these therapies, this combination, be helpful in those with decompensated heart failure.

On behalf of Carolyn and myself, we wish you a great week and we look forward to catching you next week on the Run.

This program is copyright, the American Heart Association 2020.

Circulation September 9, 2020 Issue

8 september 2020 | 20 min

This week’s episode includes author Charlotte Andersson and Associate Editor Naveed Sattar as they discuss familial clustering of aortic size, aneurysms, and dissections in the community.

TRANSCRIPT:

Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature this week has to do with aortic size, aneurysms, and predilection to dissection. But before we get to that, how about if we grab a cup of coffee and go through some of the other articles in the issue?

Dr Carolyn Lam: I got my coffee, Greg, and you know what? I'm going to start with quiz for you.

Dr Greg Hundley: All right.

Dr Carolyn Lam: True or false, in the setting of obesity and/or diabetes, cardiac substrate metabolism shifts towards increased fatty acid oxidation, while lipid accumulates in the heart? True or false? Of course, you're right. Oh, but there's a part two. Can you guess, by increasing fatty acid oxidation, will we induce or prevent obesity-induced lipotoxic cardiomyopathy?

Dr Greg Hundley: I'm going to say, because you asked it in the way you asked it, prevent.

Dr Carolyn Lam: Wow. All right. Well, the truth is we didn't really know before today's paper. The specific link between cardiac metabolism and lipotoxic cardiomyopathy was elusive and there was no specific therapy available for this condition. And these authors, Dr Rong Tian from University of Washington and colleagues, hypothesized that cardiac pathology-associated obesity would be attributable to the imbalance of fatty acid supply and oxidation. So using a diet-induced obesity model in the current study, they demonstrated that enhancing fatty acid oxidation through deletion of acetyl-CoA carboxylase 2, was sufficient to prevent obesity-induced cardiomyopathy.

So, increasing cardiac fatty acid oxidation alone does not cause cardiac dysfunction, but instead protects against cardiomyopathy in chronically obese mice. The cardiac-protective effect of increasing fatty acid oxidation and obese mice is through maintenance of Parkin-mediated mitophagy, and thus preventing mitochondrial dysfunction. These findings indicate that impaired mitophagy contributes to mitochondrial dysfunction in obese mice, and that targeting the Parkin-dependent pathway is a viable therapeutic intervention for obesity-induced cardiomyopathy.

Dr Greg Hundley: Very nice. Carolyn.

Dr Carolyn Lam: I'm going to be greedy and go on to my next paper. So Greg, do you think cardiac regeneration is possible?

Dr Greg Hundley: Well, Carolyn, I would have said, several years ago, no, but that trip that we took to China with Joe Hill and Hesham Sadek, our Associate Editor and our Chief Editor, convinced me otherwise. So I'm going to definitely answer yes on this one.

Dr Carolyn Lam: Oh, Greg, you're just too smart. And speaking of China, this next paper is from there, from co-corresponding authors, Dr Nie and Hu, from Fuwai Hospital National Center for Cardiovascular Disease and Chinese Academy of Medical Sciences and Peking Union Medical College. So, using seven genetic mouse lines, they identify that Oncostatin M is the top upregulated cytokine during neonatal heart regeneration. Oncostatin M is a pleiotropic secretory protein that belongs to the interleukin 6 family, and associates with the pathological process of dilated cardiomyopathy.

And these authors found that macrophages promote heart regeneration by secreting Oncostatin M, which promotes cardiomyocyte proliferation via a co-receptor, gp130. Employing RNA-seq and functional screening, they further found that Src-mediated gp130 triggered cardiomyocyte proliferation by activating the downstream signaling pathway involving Yap, with Y357 phosphorylation independent of the Hippo pathway. So the last thing that they did was show that gene therapy with adenovirus-associated virus and coding this activated gp130 improved heart regeneration and pumping function, thus serving as a potential therapeutic target. An amazing paper.

Dr Greg Hundley: Very nice, Carolyn. What a great summary and so much detail. Well, Carolyn, I'm going to turn our attention to catecholaminergic polymorphic ventricular tachycardia. And this article comes to us from Dr Jason Roberts, from the Western University. Carolyn, genetic variants in calsequestrin 2 can cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia, though isolated reports have identified arrhythmogenic phenotypes among heterozygotes. So in this study, a total of 112 individuals, including 36 catecholaminergic polymorphic ventricular tachycardia probands, 24 were homozygotes for compound heterozygotes, and 12 were pure heterozygotes, against 76 family members possessing at least one presumed pathogenic calsequestrin 2 variant. These were all identified.

Dr Carolyn Lam: Wow, a very precious cohort. So what did they find, Greg?

Dr Greg Hundley: This international multicenter study of calsequestrin 2 catecholaminergic polymorphic ventricular tachycardia really redefined its heritability and confirmed that pathogenic heterozygous calsequestrin 2 variants may manifest with a catecholaminergic polymorphic ventricular tachycardia phenotype, indicating a need to clinically screen these individuals. Among individuals heterozygous for a pathogenic calsequestrin 2 rare variant, medical therapy and exercise restriction are likely not necessary in the absence of the catecholaminergic polymorphic ventricular tachycardia phenotype. Though, you have to be certain over time, an intermittent clinical screening to ensure they remain phenotype-negative should be obtained.

Dr Carolyn Lam: Wow, Greg, clinically important study there. Well, I'm going to go back to the basic science world and talk about calcineurin. Now, calcineurin has long been implicated in the induction of pathological cardiac remodeling but has not been therapeutically targetable for the prevention of heart failure because of its pleiotropy and our lack of understanding of its specific protein-protein interactions and compartmentation within the cardiomyocyte.

Dr Greg Hundley: Okay. Carolyn, do you want me to give background on calcineurin?

Dr Carolyn Lam: No, Greg, you're off the hook. I'm going to give you some background on calcineurin. So, calcineurin is the calcium-calmodulin-dependent phosphatase that exists as a heterodimer, consisting of a catalytic subunit and a regulatory subunit. Now, of the three catalytic subunit isoforms, alpha, beta, gamma, it's the beta isoform that appears to be the most important for the development of cardiac hypertrophy. Binding of calcium to the calcineurin regulatory subunit enables binding of the calcium-calmodulin complex, thereby releasing auto-inhibition and freeing the enzyme to dephosphorylate downstream substrates. That's the background.

Now, in today's issue, we have this great paper from co-corresponding authors, Dr Kapiloff from Stanford University, and Dr Nikolaev from University Medical Center Hamburg. And, with their colleagues, they described the discovery of a calcineurin catalytic subunit beta binding protein Cdc42-interacting proteins 4, and I'm going to call that CIP4, which functions as a scaffold to sequester the pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates pro-hypertrophic signaling.

These findings have really important implications for understanding how cardiac calcineurin is selectively activated by stress signals, as opposed to the pleiotropic second messenger, calcium, that really floods the cardiomyocytes during each contractile cycle. Furthermore, the data provide proof of concept for an innovative therapeutic approach, whereby CIP4-anchoring activity is selectively inhibited to block the action of a small pathogenic pool of calcineurin as a means of treating heart failure. How about that? This is really discussed in an elegant editorial by doctors, Woulfe, Travers, and McKinsey.

Dr Greg Hundley: Very interesting, Carolyn. Sounds like another possibility for treating and managing heart failure. Well, let me share with you some of the other findings in our mailbag this week. First, I've got, from Professor Lang Li and Stephen Wiviott, they swap research correspondence regarding the prior publication entitled, Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus, Insights from the DECLARE-TIMI 58 Trial. And then Professor Laszlo Littmann has a nice ECG challenge for us related to a high-risk ECG that exposed some downstream worrisome vital signs.

Dr Carolyn Lam: In addition, there's a perspective piece by Dr Nambi discussing the fact that a zero-calcium score is desirable, but isn't enough to defer therapy, given that up to one-third of events will occur in this group. There's also an In Depth paper by Dr Borlaug, entitled, “Altered Hemodynamics and End Organ Damage in Heart Failure, The Impact on the Lung and Kidney,” and oh boy, this one is so beautifully illustrated. Just a must read for the understanding of the hemodynamics in the lung and kidney and heart failure. Next is a research letter by Dr Loeys on enrichment of rare variants in the Loeys-Dietz syndrome genes in spontaneous coronary artery dissection, and not in severe fibromuscular dysplasia. And finally, another research letter by Dr Arora on racial differences in serial NT-proBNP levels in heart failure management with insights from the GUIDE-IT Trial. What a rich issue, but let's move on to our future discussion, shall we?

Dr Greg Hundley: You bet, Carolyn.

Well, listeners, we're now getting to our feature discussion and it's very interesting this week where we're going to evaluate aortic aneurysms. And we have with us one of the lead authors of this paper, Dr Charlotte Andersson from Boston Medical Center, and our own Associate Editor, Naveed Sattar from Glasgow, Scotland. Charlotte, welcome to our feature discussion. Could you tell us a little bit about the background and the hypothesis that you put forward with this study?

Dr Charlotte Andersson: The background for this study was based on clinical work and what we observed in clinic. We had a few patients where we had been stricken by the fact that they came in with an acute aortic syndrome and they had a first-degree relative themself with the condition, but they did not look syndromic at all. And we started to wonder, what is the actual risk in the community, in people without obvious syndromic features of suffering from an aortic event itself. And although there are quite a few studies out there that have, to some degree, focused on the familial clustering of aortopathies, there is not a lot of information based on communities and whole entire populations. So we wanted to, frankly, estimate what is the incidence rates of aortic dissections and aortic aneurism in the community if you have a first-degree relative that has suffered from the disease themselves.

Dr Greg Hundley: How you organize your study and what was your population and what was your design?

Dr Charlotte Andersson: This study was actually based on two independent samples. First, we used the Framingham Heart study population that is very densely phenotypes over many years of spanning three generations of participants, where we looked at people who had at least one parent who had an aortic size in the upper quartile index to body-surface area and adjusted for age and sex. And we saw what's the risk of you, as a child, having an aortic size in the same upper quartile.

And second, we looked in the general Danish population, the Danish healthcare system is, as you probably know, governmental funded and we have very good registries of all hospitalizations, all outpatient visits, and so we were able to link more hard clinical events in people with and without a first-degree relative. What we did was we started time when people had an aortic dissection, we identified all the first-degree relatives in these people, and we matched them with up to 10 sex and age match controls from the general population without a first-degree relative with the disease.

Dr Greg Hundley: What did you find?

Dr Charlotte Andersson: We found that in the Framingham sample, if you had at least one parent who belongs into the upper quartile of aortic size, you had an odds ratio of two to three, adjusted for various clinical risk factors, such as hypertension and smoking yourself. And in Danish population, we found that if you had a first-degree relative with an aortopathy, the hazard rates for you developing the disease yourself was almost a tenfold-increase compared to age and sex match controls. And importantly, seemed like hazard ratios use were, more or less, unchanged when we start adjusting various known risk factors, such as bicuspid aortic valve, Marfan syndrome, and Ehlers-Danlos syndrome, normally those kinds of things. And we also found that the younger your proband were at the time of an acute event, the higher was your relative risk yourself. So among people who were below the age of 50 when they suffered an event, the hazard ratios were up to a 50-fold increase.

Dr Greg Hundley: Very nice. Naveed, what attracted you to this article as it was coming through the editorial process? And then second, how do we take the information that Charlotte's just conveyed and will be published here today, how do we take this in the context of what we already know about aortic aneurysms?

Dr Naveed Sattar: I think it's a beautiful study, so well done, Charlotte. I think it's a beautiful fusion. As Charlotte said, an in-depth cohort study, which has got very well-measured parameters of systematic points and a fantastic population-based data set from Denmark, which Sweden shares and Scotland shares and relatively small countries like us share. So small countries like Denmark punch above their weight in these kinds of studies, which is fantastic. But there's a rich seam of research that comes from these, and this is one of them. So I think that fusion of two data sets with different strengths and limitations combined giving off same signals is good.

I think, as Charlotte said, this is the first major population study to look at this question. So there's been people around the world who have got this sense that the aortic aneurism may well be familial, this provides, probably, some of the best data to suggest, yes, it definitely is.

Now the questions going forward is, okay, at what point do you screen everybody's got a family history with a proband, or do you screen those who've got a family history of younger probands? And I think what Charlotte and the team and other people around the world thar are going to look at this say,

"Okay, we now think, in addition to screening, for example, in the UK and the US we probably screen just men above 65, where most of the disease is, do we also then implement screening in younger people with family histories? And who do we screen, and when and how? And do we need to develop some kind of risk score?" And then when we do that screening, what do we do about it? Is going to be the questions and I'm sure Charlotte and her colleagues have thought about these things and it'd be interesting to see what her view is on those things. But I think it was a beautiful study in every sense.

Dr Greg Hundley: So Charlotte, he's really set you up nicely, what study do we need to perform next in this area? What are you and your group thinking about?

Dr Charlotte Andersson: Yeah, I think there are two implications of this study. First, clinical, as Naveed says. They already had a sense that aortic diseases were heritable, and I think these data definitely support that we should probably screen first-degree relatives. And I think, at some extent, this is what the guidelines already encourage us to do. So I'm not sure it would be feasible to randomize people or do a clinical trial where we screen some but not others. I'm not sure that would be ethical. I think the evidence is too strong for familial clustering and that we should probably screen these people.

But I think also, our estimates, they are so strong that I suspect that there are likely more genetic variants associated with non-syndromic aortopathies that we are not aware of just yet. So I think the next step would be to try to disentangle the genetics a little bit more. I have seen some preliminary analysis based on the UK Biobank, for instance, and I think there are more genetic variants to come up with also, more common genetic variants, at least, that we are not aware of just yet. So that would be the next step as I see it.

Dr Naveed Sattar: And that might particularity in younger probands.

Dr Charlotte Andersson: Right.

Dr Naveed Sattar: Those with the younger probands, because it looks like, as you said, the hazard ratio, the risks, are so high, it could also potentially be monogenic, but anyway.

Dr Charlotte Andersson: I agree.

Dr Greg Hundley: Well, Charlotte, Naveed, we really appreciate your time and taking this opportunity to discuss these really interesting findings and helping us understand that, truly, there may be a familial component to understanding this disease process, particularly in patients with aortic aneurysms that may go on to develop aortic dissections.

Well listeners, we hope you have a great week and on behalf of Carolyn and myself, catch you on The Run next week. This program is copyright, the American Heart Association, 2020.

Circulation September 01, 2020 Issue

31 augusti 2020 | 24 min

This week’s episode includes author Allan Sniderman and Associate Editor Anand Rohatgi as they discuss the expected 30-year benefits of early versus delayed primary prevention of cardiovascular disease by lipid lowering and management.

TRANSCRIPT:

Dr Greg Hundley: Welcome everyone to this September 1 issue, as we start into the fall in North America, and I guess we're getting into spring-ish in the Southern hemisphere. Today, it's just myself, Dr Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

And, I'm so sad because my good friend, Carolyn, cannot be with us today. However, we have a great feature for the latter half of this recording and discussing some of the benefits of primary prevention using lipid lowering therapy to help prevent cardiovascular disease. But, before we get to that, let's grab a cup of coffee and let's go through some of the other articles in this issue.

So, the first one is from the world of basic science and it's from Professor Eldad Tzahor, from the Weizmann Institute of Science. And, it's focusing on Agrin. So, this team previously reported that a fragment of the extracellular matrix protein, Agrin, promoted cardiac regeneration following myocardial infarction in adult mice. And, in this study the investigators propose to test the therapeutic potential of Agrin in a preclinical porcine model.

They performed ischemia reperfusion injuries using balloon occlusion for 60 minutes, followed by either a 3, 7, or 28-day reperfusion period. They demonstrated that local antegrade delivery of recombinant human Agrin, or RH Agrin, to the infarcted pig heart can target the effected regions in an efficient and clinically relevant manner. In fact, a single dose of recombinant human Agrin improved heart function, reduced infarct size, reduced fibrosis and reduced adverse remodeling parameters, 28 days post myocardial infarction.

Short-term myocardial infarction experiments, along with complementary mirroring studies, revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as aggregation mechanisms of action. So in summary, this team demonstrated that a single dose of Agrin was capable of reducing ischemia reperfusion injury and improving heart function. Demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure. So, this set the stage for future studies in human subjects.

Okay. Well, our next paper is clinical and evaluates exposure to air pollution and particle radioactivity with a risk of ventricular arrhythmias. And, it comes to us from Ms. Ajani Peralta from Harvard University. Now, individuals are exposed to air pollution and ionizing radiation from natural sources through inhalation of particles. So, in this study, the team investigated the association between cardiac arrhythmias and short-term exposures to find particulate matter, PM 2.5, and particle radioactivity.

So, ventricular arrhythmogenic events were identified among 176 patients with dual chamber implanted cardio defibrillators in Boston, Massachusetts, between the period of time of September 2006 and June 2010. And, patients were assigned exposures based on their residential addresses. So, what did they find? Well, in this high-risk population, those with these defibrillators, intermediate, 21-day parts per million, 2.5 exposure was associated with higher odds of a ventricular arrhythmia event onset among those with known cardiac disease and indication for ICD implantation. But this was independent of particle radioactivity. So, important information coming to us relating to air pollution and ionizing radiation in relation to ventricular events.

Next, let's get back to another informative study from the world of basic science. And, this one involves genomic binding patterns of forkhead box protein 01 and how that is implicated in the development of cardiac hypertrophy. The study comes to us from Walter Koch from Temple University and their co-investigators.

So, cardiac hypertrophic growth is mediated by changes in gene expression, as well as changes that underlie the increase in cardiomyocyte size. The former is regulated by ischemia reperfusion or loss, while the latter involves incremental increases in the transcriptional elongation activity of Pol II, that is preassembled at the transcription start site, or TSS.

The differential regulation of these two distinct processes, by transcription factors, really hasn't been explored. So, this group sought to investigate the forkhead box protein, and we're going to call it FOX01, which is an insulin sensitive transcription factor that is regulated by hypertrophic stimuli in the heart. To date, however, the scope of its gene regulation is also somewhat uncertain.

So, to address this, the investigators performed FOX01 chromatin immunoprecipitation deep sequencing, or ChIP-sequencing, in mouse hearts following seven-day isoproterenol injections, transverse aortic constriction, or vehicle injection by sham surgeries. The investigators found that FOX01 may mediate cardiac hypertrophic growth via regulation of Pol II de novo recruitment and pause release. As the latter represents the majority, or almost 59% of FOX01 bound Pol II regulated genes following pressure overload.

So, in conclusion, these findings demonstrate the breadth of transcriptional regulation by FOX01 during cardiac hypertrophy, which is important information that should be valuable for future therapeutic targeting.

Moving on from basic science and coming back into the world of clinical science. And, this next paper is from Professor Sripal Bangalore from New York University School of Medicine. And, it involves routine revascularization versus initial medical therapy in those with stable ischemic heart disease.

So, coronary arterial revascularization is often performed, as we know, in patients with stable ischemic heart disease. And, these authors conducted a PubMed Embase central search for randomized trials, comparing routine revascularization versus an initial conservative strategy in patients with stable ischemic heart disease. The primary outcome was death, and secondary outcomes included cardiovascular death, myocardial infarction, heart failure, stroke, unstable angina, and freedom from angina. And, the trials were stratified by percent stent use, and by percent statin use, to evaluate the outcomes across all of these trials.

So, 14 randomized clinical trials that enrolled 14,877 patients followed up for a weighted mean of 4.5 years with a total of 64,678 patient years of follow-up, were used for the study. Most of the trials enrolled patients with preserved left ventricular systolic function, low symptom burden, and they excluded patients with left main coronary artery disease.

So, here are the results, revascularization compared with medical therapy alone, was not associated with a reduced risk of death. The trial sequential analysis showed that the cumulative Z curve crossed the futility boundary indicating firm evidence for lack of a 10% or greater reduction in death. Now, revascularization was associated with a reduced non-procedural MI rate, but also with an increased procedural MI rate with, therefore, no overall difference in myocardial infarction incidents.

So, another point in this study is that there was a significant reduction in unstable angina and increase in freedom from angina was observed in those that underwent revascularization. Finally, there were no treatment related differences in the risk of heart failure or stroke. So in conclusion, in patients with stable ischemic heart disease, routine revascularization was not associated with improved survival, but was associated with a lower risk of non-procedural myocardial infarction, and unstable angina with greater freedom from angina at the expense of higher rates of peri procedural myocardial infarction. Now, longer term follow-up of trials is needed to assess whether the reduction in these non-fatal spontaneous events actually improves long-term survival.

Well, listeners what else is in the issue? Now, we refer to this as what's in the mailbox? So, we have a research letter from Jianyi Zhang regarding the apical resection prolongs the cell cycle activity and promotes myocardial regeneration, after left ventricular injury, in the neonatal pit. We have another research letter from Roger Foo, assigning distal genomic enhancers to cardiac disease-causing genes. What else is in the issue? There's a nice, On My Mind piece, from Anthony Wierzbicki on phenomics, not genomics, for cardiovascular risk assessment. And, there's a Perspective piece from Dr Dana Gal, regarding considerations for triaging elective cases in children with cardiac disease in a time of crisis.

Finally, we have an exchange of letters from Dr Daxin Wang and Dr Prabhakara Nagareddy regarding the previously published article, “Neutrophil Derived S100A8/A9 Amplification of Granulopoieses After Myocardial Infarction.” There's a very nice case series regarding an unusual reversible cause of acute high output heart failure complicated by refractory shock from Dr Matthew Durstenfeld. And then, finally, we have an ECG challenge from Mr. Alejandro Cruz-Utrilla, regarding giant T-wave inversion and dyspnea in the time of this coronavirus pandemic.

Well, listeners, what a great issue. And now, we get to look forward to that feature discussion from Dr Allan Sniderman, regarding the benefits of early versus delayed primary prevention by lipid lowering therapy.

Well, listeners, now we get to move to our feature discussion today and understand a little bit more about lipid management. And, with us, we have Dr Allan Sniderman from McGill University, and our own associate editor, Dr Anand Rohatgi from University of Texas Southwestern in Dallas. Allan, we're going to start with you. Can you give us a little bit of information pertaining to the background, or the hypothesis? Why did you want to perform this particular study?

Dr Allan Sniderman: Let us start from where we are in cardiovascular prevention now, which is the risk model. All of the major guidelines, throughout the world, select candidates for statin prevention based on their risk of a cardiovascular event over the next 10 years. Well, that's been a very positive development, but we need to appreciate what the limitations are. Because, tenure risk is so heavily based on age, what it boils down to is that if you're 60 and over, and a male you're going to be eligible. An increasing proportion of women will be eligible as they're older. But, if you're younger, regardless of your other causal factors, you may well not be eligible. And, the net result of that is, almost 50% of all cardiovascular events occur before 60, 65. So, half of the events are occurring before prevention even kicks in.

The second point is that you can't get be at risk until you have disease within your arterial tree. So, what we've done is, we're trying to prevent the disease that's already present. So, although it's been a wonderful step forward, we think it's time to start moving beyond that model, and trying to prevent disease itself, rather than preventing people who've already had disease.

So, what we decided to do, which we're shifting focus here from risk to causes. Risk, after all, is a consequence of causes. And, when you look at the pathology of atherosclerosis, with a few exceptions such as FH, up until the age of 30, 35, you don't have the complex lesions that can actually cause clinical events. So, we said, "Okay, we'll start at that time point. And, we'll try and quantitate the benefit of earlier intervention, versus later intervention, at different starting points." So, we based our analysis on NHANES, and we identified the people within the NHANES cohort, who would not have been eligible for prevention, based on the current American guidelines.

So, we had three age starting categories, 30 to 39, 40 to 49, and 50 to 59. And, we followed them out for 30 years. Our analysis has the same duration of the follow up, but the same final date. That has to be kept in mind because it limits the total benefit on the early starters. And, we further sub divided the groups based on non-HDL cholesterol, into those who had a level above 160, those who had an intermediate level, and those who had a low level because we'd previously shown that non-HDL identifies a high-risk group over 20 to 30 years.

We decided we'd look at two different models of the likelihood of the drug preventing events. One is the standard estimates that you would get from the statin clinical trials. But, if you reduce LDL cholesterol by a milli mol of 40 milligrams percent of your language, you reduce risk by about 22%. And, that's our conservative model. Then we took a model that's more biological and based on Mendelian randomization because, as you know, the Mendelian randomization analysis, the benefit, the reduction and event rate per milligram, per deciliter, lower LDL cholesterol is two or three fold greater than in the statin clinical trials.

So, Brian Friends had produced a formula in which you blend those two together, the statin estimate and the Mendelian randomization and it varies depending on how early you start. And, that was a more optimistic model, obviously. But the major point I emphasize is that both models showed that if you start early, you do better. Now, how surprising is that?

But the benefit depended on the level of non-HDL cholesterol. So starting at age 30, 35 in somebody who has a normal or low non-HDL cholesterol, doesn't really gain you all that much. Starting with somebody who has a high level, different story. In each of the categories, the conservative model, if you did the full 30-year prevention, you get a third to a half reduction in events. And, with the more optimistic model, you get half to two thirds reduction.

The closer you get to where you'd start with the guidelines, you're losing that benefit. Then you say, "Okay, well, how optimistic is the optimistic model?" And, all the optimistic model is saying, "Let's remember how we get disease." If we stop the formation of a new lesion, well, that's perfect prevention. Well, we're doing it, present is trying to stabilize existing lesions. The older we get, the more disease we have, the less new lesion we have, the less potential for the big game in prevention. So stopping new lesion formation, it seems to me is from clinical reasoning, a pretty biologically and clinically coherent way to formulate what your prevention strategy should be.

What we think we contributed, what we hope we've contributed with this analysis is saying, "Let's take a real step back, let's look at what we're doing and let's see how can we make a Magnus step forward in prevention?" And, the way we think you can do it is to start moving away from exclusively a risk paradigm, because that made sense. You want to treat people who were at risk. We get away from this 10-year duration and start focusing more on the causes, because when we look at an individual, we can measure the causes. Well, we talked about risks, that's a much slipperier concept, because it's a group. Is everybody in the group the same risk? They're clearly not. So, to try and get this to a much more concrete level, that's what we tried to do.

Dr Greg Hundley: Very nice, Allen. And so, Anand, why did you select pushing this paper forward? And, what do you think this means for patients with high cholesterols? They're in their 40s and 50s. Help expand on some of what Allan has, so elegantly, described for us.

Anand Rohatgi: First of all, Allan, thank you so much for doing this work and sending this to circulation. We were really excited to see this come across our desks, because at the end of the day, this manuscript, this study by Allan Sniderman and others, has very important public health consequences. And, that's why we were really interested in what they found and what they had to say about this topic.

And, really what it comes down to is, like Allan mentioned, the trials for statin just really never addressed what to do about risk in younger individuals and over a longer period of time. And so, it was really these genetic studies, the Mendelian randomization studies, that really strongly showed the cumulative exposure effect of higher cholesterol levels, over time, and the benefits of maintaining really low levels. And so, what I think this paper does is it translates those scientific studies, those genetic studies, into a public health concept that's easily digestible for physicians, for clinicians, for people, for patients and stakeholders about what does this all mean? How can we benefit and when?

And, I think it's very clear, the earlier you start, the more benefit you get over the life course. And, honestly, the take home message to me, it seems like for most of adulthood, the being able to maintain low risk and low cholesterol levels is the best path forward and not waiting until you find something wrong. And so, we were very, very excited about seeing that message translated in such an easy manner and compelling manner by Allan's work.

Dr Greg Hundley: Very nice, 40 to 49-year old with non-HDL cholesterols greater than 160 milligrams per deciliter, would be expected to reduce their average predicted 30-year risk by 17%. That's just amazing.

Allan, very quickly, in a minute, what do you think is the next study that needs to be performed in this area?

Dr Allan Sniderman: I don't think we're ever going to get the primary prevention trial that we want, because it's too many people, too early, and we already know too much. I think the thing that we really need to do is figure out how we're going to most accurately measure the cause within the individual. I'll put in a plug for FOV, because I think it is a more effective measure, even the non-HDL cholesterol. And, I think that when we commit people or when we invite people to take medications early in life, we ought to be doing it on the strongest ground possible.

I want to say thank you to be review process at Circulation, because the final paper that came out is not the paper that went in. The reviewers made superb, tough criticisms of this paper and not of the calculations, but of the way we were expressing it. And, they forced us to rethink and reimagine the context, in which the final form of this paper appears. So, we have a big thank you to our reviewers. We have a thank you to the patients of the editorial staff at Circulation. And, I have a big thank you to my collaborators, because they're really the strength of the paper.

Dr Greg Hundley: Very nice, well listeners, it's been another great week here at Circulation and another very important piece of information in this feature discussion regarding monitoring and evaluating non-HDL cholesterol in the earlier years, and really considering initiation of statin therapy, to prevent the atherosclerotic lesions from forming, not just stabilize them later in life afterwards.

Thanks to Anand Rohatgi and also Allan Sniderman for bringing us this wonderful article. We hope you have a great week. This program is copyright the American Heart Association 2020.

Circulation August 25, 2020 Issue

24 augusti 2020 | 31 min

This week’s episode of Circulation on the Run has 2 Feature Discussions. Associate Editor Ntobeko Ntusi discusses the article "Prevalence of Infectove Encocarditis in Streptococcal Bloodstream Infections is Dependent on Streptococcal Species." Then, author Anumpam B. Jena and Associate Editor Sandeep Das discuss trends in new diagnoses of atrial fibrillation after the release of an ECG-capable smartwatch.

TRANSCRIPT:

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature this week involves infective endocarditis and looking at that in streptococcal bloodstream infections. Are they dependent on the different species of streptococci? But before we get to that, how about we grab a cup of coffee and start off and discuss other papers in the issue. You want to go first?

Dr Carolyn Lam: Sure, Greg. I got my coffee, but I want to start with a quick question. So do you think it's safe and efficacious to prescribe SGLT2 inhibitors to patients with Type 2 Diabetes and concomitant peripheral artery disease?

Dr Greg Hundley: Ah, Carolyn, very good question. I don't know if it's right or wrong. A little bit of controversy here.

Dr Carolyn Lam: Let's explain that controversy. So patients with peripheral artery disease are at heightened risk of cardiovascular complications. However, there's also an increased risk of amputation that was observed with canagliflozin in one prior trial. Now, the SGLT2 inhibitor dapagliflozin was shown to reduce the risk for hospitalization for heart failure and kidney events in patients with Type 2 Diabetes in the DECLARE–TIMI 58 trial. So authors Dr Bonaca from University of Colorado School of Medicine and colleagues examined the cardiovascular and kidney effects and the risk of limb related events in patients with and without peripheral artery disease in the huge DECLARE–TIMI 58 trial, including more than a thousand patients with peripheral artery disease.

Dr Greg Hundley: So this could be really helpful to answer this question. What did they find, Carolyn?

Dr Carolyn Lam: Well, patients with versus without peripheral artery disease were indeed at higher risk of major adverse cardiovascular events, cardiovascular death, or heart failure, hospitalization and kidney events. They also had consistent benefits for the outcomes of cardiovascular death or heart failure hospitalization as well as progression of kidney disease with dapagliflozin. Now ,patients with peripheral artery disease also had a higher risk of limb events, but there was no consistent pattern of incremental risk observed with dapagliflozin. So the take home, diabetes patients with peripheral artery disease are at risk of heart failure and kidney events and dapagliflozin is beneficial with no patterns of increase limb risk.

Dr Greg Hundley: Very nice, Carolyn. Boy, that is very helpful and a nice take home message for all of us administering these agents. Well, Carolyn, my first study comes from Professor Magnus Bäck from the Koralinska Institute. And the aim of this study was to identify the role of omega−3 polyunsaturated fatty acids, derived specialized pro resolving mediators, or SPMs, in relation to the development of aortic valve stenosis. The synthesis of specialized pro resolving mediators are potent beneficial anti-inflammatory agents. They have pro resolving and tissue modifying properties that are useful in managing patients with cardiovascular disease.

Dr Carolyn Lam: Interesting. So what did these authors find?

Dr Greg Hundley: This study showed that human stenotic aortic valves contain decreased levels of n-3 PUFA, and that n-3 PUFA treatment decreased aortic valve calcification, and aortic valve leaflet area in murine models’ concomitant with improved aortic valve hemodynamics. The pro resolving lipid mediator, resolvin E1, which is derived from the n-3 PUFA enoic acid, or EPA, exerted protective effects on valvular interstitial cell calcification and valvular inflammation through its receptor, chemR23. And therefore Carolyn, further clinical evaluation of n-3 PUFA treatment may open up novel therapeutic opportunities for preventing the progression of aortic valve stenosis.

Dr Carolyn Lam: Wow, really interesting, Greg. Just more and more data on these omega−3 PUFAs, huh? So cool. Well, the next paper is kind of related in the lipid world. Do you think treating to a low LDL cholesterol target of less than 70 milligrams per deciliter may impact carotid plaque evolution?

Dr Greg Hundley: I would think so. It seems like that target is beneficial in many ways.

Dr Carolyn Lam: Well, good guess, Greg. But I'm going to tell you about a study that actually looked at that. First of all, recall that the treat stroke to target, or TST trial, showed the benefit of targeting an LDL cholesterol concentration of less than 70 in terms of reducing the risk of major cardiovascular events in 2,860 patients with ischemic stroke with atherosclerotic stenosis of the cerebral vasculature. Now, today's paper describes results of the parallel TST plus study, which included 201 patients assigned to an LDL cholesterol concentration of less than 70 versus 212 patients assigned to a target of a hundred. To achieve these goals, investigators led by corresponding author, Dr Amarenco from Bichat Hospital in Paris, France, allowed investigators use the statin and dosage of their choice, and added ezetimibe as needed. After certification of ultra-sonographers, carotid ultrasound examinations were performed at baseline and at two, three, and five years, and blindly analyzed at a central core laboratory.

Dr Greg Hundley: Very nice, Carolyn. So what did they find?

Dr Carolyn Lam: After a median follow-up of 3.1 years, patients in the lower target group had a similar incidence of newly diagnosed carotid plaque compared to the higher target group, but significantly greater regression of carotid atherosclerosis as measured by the common carotid intima media thickness. So this really further strengthens the concept that the lower the LDL cholesterol, the better the clinical and atherosclerosis outcomes.

Dr Greg Hundley: Very nice, Carolyn. Another study emphasizing that very important point. Well, Carolyn, my next study comes from Professor Abdelkarim Sabri from the Temple University School of Medicine. So studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial. In this study, the authors analyzed protease activated receptor or PAR4 expression in mouse hearts with myocardial infarction, and investigated the effects of PAR4 deletion on cardiac remodeling and function post demise by echocardiography, quantitative immunohistochemistry, and flow cytometry.

Dr Carolyn Lam: Oh, okay. What did they find, Greg?

Dr Greg Hundley: Three things. First, PAR4 deficiency leads to cardiac hemorrhage and increases the rates of cardiac rupture following chronic myocardial infarction. PAR4 deficiency in neutrophils, but not in platelets, impairs inflammation resolution and myocardial healing after myocardial infarction. And finally, adoptive transfer of neutrophils can be used as a novel therapy to modulate the inflammatory response and improve cardiac remodeling and function following myocardial infarction.

Dr Carolyn Lam: Okay, what's the take home message?

Dr Greg Hundley: It's a little tricky. So acute transient administration of par four inhibitors may provide a new approach to prevent early inflammation and myocyte loss immediately after ischemic injury. The keyword is immediately. But importantly, prolonged P4 inhibition strategies could impair myocardial healing and increased cardiac hemorrhage and the rates of myocardial rupture following infarction. PAR4 inhibition therapies should be limited to the acute phases of the ischemic and fault, and it should be avoided for the chronic treatment post myocardial infarction. Really intriguing, Carolyn.

Dr Carolyn Lam: Very nice and elegant results, kind of like yin and yang, huh?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: All right. Let's sum up with the other papers in the issue. There's a white paper by Dr Psotka on challenges and potential improvements to patient access to pharmaceuticals with examples from cardiology. There's a perspective by Dr Armstrong comparing the benefit of novel therapies across clinical trials, and that provides important insights from the VICTORIA trial. There's an ECG challenge by Dr Chu regarding a young male with incessantly alternating tachyarrhythmias.

Dr Greg Hundley: Very nice, Carolyn. Well, in my mail bag, I have an on my mind piece from Dr Jamil Tajik relating to, our favorite, the art and science of occultation. Well, Carolyn, how about we get on to that feature article and talk a little bit more about those little devils, the streptococci?

Dr Carolyn Lam: Yeah, let's go, Greg. Infective endocarditis is the topic of our feature paper today. Now, we all know it's a life threatening disease, and despite its relative rarity, it's still consumes a disproportionate share of healthcare resources, and its annual mortality is still really high, exceeding 20%. Now, I think we all recognize that improved outcomes are critically dependent on a timely diagnosis and early investigation. The problem is the clinical presentation is less and less likely that classical textbook presentation, and the clinical suspicion is often triggered after microbiological identification of potential causative organisms in the blood. And while we as a medical community are usually aware of the dangerous of staphylococcal bacteremia, I think there's a lot less appreciation of the propensity of different streptococcal species to cause infective endocarditis. Greg, my dear partner, greatest friend, and colleague, do you agree?

Dr Greg Hundley: Yes, Carolyn. So this paper and this feature addresses bacterial endocarditis and focuses on streptococcal infections just as you've described. Now, streptococci I frequently cause infective endocarditis. Yet, the prevalence of infective endocarditis in patients with bloodstream infections caused by different streptococcal species is unknown. So in this study, Dr Shamat and associates aim to investigate the prevalence of infective endocarditis at species level in patients with streptococcal bloodstream infections.

Dr Carolyn Lam: Now, we're taking a lot of pains to describe this paper, Greg and I, because we didn't manage to get hold of the authors this time. We certainly have our editor who managed the paper and that's Ntobeko Ntusi from University of Cape Town. So welcome Ntobeko, and thank you so much for discussing this paper with us. But before we get to that, I think Greg and I are going to try to, in our usual fashion, get to the bottom of describing. Here's something I learned that I didn't know before. That the ESC guidelines for example, are primarily based on the modified Duke criteria, which include blood cultures, mentioning viridians streptococci. Remember those? Viridians streptococcus, or strep bovis, as a diagnostic major criterion for streptococcal infective endocarditis.

And yet, the term viridians is based on bacterial culture using green hemolysis on blood agar plates, which is outdated. So I didn't realize that. It's outdated and inconsistent because some of the included streptococcal species do not even cause hemolysis, and other species are able to produce different kinds of hemolysis. And thus, we really need more details on specific streptococcal types that are much more current. And when we face these different streptococcal species, they're not mentioned in the guidelines and so we need more data. So that's why this paper is so important. So Greg, now over to you. Do you mind to describe what the authors did?

Dr Greg Hundley: Sure, Carolyn. So these investigators identified and assessed all patients with streptococcal bloodstream infections from the period of time of 2008 to 2017 in the capital region of Denmark. And data were cross-linked with Danish nationwide registries for identification of concomitant hospitalization with infective endocarditis. In multi-variable logistic regression analyses, the authors investigated the risk of infective endocarditis according to some of those species that you just mentioned. And they adjusted their analyses for age, sex, greater than or equal to three, positive blood culture bottles, native valve disease, prosthetic valves, prior episodes of infective endocarditis, and whether or not they may have had an implanted cardiac device.

Dr Carolyn Lam: Great, great. So tell us the results, Greg.

Dr Greg Hundley: So Carolyn, they had 6,500 plus cases with streptococcal bloodstream infections. And the average age of the patients was 68 years, and a little more than half. So 52% to 53% were men. The prevalence of infective endocarditis overall was 7%. Now, the lowest infective endocarditis prevalence was found with strep pneumoniae and strep pyogenes, ranging from 1.2% to 1.9%. the highest infective endocarditis prevalence, and that was found with strep mitis or oralis at 19%. Streptococcus gallolyticus, formerly known as strep bovis, at 30%. Strep sanguinis at 35%, and strep mutans at nearly 50%, at 48% overall. So in multi-variable analysis, using the strep pneumonia at 1.2% as a reference, all species except strep pyogenes were associated with a significantly higher infective endocarditis risk. Again, the highest with the odds ratio of strep gallolyticus is at an odds ratio of 31 ranging up to straight mutans with an odds ratio of 81.3.

Dr Carolyn Lam: Whoa, Greg, that was beautifully summarized, and frankly, beautifully pronounced. I don't think I could have done that with all the species. That is so cool. And in case everyone didn't get it, I strongly suggest you refer to figure three of this beautiful paper. It shows the prevalence of infective endocarditis in bloodstream infections with the different streptococcal species, all in one figure. And Ntobeko, with that introduction, if you may, by both Greg and I, could you please let us behind the scenes? Tell us what you first thought when this paper came across your desk and perhaps what the editors’ thought was so important about this paper.

Dr Ntobeko Ntusi: Thank you very much, Carolyn and Greg. So this is an important paper coming out of circulation. And while infective endocarditis may not be so harmonic in North America and western Europe, in many parts of the world, including where I come from in Sub-Saharan Africa, with a high prevalence of rheumatic heart disease, it remains an important cause of morbidity and mortality. And we forget that it's a disease with very high inpatient mortality of up to 50% in many countries. And of course in those with rheumatic heart disease, streptococcal bloodstream infections remain an important cause of infective endocarditis.

So when I saw this paper, I very much enjoyed reading it. I thought it was well written and beautifully illustrated. In some ways, even though I say it's an original paper, it has a feel of a review because the discussion, as well as the figures and tables, are quite instructive. And the comments from the reviewers were very much aligned with my own thinking that there were a number of important new learnings coming out of this paper. The first important message for me was that the distribution of streptococcal infections in the population was not uniform and I had assumed infections to be broadly the same across the population. And contrary to what I thought, the risk of infective endocarditis was inversely related to the frequency of streptococcal bloodstream infections in the population.

In other words, the most common streptococcal blood infections that are very low prevalence of infective endocarditis. And that leads to the second important learning from this paper, which is that if you are a clinician evaluating a patient with suspected infective endocarditis, the risk of infective endocarditis should be evaluated on a species level, as the species from Greg's description is probably the most important determinant of the likelihood of developing infection. And then the other important, I think, take home message from this paper, I'm looking at the results of multivariate regression analysis, is that it confirms much of what we know from studies with older patients studies focusing primarily on staphylococcal bloodstream infections as well as studies focusing on device therapies.

And that message is that the risk of developing infective endocarditis, even with streptococcal blood infections is related down to presence of native or valve disease. Those with trust that tech devices, intracardiac devices, and of course, the number of fat blood culture bottles that are positive, which is something that is well accepted and established in clinical practice. Thank you, Carolyn.

Dr Carolyn Lam: I just love those three take home messages. So beautiful. And I really also love that you invited this fantastic editorial, Dr Prendergast, Dr Allen, and Dr Klein. I thought it was wonderful the way they summarized the paper, put it into context, and perhaps, I could borrow their words and also explaining that they pointed out that we do need to be cautious about interpreting this being a retrospective series classified by diagnostic coding. And of course, by design, because of that, we can't fully attribute causal associations.

They also pointed out that this paper, I believe did not include echocardiographic data as one of the variables. And so of course, that could be something that could be further explored in future studies. And I'd love your thoughts on what they also said about before we extrapolate regional data, I mean, it's all from Denmark after all, to other regions, this work should probably be considered something that should inspire extension of further studies and prospective evaluations in other areas, and yet never losing sight of the fact that this informative paper will of course be of considerable interest to not just cardiologists, but also infectious disease specialists, because we're often called to sort of assess, "All right, how much do you need to work up for infective endocarditis if you see this specific streptococcal bacteremia?" And this paper definitely puts us strides ahead in this area. Would you agree with that, Ntobeko, and anything to add?

Dr Ntobeko Ntusi: Indeed, Carolyn. So I was delighted that the review, the editorial, was co-authored by cardiologists and infectious disease specialists. We might view as they balanced in as one of the modifications to the original submission. We actually posed that question to the office that how can we be certain in the absence of echocardiographic data that the diagnosis was in fact infective endocarditis in patients? And so they went back and performed a sensitivity analysis and triangulated the principle diagnosis of infective endocarditis with the treatment of patients in the duration in hospital. And that sensitivity analysis in fact strengthened our believe that this wasn't fit the diagnosis of infective endocarditis. And I think your point is well taken that similar studies need to be conducted in different regions of the world and this field will be strengthened by large amount of prospective studies on top of the plethora of retrospect data that we have.

Dr Greg Hundley: Well listeners, we have a second feature discussion this week. A very interesting article pertaining to the use of smartwatches and detection of atrial fibrillation. And to present this work, we have Dr Bapu Jena from the Harvard Medical School, and our own associate editor from University of Texas Southwestern Medical Center in Dallas, Dr Sandeep Das. Welcome gentlemen. And Bapu, perhaps, could you tell us a little bit about the hypothesis and the background of this material?

Dr Anupam B. Jena: Sure. So you probably are aware that in December of 2018, Apple released this new watch and this watch made a lot of buzz in part because it featured this single lead EKG that the company said would be able to detect atrial fibrillation. And there was this question among many, at least certainly among clinicians, as to whether or not we would see a large increase in atrial fibrillation diagnoses after this watch was released onto the market. And then the second question was, would we be picking up worrisome cases of atrial fibrillation that we needed to act on, or would we be picking up cases that patients probably would have been okay living with and would never have known that they were living with?

We were lucky to be able to work with a company called Athenahealth. Athenahealth is a nationwide cloud-based healthcare information technology company. What that allowed us to do was to do a very early analysis of the change in atrial fibrillation diagnosis after the Apple Watch was approved on the market. So that's the data we use is from small physician practices. It's not nationally representative, but these practices are all across the US. The data from Athenahealth have been used in other studies, including some by myself and other colleagues.

In terms of the method that we applied; it was pretty straight forward. So what you basically want to see is before and after December of 2018, do we see a market spike in the diagnosis for atrial fibrillation? Again, these are diagnoses that physicians who are in these offices would be making and that we would be seeing in the electronic health records of their practices. Now, the problem is, is suppose over time, atrial fibrillation diagnoses are going up. So if we looked at the first six months of 2019 compared to the last six months of 2018, and we saw an increase, we obviously wouldn't want to attribute that solely to the Apple Watch because atrial fibrillation diagnoses may be going up for a lot of other reasons. What we said as well, let's at least try to account for the possibility that there are seasonal trends at play in the diagnosis of atrial fibrillation.

Dr Greg Hundley: Very nice. What did you find?

Dr Anupam B. Jena: So the basic finding is as follows that we didn't really see a differential increase in atrial fibrillation diagnoses. So for example, in the months before the watch was released, in this population, about 0.4% of all visits had an atrial fibrillation diagnosis. 0.4%. If you look at the year after the app release, about 0.4% of visits have the diagnosis. If you look one year back, you also find that one year before in the pre period, there is about 0.36% of visits were for atrial fibrillation, and that increased the 0.39%. So the difference in difference change is basically about zero. Meaning, we found that there was no increase in atrial fibrillation diagnoses. The second thing that we did is we looked at high income zip codes, and we looked at zip codes with the population of individuals would be such that we might expect an increase. And we found no changes in either one of those two subgroups.

Dr Greg Hundley: Very good. Well, Sandeep, help us put this in the context of using these watches and then also using these watches to identify patients with atrial fibrillation.

Dr Sandeep Das: Absolutely. So let me first just add a comment that Bapu was a little too modest to blow his own horn, but he's really built a lovely research program of identifying and answering really interesting questions in large datasets. So the fundamental question here about whether the use of the Apple Watch and these detection algorithms would be associated with a big spike in diagnosis of atrial fibrillation was extremely important or is extremely important. So that was really the hook. I knew it was going to be something interesting. In our heart of hearts, we're all a little worried that people are going to have wearables. There's going to be an 8 million people presenting with abnormal findings on their watch and it's going to break medicine. So that was really kind of the context and the key for what made it interesting to us.

Dr Greg Hundley: Very nice. And so what do you think, maybe start with Babu, and then come back to Sandeep. What do you think will be the next study in this area using these devices as they pertain to patients with atrial fibrillation?

Dr Anupam B. Jena: Yeah. Great question. So I think there's two things that come to mind. So first is this was really an early analysis. I do expect that as the Apple Watch grows in popularity and as other similar such devices get introduced to the market, that we probably will pick up patients with atrial fibrillation who otherwise wouldn't have been diagnosed. I think that's less likely, but would be diagnosed earlier than they otherwise would have. So I think that if we look a couple of years out, we probably will find different answers that we found here. But as Sandeep said, at least in the first year after the watch was introduced to the market, we didn't break the bank. So I think this first natural question is to look longer out. And I think the second thing, which is particularly interesting to me at least, is that this potentially gives us a nice natural experiment to understand whether or not all patients with atrial fibrillation or what are the other factors that we should be thinking about in terms of benefits?

Dr Greg Hundley: Very good. Sandeep, do you have anything to add?

Dr Sandeep Das: So I agree with that answer entirely. I think that one of the things that really is going to be the $64,000 question is what does wearable diagnosed atrial fibrillation mean? So we were pretty good. As Bapu said, we have well established history of understanding what to do with patients that have atrial fibrillation that we diagnose in conventional ways. People either present with symptoms or are diagnosed externally in the hospital. But what does it mean if you're perfectly fine and you just have a watch that gives you an alarm? What are the implications of that? Because there are therapies generally revolve around anticoagulation in a large fraction of patients with atrial fibrillation. And that's the big deal.

If we're going to commit people to lifelong anticoagulation, based on what they're watch told us, is that the right thing to do? So I think that to me, the most important question going is what does a diagnosis of a-fib by wearable mean for downstream treatment implications and outcomes? And then the larger scope is also how can we then incorporate the data that we're going to continue to get from wearables into practice? So studies on sort of the practical downstream implications of wearable technology on utilization are also going to be super important and interesting.

Dr Greg Hundley: Very good. Well, I want to thank you Bapu, and also thanks Sandeep for your time today. And just sharing this new research using Apple smartwatches and trying to diagnose atrial fibrillation and compared it at least in this first year to, I guess, historical controls, not an overabundance or mass increase in the diagnosis of atrial fibrillation. And as you both have identified more to come with research on using these watches in the future for management, and then how we might improve therapeutic interventions through the use of these devices. Well, listeners, we hope that you have a great week and we look forward to catching you on the run next week. Take care. This program is copyright of the American Heart Association, 2020.

Circulation August 18, 2020 Issue

17 augusti 2020 | 25 min

This week’s episode of Circulation on the Run features author Ami Aronheim and Associate Editor Thomas Eschenhagen as they discuss early cardiac remodeling that promotes tumor growth and metastasis.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor of the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, today we're taking a look at the cardio-oncology world in our feature discussion, but in a very interesting reverse way. Cardio-oncology, what would you think of? I suppose the effects on the heart of cardiotoxic drugs that we use in oncology, right? But this feature paper looks at it the other way around and says does the heart and its remodeling promote tumor growth and cancer? Terribly interesting data coming right up after we discuss a couple of papers, well, all the papers in today's issue.

So I want to start. Greg, do you remember what parasites are and why they're important?

Dr Greg Hundley: Well, Carolyn, this is actually one of the things that I do remember because we study the parasites when we're looking at microcirculatory dysfunction after the administration of potentially cardiotoxic agents for treatment of cancer. But how about you tell us a little bit more.

Dr Carolyn Lam: This is going to be very basic just for all of us. Now, the blood vessels are composed of endothelial cells and mural cells. Endothelial cells line the vascular lumen. Whereas the mural cells, which include faster smooth muscle cells and parasites adhere to the abluminal surface of the endothelium. Parasites regulate vessels stabilization and function, and their loss has been associated in diseases such as diabetic retinopathy, vascular malformation, stroke, and cancer. Just like you said, Greg.

Now here we have a series of elegant experiments by Dr Mariona Graupera from IDIBELL in Barcelona and colleagues who use genetic mouse models to identify the specific molecular signature of mural cells at early and late stages of the energetic process and unveil their biological relevance. Their results show that phosphatidyl inositol 3-kinase or PI3K-beta is the main regulator of parasite, proliferation and maturation in vessel growth. PI3K-beta deletion in parasites triggered early parasite maturation, whereas exacerbated PI3K signaling delayed parasite maturation, and thus vessel maturation during angiogenesis.

Dr Greg Hundley: So clinically what's the take home message here.

Dr Carolyn Lam: The proposed model of mural cell maturation together with the tools developed would be instrumental for the characterization of mural cells in pathologies associated with deregulated vessel growth, such as ischemia stroke, vascular malformation, diabetic retinopathy, and cancer. The therapeutic potential of modulating parasite biology through PI3K signaling provides a new window of clinical intervention for vascular related diseases in which parasite dysfunction contributes to their onset and or progression.

Dr Greg Hundley: Very nice, a very important cell type Carolyn. Well, my paper comes from Professor Xiang Qian Lao from The Chinese University of Hong Kong. In this paper, the authors investigated in 140,072 adults all greater than the age of 18, without hypertension who joined a standard medical screening program with 360,905 medical exams that occurred between the years of 2001 and 2016. They assess the joint associations of habitual physical activity and long-term exposure to find particulate matter with the development of hypertension in Taiwan.

Dr Carolyn Lam: Wow. A huge study. So what did they find Greg?

Dr Greg Hundley: After adjusting for a wide range of co-variants including a mutual adjustment for physical activity or particulate matter, a higher physical activity level was associated with a lower risk of hypertension. Whereas a higher level of particulate matter was associated with a higher risk of hypertension. No significant interaction was observed between physical activity and particulate matter.

So Carolyn in conclusion, a high physical activity and a low particulate matter exposure were associated with a lower risk of hypertension. What we would expect the negative association between physical activity and hypertension remain stable in people exposed to various levels of particulate matter. The positive association between particulate matter and hypertension was not modified by physical activity. Thus, Carolyn the authors believed their results indicate that physical activity is a suitable hypertension prevention strategy for people residing in relatively polluted regions.

Dr Carolyn Lam: Oh, thanks for summarizing that. So well, Greg, Hey, I've got a question for you. Do you measure a high density, lipoprotein cholesterol or HDL cholesterol? Do you measure the levels or do you measure the particle concentration in your clinical practice?

Dr Greg Hundley: I think just the levels Carolyn.

Dr Carolyn Lam: Yeah. Same, but there's a lot of data coming out about the particle concentration. Let's review a little bit about that. So the HDL cholesterol is an established athero-protective marker, particularly for coronary artery disease, but HDL particle concentration may better predict the risk. However, the associations of HDL cholesterol and HDL particle concentration with ischemic stroke and with myocardial infarction among women and blacks has not been well defined. And so Dr Rohatgi from UT Southwestern and colleagues analyzed individual level participant data in a pool cohort of four large population studies without baseline atherosclerotic cardiovascular disease. These were the Dallas Heart Study, the ERIC study and the MISA study, as well as the PREVENT study.

Dr Greg Hundley: What did they find? Were there any unique pieces of data related to either sex or those of black race?

Dr Carolyn Lam: They found that HDL particle concentration is inversely associated with the specific endpoint of ischemic stroke overall and among women. Whereas HDL cholesterol was not associated with ischemic stroke. Neither HDL particle concentration nor HDL cholesterol levels were associated with myocardial infarction in blacks. Thus HDL particle concentration, but not HDL cholesterol may be a useful risk marker for ischemic stroke. HDL particle concentration may be a useful risk marker for both myocardial infarction and ischemic stroke among women. There is likely minimal utility of HDL markers for risk prediction of myocardial infarction in the black population.

Dr Greg Hundley: Thanks Carolyn. That was such a great introduction and overview and then the results was so clear. Carolyn, my next paper comes from Dr Peter Willeit from the Medical University of Innsbrook. In this paper, the author systematically collated carotid intima-medial thickness data from randomized controlled trials. The primary outcome was a combined cardiovascular disease endpoint defined as myocardial infarction, stroke, revascularization procedures, or a fatal cardiovascular event. The authors estimated intervention effects on carotid intima-medial thickness progression and incident CVD for each trial before relating the two using a Bayesian eta- regression approach.

Dr Carolyn Lam: Oh, this is important. So what did they find?

Dr Greg Hundley: Carolyn, they're going to have 10 micrometer per year evaluations. So across all intervention, each 10 micrometer per year reduction of carotid intima-medial thickness progression resulted in a relative risk for cardiovascular disease of 0.91 with an additional relative risk for cardiovascular disease of 0.92 being achieved independent of carotid intima-medial thickness progression. So combining these results, the authors estimate that interventions reducing carotid intima-medial thickness progression by 10, 20, 30 or 40 micrometers per year would yield relative risks of 0.84, 0.76, 0.69 or 0.63 each incrementing with the magnitude of reduction in micrometers per year. Results were similar when grouping trials by type of intervention. Time of conduct, time to ultrasound follow-up, availability of individual participant data, primary versus secondary prevention trials, the type of carotid intima-medial thickness measurement, and the proportion of women in the studies.

Dr Carolyn Lam: So could you summarize that Greg?

Dr Greg Hundley: You bet, Carolyn. So the extent of intervention effects on carotid intimal-medial thickness progression predicted the degree of cardiovascular disease risk reduction. This provides a missing link supporting the usefulness of carotid intimal-medial thickness progression as a surrogate marker for cardiovascular disease risk prediction in clinical trials.

Dr Carolyn Lam: Indeed. Thanks, Greg. It's important because it also quantifies that risk reduction. Very nice. Now let's just round up with some other papers in the issue. There is a perspective paper by Dr Bunch on Dementia and atrial fibrillation, a research letter by Dr Ellinor on myocyte specific upregulation of ACE two in cardiovascular disease, the implications for our SARS-coronavirus to mediated myocarditis. There are letters to the editor regarding the article small extra cellular macrovesicles mediated, pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanism, exacerbating ischemia reperfusion injury in diabetic mice. These letters were by Dr Li with response by Dr Ma. There's a research letter by Dr Natarajan on genetic variation and cardiometabolic traits and medication targets and the risk of hypertensive disorders of pregnancy.

Dr Greg Hundley: Carolyn, I've got a couple other features to describe. Aaron Baggish and Ben Levine provide an On My Mind piece, related to sports after COVID-19. Jeffrey Smietana has an ECG challenge regarding an ELVAD artifact. Then finally, Bridget Kuhn has cardiology news related to an announcement from the Association of Black Cardiologists calling for an urgent effort to address health inequality and diversity in cardiology. Can't wait to get to that feature discussion and that really unique twist in cardio-oncology.

Dr Carolyn Lam: Here we go. Greg.

Based feature discussion. We are diving into the world of cardio-oncology. Now, usually that refers to the intersection between cancer and cardiovascular disease, where we usually talk about cancer and cancer treatment effects on the cardiovascular system. But emerging data now suggests the concept of reverse cardio-oncology, whereby heart disease potentiates cancer. Today's feature paper really provides very important and significant preclinical data to support this. I'm so pleased to have with us, the corresponding author, Dr Ami Aronheim from Israel Institute of Technology, as well as our associate editor, Dr Thomas Eschenhagen from University Hospital Hamburg Eppendorf in Germany. Ami, thank you very much for joining us today. Please. Could you walk us through your very elegance study and the results?

Prof Ami Aronheim: We used a model, which is called the transfers, all the constriction, which promotes pressure overload on the heart. Actually following this procedure, we implanted cancer cells into mice and we followed the growth of these tumors. Actually we found out that the tumors of a tuck operated mice is growing much faster. Also when we used a metastatic model, namely, when we injected cells into the tail vein, we obtained more metastatic lesions in the lungs. Actually we found out that the serum from these mice is able to promote the variation of cancer cells in vitro. Then we also identified a protein, which is potentially promoting these cell proliferation in vitro.

Dr Carolyn Lam: That is really significant. I mean, am I right that this is the first study to show that cardiac remodeling actually promotes tumor growth and metastasis and this is probably via secreted factor.

Prof Ami Aronheim: This is the first paper showing that early events of cardiac remodeling promote cancer cell proliferation. It is known that heart failure by the work of De Boer’s group, that heart failure is promoting cancer load in mice. This paper was also published in Circulation 2018.

Dr Carolyn Lam: Indeed. Thank you for reminding me about that. And I am a huge fan of Rudolph de Boer and his work. Indeed. Could I ask though, in your study, did you identify a particular secreted factor?

Prof Ami Aronheim: We looked at the RNA seq from conduct remodeled heart, and we looked for secreted factors in the heart and we focused on two secreted factors CTGF and periostin, which are known to promote cancer growth. And indeed we found in our mice models that reduced in level is increased in the serum of mice of tuck operated mice. Once we deplete the serum from periostin, we ambulated this increase in cell proliferation.

Dr Carolyn Lam: Wow. So periostin appears a culprit, but I'm sure the listeners are dying to know. Was there any human data that you had that supported the animal findings?

Prof Ami Aronheim: The model in mice, the tack operation, it's hard to find the right model in human because the operation is really rapid. When the mice wake up, they have this pressure overload, the only disease which in human correlates or is mimicked by the tag is Altucher's stenosis, which is the restriction of the outtake evolve, the right aortic valve]. And we looked in these patients and what we found out, we looked at the echo cardiography data of a lot of patients. We actually found out that for young basically patients 40 to 60 years old, if they have moderate to severe aortic stenosis, they have higher risk to develop cancer about 1.6-fold higher than our external these patients. Although I must say with caution that this size group is quite small and it should be repeated with much higher number of patients.

Dr Carolyn Lam: Wow. Thank you so much, Ami. Thomas, I have to bring you in here. Thank you for managing this very remarkable paper. Could you share some thoughts on what you think this means for the field?

Thomas Eschenhagen: We all immediately as editorial team like this paper. When it came in on the background of the different paper, it really provides significant additional evidence that this interaction between cancer and the heart is two sided. And that's, as you said in the intro, that's really very important. And it's all very interesting that apparently these two different models used by Rudolf de Boer, which wasn't ischemia myocardial injury model. And here it's a hypertrophy model with early remodeling. They both do similar things, but apparently by different mechanisms. Because the number of the factors identified in the de Boer paper do not match with, with these two factors, CTGF and periostin. And for both, I think we have now convincing evidence that they may play a role, but it also shows that this is probably a quite complex interaction between the heart and the cancer. That makes it extremely interesting.

Of course it's important because it's such a common comorbidity, I mean, cancer, cardiovascular diseases, are the most prevalent and the second most prevalent diseases is cancer. So this interaction must be very, very important. And it's very good that these two papers now focus of you on the reverse side and not only on the classic cardiac toxicity side, which me as pharmacologists, of course, we, I was always interested in.

Dr Carolyn Lam: Yeah, indeed. I mean, Thomas me too. As a heart failure clinical trial list and epidemiologists, if I may, I always thought it was just shared risk factors, you know, age being particularly one of them.

Thomas Eschenhagen: Obviously, as you said, shared risk factors do play a role must, must their role. So it's certainly not only this direct interaction, but this new paper shows that there is in addition to this risk factor model, something specific. And that of course could be, I mean, at least theoretically be addressed.

Dr Carolyn Lam: For both Thomas and Ami, what do you think are the implications now? I mean, should we be screening all patients with aortic stenosis more closely for cancers? What do you think are the clinical implications? Maybe Ami first?

Prof Ami Aronheim: I think cardiovascular disease patients are already watched very carefully beforehand. But certainly I think that they should be also observed for cancer specifically. So yes I believe it should be. Also I this cardiovascular treatment should consider to make them early as possible to avoid any interaction with cancer.

Dr Carolyn Lam: Yeah, that completely opens the field to, for example. Early aortic valve replacement, reducing subsequent cancer risk, like you mentioned in your paper, I mean, that's just mind blowing. Thomas, what do you think?

Thomas Eschenhagen: I agree, 10 years ago, we said that more cancer patients, particularly those under treatment should be sent to the cardiologist to look for the heart. Now we will say the other way around as well. We really need to look more carefully for cancer. So I think this paper and the other one have the consequences we should do more here. There's also obviously a number of very interesting questions because one of the findings I found fascinating in this paper by Ami and this group was that this mouse strain, which finally did not show the classical science of remodeling after transverse aortic striction. So no BNP, no NP, no BDMEC increase in this small strain. There was no increase in cancer growth.

Very interesting, because normally you would think somehow that these mice, which were kind of normal in the cardiac response would be worse, but in this respect they were better. So that's a very interesting aspect. The second aspect I found really fascinating is the human data suggest, I guess it's quite preliminary data, but there's a suggestion here that this interaction is mainly seen in younger patients. And I'm not quite sure what that means, but it's something to look at.

Dr Carolyn Lam: Wow. Thanks for highlighting those Thomas. So Ami maybe the last word from you. Given all of this remaining questions and so on, what are your next steps?

Prof Ami Aronheim: First, I wanted to comment something more wide view for this interaction that we find with cancer. I think all the organs actually communicate with one another. The fact that we are looking on a heart and cancer, this is due to the fact that it's easy. We have the models working in the lab and it's easy. But I'm sure if we're going to look to other diseases and other organs, there will be other connections of the heart with other organs and other diseases and maladies, which by conducting modeling, they will promote or maybe even reverse other maladies. So I'm sure that there is a communication between all organs, many organs altogether, and they will affect one another.

Our directions currently are to look more precisely for the periostin story because we follow this mainly in vitro and would like to follow it in vivo. Also I think this mice model are nice, but to look also in human, where the periostin in aortic stenosis patients, where then, we can find out earliest in, in the serum before intervention, and to look after whether this secreted factor goes down or reduced. Also we are looking in other transgenic model that we generated along the years, which are known to result in cardiac modeling. We want to see whether these mechanisms are similar or different and whether they can promote also cancer progression. The use of these transgenic mice is very nice because we can induce them and we can shut down them so we can learn more about the kinetic, which influence one another, and exactly whether they can be reversed or not.

Dr Carolyn Lam: Thank you so much Ami for sharing your thoughts on those future actions, a lot of work and such worthwhile areas to explore. Thank you too, Thomas for sharing your thoughts.

Listeners. Thank you for joining us today on circulation on the run.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation August 11, 2020 Issue

10 augusti 2020 | 25 min

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, guess what we're discussing for the feature discussion? We're talking about sugar sweetened beverage tax. Isn't that interesting? We talk about sugar sweetened beverages and their health impacts, but don't actually look at how tax policies may impact cardiovascular outcomes. So this paper is super interesting, can't wait to get to it, but I really want to get my cup of coffee and discuss a couple of other really cool stuff in today's issue. I'm going to start. Do you think about factor V Leiden much?

Dr Greg Hundley: Carolyn, we are early in August and we have all new house officers rotating, and actually we do discuss factor V Leiden, and we think about Protein C and Protein S deficiencies, et cetera. But how about if you tell us about your paper and educate us a little bit more on the topic?

Dr Carolyn Lam: Okay. So first of all, it's Leiden or Leiden, I'm not sure. So I'm going to go with your pronunciation. Factor V Leiden is a genetic variant leading to alteration of the inactivation site of factor V, which in turn leads to activate a Protein C resistance and a prothrombotic state, just like you said, Greg. Affecting almost 5% of the Caucasian population, carriers of a factor V Leiden mutation have a fourfold higher risk of venous thromboembolism. However, the risk of arterial atherothrombotic events, such as myocardial infarction or stroke, conferred by the presence of this variant is less certain. So Dr Patel from University College London, and Dr Asselbergs from University Medical Center Utrecht and colleagues assess the association of the factor V Leiden polymorphism with subsequent atherothrombotic events, including mortality in individuals with established coronary heart disease using an individual level data meta-analysis of 25 prospective studies from the genetics of subsequent or GENIUS coronary heart disease consortium.

Dr Greg Hundley: Well Carolyn, what did they find?

Dr Carolyn Lam: In nearly 70,000 patients with established coronary heart disease, factor V Leiden was not associated with an increased risk of further atherothrombotic events or death compared to non-carriers. A post hoc analysis, however, suggested that factor V Leiden carriers with established coronary heart disease may gain greater protection from subsequent coronary heart disease, death, or myocardial infarction from dual antiplatelet therapy compared to non-carriers. The routine assessment of factor V Leiden genotype to improve risk stratification in secondary prevention settings is therefore unlikely to be of value and is not recommended. However, further work is required to understand if there may instead be a pharmacogenomic role for factor V Leiden status to help personalize treatment with intensive antiplatelet therapy.

Dr Greg Hundley: Very nice, Carolyn. Well, my next paper is from Dr Michelle O'Donoghue from Brigham and Women's Hospital, and creates an interesting question for you, Carolyn. Would you be comfortable discontinuing aspirin three months after PCI in lieu of continuing a P2Y12 inhibitor?

Dr Carolyn Lam: Ah, big, big question. Not until guidelines change, but tell me, tell me, tell me, Greg, what this paper said.

Dr Greg Hundley: Well, before we get some of these more randomized trial, this study included a meta-analysis of 32,145 patients, 14,095, or 43%, with stable coronary artery disease and 18,000, nearly 56%, with ACS from randomized trials during the time period of 2001 to 2020. And they had to study discontinuing aspirin one to three months after PCI with continued P2Y12 inhibitor monotherapy compared to traditional dual antiplatelet therapy. Five trials were included, and the follow-up duration range from 12 to 15 months after PCI. The primary bleeding and MACE outcomes were the pre-specified definitions in each trial.

Dr Carolyn Lam: An important study. So what did they find, Greg?

Dr Greg Hundley: Well in the experimental arm, background use of a P2Y12 inhibitor with Clopidogrel in 16.5% of cases, and prasugrel or ticagrelor in 84% of patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. So the results, discontinuation of aspirin therapy one to three months post PCI significantly reduced the risk of major bleeding by 40% compared to dual antiplatelet therapy with no observed increase in the risk of MACE, myocardial infarction, or death. The findings were consistent among patients who underwent PCI for an ACS in whom discontinuation of aspirin after one to three months reduced bleeding by 50%, to 1.78% versus 3.58%, and did not appear to increase the risk of MACE where both were 2.5% and 2.98%.

Dr Carolyn Lam: Nice, Greg. Could you summarize the take home message for us?

Dr Greg Hundley: Sure, Carolyn. So in summary, discontinuation of aspirin with continued P2Y12 inhibitor monotherapy reduced the risk of bleeding when stopped one to three months after PCI. An increased risk of MACE was not observed following discontinuation of aspirin, including patients that had previously sustained ACS.

Dr Carolyn Lam: Thanks Greg. Well, my next paper is a preclinical one showing that circular RNAs delivered via extracellular vesicles may be a new treatment for ischemic stroke.

Dr Greg Hundley: Oh my goodness. Carolyn, can you orient us to circular RNAs and these extracellular vesicles?

Dr Carolyn Lam: Sure, Greg. I decided not to quiz you on them. Circular RNAs are a type of endogenous non-coding RNA molecule characterized by back splicing and covalently closed continuous loops, hence circular. Previous studies have demonstrated that multiple circular RNAs have functional roles relating to ischemic brain injury. Although administering circulating RNAs using lentiviruses is efficient for experimental examination, this route is limited for clinical translation due, of course, to disadvantages in onset time and safety issues. So this is where the extracellular vesicles come in as a potential cargo delivering system, if you may, for brain remodeling after stroke. These extracellular vesicles are lipid membrane vesicles of 30 to 150 nanometers in diameter that are released by cells and can cross the blood brain barrier and have been shown capable of carrying proteins, lipids, and nucleotides as their cargo.

So today's co-corresponding authors, Dr Yao from Medical School of Southeast University in Nanjing, and Dr Wang from Chinese Academy of Sciences Kunming, Yunnan in China envisioned the potential of delivering candidate circular RNAs to the brain in vivo by constructing engineered extracellular vesicles bearing circular RNAs. They initially explored this circular RNA delivery strategy idea in the context of their ongoing work regarding the functional roles of circulating RNAs in ischemic brain injury. Their microarray based profiling of acute ischemic stroke patients reveal that a circular RNA generated from the SCM-polycomb group protein homolog 1, or SCMH1 gene, is decreased in plasma of acute ischemic stroke patients and confirmed that a similar decrease occurs in stroke model mice. So they successfully engineered extracellular vesicles with circular SCMH1 over-expression and were thus able to experimentally characterize the ischemia related functional benefits of this circular RNA administration in stroke models in both mice and macaque monkeys. Cool, huh?

Dr Greg Hundley: Yeah. Very nice, Carolyn. That was a great explanation. My study comes from Dr Juyong Kim from Stanford University School of Medicine, and Carolyn, this study combined RNA sequencing, chip sequencing, ATEC sequencing, and in vitro assays in human coronary artery smooth muscle cells with single cell RNA sequencing, histology, and RNA scope in a smooth muscle cell specific lineage tracing aryl hydrocarbon receptor knockout mouse model of atherosclerosis to better understand the role of the aryl hydrocarbon receptor in vascular disease. This aryl hydrocarbon receptor, heretofore AHR, is an environment sensing transcription factor that contributes to vascular development.

Dr Carolyn Lam: Wow, what a comprehensive study. So what do they find?

Dr Greg Hundley: The authors identified a novel population of cells derived from smooth muscle cells, termed condramyocytes, which have gene expression features of cartilage and bone formation within an atherosclerotic lesion. In addition, the environment sensing transcription factor aryl hydrocarbon receptor plays an important role in smooth muscle cell differentiation, ossification, and maintains the smooth muscle cell derived fibrous cap structure.

Dr Carolyn Lam: Interesting. Okay, you know what I'm going to ask. What are the clinical implications?

Dr Greg Hundley: Yeah, I knew you'd ask me that, Carolyn. So human genetics suggests a protective role of the aryl hydrocarbon receptor in the smooth muscle cell during atherosclerosis, and therapies targeted to increase the aryl hydrocarbon receptor activity in smooth muscle cells may confer protection against adverse calcific remodeling of the atherosclerotic plaque. This study also highlights a methodological advance, and further characterization of the pathways that direct the modulation of smooth muscle cells during atherosclerosis at the single cell level may be able to identify potential therapeutic targets to mitigate the risk of atherosclerosis.

Dr Carolyn Lam: Oh, I like that summary, Greg. Thanks. Now, let's move on to other things in today's issue. There's a perspective by Dr Al-Lamee on the ISCHEMIA trial asking was it worth the wait? There's also a perspective by Dr Levine on the ISCHEMIA-CKD trial, providing contemporary randomized clinical data at last in this important population. There's a white paper by Dr Emmaullee on Fontan-Associated Liver Disease, screening, management, and transplant consideration. And finally, there are letters to the editor from Dr Helgestad, Chieffo, and Waksman, with replies from Dr Amin on the article The Evolving Landscape of Impella Use in the United States Among Patients Undergoing PCI With Mechanical Circulatory Support.

Dr Greg Hundley: Very good, Carolyn. Well, I have a few other items in the mail bag. Xiang Cheng has a research letter entitled Cardiac Troponin I is an Independent Predictor for Mortality in Hospitalized Patients with Coronavirus Disease 2019. Also, Corinne Frere has a research letter regarding the Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy, and they provide insights from a perspective single center cohort study. And finally, Dr Jeffrey Wagner has an ECG challenge regarding the infamous is it VT or not VT? Well, Carolyn, how about we get on to that feature discussion.

Dr Carolyn Lam: Let's go, Greg. Beverage Texas are a promising policy approach to reduce consumption of sugar sweetened beverages. And as we know, these are linked to adverse health outcomes, such as Type 2 diabetes and obesity. Now these taxes have been adopted by seven localities in the United States, and in more than 40 countries around the world using different tax designs, but until now a critical answered question where we lack empirical data is the health impact of these beverage taxes. That is until today's feature paper, and I'm so pleased to have with us, Dr Yujin Lee from Friedman School of Nutrition Science and Policy, Tufts University, as well as our associate editor, Dr Naveed Sattar from University of Glasgow. Welcome both, and Yujin, could I start with you please? What an interesting and important idea to look at this. Could you start by perhaps first explaining to us what are the different types of tax designs?

Dr Yujin Lee: There are three types of tax design. First, the volume tax is taxing sugar sweetened beverages based on the volume. For example, a penny per owns for volume tax. So the tax rate is same whether a beverage contains 5 or 20 grams of added sugar for 8 ounces. The second design is the absolute sugar content tax, which is taxing beverages based on the sugar content regardless of the volume. So for example, one cent per one teaspoon of sugar, or one cent per one gram of sugar. Lastly, tier tax is hybrid of volume and absolute sugar content tax. For example, creating different tiers products based on the sugar content and taxing based on the volume at different rates. So for example, the American Heart Association suggested three tiers. First, no tax on beverages with less than five grams of added sugar per eight ounces. And second, 1 cent per ounce on beverages with 5 to 20 grams of added sugar per 8 ounces. And lastly, 2 cents per ounce on beverages with more than 20 grams of added sugar per 8 ounces.

Dr Carolyn Lam: Great. So thank you for explaining that. I mean, to be honest, I didn't even realize there were so many different tax designs. Now, could I understand a bit better? So in the US, are they mostly volume-based? And then perhaps you could tell us how did you go about your study of comparing these things, and looking on their impact on outcomes.

Dr Yujin Lee: Sure. So as you mentioned, all seven US locality have been implementing the volume tax, and in this study, this is the modeling study, so we're using the nationally representative data and using a microsimulation model, and we wanted to compare and estimate the health and economic impact of the volume, absolute sugar content. And the tier tax designs in the United States.

Dr Carolyn Lam: Great. And tell us what you found.

Dr Yujin Lee: What we found is we found that implementing a volume-based sugar sweetened beverage tax could prevent 850,000 cardiovascular events and 270,000 diabetes over a lifetime of current US adults aged 35 years or older. And this tax design could save tens of billions of dollars in healthcare costs. In addition, taxing sugar sweetened beverage based on their sugar content, for example, the tier or absolute sugar content based tax design, could generate about double the health and economic benefits compared to the volume tax.

Dr Carolyn Lam: Wow, that is so intriguing. Naveed, I have to bring you in here. So in the UK they use a tier tax. Do you? And what are your thoughts?

Dr Naveed Sattar: Oh, well clearly, Carolyn, I mean, I think taxation of sugar sweetened beverages is something that all of us can agree on is beneficial. I think it's really important that many other countries and states consider this. I'm surprised that only seven states in the US are currently doing this. And in some respects, this papers is very timely. It's based on modeling. I mean maybe you can come back to Yujin about how good the modeling is, but if you think about the issue we have now in terms of health inequalities and COVID related deaths, going forward we need mechanisms to help reduce health inequalities. And this particular paper will flag up that places need to think about sugar sweetened beverage taxes and how best to do them.

And I completely agree, they should be based on sugar content. I don't see why they should be more convoluted than that. And although Yujin explained it, it still seems a bit complex to me, the different mechanisms, but I think your paper is very timely and very important. And for me, the key question for Yujin is people looking at this may say well, how robust is that model? How do we know how accurate you've been in terms of the money saved, because that's going to be really important going forward, and in particular, the number of lives or cardiovascular and diabetes cases prevented?

Dr Yujin Lee: Sure. So let me explain how we estimated how many cases of cardiovascular disease and Type 2 diabetes were prevented. So we use a microsimulation model, which is a computer simulation model, which is developed by the research team, led by Dr Thomas Casiano and Harvard School of Public Health. So this model predicts the probability of an individual experiencing cardiovascular disease or diabetes based on each person's risk factor, such as sex, age, total cholesterol, or smoking or diabetes, and also their SSB-consumption also be part of this input. So it estimate the probability of one person, individual, developing the future cardiovascular disease, or Type 2 diabetes, and it estimate how this prevention can save healthcare costs associated with these diseases. So in this study, this model simulates the status quo, so the way things now stand, and also it assimilate the three different tax design. After that, we compute the health outcome and costs associated with this policy options and, by comparing this model, outputs for these three tax design with the status quo.

Dr Naveed Sattar: Has any country got long enough perspective data that have implemented such taxes to validate the model, or is that still to come? I mean it would be nice to get it validated in real life, but I think most people would accept that reducing sugar in beverages is a really good thing, and presumably the part of the mechanisms by reducing weight, and reducing all of the implications of excess calorie intake, particularly refined sugar, on a variety of different diseases. Is that fair?

Dr Yujin Lee: Yeah, and I wanted to make a point that, since this is a modeling study, so our study cannot prove the health and economic impacts of this tax design in the United States, so rather our estimates provide evidence that can be considered and incorporate into the design, and implementation, and evaluation of future SSB taxes.

Dr Carolyn Lam: That's a really good point. And maybe just to round up, Yujin, could I just ask you to were any particular individuals in the population simulated to experience larger gains? We know that it's exactly like Naveed said, it's the minorities, it's perhaps lower income region individuals who might need this more. I mean did your simulation show anything to that effect?

Dr Yujin Lee: We also investigate this tax design and how this influence in sub population. Particularly we found that the SSB taxes have a larger benefit among younger adults, minorities, and adults with the lower income. Given that these population, their SSB consumption is higher than the other group, so this SSB tax implementation gives them a greater health and economic benefit to these subpopulations.

Dr Carolyn Lam: Thank you so much, Yujin, for this really, really, I think, novel and very important data. Naveed, could I give you the last say as the associate editor who is managing this, and you even invited an editorial, which I liked very much, the title, Simple is Better for Local Beverage Tax Policy Diffusion. It's kind of in line with what you've been saying, but maybe some take home messages?

Dr Naveed Sattar: Obviously in Circulation, we get lots of beautiful papers that very molecular depth and various other factors, but actually this paper brings us back to the reality that for many of the diseases that we treat, diet and drink intake is really relevant to our diseases and the likelihood of diseases, and there are simple mechanisms whereby we can help people in the community to actually lead better lifestyles that also are actually economically beneficial. And I think that in this paper, if it was to be implemented and looked at seriously by many states in the US, by many other countries to go along this route would have huge potential benefits on health, And it's really important at this time, given what's happened with the pandemic, and as we move forward over the next 5 to 10 years. So I think it's really timely and I congratulate the authors on it.

Dr Carolyn Lam: Well, listeners, you heard it right here, novel, impactful data. That's what Circulation is about. Thank you for listening to Circulation on the Run. Don't forget to tune in again. Next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation August 4, 2020 Issue

3 augusti 2020 | 21 min

Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains?

Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe?

Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress.

Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find?

Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease.

Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same?

Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different.

Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.

Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common?

Dr Greg Hundley: I definitely need phone a friend.

Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms.

Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI.

Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg?

Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate.

Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find?

Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points.

Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR.

Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found.

Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock.

So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation.

Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too.

Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies?

Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease.

We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function.

Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not?

Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome.

But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease.

Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts.

Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution.

And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It’s just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them.

Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community?

Dr Damien Bonnet: And that there are clinical issues. So the first one is to see or to look at potential cardiac residual anomalies, mitochondrial or coronary arteries aneurism, because today we have not precise information of that.

The second is probably observational because it will be difficult to randomize young children, is what is the optimal treatment at baseline or what is the optimal strategy? And is it possible to stratify the strategy as I just said, but I don't have evidence for that. And for the long term, I think that trying to identify why only some children have this disease and why the other don't have, if there is any genetic susceptibility, it will be something interesting. And potentially as we discussed already together, it might give us some keys to better understand Kawasaki disease as well.

Dr Gerald Greil: Thank you so much for summarizing that. I mean, we are all very much looking forward to working together with you and other groups around the world to get a little bit more and better insight in this kind of type of disease and how to treat them best and how to follow them up best.

Dr Carolyn Lam: Thank you so much, Damien and Gerald. I mean, I'm sure I speak behalf of the entire audience that I learned a lot just listening to your very open and honest conversation of what we've seen, what we've experienced, what we don't yet know. Listeners, you have to refer to a beautiful accompanying editorial that Gerald invited, and it is by Dr John Simpson and Dr Jane Newburger from Evalina London Children's Hospital and Harvard Medical School, respectively.

Thank you so much for joining us today. And please remember, you've been listening to Circulation on the Run. Tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation July 28, 2020 Issue

27 juli 2020 | 22 min

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Our feature paper today discusses trans-ethnic genome-wide association studies and the insights in the genetic architecture and heritability of long QT syndrome, a massive study that we will be digging into, but only after we talk a little bit about the other papers in this week's issue. And I'm going to start, Greg. Are you ready with your coffee?

Dr Greg Hundley: I am.

Dr Carolyn Lam: The first original paper really represents seminal work, showing that the endothelium can directly regulate obesity and insulin resistance. Now, as obesity develops, there is a decline in adipose tissue vascularity, which seems counterintuitive, and an increase in fibrosis.

So authors, led by Dr Chen from the Irell and Manella Graduate School of Biological Sciences in the City of Hope, speculated that the reduction in vascularity in this adipose tissue might have an adverse effect on adipose tissue function. Now, these authors previously identified Argonaute-1, or AG01, a key component of microRNA-induced silencing complex, as a crucial regulator in hypoxia-induced angiogenesis.

So in the current study, they aim to determine the AG01-mediated endothelial cell transcriptome, the functional importance of AG01-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity.

A new mouse model with genetic deletion of AG01 in the endothelium was useful to investigate the importance of endothelial regulation of adipose tissue function. The findings were that in mice fed high fat, high sucrose diet, the suppression of endothelial AG01 promoted adipose tissue browning, and led to an anti-obesity phenotype. Endothelial cell AG01 thrombospondin-1 pathway was induced in the endothelium from human donors with insulin resistance.

In total, this study suggests a novel mechanism, by which endothelial cells through AG01 thrombospondin-1 pathway controls vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.

Dr Greg Hundley: Interesting, Carolyn. So tell me about this clinically. Where do we take this from here?

Dr Carolyn Lam: I thought you would ask. So endothelial dysfunction, per se, can cause metabolic dysregulation, rendering targeting dysfunctional endothelium, a potential therapeutic strategy to counteract obesity, and metabolic disorders. So this study really opens a door to that.

Dr Greg Hundley: Very nice. Well, I've got another basic science paper, and it evaluates single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. And it comes from Dr Jiangping Song from the State Key Laboratory of Cardiovascular Disease of Fuwai Hospital, and the National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, and Peking Union Medical College.

So Carolyn, the study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy, and to identify the genes contributing to the inflammatory response to myocarditis.

So mice were treated with myosin heavy chain alpha-peptides to generate an experimental autoimmune myocarditis model. The investigators performed single-cell RNA sequencing analysis of CD45 plus cells extracted from mouse hearts during different experimental autoimmune myocarditis phases, including normal control, acute inflammation, subacute inflammation, and then in the myopathy phase. Also, human heart tissues were collected from surgically removed hearts of patients who had undergone heart transplantation.

Dr Carolyn Lam: So what did they find, Greg?

Dr Greg Hundley: Well, Carolyn, a comparison of the single-cell RNA sequencing data from different experimental autoimmune myocarditis phases suggested that some cell clusters, such as macrophage cluster 2 and Th17 cells, were associated with the inflammatory response in the experimental autoimmune myocarditis model.

The HIF1A expression level correlated with the extent of the inflammatory response, and PX-478, a HIF1A inhibitor, alleviated the inflammation during the different experimental autoimmune myocarditis phases.

Immunohistochemical staining revealed that HIF1A expression was upregulated in autoimmune myocarditis from the tissue samples from the explanted hearts. Thus, the HIF1A inhibitor alleviated inflammatory cell infiltration, and that may serve as a potential therapeutic target in clinical practice.

Dr Carolyn Lam: Wow. That is some serious clinical implications. Well, my next paper is really the first systematic echocardiographic evaluation of consecutive patients requiring hospitalization due to COVID-19, and it comes from Dr Topilsky and colleagues from Tel Aviv Medical Center.

Dr Greg Hundley: So Carolyn, what did they find in this series?

Dr Carolyn Lam: So among a hundred consecutive patients diagnosed with COVID-19 infection who underwent complete echocardiographic evaluation, within 24 hours of admission, only 32% had a normal echocardiogram at baseline. The most frequent abnormality was right ventricular dilatation or dysfunction.

Among patients developing clinical deterioration during follow-up, which were 20% of these hospitalized patients, repeated echocardiograms showed further deterioration of the right ventricular parameters, probably related to increased pulmonary resistance. Five of these patients had deep vein thrombosis.

Dr Greg Hundley: Carolyn, my next study comes from Dr Stephen Fremes, and it's a modeling study out of the University of Toronto. It modeled TAVR versus SAVR valve durability to determine the effects on life expectancy across a broad range of age.

Dr Carolyn Lam: Interesting. And what were the results?

Dr Greg Hundley: Well, based on their simulation models, the durability of TAVR valves must be 70% shorter than that of surgically replaced valves to result in reduced life expectancy in patients with similar demographics to recent trials.

However, in younger patients, the threshold for TAVR valve durability was substantially higher. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40% and 50% shorter than surgical valves in 40, 50 or 60-year-old patients, respectively.

So Carolyn, these findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low-risk patients, based on current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors, such as life expectancy.

Dr Carolyn Lam: Thanks Greg, for that summary. Well, let me tell you about other papers in this issue. There are a pair of letters to the editor by Dr Opotowsky, and a response by Dr Goldberg regarding the paper results of the Fontan Udenafil Exercise Longitudinal, or FUEL trial.

There's a research letter by Dr Strik, Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. There are two On My Mind papers, the first, Telemedicine and Forgotten America by Dr Julien, and the second, The COVID-19 Pandemic: Ethical and Scientific Imperatives for "Natural" Experiments by Dr Lewis.

Dr Greg Hundley: Very nice. Well, Carolyn, I've got a research letter evaluating the effect of evolocumab on atherogenic lipoproteins during the peri and early post-infarction period. It's a placebo-controlled randomized trial from Dr Gary Gerstenblith.

Sarah Cuddy also worked through a tough case of cardiac amyloid when a fat biopsy was negative, but imaging studies of the heart suggested cardiac amyloid.

Carolyn, I've also got an On My Mind piece, and it's entitled, Can Old Ally Defeat a New Enemy? And it's by Dr Paul Gurbel, and he discusses the use of inhaled aspirin to treat patients with COVID-19.

And then finally, Carolyn, I have a prospective piece from Dr Robert Lefkowitz who discusses β-arrestin-biased angiotensin II receptor agonists for treatment of COVID-19. Well, Carolyn, what a great issue, and let's get onto that feature discussion.

Dr Carolyn Lam: Yay. Let's go, Greg.

Dr Greg Hundley: Well, listeners. Now we're turning to our feature discussion, and we are very fortunate to have Professor Connie Bezzina from Amsterdam University Medical Center to talk to us about her paper related to long QT syndrome.

Welcome, Connie. And I was wondering, before we get started in discussing your paper, could you tell us a little bit about the background in this area? And then, what was the hypothesis that you wanted to address?

Prof Connie Bezzina: So over the last 20 to 30 years, we've learned a lot about the genetic underpinnings of inherited cardiac disorders associated with sudden cardiac arrest. And basically, we've learned a lot about mutations in specific genes that co-segregate with these disorders within families.

However, two outstanding features have remained unresolved. Essentially, the first unresolved issue is the fact that we observe, oftentimes, a low disease penetrance and variable disease expression within families, which means that not everybody within a family that carries a familial mutation is affected by the disorder.

But two, so among those that are affected, some are affected more severely than others. So some people would have only the ECG abnormality, whereas other people, for instance, would have the ECG abnormality and arrhythmic events. And you could also have individuals, indeed, who don't even manifest any disease manifestations. This is one of the outstanding challenges.

The other outstanding challenge is the fact that, despite extensive genetic testing of the known genes in some probands and some families, they remain genetically lucid, in that we don't find a likely genetic defect in a minority of families. And of course, that hinders genetic testing and implementation of genetic testing in such families.

Dr Greg Hundley: What was the question you were going to answer with your study? And tell us a little bit about your study design and your study population.

Prof Connie Bezzina: Yeah, so essentially, we figured that assigning these disorders to one large genetic defect might be an oversimplification of biological phenomenon. So we hypothesized that even in these Mendelian disorders, the inheritance of additional genetic factors alongside the familial mutation could contribute to risk. Of course, there will be other factors such as environmental factors, which we did not tackle in the study.

The central hypothesis of the study was that common genetic variation, which is present in the germ population, could modulate the effect of the familial genetic defect of the Mendelian mutation.

So in order to do this, we assembled a large consortium of investigators from multiple centers in Europe, in North America and Japan, worldwide, to bring together about 1700 probands with the long QT syndrome. So we tested this hypothesis in the long QT syndrome because we figured, among the rare inherited rhythm disorders, it's one of the more common disorders. Also, because each individual center has too few patients. To do this locally, we put this group of investigators together to come up with 1700 probands.

The study design was a genome-wide association study with a case-control design, where we tested the association of millions of SNPs littered across the genome with susceptibility for the disorder. So this led us to identify three single-nucleotide polymorphisms that are associated with susceptibility for the long QT syndrome.

What we immediately saw is that, actually, these three SNPs, perhaps not surprisingly at all, had been previously associated with the extent of the QT interval, with QT interval in the general population. This is not surprising, of course, because repolarization is a central part of physiological mechanism in the long QT syndrome. So this basically indicated overlap between genetic control of the QT interval in the germ population and susceptibility to the long QT syndrome.

So the fact that the three SNPs that we identified as long QT syndrome susceptibility SNPs had been associated with QT interval duration in the germ population, we felt that that was pointing to assure genetic underpinnings between these two phenotypes.

So we went on to investigate that by looking at the correlation between the odds ratio for long QT syndrome susceptibility and the effect that these SNPs have on QT interval in the germ population. And in fact, we found a very high correlation between those. So essentially, this pointed to sure genetic factors between QT interval in the germ population and long QT syndrome susceptibility.

Of course, we wanted to look for disease variability. The next thing we wanted to do was whether these SNPs could actually explain disease variability. Now, this was perhaps the most disappointing part of the study, because when we constructed a polygenic risk score based on SNPs that impact on the QT in the germ population, we found no relation to QT interval among patients, and also no relation to life-threatening arrhythmic events among the patients.

We think that this is because our patients... or probrands. They're primarily probands, so they are all more sick. So we didn't have enough variability in our patient set to identify an association with disease variability. And in fact, this is at variance with previous studies that tested individual SNPs, and even our own studies with smaller polygenic risk scores that did find an association between a polygenic risk score based on QT SNPs and QT prolongation and events among patients.

So we think that this is certainly something to study further in the future, in larger patient sets where we not only have the probands, but also their relatives, their mutation-carrying relatives, which will give us a bigger variability to actually test this hypothesis. So we think that looking at probands actually was a very good design to find susceptibility variance but was not maybe a good design to find SNPs or polygenic risk scores to test their effect on disease variability.

Dr Greg Hundley: It sounds like you've found certain gene low PSI that indicate a predilection for prolongation of the QT interval, but not necessarily are those gene low PSI consistent with who's going to experience an adverse cardiovascular event as a result of their genetic constitution. Is that a fair statement?

Prof Connie Bezzina: Well, I think that the setting, because we had probands, they were the most sick people in their families. I think to have stronger conclusions on that, we need to test the polygenic risk scores in families where there are people who are differentially affected.

Dr Greg Hundley: I see. I-

Prof Connie Bezzina: We had too-narrow of a variability in a probands-only design, as opposed to a study where we would have probands who are severely affected and mutation-carrying relatives who are less severely affected.

Dr Greg Hundley: Very nice. So that puts that clearly into context. This was a massive effort. You have quite a list of investigators, and you mentioned you had to gather so many sites. How would you conduct that next study? Would you need another large collection of individuals and many sites to take that on?

Prof Connie Bezzina: Yes. I'm a geneticist, and geneticists always want larger, larger numbers, and I'm also one of those. So I'm interested in explaining as much as possible into individual variability. And I think to do that properly, I think we should go preferably for a similar design where we will approach the same centers. And hopefully, we can organize the next study, which will have these probands and their relatives.

Dr Greg Hundley: Now, just quickly, for us working in the clinic, how should we approach genetic testing in patients with long QT?

Prof Connie Bezzina: At the moment, I think our findings don't have an immediate impact. I think our findings tell us about the genetic architecture of the disorder. And actually, one thing I haven't gone into yet is the fact that what we also found is that patients who do not have mutations in the no-long QT genes, which were called mutation-negative, which are about 20% of all long QT syndrome probands, actually have a higher burden of these common variants that prolong the QT interval.

So we think, actually, that mutation-negative long QT syndrome probands will not have a Mendelian large effect variant but will have perhaps a higher burden of these QT-prolonging alleles.

Therefore, I think this has direct implications for clinical genetics of these patients, because if you have a proband in whom you don't find a mutation in the known genes, you could think that maybe it is not monogenic, which has implications because you don't have a single genetic defect to test on that family. One would need to keep follow-up of more family members until we understand more about the genetics of those individuals.

Dr Greg Hundley: So Connie, this has been just a wonderful discussion. Any additional studies examining the genetic architecture of individuals that we need to think about for the future?

Prof Connie Bezzina: Sure. So for long QT syndrome in particular, as additional SNPs that modulate the QT interval in the germ population are identified, it will be very important to incorporate these into larger polygenic risk scores, and see whether we could have a better discriminative capacity of such polygenic risk scores in discriminating between severely affected and less severely affected people, or who is more at risk for an arrhythmic event.

Outside of long QT syndrome, I think there's a lot of work to be done with respect to the likely complex inheritance of many of these disorders that we previously considered to be Mendelian. So for instance, ongoing work in our group concerns Brugada syndrome, where we're seeing the same kind of thing, and hypertrophic cardiomyopathy, where we're seeing the same kind of inheritance.

Dr Greg Hundley: Well listeners, on behalf of both Carolyn and myself, we look forward to catching you on the run next week. Take care. This program is copyright the American Heart Association 2020.

Circulation July 21, 2020 Issue

20 juli 2020 | 26 min

This week’s episode of Circulation on the Run features author Robert Yeh and Associate Editor Brendan Everett as they discuss the article "Use of Administrative Claims to Assess Outcomes and Treatment Effect in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings from the EXTEND Study."

TRANSCRIPT

Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week, we're going to examine outcomes in patients that have undergone transcatheter aortic valve replacement or TAVR. I can't wait to get to the results from the EXTEND study. But before we do that, how about we grab a cup of coffee and start in with some of the papers and maybe I'll go first this time.

My paper involves a validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy. And the corresponding author is Dr Seema Mital from the Hospital for Sick Children. Well, Carolyn in this study, the objective was to develop and validate a sudden cardiac death risk prediction model in pediatric hypertrophic cardiomyopathy to guide sudden cardiac death prevention strategies.

To address this, the authors performed an international multi-center observational cohort analysis. Phenotype positive patients with isolated hypertrophic cardiomyopathy, who were under the age of 18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of sudden cardiac death events at five years of follow-up. That included sudden cardiac death, resuscitated sudden cardiac arrest, and aborted sudden cardiac death, that is, an appropriate shock following primary prevention ICD.

Carolyn Lam: Nice. What did they find?

Greg Hundley: Well, overall 572 patients met the eligibility criteria with 2,855 patient years of follow-up. The five-year cumulative proportion of sudden cardiac death events was 9%. Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter Z scores, LV posterior wall diameter Z scores, LA diameter Z scores, peak LV outflow tract gradients, and the presence of a pathogenic variant.

Now, unlike adults, LV outflow tract gradient had an inverse association and family history of sudden cardiac death had no association with sudden cardiac death. The combination of clinical and genetic data were developed to predict five-year freedom from sudden cardiac death.

In conclusion, the authors study provides a validated sudden cardiac death risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. These results therefore raise the possibility that an individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for these children prior to an ICD insertion.

Carolyn Lam: Very interesting. Well, Greg, have you ever wondered what are the temporal trends in the burden of comorbidities and risk of mortality among patients with heart failure with preserved ejection fraction or HFpEF and heart failure with reduced ejection fraction or HFrEF? Well, the next paper comes from Dr Caughey and colleagues from University of North Carolina and North Carolina State University who performed an analysis of the community surveillance component of the atherosclerosis risk in communities, or ARIC study, and they found a significant increase in the burden of comorbidities among hospitalized patients with HFpEF as well as HFrEF across both sexes. Higher number of comorbidities was associated with higher risk of one-year mortality with a stronger association noted among patients with HFpEF compared to HFrEF. The one-year mortality risk associated with increasing comorbidity burden also increased over time.

Greg Hundley: Interesting, Carolyn. So more comorbidities in HFpEF versus HFrEF. How do we use this clinically?

Carolyn Lam: This study demonstrated a shift from ischemic etiology heart failure to multi morbidity heart failure over time, particularly among patients with HFpEF. This really highlights the importance of a holistic approach in targeting multimorbidity burden and guiding the management of patients with heart failure.

Greg Hundley: Very interesting. Well, Carolyn, my next paper comes from Professor Matthias Nahrendorf from Mass General Hospital and involves the relationship between bone marrow endothelial cells and myelopoiesis in those with diabetes.

Carolyn, this study investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. The authors utilized three types of mice with diabetes, including a streptozotocin model, a high fat diet model, and a genetic induction using leptin receptor deficient mice. They assayed leukocytes, hematopoietic stem cell and progenitor cells, and endothelial cells in the bone marrow with flow cytometry and expression profiling.

Carolyn Lam: What did they find?

Greg Hundley: Well in diabetes, they observed enhanced proliferation of hematopoietic stem cells leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less CXCL-12, a retention factor promoting hematopoietic stem and progenitor cell quiescence. Transcriptome wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor signaling in mice with diet induced diabetes.

In summary, Carolyn, in diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow haematopoiesis specifically diabetes reduces endothelial production of CXCL-12, a quiescence promoting niche factor that reduces stem cell proliferation. The authors also describe a previously unknown counterregulatory pathway in which protective endothelial EGFR signaling curbs hematopoietic stem cell and progenitor cell proliferation as well as myeloid cell production.

Carolyn Lam: Wow, thanks for explaining all of that, Greg. For this next paper, we're going to switch tracks a little. This comes from Dr Drakos and colleagues from University of Utah in Salt Lake City. They noted that significant improvements in myocardial structure and function have been reported in some advanced heart failure patients. This is they're going to call responders and the responders improve the myocardial structure and function following left ventricular assist device induced mechanical unloading.

This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Dr Drakos and colleagues hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, which may mediate myocardial recovery in these responders.

To test this hypothesis, they prospectively obtained paired left ventricular atypical myocardial tissue from non-failing donor hearts, as well as responders and non-responders at left ventricular assist device implant and at transplantation. They conducted protein expression and metabolic profiling and evaluated mitochondrial structure using electron microscopy.

Greg Hundley: Interesting. What did they find, Carolyn?

Carolyn Lam: The recovering heart appears to direct glycolytic metabolites into pentose phosphate pathway and one carbon metabolism, which could contribute to cardioprotection by generating NADPH to enhance biosynthesis and by reducing oxidative stress. This new information could redirect future translational investigations to efforts to identify novel therapeutic targets for myocardial recovery in patients with chronic heart failure.

Well, Greg, can I tell you a little bit more about what else is in this issue? There's a letter by Dr Wang regarding the article, A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction, and there's also a response by Dr Yan. In Cardiovascular Case Series, there's a paper by Dr Michelena on the nosology spectrum of the bicuspid aortic valve condition, the complex presentation of valvular aortopathy. That's so interesting.

There's a research letter by Dr Gaudino on the response of cardiac surgery units to COVID-19, an internationally based quantitative survey. As well as another research letter by Dr Salem on cardiovascular toxicities associated with Hydroxychloroquine and azithromycin and analysis of the World Health Organization pharmacovigilance database.

There is a perspective piece by Dr Jacobs entitled The Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA's Mission: Lifeline.

In cardiology news, Tracy Hampton reviews three papers, one, Video-Based AI for Beat-to-Beat Assessment of Cardiac Function in Nature, 2020. Two, Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by single Nucleus RNA Sequencing, that is in developmental cell 2020. And three, ATP and Voltage-Dependent Electro-Metabolic Signaling Regulates Blood Flow in the Heart, the proceedings of the National Academy of Science, 2020.

Greg Hundley: Very nice. Well, I've got an in-depth review from Dr Bin Zhou regarding the heart regeneration by endogenous stem cells and cardiomyocyte proliferation, controversy, fallacy, and progress. And then there are three on my mind pieces. The first is from Dr Rashmee Shah regarding machine learning and artificial intelligence. Do we need more data, or do we need the right data? The next one is from Sharon Reimold and it discusses the importance of gathering historical information on risk factors when seeing patients with, or suspected, of COVID-19. And then finally, Dr Prateeti discusses ethical challenges in cardiology during the COVID-19 pandemic.

Well, Carolyn, what a great review. How about we proceed to that feature discussion?

Carolyn Lam: Let's go.

Greg Hundley: Well listeners, we are now turning to our feature discussion and this week we have Dr Robert Yeh, also Bobby Yeh, from Beth Israel Hospital and our own associate editor, Dr Brendan Everett from Brigham and Women's Hospital. Welcome gentlemen. Bobby let's start with you. Can you tell us a little bit about some of the background related to your study, and then what hypothesis were you trying to address?

Robert Yeh: The study that we performed is the sub study of what we're calling the EXTEND study, which is an NIH funded group of investigations meant to really examine what the value is of real world data and how it can augment clinical trial evaluations of medical devices and therapies.

We know that randomized clinical trials remain the gold standard for therapeutic evaluation, but they are expensive, difficult to do, and sometimes impractical. Real world data is cheaper, it's potentially more efficient to do observational research studies, and in fact the 21st Century Cures Act explicitly asks, among other things, that the FDA explore the use of real-world data for regulatory evaluations.

People have problems with real world data, of course, they have their own inherent challenges which are subject really to confounding. What we thought about is, well, there's probably this middle ground that we and others have proposed, which is can't real world data somehow supplement or augment randomized clinical evaluations, and in particular, in our question, can real world data be the provider of outcomes in place of adjudicated clinical trial outcomes?

What we did is we took two large pivotal randomized clinical trials of transcatheter aortic valve replacement, namely the CoreValve, high risk, and intermediate risk trials. Otherwise, the intermediate risk trials known as the SURTAVI trial. And we found those patients in those trials and then linked them with real world data from administrative claims databases in Medicare.

Our hypothesis was that had the trial been evaluated in terms of outcomes by the Medicare claims instead of the clinical trial adjudicated outcomes. Our main question was, would we have had the same findings within those trials? Would the primary hypothesis of those trials still have been met with this alternative clinical trial end point ascertainment strategy?

Greg Hundley: In your study design, how did you accomplish the comparisons? You've told us a lot about the study population. Was this everyone from those two studies or was this a subgroup of them? Maybe just expand on that a little bit.

Robert Yeh: Good question. This is a US based comparison, so we have claims for US patients, and most patients in these trials were in the United States, but the CoreValve trial and the SURTAVI trials, we took all of this patients and then tried to find those patients who we could also find in Medicare claims.

It turns out that in order to qualify for Medicare, you have to be over 65 years of age, under most circumstances. And so it's limited to really those patients over age 65, who we could then search for in Medicare and then within Medicare, there's two types of insurance, fee for service and Medicare Advantage managed care. And what we can only find are those patients who are in Medicare fee for service, which represents somewhere between two thirds and three quarters of patients age greater than 65 or older. So it is a subgroup of patients in these two large pivotal randomized trials.

We've compared those who could not be linked versus those who could, find large part, from some of the age differences, which are just inherent in looking at Medicare, there are really not that many differences between those two groups.

Greg Hundley: Bobby, what did you find?

Robert Yeh: We found those patients. So now we have this situation where we have patients in trials, and we can look at them from two lenses. The same group of patients, one lens is through the clinical trial lens and the second is through the lens of real-world data, those exact same patients.

We found that whether or not we ascertained their outcomes via claims or with clinical trial adjudication, essentially the primary hypotheses were identical, that in both scenarios, the transcatheter aortic valve was non-inferior to the traditional surgical aortic valve replacement, that the effect sizes and the hazard ratios, the confidence intervals, they were roughly the same. In fact, for the primary endpoint of the high-risk pivotal study, which was all cause mortality, it was identical. It turns out that Medicare claims and what we called the denominator file very accurately identifies exactly when a patient dies. It does so equally well compared to rigorous clinical trial adjudication.

For SURTAVI the primary endpoint was combined death or stroke in that case, stroke is reasonably accurate. There were a lot of deaths that also drove that combined end point. And the net result was that really very similar, both effect sizes and primary, P values for those comparisons.

Greg Hundley: Now how about secondary analysis?

Robert Yeh: I think the secondary analysis that's where you had some variability. There are some types of outcomes in this device specific trial that are procedure oriented. Pacemakers are a concern. Aortic valve reintervention is a concern. Those end points in billing claims turns out are quite accurate. You can understand why. I think providers and institutions, when they do a service that requires insertion of a new device, they want to get paid for those devices and they do that billing accurately.

But there are other claims which I think are a little bit more subjective, diagnoses that are more subjective, those like bleeding or cardiogenic shock, those things actually started to look different. And in fact, in some cases started to give you different inferences if you used the clinical trial data versus the real-world data. And so if I were to summarize it, I would say that mortality looked absolutely pristine identical between the two groups that some diagnoses, particularly procedural ones, looked quite good, sufficient, I think, for an accurate estimation of the treatment effect size as well as the magnitude of the risk, but then some end points, I think the softer more subjective endpoints are slightly different.

Greg Hundley: Thank you so much, Bobby. Now we're going to turn to our associate editor, Dr Brendan Everett, who has helped work this article through the entire editorial process and is also an expert epidemiologist. Brendan, we have randomized trial data versus real world data. How do you interpret these results in the context of how we're conducting studies both now and then how we will conduct them in the future?

Brendan Everett: If you think of observational research and clinical research on a spectrum with truly just observational studies on one end, where you were trying to look at an exposure and an outcome and adjusting for potential confounders, to tightly controlled randomized trials on the other, Bobby's group has managed to create a hybrid, which I think gives us some opportunity to not have to be either on one and or the other of the spectrum.

What I mean by that is that there are a couple key features of trials that are retained in the approach that Bobby used, and his group used. He mentioned those, but I want to emphasize them. I think the key thing is that there's a randomization step. From the perspective of an epidemiologist, that's key because it balances between the people who get your therapy, in this case a TAVR and don't get the new therapy…confounders that you can measure and confounders that you can't measure, the unmeasured confounders. So it allows some balance between the two treatment groups so that you can be sure, at least at baseline, that they're similar groups and what you're measuring after that point is the effect of the intervention.

The key piece that Bobby replaced is the classical trial ascertained end points where investigators are asked if their patient had one of these outcomes such as a stroke or a death, and then they're adjudicated independently.

As he pointed out, I think there are many of those outcomes, at least in this particular application, are really well collected by billing data. And in fact, some might argue that in some cases they're actually better collected. There's a higher sensitivity, if a somewhat lower specificity for the events of interest.

I think the key question, and you touched on this, Greg, is what about the outcomes that maybe are not collected quite as well by billing data? In particular, remember that any clinical trial is looking at both the efficacy of a novel treatment as well as its safety. You ultimately, at the end of the trial, want to be able to compare efficacy with safety, to make a decision, in this case from the FDA, a regulatory decision about whether to approve the device or the drug.

The question becomes, what safety events are you worried about and how reliably are you going to be able to collect them with claims data? In this case, I think Bobby mentioned that the bleeding data maybe was not quite as good as some of the other safety concerns that are common in TAVR.

I think when you look to apply this approach, which I think is ingenious, to a different research question, you have to ask whether or not the end points, the efficacy end points, and the safety end points that you're collecting will be done in a valid and consistent and sensitive way with claims data as compared with the traditional trial ascertainment process. In this case, I think they were, but that's not always the case. We can all think of examples where you might run into some trouble depending upon what your end points are.

Greg Hundley: Well, gentlemen, this has been really an informative study to present and talk about in this feature discussion. I want to ask you both just briefly, in a minute or so, what do you see as the next step forward in research in this particular area? Maybe Bobby you first and then we'll follow with Brendan.

Robert Yeh: I think that there are a couple of different areas that really need to be pushed forward. One, and Brendan alluded to this, is because these studies are really domain specific this validation does not tell us that all claims can be used to answer all questions, that in this particular question it worked, but in others it might not, so more validation work in different fields, different randomized trials, need to be done.

We're doing some of those, but they need to be done throughout so we can really get a better sense of what are the types of questions that are best answered by this type of linkage approach.

The second that is more operational, we were limited to Medicare claims data, so for questions for patients who are younger than 65, this approach just doesn't work. Whereas a place like Sweden can do a large national registry like they did in the TASTE randomized clinical trial and do this for their entire country.

We do need to develop better systems that have comprehensive real-world data collection. Maybe those involve more consolidated electronic health system, health record data that are available in big integrated health systems, for example, but a better system needs to be developed that can answer questions among more than just Medicare fee for service patients.

Greg Hundley: Very good. And Brendan?

Brendan Everett: Well, I think it's a really promising approach to trying to lower the cost of clinical trials and to do valid research on the effect of some treatments as compared to others. From my standpoint, we have to be careful that we don't try and shortcut the process too much. In particular, I think the randomization step, at least for novel treatments, is of fundamental importance. And of course, to do that, you have to collect a population that is then willing to be randomized to option A or B.

There's a lot of upfront work that is not eliminated by looking solely at the outcomes, using this technique to look at the outcomes. There's a lot of upfront work to collect the patients and then randomize them.

I think also it's important, as we saw recently, that the quality and validity of the database be ascertained and be well-established both with the investigators and the providers of the database. We can see that sometimes, if you're not careful, you can come up with outcomes that are not correct because of the example. Of course, I'm alluding to is the two papers in Lancet and the New England Journal that had to be retracted that were large database studies as well.

The quality of the underlying data remains paramount. That, of course, is where a lot of the elbow grease comes in. It's not just in the ascertainment of the events, but a lot of the stuff that leads up to counting the events at the end of the study.

Greg Hundley: Well, listeners, this has been just a superb discussion. On behalf of Carolyn and myself, we wish you another great week and look forward to catching you on the run next week. Take care.

This program is copyright, the American Heart Association 2020.

Circulation July 14, 2020 Issue

13 juli 2020 | 26 min

Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Greg, today's speaker paper is really special on a number of levels. First, it's a research letter and secondly, it's actually basic science. Now, this tells you it's got to be really special. Well, I'll just give you a hint. It talks about a new therapy for stroke. I'm going to leave it at that, leave you guessing because you've got to hang on as we tell you about the rest of the issue and then listen to the feature discussion. Now, the first original paper here, I want to describe as a basic paper focusing on PDE4B in heart failure.

Dr Greg Hundley: All right, Carolyn, I'm not even going to let you start to quiz me on this. Can you tell me what in the world is PDE4B?

Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really represent a highly diverse super family of enzymes among which PDE3 and PDE4 are the main phosphodiesterases that degrading cyclic AMP with a high affinity in the heart. The cyclic AMP hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key negative regulator of cardiac beta-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal calcium handling and PDE4B is decreased in pressure overload hypertrophy suggesting that increasing PDE4B in the heart may be beneficial in heart failure. These authors led by Dr Vandecasteele from Inserm tested this hypothesis in elegant experiments involving both human cardiac tissues and transgenic mouse lines.

Dr Greg Hundley: Carolyn, that was just a wonderful explanation and I really learned about these phosphodiesterases. Now, tell me what did they find in their study?

Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was decreased in human failing hearts. Cardiac over expression of PDE4B in mice, resulting in a 15-fold increase in cyclic AMP hydrolysis decreased cardiac contraction and protected against the cardiotoxic effects of chronic beta-adrenergic stimulation. Whereas transgenic mice with a 50-fold increase in cardiac cyclic AMP hydrolysis underwent maladaptive remodeling. Furthermore, cardiac PDE4B gene transfer with serotype nine adeno associated viruses resulted in a significantly lower increase in cardiac PDE4B and protected against chronic catecholamine stimulation and transaortic constriction without depressing basal cardiac function. These results overall suggest that a moderate increase in cardiac PDE4B is beneficial to counteract the detrimental effects of excessive sympathetic system activation in heart failure and increase in PDE4B in the human heart could be achieved by gene therapy with adeno associated viruses or by using recently developed small molecules with PDE4 activating properties.

Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps this'll work its way into heart failure management. Well, my study, our first study to describe involves the comparative efficacy and safety of oral P2Y12 inhibitors and acute coronary syndromes. It's a meta-analysis of 52,816 patients from 12 randomized trials. It comes to us from Professor Eliano Navarese from Nicholas Copernicus University. All right, Carolyn, here's your quiz. Have you wondered which PGY inhibitor is optimal for reducing risk of adverse cardiovascular events?

Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered, but you're going to tell us the results.

Dr Greg Hundley: It's getting harder and harder to trip you up Carolyn. Very clever, okay. This study aims to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in acute coronary syndrome by meta-analysis of 12 randomized clinical trials. Again, involving those 52,816 patients with ACS.

Dr Carolyn Lam: Wow. What did they find Greg?

Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly reduced cardiovascular mortality and all-cause mortality. Whereas there was no statistically significant mortality reduction with prasugrel.

Dr Greg Hundley: Next, compared with each other there were no significant differences in mortality with prasugrel versus ticagrelor. In addition, compared with clopidogrel, prasugrel reduced myocardial infarction, whereas ticagrelor showed no risk reduction.

Dr Greg Hundley: Now stint thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel. Compared with clopidogrel, both prasugrel and ticagrelor significantly increased major bleeding. There was no significant difference between prasugrel and ticagrelor for all outcomes explored.

Dr Carolyn Lam: Summarize that for us.

Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced ischemic events, but increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. So a really nice summary evaluating these P2Y12 inhibitors,

Dr Carolyn Lam: Indeed. Question for you, Greg, what is the prevalence of deep venous thrombosis, a DVT and its risk factors, prognosis and potential prophylaxis strategies for hospitalized patients with COVID-19? That's what the next paper is about. It is a single center observational study of 143 hospitalized patients confirmed of COVID-19. And this is from co-corresponding authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher Hospital for Children in Philadelphia, United States, they found that DVT was found in a high percentage of these patients. Forty-six percent of the 143 patients and was associated with adverse outcomes with CURB-65 score three to five. Padua prediction score four a more and D-dimer greater than one microgram per mil, which in combination predicted DVT with a sensitivity of more than 88.5%. Thrombo prophylaxis was associated with lower DVT in a subgroup of patients with high Padua prediction score.

Dr Greg Hundley: Now, what does this mean for all of us in this era of COVID-19?

Dr Carolyn Lam: So this suggests that DVT is more common in hospitalized patients with COVID-19. So ultrasound screening of high-risk patients, as I mentioned before, may be indicated for the more prevention of DVT with low molecular weight heparins in high risk patients, such as those with a high Padua prediction scores may reduce DVT in hospitalized patients with COVID-19. Of course more work needs to be done, but a very interesting paper.

Dr Greg Hundley: What a fantastic description. Well, my next paper is more from the world of basic science and involves phosphodiesterase 3A in arterial hypertension and comes to us from Dr Enno Klussmann from the Max Delbruck Center for Molecular Medicine. So Carolyn, autosomal dominant hypertension with brachydactyly clinically resembles salt resistant, essential hypertension and causes death by stroke before the age of 50 years. So in this study, the authors use genetic mapping, sequencing, transgenic technology, CRISPR-CAS based nine gene editing, immunoblotting, and fluorescence resonance energy transfer to identify new patients perform extensive animal phenotyping and explore new signaling pathways related to hypertension with brachydactyly.

Dr Carolyn Lam: Wow. So what did they find, Greg?

Dr Greg Hundley: Well, Carolyn, the authors described a novel mutation within a 15 BP region of the PDE3A gene, and define this segment as a mutational hotspot in hypertension with brachydactyly, the mutations cause an increase in enzyme activity, a CRISPR-Cas9 generated rat model with a nine BP deletion within the hotspot analogous to human deletion recapitulated the hypertension with brachydactyly in mice, mutant, transgenic PDE3A over expression and smooth muscle cells confirmed that mutant PDE3A caused hypertension. The afferent signaling found in these models was associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.

Dr Carolyn Lam: Gosh, so what are the clinical implications? Greg?

Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance and cause hypertension. These authors presented two new animal models that serve to elucidate these underlying mechanisms further, and their findings could facilitate the search for new anti-hypertensive treatments.

Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually one we've already discussed in our special COVID-19 edition and that was aired on 22nd, May, 2020. That's the paper from Dr Poissy and Susen from University Lille in Inserm, and they reported a case-series of COVID-19 patients with pulmonary embolism in their institution of Lille University Hospital. So, please everybody remembers to tune in to that as a refresher. Also in today's journal, the issue of COVID-19 coagulopathy in venous thromboembolism is further discussed in an editorial by Dr Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more about other papers in this week's issue. There are letters to the editor from Dr Mueller and from Dr Gulati all about the paper incidents, trends and outcomes of type two myocardial infarction in the community cohort. There's a letter from Dr Siontis on the blood pressure myocardial infarction paradox.

Dr Carolyn Lam: Does hypertension exert a protective effect in type two MI? In the ECG challenge Dr Di Cosola talks about the high, the low end, the narrow QRS in a peripartum cardiomyopathy. There's an online mind piece by Dr Kohli entitled surfing the waves of the COVID-19 pandemic as a cardiovascular clinician, a perspective piece by Dr Albert titled "The Heart of the Matter Unmasking and Addressing COVID-19's Toll on Diverse Populations". In Paths the Discovery series, Dr Rutherford talks about serial innovation to bring transformative precision medicines to people with serious diseases. And this is a conversation with Dr Jeffrey Leiden.

Dr Greg Hundley: Very nice. Carolyn, I've got a couple other papers to discuss similar to your paper on DVT, Professor Lin Cai has a research letter involving the extremely high incidents of lower extremity, deep venous thrombosis in 48 patients with severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum Saeed from University of Pittsburgh discusses reinforcing cardiology training during a pandemic. It's an open letter to our leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads to major changes for cardiologists in training. And then finally, Dr Stephen Archer from Queens University provides a nice perspective on differentiating COVID-19 pneumonia from ARDS and high-altitude pulmonary edema, and what are the therapeutic implications. And now Carolyn, how about we get onto that feature discussion, one of the unusual times where we emphasize an important point in a research letter?

Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I think one of the most impactful, basic science papers we have, and that is why we're discussing it. I am so pleased to have the first author Dr Luca Liberale from University of Zurich, as well as Dr Peipei Ping associate editor from UCLA. So welcome both. Luca, I really need your help here. Can you please explain what your experiment was and your main findings?

Dr Luca Liberale: We really happy that we could set up an experiment design, which has some kind of translation of value. So, differently from any other set up involving the tandem middle cerebral artery occlusion, which is among the most used model for ischemic stroke in basic science. In this case, the treatment is done post-ishchemically. So the mice received the neutralizing antibody against IL-1α only after they scan making salts. And we specifically thought to duties to keep the translational relevant side. As I said before, and trying to mirror the case of a patient, we think come have a stroke that goes to the emergency department, and he is eligible for revascularization therapy. And together with this revascularization therapy being at EPA or whatever for it, it received is also the kind of anti-IL-1α treatment. And another good translation of relevancy we thought this may have is that identifying of IL-1α antibody is already available in the market and being in many phase three trial. So we thought this is a ready to go, ready for the translation from the bench to the bedside, as we used to say.

Dr Carolyn Lam: It's just so interesting because when we think about ischemic stroke, you know, we think about thrombolysis as practically the only thing we can do, and forgive me I'm not in neurologist here, but this is so unique to go with an anti-inflammatory mechanism. Now, when you see that this neutralizing antibody is currently in use, do you mean in cancer in other diseases?

Dr Luca Liberale: Mainly it's cancer, but it's also other dermatological diseases. It's not only cancer, but oh yes, definitely. Cancer is one of the major fields of its application.

Dr Carolyn Lam: Wow. So with that very interesting background, could you tell us about the experiment and what you found?

Dr Luca Liberale: What we found is that after inducing ischemia in the animal for 45 minutes, we let them reperfuse for 48 hours during which the animal are under the treatment. So they received a bolus of anti-IL-1α immediately at the time of reperfusion. So when we take out from the carotid artery, the filament, and they received these volumes and they are let survive for 48 hours. So they are free to go in the cage, to seek drinks. After 48 hours, we assessed the neurological deficit and we sacrifice the animal to assess the stroke size by using the quite common PTC staining. And what we could find is that indeed the treatment with the higher dose, because we use two doses, and we could see a dose response, could that reduce the stroke size by 36% as compared to the treatment with the isotype control. And this went together with a significant reduction in that neurological impairment. So it's not only an experimental reduction, but it's also physiologically relevant for the animals.

Dr Carolyn Lam: That really is incredible, and the way you manage to convey such a lot of data in a research letters is also remarkable. So, to the audience, you have to pick this up. It's a succinct read, just this one central figure that tells the whole story, and you're about to hear from Dr Ping. Dear Peipei, if you could tell us what the significance of this paper is, maybe some of the discussions that occurred behind the doors, so to speak among the editors.

Dr Peipei Ping: We were super impressed with the fundamental message of the submitted report. Carolyn, as you are fully aware, most ischemic studies speed that in the heart or in a brain model, often select mechanisms that must be activated pre the event you bent of ischemia to induce a protective effect, a neurological protective effect in stroke or cardioprotective effect in the heart. So, as an associate editor who spent her entire 30 years career in this area of study, we often fascinated about the sentencing or the naiveness of the basic scientists in this area. Because you would have to plan an ischemia in the patient knowing when that to happen. And then before that happens, activate all these beautiful signaling and mechanisms, everything you have generated to prevent that ischemia. So the search for the possible mechanistic understanding of a post-ischemic event rescue mechanism has been going on for decades. And it's very, very challenging, Carolyn.

Dr Peipei Ping: The beauty of the study is it utilized already in clinical trial, existing human antibody inhibitor, interleukin alpha-one antibody. You said antibody. So the reagent is already bile approved. Then examine very carefully in a post-ischemic fashion to see how relevant that agent in a time window reasonable to rescue ischemic injury. You can already tell from Lucas introduction; the results are profound, and it has stimulated many discussions in the field. It's very relevant to clinical center piece, even though it's still at that translational stage. So we saw this as a beautiful representation of how clinicians and scientists capable of not only bring something from the bench to the clinic or the clinic or to the bench. This is something comes to a full circle. It went from clinic where the reagent was used and created for something to the bench, understanding mechanistic insight, have a beautiful animal of human disease stroke model to test them and then take it to the clinic again.

Dr Carolyn Lam: Goodness, Peipei. I love the way you put that. I actually didn't see that Luc[a], till you put it that way. I do have a couple of questions for Luca though. I understand you made it very clear in your paper that the human monoclonal antibody is in clinical use, but in this experiment, you had to use the rodent equivalent because the human antibody doesn't block the rodent IL-1α, which is very reasonable. But then it brings the question, how closely does this rodent model recapitulate thrombotic ischemic, or a stroke in humans? I mean, what do you think?

Dr Luca Liberale: Well, what we see when we use our usual approach, this is a model that we're using in our center for molecular cardiology here in Zurich, and this been used in that specific group of Professor Ameche for many years. And this is usually quite well accepted as a model. So that, that the timeframe is 45 minutes of ischemia and 48 hours of reperfusion. I'll got to quite mirror the acute phase of an acute ischemic stroke, which is actually where we think that the inflammatory pathways can play the major roles. Also. I mean, everybody of us know that the recent anti-inflammatory trials confirmed this, that reducing the inflammation and the inflammatory pathways is good but can also be harmful.

Dr Luca Liberale: So in the case, we can use an approach, which is limited in the time, maybe really close to that acute phase, really during the acute rates goes to the acute event. Well, maybe this can be quite useful and quite a translationally relevant that prolongs inactivation of such pathways as result. They can ask some for, so the balance in between the benefits and the harms cannot be that clear, can, I mean, needs to be quite well addressed.

Dr Carolyn Lam: And that actually brings me to the next question. You know, the word translational has been mentioned quite a number of times here. So can you give us a sneak-peak on what the translational plans that your team may have? What's the next steps?

Dr Luca Liberale: The next steps now is back to the company. So our basic findings are here. They will be published soon, and now it's all about the clinical scientist, and how they want to implement these basic findings into the clinic.

Dr Carolyn Lam: So target engagement and mechanistic information as well. Peipei, could I just give you the last word, if you don't mind, maybe a bit of a cheeky question. What would you have loved to see in this paper or in a subsequent paper that offers a step closer to translation?

Dr Peipei Ping: I think this study has shown most necessary components as a basic science research paper. I think the next level closer to the translation as Luca has already alluded to, has to do with both efficacy studies, as well as safety studies, and those actually would need to be done in the clinic because the mouse model. I think it's a fantastic model to offer these lines of information. Ischemic-wise I think it's very strong and translational value is very high and that was the predominant reason we voted to accept the paper. As you know, the accept and raise of circulation is very, very low as our bar is very high.

Dr Carolyn Lam: Very nice. So target engagement and mechanistic information as well. Congratulations, Luca. Thank you so much Peipei for your great comments. Now, listeners, you heard it first time here on Circulation on the Run. Thank you for joining us today.

Dr Greg Hundley: This program is copyright at the American Heart Association, 2020.

Circulation July 7, 2020 Issue

6 juli 2020 | 24 min

Dr Carolyn Lam: Well, the Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature involves the Compass trial, and we'll be talking about a comparison of low-dose rivaroxaban plus aspirin compared to aspirin alone in patients with chronic vascular disease. But before we get to that, how about if we break away and discuss a few other papers. And I'll go first this time, because this week we're going to introduce another new feature in addition to Carolyn's Quiz.

Dr Carolyn Lam: Wait a minute. This was not on the script. What's going on, Greg?

Dr Greg Hundley: It's on the script!

Carolyn, let me get to my first paper. It's from Professor Junling Liu from Shanghai Jiao Tong University School of Medicine, and it involves branched-chain amino acid catabolism and how that may promote thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.

But first, we've got a new feature to add to Carolyn's Quiz. It's called Way or No Way.

Dr Carolyn Lam: Just so everybody knows. This was a one-way decision to add this new component of Carolyn's Quiz, but okay, I'm all for it. Go, Greg!

Dr Greg Hundley: Okay. All right. It's a fast, quick question where our listeners seek your guidance regarding an important scientific discovery from one of our published manuscripts. Are you ready?

Dr Carolyn Lam: No.

Dr Greg Hundley: Okay. Here's your question. Do branched-chain amino acids promote arterial thrombosis. Way or no way?

Dr Carolyn Lam: Maybe?

Dr Greg Hundley: Okay, Carolyn.

Dr Carolyn Lam: I have a feeling you're going to tell us yes, although I wouldn't have guessed that straight away.

Dr Greg Hundley: Okay. Remember that branched-chain amino acids are essential nutrients, including leucine, isoleucine, and valine, and they serve as a resource for energy production and the regulator of important nutrient and metabolic signals.

In this study, the activity of human platelets from healthy subjects before and after ingestion of branched-chain amino acids were measured. PP2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation.

Dr Carolyn Lam: Now okay, okay. So what did they find? Way or no way?

Dr Greg Hundley: Ingestion of branched-chain amino acids significantly enhanced the activity of platelets in response to agonists and increased the risk of arterial thrombosis. The branched-chain amino acid catabolic pathway-driven propionylation of tropomodulin-3 at K255 was found to be an important mechanism underlying the branched-chain amino acid-facilitated platelet activation, and elevated levels of branched-chain amino acids and enhanced expression of positive regulators of branched-chain amino acid catabolism in platelets were found probably responsible for the high platelet activity in type 2 diabetes mellitus.

Dr Carolyn Lam: Very interesting. So yes, it is possible. And what is the clinical implications?

Dr Greg Hundley: Right, Carolyn. Branched-chain amino acids, or their catabolites, enhance the risk of arterial thrombosis in small animals, and perhaps future human subject studies, that restrict branched-chain amino acid intake or target branched-chain amino acid catabolism may serve as a novel strategy for anti-thrombosis therapy.

Dr Carolyn Lam: Interesting. Okay, Greg. Here you go. Question for me. Have you heard of Home Time?

Dr Greg Hundley: Home Time? Yes. Home Time. It's not like time out for our kids, but we've been having a lot of Home Time in this COVID-19 with our families.

Dr Carolyn Lam: All right. Touché. Touché. Home Time! Did you know it is a patient-centered outcome measure that accounts for rehospitalization mortality and post-discharge care? In the paper I want to talk about, Dr Pandey from UT Southwestern and colleagues aim to characterize risk-adjusted 30-day Home Time in patients with acute myocardial infarction as a hospital-level performance metric, and to evaluate associations with risk-standardized readmission rates. The study included almost 985,000 patients with AMI hospitalization across almost 2,400 hospitals between 2009 and 2015 derived from a hundred percent of Medicare claims data. And they found that 30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varied across hospitals, was associated with post-discharge readmission and mortality outcomes, and meaningfully reclassified hospital performance compared with the 30-day readmission and mortality metric.

Dr Greg Hundley: Very nice, Carolyn. Well, I'm coming back at you again with another quiz. But first, this paper is from Kamal Khabbaz from Beth Israel Deaconess Medical Center and the Harvard Medical School, and it's going to assess whether left atrial appendage closure or exclusion during bypass surgery has impact on short-term outcomes.

So, Carolyn, here's your quiz. Do you think that patients receiving CABG with atrial fibrillation should undergo ligation of their left atrial appendage?

Dr Carolyn Lam: Well, I think there's definitely equipoise there. On the one hand, you're already in a surgery. Why not just ligate it? It's not like we need a left atrial appendage. And then on the other hand, I suppose it extends the surgery, it involves some risk, and we don't know if it actually prevents further events. Did I answer that right?

Dr Greg Hundley: Yes. Quite the politically correct answer, I think. Now, the objective of this study was to evaluate the impact of left atrial appendage exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. The study analyzed 250,287 CABG patients, of whom 7% received left atrial appendage closure. Only patients with a history of atrial fibrillation were included in the analysis, and the primary outcome was 30-day readmissions following discharge. Secondary outcomes included hospital mortality and stroke. And to assess the postoperative outcomes, the team utilized multivariable logistic regression models, and they adjusted for clinical and demographic co-variables.

Dr Carolyn Lam: Great. So what did they find, Greg?

Dr Greg Hundley: Okay. Couple of conclusions. First, left atrial appendage exclusion was associated with a greater risk of postoperative respiratory failure, acute kidney injury, but it did not significantly change the rate of blood transfusions or the occurrence of cardiac tamponade. Second, left atrial appendage exclusion was associated with a nonsignificant reduction in stroke, no difference in in-hospital mortality, and a greater risk of 30-day readmissions. Number three, after adjusting for these co-variables, left atrial appendage ligation remained a significant predictor of this 30-day readmissions. And so, Carolyn, in this study, it looks like left atrial appendage exclusion during isolated CABG in patients with AFib is associated with a higher rate of 30-day readmissions.

Dr Carolyn Lam: Thanks, Greg. Well, let me talk about what else is in this issue. First is a pair of letters, one from Kai Wu regarding the article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared to Men With HFpEF: Insights From PARAGON-HF" and the response from Dr John McMurry. There are also two On My Mind pieces, one entitled "COVID-19 Arrhythmic Risk and Inflammation: Mind the Gap" by Dr Lazzerini, and another entitled, "Obesity, A Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms" by Dr Naveed Sattar.

There are two perspective pieces, "Establishment and Management of Mechanical Circulatory Support During COVID-19 Pandemic" by Dr Pham, and "The COVID-19 Pandemic: A Global Natural Experiment" by Dr Blake Thomson. There's an in-depth paper entitled "The Science Underlying COVID-19: Implications for the Cardiovascular System" by Dr Peter Liu. This is important. This one's an editor's pick, so don't forget to read this.

There's an ECG challenge by Dr Praveen Gupta on "Chest Pain with ST Elevation: Looking Behind the Masquerade." In Cardiology News by Tracy Hampton, she reviews the literature and highlights three papers, one, "A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors" in Cell 2020; two, "Noninvasive Localization of Cardiac Arrhythmias Using Electromechanical Wave Imaging" in Science and Translational Medicine 2020; and three, "Somatic Gene Editing Ameliorates Skeletal and Cardiac Muscle Failure in Pig and Human Models of Duchenne Muscular Dystrophy", and that in Nature Medicine 2020.

For the President's Page, we have a piece by Keith Churchill, who's the Executive Vice President and CEO of Yale New Haven Hospital entitled "The Compelling Need to Address Uncertainty, Anxiety, and Financial Peril for Patients".

There's Highlights from Circulation Family of Journals by Sara O'Brien, including "Factors Associated With Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results From the ORBIT-AF" from Circulation Arrhythmia and Electrophysiology. There's "Association Between Sleep Disordered Breathing and Left Ventricular Function: A Cross-Sectional Analysis of the ECHO-SOL Ancillary Study" from Circulation Cardiovascular Imaging. There's also "The Impact of a 10 Rules Protocol on COVID-19 Hospital-Related Transmission: Insights from Padua University Hospital in Italy" from Circulation Cardiovascular Interventions. There's "The Association of an AMI Readmission-Reduction Program with Mortality and Readmission" from Circulation Cardiovascular Qualities and Outcomes. And finally, "Treatment Differences in Chronic Heart Failure Patients with Reduced Ejection Fraction According to Blood Pressure" in Check HF, and that's in Circulation Heart Failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a few Research Letters that I reviewed. First is from Professor Puck Peltenburg, and the Research Letter involves children and adolescents from Brugada syndrome families in which only the SCN5A mutation carriers develop a type one ECG pattern induced by fever. And the second research letter is from Dr David Saadoun, and this evaluates the long-term outcome and prognosis factors associated with isolated aortitis. And then finally, Carolyn, there's a very nice piece related to the current status of cardiovascular medicine in Israel from Professor Ran Kornowski at the Rabin Medical Center.

Well, Carolyn, what a packed issue we have, and how about now we get on to that feature discussion?

Dr Carolyn Lam: Let's go, Greg.

Dr Greg Hundley: Well, listeners, we have a wonderful feature discussion for you in this next segment. We have Professor Keith Fox from Edinburgh and our own associate editor, Professor Stefan James from Uppsala. And we're going to discuss anticoagulation and antiplatelet therapy and rivaroxaban and aspirin and results from the COMPASS trial.

Keith, could you tell us what was the background information and what was the hypothesis that you wanted to test with your study?

Professor Keith Fox: The hypothesis was whether the combination of a very small dose, a quarter of the dose tested here, of a NOAC alongside an antiplatelet would be superior to aspirin alone, or we also tested a half dose of the NOAC by itself. And the overall trial showed that the quarter dose of rivaroxaban plus aspirin was substantially superior to aspirin alone in preventing cardiovascular death, MI, and stroke, with its biggest impact on strokes and cardiovascular death. So that's the trial as a whole.

But our specific goal here was to look at the question of net clinical benefit because clinicians are challenged by any therapy that has a balance of both potential hazard, like bleeding risk, and benefit. So what we analyzed here were the pre-specified characteristics of net clinical benefit in terms of life-threatening and major bleeding into a critical organ, plus cardiovascular death, MI, and stroke. And I asked the question, what was the net clinical benefit?

Dr Greg Hundley: Net clinical benefit. Now, tell us a little bit about what population you were looking to understand net clinical benefit, and then what was the study design?

Professor Keith Fox: This is the whole of the COMPASS trial without the arm that tested rivaroxaban alone, because that did not show significant benefit. So this is the remaining 18,000 patients, double-blind randomized trial. And the trial, as a whole, was stopped early on the recommendation of the DSMB because it met the criteria for benefit by four standard deviations. Now, what's unusual about this is the population of our patients and vascular risk. So these are people who in the past would just be treated with aspirin. So they're not post-MI. They are people with chronic vascular disease, either peripheral or coronary. And in the past, on top of standard secondary prevention care, they would only have got aspirin.

Dr Greg Hundley: And what were the results?

Professor Keith Fox: There was a 20% reduction in terms of the net clinical benefit favoring the combination of rivaroxaban and aspirin, and that net clinical benefit being the combined impact of cardiovascular death, MI, stroke, fatal bleeding, or bleeding into a critical organ.

Dr Greg Hundley: And did you find the same results in, for example, older versus some of the younger patients? Or were there any other high-risk subgroups, those with impaired renal function or those with heart failure where you saw particular differences?

Professor Keith Fox: Yes, Greg. This is a really important issue. If one looked at the whole trial, the number needed to treat to prevent one of these adverse events, N equals 52. But then if we looked at some of the higher-risk cohorts, which we defined prospectively ... For example, these were the risk factors like polyvascular disease, impaired renal function, ambulant heart failure, or diabetes. And if you had all four risk factors, the number needed to treat was nine. If you had three risk factors, it was 12. Two risk factors, 31. So I think there's clearly a message for clinicians to be able to identify people with a combination of these risk factors, one or more, in order to get the most benefit and the least hazard.

Dr Greg Hundley: Very interesting. Any speculation on mechanism?

Professor Keith Fox: Yes. One of the things that we've done in the past is we've hammered one antithrombotic pathway. Like, for example, we've used more and more potent anti-platelets or combination of anti-platelets. But perhaps one of the things that we've forgotten is the fact that the platelet activation pathway is triggered by thrombin activation and vice versa. So the concept that was new behind the whole COMPASS study was that augmentation of the antithrombotic effects by combining a very small dose of a novel anticoagulant would be beneficial. And the critical question is, would it be sufficiently beneficial without producing a lot of bleeding? So that's why we did this particular analysis.

Dr Greg Hundley: So lower doses of some of these drugs. Well, Stefan, can you help us put these study results into context with what we know today about using aspirin alone, rivaroxaban, et cetera?

Professor Stefan James: The reason I think this study's so important and interesting is that, first, it's a very common population that we see now in the practice, patients with a stable phase of atherosclerotic disease, both coronary and peripheral vascular. And we need to take care of these patients better. Until now, we have not had very great alternatives for these patients. Now, we've learned what Keith said, that if you combine a low dose of both anti-platelet and antithrombin, you can inhibit and reduce the risk of ischemic events. And the other important finding here is that, I think conceptually very interesting, that if you are able to reduce their number of ischemic complications or thrombotic complications, but not doing that to such an extent that bleeding increases too much, not to an extent that bleeding causes fatal events, then you can find a nice balance between safety and efficacy that can lead to substantial reductions and improvements in terms of the clinical benefit.

And that's what we see here in this trial. You can see that there is a reduction of thrombotic events, ischemic events, and there is also some bleeding, but not to such an extent that it affects overall survival and the overall event rate in these patients. And particularly in patients at high risk that you pointed out, these patients have a very high event rate. Although the relative benefit is similar, the absolute benefit is quite impressive.

Dr Greg Hundley: Just very exciting to me. Very low doses of some of these common drugs. What's the next study in this field, Keith?

Professor Keith Fox: We've got a big gap because we know that modern dual antiplatelet therapy works really well after an acute coronary syndrome and it's highly effective. In the longer term, we know, for example, from some of the studies with ticagrelor that there are cohorts that do well for a period of time after ACS, but really we don't know the bridge between this period and the long term and what role this therapy may have after essential dual antiplatelet therapy.

Dr Greg Hundley: Stefan, do you have any thoughts?

Professor Stefan James: I agree with Keith. This transition period, when is patient transitioned from being an acute coronary syndrome patient to a chronic coronary syndrome patient? When does that happen? And then probably it differs between individuals and type of events, and so we need to understand more of when is this patient acutely affected and when do we need potent dual antiplatelet therapy? And when can we transition to a more stable phase in which we can inhibit thrombotic events, ischemic events, but not increased bleeding to such a degree that it affects overall survival? And so I think we need to learn a lot more about that transition period and these subgroups of patients of different risks and risks of ischemic events and bleeding events.

Dr Greg Hundley: Keith, how would you go about conducting a study in that regard?

Professor Keith Fox: I think really one of the very interesting questions is whether the combination of the standard of care of, for example, aspirin and ticagrelor may be better, worse, or the same than this therapy instituted at the end of the period of essential dual antiplatelet therapy. And we need to know that.

Dr Greg Hundley: In closing and summing up, Keith, are there any concepts that we want to take home here?

Professor Keith Fox: I think that there are two key concepts. One is the synergy between the anticoagulation system and the antiplatelet system, with the potential to use very low doses, to minimize bleeding risk, yet have the benefits. That is the first concept. The second concept is that these chronic vascular disease patients Stefan has described are at continuing risk of vascular events, especially stroke, myocardial infarction, and cardiovascular death. And these can be modified.

Dr Greg Hundley: And Stefan, any thoughts from you in closing?

Professor Stefan James: I think this paper and the work that Keith has described is fantastic and fascinating to think about because these populations are incredibly large, and they are not doing well. They have a high risk of events, and we tend to forget that, and so we need to both identify them and start treating them now, as we have some evidence, but we'll also need to learn more of how to identify them, how to select them appropriately, and how to identify the transition from acute events to chronic events or current chronic phase of the disease.

Dr Greg Hundley: Well, listeners, I want to thank both Professor Keith Fox and our own associate editor, Professor Stefan James, for this very interesting presentation of lower doses of anticoagulant and antiplatelet therapy in patients with chronic vascular disease and really being able to reduce events and diminish bleeding.

On behalf of Carolyn and myself, we want to wish you a great week and look forward to catching you next week. Take care.

This program is copyright of the American Heart Association 2020.

Circulation on the Run: Special Conversation with Former and Current Editors-in-Chief of Circulation

29 juni 2020 | 16 min

This week’s episode is special: we have the former and current Editors-in-Chief of Circulation on Circulation on the Run. Join Dr Amit Khera, Digital Strategies Editor of Circulation, as he speaks with Dr James T. Willerson, Editor-in-Chief from 1993 to 2004; Dr Joseph Loscalzo, Editor-in-Chief from 2004 to 2016; and Dr Joseph A. Hill, the current Editor-in-Chief. They will discuss the history of Circulation and how it continues to evolve.

TRANSCRIPT

Dr Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation from UT Southwestern Medical Center in Dallas. Today we have a very special Circulation on the Run. We have three Editors-in-Chief from Circulation. First, we have Dr James Willerson, who was the Editor-in-Chief from 1993 to 2004. He's a President Emeritus at the Texas Heart Institute. We also have Dr Joseph Loscalzo, who was Editor-in-Chief from 2004 to 2016, the Chairman of Department of Medicine from Brigham and Women's Hospital. And finally, Dr Joseph Hill, the current Editor-in-Chief, the Chief of Cardiology at UT Southwestern Medical Center. Welcome, gentlemen.

Dr Joseph Hill: Thank you.

Dr James Willerson: Thank you.

Dr Joseph Loscalzo: Thank you.

Dr Amit Khera: Dr Willerson, I must say, looking over the tenure prior to Dr Loscalzo, you had one of the longest tenures ever as Editor-in-Chief of Circulation, and certainly a lot happened in the practice of cardiology during that period. It was a really formative period in cardiology. As you think back, what were some of the most important topics that you covered during that time as Editor-in-Chief, thinking about the evolution of cardiovascular care and science at that time?

Dr James Willerson: You have to remember, there have been many editors at Circulation. We all build on the shoulders of others, certainly I did. I really wanted Circulation to be the premier cardiovascular journal in the world. I wanted it to be much like the New England Journal of Medicine, but the New England Journal of Medicine Circulation of Cardiology. I wanted to publish it every week. We got permission to do that. That wasn't easy, but we were fortunate. I've been accused of wanting to publish it every day. There's actually some truth to that. I didn't make that. I didn't try very hard. I wanted to be able to present the information, important information, to everybody who cared about cardiovascular medicine: physicians, scientists, students, nurses, those who cared for people, and I wanted to do it frequently. I wanted to publish it quickly. So, we had some success with that. There are many other things that are well-known to the other editors, all of whom have built before me and after me, and I'm very proud of them.

Dr Amit Khera: Well, thanks for that. And certainly, as you pointed out, this has been an evolution where you took the gauntlet, if you will, from the people before you, and then built on that and had many advances. I guess after you, Dr Loscalzo, you I think did have the longest tenure if I saw of any of the editors and similarly, a lot of evolutions in cardiovascular care and a lot in science, particularly during your time. Tell us a little bit about any particular papers or topics that you focused on, or that really were revolutionary in the cardiovascular space during your tenure.

Dr Joseph Loscalzo: I'll pick up where Jim left off and just make the case that as you're suggesting, I mean, there's sort of been a natural transition of the kind of science that Circulation has been publishing over the tenure of the three editors here today. Before Dr Willerson, it was largely physiology and excellent clinical science. Jim really expanded the scope of what Circulation published to begin to put in press in its pages, fairly basic and translational science as well. I picked up from what he'd laid the groundwork for to expand the scope of that science. And as you know, expand it to the point that we had to develop daughter journals that would pick up the mantle in each of these increasingly subspecialized areas.

So, it's hard to think about those papers that I found have the greatest impact because every field had several of them in my several years as editor. As you know, the subspecialty journals that we established, which remain active to the current time, are also broad in their scope from outcomes based research to genomics and proteomics insistence, cardiovascular medicine, to everything in between, imaging, intervention, heart failure, and electrophysiology to arrhythmias. Each of these was led, and continues to be led, by outstanding leaders in their subspecialty fields.

I think the beauty of Circulation in contrast to even fine journals like the New England Journal of Medicine, is that Circulation has been able to put on its pages those studies that really do span quite a spectrum. We don't shy away from very basic studies. That actually began with Jim, I must say, because that wasn't the case previously. And of course, we move right through to epidemiology and outcomes based research. And the impacts have been broad in each of those fields, as witnessed by the excitement and uptake of the journal, measured however you wish, by impact factor, or citations, or the frequency with which it's referred to in the lay press. So, I think that tradition certainly continues under the current editor with papers of extraordinary impact.

Dr Amit Khera: Thanks for that. I think your point about the evolution of science over time from Dr Willerson and certainly during your tenure and beyond to the breadth of Circulation currently. You also touched on the subspecialty journals. That happened in your watch and that was quite a marked change in cardiovascular medicine to have that explosion of new journals, if you will. What do you think the impact of those subspecialty journals has been for the cardiovascular field?

Dr Joseph Loscalzo: We struggled with the idea about whether or not we should pursue that kind of fragmentation. What really pushed us was the fact that the acceptance rate remains quite low, in those days, probably eight or so percent range at its nadir. So, we were rejecting a lot of really excellent papers which wound up in competitor journal pages, that we would like to have accepted and been given the scrutiny of the careful reviews and editorials that accompany papers accepted by Circulation. We felt the best way to do that under the circumstances was to create these daughter journals. They succeeded, in many respects, beyond our wildest imagination. The numbers of papers that were published in the family increased, I think in the first two or three years, by at least 2-to 3000.

So, that really speaks to the fact that we kept the best papers in the family. We gave them the right kind of audience. Some of these would have been too technical or too highly specialized to have been published in Circulation proper, but certainly of the highest quality and of significant relevance to the subspecialist. So, we think that it was a successful experiment. Now it's sort of become tradition. I think that the question that will always come up, of course, is can we fragment things more? I would say one of the best reasons to make the case that this was a successful experiment is that if imitation's the sincerest form of flattery, the New England Journal is now going to start three subspecialty journals. In fact, in my role now as an editor of the New England Journal, editor-at-large, they asked my input in how to design those daughter journals and what to expect from them.

Dr Amit Khera: Well, I think that's a great point. It certainly has been a resounding success and as you pointed out, imitation is the best form of flattery. I'm going to pivot now to Joe Hill. Dr Hill, you have certainly been the beneficiary of all the great work that these two editors have done in the past. You've inherited a very successful journal and also have crafted your own vision for where you want Circulation to go in your mark. Tell us a little bit about some of the new initiatives you've tried to implement, leveraging on these past successes.

Dr Joseph Hill: Thank you, Amit, it's an honor and a privilege to be in this conversation, frankly. I mean, Dr Willerson made this a weekly journal. That was back in the day when FedExes were flying around. Everything was paper. That kind of volume with that technology is impressive. And Dr Loscalzo, who has been a friend and mentor for many, many years, spearheaded the subspecialty journals, as we just heard, and took the journal to yet new heights. Each of you has been a pioneer and we've been fortunate to put together a team that I think has moved in exciting directions. We've leveraged technology now, such that we have our video conference meetings. We meet in a video conference with editors from 17 different countries. We have a third of our editors in Dallas, where I live, a third in the US outside of Dallas, and another third in 16 other countries.

It turns out we alternate the time of that meeting each week because there's no single hour of the day that works around the globe, so we move it around to capture Asia or to capture California in alternating weeks. That has been a thrill and, honestly, I believe a robust success. We have leaders on the ground in all these different countries. We have a highly diverse team across the different subspecialty domains of cardiology, across different geographic regions, across race and sex and gender lines. It is an amazing team. And Amit, who leads our robust digital efforts, including this podcast and our efforts on social media, again, the opportunity now in the 21st century to take these initiatives forward has been a real privilege.

Dr Amit Khera: It's ironic that Circulation was doing Zoom before everybody else was in the modern era. I'm going to pivot back to Dr Willerson. As Dr Hill just mentioned during your tenure how the volume of papers was handled, FedEx and sort of the nature of the journal publishing process. And now in the modern era, we have so much different information. We have a huge volume of journals. We have online, we have Twitter, we have podcasts. We have people that are consuming information in so many different ways. Tell us from your perspective, what's the role of the scientific journal currently and how has it changed at all in the last few decades?

Dr James Willerson: It's always going to continue to evolve. It's about as good as it can be right now with Dr Loscalzo and Dr Hill's leadership, and I'm really proud of them. There'll be more. We can't even imagine what it will be in two or three years. Of course, it'll be better and better, faster, almost momentary. Thank you, Dr Hill.

Dr Amit Khera: Thank you for that. I think we all look forward to seeing how this evolves more rapid information, rapid turnaround. I'm certain that will change. Dr Hill, you had a comment on that?

Dr Joseph Hill: We live in an era now where peer review is under attack in many ways and pre-print journals, blogs and so forth. And one of the things that I've really seen, and we've all seen, is how the peer review process, and we're all authors, right, we live on the other end of that stick, but it really is important. It makes a big difference. And people who are anxious to accelerate that process, I totally get it. We work very hard to do that. At the same time we, following the traditions here, have an intentionally redundant review process where every paper is evaluated by multiple editors and multiple peer reviewers. On a number of occasions, we've avoided a pothole, or we've improved a paper many, many times. And that is something that has really been impressed on me that I think people who aren't on this side of the editorial fence might not appreciate as much.

Dr Amit Khera: I think that's an important point about sort of the rigor about the way that articles come out in Circulation. And Dr Loscalzo, maybe as an extension of the last question, what do you see as some of the challenges going forward or opportunities for Circulation? You think about where it's been, but what are some of the things that you look forward to for Circulation in the future and what are some of the things you're concerned about?

Dr Joseph Loscalzo: Well, I too am concerned about this issue of peer review being under attack, and I'm particularly concerned about it for papers that have direct clinical impact. A good example of that concern, of course, are papers published, or at least publicly released, on non-peer reviewed websites like the archive sites because of their importance in the COVID epidemic, potentially. We all know of cases of drugs, at least in test tubes, with cultured cells and viruses appear to be effective that have adverse clinical consequences.

So that, and more than in any other sphere of science, ensuring that proper peer review from as many perspectives as possible is always a part of the process is absolutely critical for clinical medicine. And to me, the threat that this need for acceleration and rapid peer review poses and the sort of socialization of the transmission of scientific information that we're all interested in doing really has to have the brakes put on it a bit for the clinical science that the journal represents for this very important reason. Not to say we want to slow things down, we want to make sure that the best possible reviews are performed before we release it to the public.

I know that, as Joe was pointing out, one of the most exciting parts of the role of when I led the journal was the weekly meeting. We had a face-to-face meeting because all of our associate editors, save one, was actually physically proximate and they could travel to our conference room. But it's a wonderful exercise to have people of very different perspectives, from basic scientists, to clinical electrophysiologists, to outcomes researchers, make comments on papers that were completely outside their sphere.

The argument, of course, is if one can write and transmit a thought with the clear intent in a way that's rigorous and logical, that any reasonably bright person with reasonable scientific background should be able to understand it. And often these folks with very different scientific backgrounds have perspectives that very clearly improved the paper when they were acted upon. That's a process that doesn't exist in many other journals, I have to say. And I would encourage Joe, which I know, well, he's doing this because he enjoys it and he recognizes its importance, and Joe's successors continue to do that as well because that will ensure the value of the journal through all of the challenges that it is going to have to face in the next decade or two.

Dr Amit Khera: I think that was a great point. We're certainly seeing candy bowl examples of the importance of this rigorous process of the editors looking through it carefully and, as you both mentioned, peer review. Joe Hill, I'm going to let you maybe have the last word. I know how hard the three of you have historically worked on your craft for the journal, how much effort you've put in, but I also know it's quite a rewarding job. What would you see as the best part of being Editor-in-Chief of Circulation?

Dr Joseph Hill: Oh my, I'm learning something every day. I've been on about a steep a learning curve as when I was an intern at Dr Loscalzo's hospital long ago. Under Dr Willerson's term, I imagine many, many studies came in on acute coronary syndromes and thrombolytic therapy, primary PCI, antiarrhythmic drugs. We haven't seen an antiarrhythmic drug paper except for a recent review we did, but for quite a long time. It's artificial intelligence, it's big data, it's the UK Biobank, it's Omix, it's incredibly sophisticated genetics and genomics and basic science with genetic manipulations, IPS cells.

It's a very different world now than it was 10 years ago, 20 years ago and it certainly will be again, 10 and 20 years down the road. We are now approaching, I will say, 600 COVID related papers, and they're still coming in at a record pace. The world has changed. As I said before, this is the 70th anniversary of this storied journal. And it is truly my honor to be able to stand on the shoulders of Doctors Loscalzo and Willerson.

Dr Amit Khera: Thank you. I think that's a great way to end this podcast and congratulations on the 70th anniversary. It truly has been a privilege to chat with the three of you today. I want to thank you not only for what you've done for Circulation, but for the field of cardiovascular medicine. This is Amit Khera, digital strategies editor for Circulation. Next week we're back to our usual podcast with Carolyn Lam and Greg Hundley. Take care.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation June 23, 2020 Issue

22 juni 2020 | 18 min

Today’s episode discusses the paper “Randomized Comparison of the Polymer-Free Biolimus-Coated Biofreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial”

Dr Carolyn Lam and Dr Greg Hundley also discuss the following:

“Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis” by Shah et al. “Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage” by Joutel et al. TRANSCRIPT

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn our feature article this week, we're going to dive into evaluating stent efficacy and looking at biodegradable stents and polymer free stents, and I can't wait to get to that feature.

But before we do that, how about we get to other articles in our journal today? Would you like to start?

Dr Carolyn Lam: You bet, Greg. So this paper describes temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis in Scotland.

Dr Anoop Shah from University Center for Cardiovascular Science at University of Edinburgh, and colleagues used a Scotland wide individual level linkage approach to identify all patients hospitalized with infective endocarditis from 1990 to 2014, and linked their records in national microbiology, prescribing and morbidity and mortality datasets.

Dr Greg Hundley: Interesting, Carolyn. So what did they find in this study?

Dr Carolyn Lam: The crude incidence rate of infective endocarditis hospitalizations increased from 1990 to 1995 but has remained relatively static thereafter with both short and long-term adjusted case fatality rates showing a steady decrease over the last 25 years. However, the incidence rate has doubled in the elderly.

Importantly, there was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines. The majority of patients with endocarditis in their cohort did not have positive blood cultures. However, in those that did have positive microbiology, staphylococcus and enterococcus conferred the highest risk for all-cause mortality.

Dr Greg Hundley: Ah, very interesting. More in the world of endocarditis. Well, Carolyn, my paper is also interesting and it involves both mouse and human experiments to identify the etiology of deep intercranial hemorrhagic stroke. Now I'm not going to quiz you this week because I think you're going to want to quiz me in anticipation of some of these exciting study results.

A little bit of background. First of all, the study comes from Dr Anne Joutel from INSERM and it has been thought that smooth muscle cell degeneration at the site of arterial wall rupture may be sufficient to cause hemorrhage. However, deep intracranial hemorrhages are rare in some aggressive small vessel diseases that are characterized by significant arterial smooth muscle cell degeneration.

Therefore, the authors hypothesized that a second cellular defect may be required for the occurrence of intercranial hemorrhage. So to address this hypothesis, the author studied a genetic model of spontaneous deep intercranial hemorrhage in mice, and analyzed cerebral retinal micro vessels, performing genetic rescue experiments, vascular reactivity analysis, and computational modeling.

And in the human experiments, they examined post-mortem brain tissues from patients that had sporadic deep intercranial hemorrhage.

Dr Carolyn Lam: Wow, that's a lot of work from mice to men. Well, let's start with the mice. So what did they find there, Greg?

Dr Greg Hundley: Right, Carolyn. So the authors identified in the normal cerebral retinal vasculature, a novel segment between arterials and capillaries herein called the transitional segment, and that is covered by neural cells distinct from smooth muscle cells and parasites.

In Col4a1 mutant mice, this transitional segment was hyper muscularized with a hyperplasia of neural cells expressing more contractile proteins, whereas the upstream arterial exhibited a loss of smooth muscle cells.

Moreover, the hyper muscularization of the retinal transitional zone increased its contractility in tone and raised the intravascular pressure in the upstream feeding arterial.

Dr Carolyn Lam: Wow, masterful explaining, Greg. Okay. What about in the humans?

Dr Greg Hundley: Well, the author similarly found that hyper muscularization of the transitional segment and focal arterial or smooth muscle cell loss in brain tissues from patients were observed in those with sporadic deep intercranial hemorrhage.

Dr Carolyn Lam: Okay, so put it together for us, Greg.

Dr Greg Hundley: Right. So the results suggest that hyper muscularization of this transitional segment is involved in the incurrence of intracranial hemorrhage in these studied mice, and this hyper muscularization in this zone raises the intravascular pressure in the upstream feeding arterial and promotes its rupture at the site of smooth muscle cell loss.

The human data corroborate these findings indicating that these two mutually reinforcing vascular defects may represent a general mechanism of deep intercranial hemorrhage. Really interesting results.

Dr Carolyn Lam: Not just interesting, but very, very nicely summarized. Thanks Greg.

Well, other very interesting papers in today's issue include a research letter by Dr Tiantian Li et al, entitled Associations Between Short Term Exposure to Fine Particulate Matter and Cardiovascular Disease Hospital Admissions After Index Myocardial Infarction. A case crossover study from Beijing, China.

There's also a white paper from Dr Milton Packer on the role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient over abundance. This beautiful white paper presents a mechanistic framework that may explain the findings of large scale randomized trials of SGLT-2 inhibitors and the close association of ketogenesis and erythrocytosis with the cardio protective and renal protective benefits of these drugs. Interesting.

There's also a series of papers on COVID-19, including an online white paper by Dr Franz Messerli on COVID-19 and renin-angiotensin blockers, current evidence and recommendations.

A perspective paper by Dr Michael Givertz on the challenges in heart transplantation in the era of COVID-19. Another online paper by Dr Harsimran Singh entitled New York City innocence lost, cardiology in the COVID-19 pandemic.

Dr Greg Hundley: Wow, Carolyn, this issue is just truly full of a lot of articles in addition to our original research.

So I have an exchange of letters to the editor between Richard Sutton and Dr Ben Levine regarding Dr Levine's previously published tilt table manuscript.

Next, Dr James Byrd from the University of Michigan offers a perspective on pausing clinical research during the COVID-19 pandemic.

Dr Comilla Sasson from the American Heart Association heads a very large group of authors to provide a very nice piece on guidance for life support during the COVID-19 pandemic.

Next, Professor Guilo Stefanini from Humanitas University has a research letter regarding ST elevation myocardial infarction in patients with COVID-19, both the clinical and the angiographic outcomes.

And then finally, another ECG challenge from Dr Adrian Baranchuk entitled an ominous ECG sign in critical care.

Well, Carolyn, what a great issue, and let's get on to that feature discussion to learn a little bit more about bio resorbable intercoronary stents.

Dr Carolyn Lam: Great. Let's go, Greg.

Dr Greg Hundley: Well, listeners, We're here for our feature discussion. And today we have Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, one of our own associate editors.

Lisette, could you tell us a little bit about the background for your study of intercoronary stenting and what was the hypothesis that you wanted to address?

Prof Lisette Jensen: The overall background or aim for this program is that we want to have a quality control of what we put into the patients, what stent we put in, and also we wanted to do as much research as possible, and we want to do it if it's possible on a low budget.

For the present study, the Sort Out IX, before we did the study, we knew that the Bio Freedom stent was doing very well with a short time of dual antiplatelet therapy in patients with high bleeding risk. At the same time, we knew that the Orsiro stent was doing very well in all common populations, we used it in Sort out VII also.

We wanted to see how the Bio Freedom stent, the one you could use with a short time of dual antiplatelet therapy, how it was compared to a gold standard stent. In this study, we did not shorten the treatment time with dual antiplatelet therapy, but we followed the guidelines with six months for patients with stable angina, and 12 months for patients with acute coronary syndrome.

Dr Greg Hundley: Can you just remind our listeners, what's the difference between the Bio Freedom stent and then Orsiro stent?

Prof Lisette Jensen: There's several differences. The strut thickness of the two stents differs. The Orsiro stent is an ultra-thin stent strut and the Bio Freedom stent is 120 microns. Also, the Bio Freedom stent is free of a polymer, compared to the Orsiro stent where the polymer is biodegradable and is degraded in one to two years.

And also the drug is sirolimus in the Orsiro stent and it is released within three months compared to the Bio Freedom stent where most of the drug biolimus is released within one month.

Dr Greg Hundley: So the Bio Freedom is a stainless-steel drug coated stent, and the Orsiro stent is a biodegradable stent. So can you tell us what was the study design, and then the study population?

Prof Lisette Jensen: It was a randomized trial and we enrolled 3,151 patients. They were randomized one to one, two to two stent groups, and we followed the patients. The primary endpoint was after one year, and this is what we're going to publish now in the journal, and we plan to do up to five years follow-up in the patients.

Dr Greg Hundley: And what outcomes were you looking for?

Prof Lisette Jensen: The primary endpoint was MACE, and that was a composite endpoint of cardiac deaths, target lesion revascularization, and myocardial infarction, not clearly related to any other segment that the index listed.

Dr Greg Hundley: So 3,151 patients, so a very large study. Can you tell us a little bit about your study outcomes?

Prof Lisette Jensen: The outcome was the primary end point after one year was, we saw MACE rate in the Bio Freedom treated patients was 5.0% compared to 3.7% in the Orsiro group. And the study was designed as a non-inferiority study, so with these numbers, Bio Freedom stent did not meet the criteria for non-inferiority.

Dr Greg Hundley: And were there any particular patient populations or subgroups where you saw differences in performance from one stent versus the other?

Prof Lisette Jensen: We looked into several predefined subgroups, which are also in the paper as figure three where we did a force plot, and in all the pre-specified subgroups, including indication for PCI, acute coronary syndrome or stable angina, young patients, old patients, diabetic, non-diabetic, gender, we did not see any significant difference.

Dr Greg Hundley: Well, Dharam, I'd like to switch over to you a little bit. Can you help us put this study in perspective to the other world's literature related to intercoronary stenting?

Dr Dharam Kumbhani: You know, one of the biggest advantages of the way they enroll patients is they tend to be a lot more inclusive than many of the other trials that are done. So typically isn't all common population.

So, now and again, I think it was an important trial because as she just outlined, it compares the Bio Freedom stent, which is a polymer free stent to a biodegradable stent. And this was really the first comparison of this Bio Freedom stent with a more contemporary stent that is used in clinical practice.

There have been a couple of other trials like the industry three and industry two trial which have compared it with bare metal stents. We know that this stent has a better performance than that, but when you compare it with, especially the thin struts or Orsiro, the latest in this class of DES, it is the thinnest strut, one of the thinnest strut stents that is in the market. The strut thickness, we know it really correlates quite well in stent restenosis.

I think this really helps move the field forward in terms of having data available for this comparison, and it suggests that perhaps in this kind of pragmatic design, that this Bio Freedom stent did not necessarily in the timeframe that they studied, meet the criteria for non-inferiority compared with the Orsiro stent.

So I think there's still valuable insight. The stent is not yet approved in the US. None of the Bio Freedom stents are available in the US. This is CE Mark, but not available in the US.

So I think this does add to the overall body of literature for this group of stents.

Dr Greg Hundley: I would like to ask you both, perhaps one at a time. Lisette, you first. What do you see is the next research study that needs to be performed in this field? Lisette.

Prof Lisette Jensen: Can I just give one more comment to what Dharam mentioned with the restenosis, because that was actually what we saw in the Sort Out IX. We had a higher rate of the target lesion revascularization rate in the Bio Freedom stent group, so the efficacy was less.

It could be because of the bigger stent struts, pushing us in a direction where we should use stents with thinner stent struts. And also we saw that the safety did not differ as we saw the equal number of stent thrombosis within one year.

I think what we should do next is maybe we should continue to work on the thin stent struts, and then also for the patients, the bleeding matters a lot. So it should be better to reduce the bleeding time to develop devices where we can reduce the treatment time for dual antiplatelet therapy.

Dr Greg Hundley: Very good. Dharam, your thoughts?

Dr Dharam Kumbhani: I would definitely agree. I think one of the most appealing aspects of this group of stents, because they don't have polymer, the ability to shorten the duration of antiplatelet therapy. And over the last couple of years, we've seen an incredible change in how we think about dual antiplatelet therapy and a number of trials have really challenged that dogma.

So I really think that a stent like this, I think it will be very interesting to study this in patients who are either high bleeding risk. This does perform better than bare metal stents, we know that. So conceivably we can get away with a much shorter duration of dual antiplatelet therapy, or just a lower duration of dual antiplatelet therapy in general.

So I would think that that would be one of the next areas of research in a randomized fashion for this group of stents.

Dr Greg Hundley: Well, listeners, we've had a wonderful conversation here with Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, related to some new evolutionary thoughts in intercoronary stenting.

For all our listeners out there on behalf of Carolyn and myself, we wish you a great week and look forward to speaking with you next week.

This program is copyright of the American Heart Association 2020.

Circulation June 16, 2020 Issue

15 juni 2020 | 24 min

Today’s episode discusses issues pertaining to the management of ST-elevation myocardial infarction in low and middle-income countries.

Dr Carolyn Lam and Dr Greg Hundley also discuss the following:

Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation by Sadek et al. Autoantibody Signature in Cardiac Arrest by Li et al. Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults by Kim et al. TRANSCRIPT

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week is a little bit different from what we've done in the past with original manuscripts, we're going to focus on issues pertaining to the management of ST-elevation myocardial infarction in low- and middle-income countries. Oh my Carolyn, there's so many different things to consider. There are knowledge gaps, how we manage patients, how we get from one center to another, even just defining those centers. And this could be a very nice blueprint for future governments to use in managing these patients. But before we get to that feature, how about we have a little bit of a chat on some of the other articles in the issue?

Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do some but not all patients with severe aortic stenosis develop otherwise unexplained reduced systolic function?

Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens to do with one of our favorite magnetic resonance spectroscopy measurements, including creatine kinase.

Dr Carolyn Lam: You are just too smart, Greg Hundley!

Dr Greg Hundley: I had the opportunity to manage this one through the whole editorial board review.

Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of Oxford hypothesized that reduce creatine kinase capacity and or flux would be associated with the transition to reduce systolic function in severe aortic stenosis. So they looked at 102 participants recruited into five groups. One, those with moderate stenosis. Two, severe aortic stenosis with ejection fraction above 55%. Three, severe aortic stenosis with ejection fraction less than 55%. Four, healthy volunteers with non-hypertrophied hearts with normal systolic function. And five, patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function who are undergoing cardiac surgery and donating left ventricular biopsies.

Now, all these groups underwent CMR, cardiac magnetic resonance imaging, and 31 phosphorous magnetic resonance spectroscopy from myocardial energetics. And they also had left ventricular biopsies. So Greg, I know you know what they found, and so let me lunge right into it. They found that total creatine kinase capacity was reduced in severe aortic stenosis with median values lowest in those with systolic failure, consistent with reduced energy supply reserve.

Despite this, in vivo magnetic resonance spectroscopy measures of resting creatine kinase flux suggested that ATP delivery was reduced earlier at the moderate aortic stenosis stage, but where left ventricular functions still remain preserved. These findings thus suggest that significant energetic impairment is already established in moderate aortic stenosis and a fall in creatine kinase flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with aortic stenosis severity, this could increase susceptibility to systolic failure. As such, targeting creatine kinase capacity and our flux may be a new therapeutic strategy to prevent or treat systolic failure in aortic stenosis.

Dr Greg Hundley: Very nice, Carolyn. That is a very challenging explanation. And boy, you walked us through it just perfectly. And I'm so glad you're here as an expert in heart failure and transplantation to get us through this next quiz. So Carolyn, can you name several of the primary causes of heart transplant related mortality?

Dr Carolyn Lam: All right. Rejection, infection, malignancy and allograph vasculopathy, of course.

Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful job. So this paper comes from Dr Alexandra Loupy, and the study focused on the etiology of transplant related vasculopathy, the last one that you just named, from a population-based perspective. So 1,310 heart transplant recipients from four academic centers spread across Europe and the United States underwent prospective protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical histological and immunological parameters. The main outcome was prediction for cardiac allograph vasculopathy trajectory.

Dr Carolyn Lam: Interesting. So what did they find?

Dr Greg Hundley: So Carolyn, over a median follow-up post-transplant of about six and a half years, 4,710 coronary angiograms were analyzed, and four distinct profiles for allograph vasculopathy trajectories were observed. These four trajectories were characterized by one, patients without allograph vasculopathy at one year and non-progression over time. And that was about 56% of the patients. Second, patients without allograph vasculopathy at one year and late onset slow allograph vasculopathy progression. And that was about seven and a half percent of patients. Third, patients with mild allograph vasculopathy at one year and mild progression over time. And that was about 23% of patients. And finally, a fourth category, patients with mild allograph vasculopathy at one year and accelerated progression. And that was about 13% of patients.

Dr Carolyn Lam: Huh? So what most predictive?

Dr Greg Hundley: Well Carolyn, six early independent predictors of these trajectories were identified. One, donor age. Second, donor male gender. Third, if the donor used tobacco. Fourth, recipient dyslipidemia. Fifth, class two anti-HLA donor-specific antibodies. And finally, acute cellular rejection greater than 2R. The four allograft trajectories manifested consistently in the US independent cohort with similar discrimination, and in different clinical scenarios, and showed gradients for all caused mortality.

Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg?

Dr Greg Hundley: Well, because this study identified these four trajectories and their respective independent predictive variables, they provide the basis for a trajectory-base assessment of heart transplant patients for early risk stratification. And therefore, we might be able to develop monitoring strategies and form clinical trials around those to determine the efficacy of perhaps these predictive models.

Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on Tet-methylcytosine dioxygenase 2, or TET2.

Dr Greg Hundley: Carolyn, what is that?

Dr Carolyn Lam: Well, I'm glad you asked me before I asked you. So TET2 is a key enzyme in DNA demethylation. And the gene TET2 encodes an epigenetic regulator that demethylates cytosine. Somatic mutations of TET2 occur in cardiovascular disease and are associated with clonal hematopoiesis inflammation and at first vascular remodeling.

The current paper by Dr Archer from Queens University Kingston in Ontario, Canada, and colleagues, is novel because it's the first to examine the role of TET2 in pulmonary arterial hypertension. And they did this by evaluating exome sequencing data from the largest PAH cohort assembled to date, including 2,572 patients in the PAH Biobank. Unlike prior genetic studies, the biobank includes patients with associated PAH. Now, this is important. This is the category that includes patients with connective tissue disease such as scleroderma. This biobank also included non-European ancestry. So these are the novel aspects.

The authors performed gene-specific rare variant association analyses using up to 1,832 cases of European origin from the PAH Biobank, and transcriptomic analysis in an independent cohort to assess TET2 expression.

Dr Greg Hundley: Carolyn, so what did they find regarding to TET2?

Dr Carolyn Lam: In the entire cohort, they identified 12 predicted deleterious variants of TET2 novel to PAH. 75% predicted germline and 25% predicted somatic variants. None of the variant carriers were responsive to acute vasodilator challenge. Now, this is the first time that putative germline TET2 mutations have been associated with a human disease. They also identify ubiquitous downregulation of the expression of TET2 in the peripheral blood mononuclear cells of idiopathic PAH and associated PAH patients.

Finally, they evaluated TET2 depleted mice and demonstrated that they spontaneously developed inflammation, pulmonary vascular obliteration and pulmonary hypertension, thus providing biological plausibility that disorders in this pathway can indeed cause PAH. This is discussed in an editorial by Dr Soubrier from INSERM, entitled, TET2: A Bridge Between DNA Methylation and Vascular Inflammation.

Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a couple other articles in our issue. First, Dr Amr Abbas has a letter to the editor regarding actuarial versus echocardiographic outcomes following TAVR, evaluating gradients, leaks, areas and mortality with responses by Flavin Vincent and from Laurent Fauchier. We have Dr Miguel A. Arias again presenting another EKG challenge for us. Next, professor Giovanni Esposito has a research letter involving PCI rates for ACS during this COVID-19 pandemic. Next, Dan Roden from Vanderbilt has a consensus report related to QTC prolongation during the coronavirus pandemic. And finally, professor Marco Roffi has an on my mind piece related to STEMI and COVID-19 pandemics.

Dr Carolyn Lam: Oh, there is a series of on my mind papers in this week's issue. “The Future of Cardiovascular Prevention: Unprecedented Times,” by Laurence Sperling. “Primary and Secondary Prevention Of Cardiovascular Disease in the Era of Coronavirus Pandemic,” by Erin Michos. “Reperfusion of STEMI in the COVID-19 Era: Is it Business as Usual?” by Dharam Kumbhani.

And finally, we also have a research letter by Dr Lili Jong, addressing immune checkpoint inhibitors which are increasingly applied to a broader range of cancers and their potential toxicity causing myocarditis. And this letter describes the association of timing and dose of cortical steroids in immune checkpoint inhibitor associated myocarditis and cardiac outcomes.

Dr Greg Hundley: How about we discuss how we might want to manage ST-elevation myocardial infarctions in low- and middle-income countries?

Dr Carolyn Lam: You bet. Let's go, Greg.

Dr Greg Hundley: Well listeners, now we get to turn to our feature article. And we're very privileged today to have Dr Chandrashekhar from The University of Minnesota. And he and a large group of authors have put together a paper discussing the resources and infrastructure really necessary to manage ST-elevation myocardial infarction in low- and middle-income countries. Welcome Chandra. So we're going to call him Chandra for short as he is known internationally. Chandra, can you tell us a little bit about this prevalence of STEMI in low- and middle-income countries, and then also about the constitution of your writing group and what you were trying to do to address this issue?

Dr Chandrashekhar: The issue we are trying to address is, as you know, the low- and middle-income countries, there are about 80 plus countries constituting this group, and they account for something like 5.8 billion people around the world. And it's so interesting that 80% of the MIs that happen on the face of this earth are probably happening there, in areas which don't have resources to effectively deal with this condition, unlike the US or European countries and developed countries.

So this group got together to create some outlines of how to optimize care in low- and middle-income countries. And we got together groups which have extensive experience in dealing with this problem. It was a coalition of frontline clinicians as well as major organizations, including the Indian Council of Medical Research, the premier research body in India, a public health foundation of India which is a nongovernmental organization extensively involved in this, The Population Health Research Institute in Canada, the Latin America Telemedicine Infarct Network called LATIN, The Pan African Society of Cardiology and The South African Society of Cardiac Interventions, and an NGO in India called STEMI India. So we took experienced people from a number of different countries and created this group.

Dr Greg Hundley: Very good. Now, were there knowledge gaps or implementation gaps, maybe help distinguish those two terms for us, that you had to address when just starting your effort?

Dr Chandrashekhar: Yeah, absolutely. So let's start with the knowledge gap. As you know, there are excellent guidelines both in the United States, as well as Europe. Of course, there are STEMI guidelines in the UK and Australia and New Zealand, but these guidelines are not very applicable to low and middle income countries due to a number of reasons, due to porosity of resources, due to poverty, overcrowding, lack of infrastructure, and a bunch of other reasons that you can imagine.

So if we recommend somebody needs total balloon time under certain threshold, it's nearly impossible to meet this in most places in the low- and middle-income countries. And so there is a significant amount of implementation gap as well as knowledge gap, because the guidelines that are tailored to Western societies don't fit very easily in low- and middle-income countries. It's like fitting a round peg in a square hole.

So that's why we thought we should create something very focused, right? And there are implementation gaps in the sense infrastructure-based as well as resource-based. And knowledge gaps, for example, we don't know what the dose of dual antiplatelet therapy is optimal in these patients, for example, ticagrelor may have a higher effect in some Asian populations with small body habitus.

Similarly, as you know, statin doses, especially in the far east are much lower than what are prescribed here. So these are the kinds of challenges that we are applying and try to suggest some solutions.

Dr Greg Hundley: It sounds like definitions could differ, management strategies could differ, pharmacologic versus invasive, even centers that would manage the patients. Can you describe some of those issues for us?

Dr Chandrashekhar: Right. So that was the biggest challenge we had. So we had to create some resource infrastructure appropriate management paradigms for low- and middle-income countries. To give you an example, primary PCI, which is something we take for granted within our milieu, if you think about it, you and I probably didn't give thrombolytic therapy in the last 15 years. So this is a day-to-day thing in low- and middle-income countries. Most of the patients either they come so late that they don't get any reperfusion therapy for STEMI, or if they do, thrombolytic therapy is are very common mode of treatment there.

And so we had to create a way for them to get the optimized care. And so we divided the localities into different levels, from level one to level five. Level one being the most remote area and five being the one which is most equipped and can implement all the Western standards and guidelines.

And so we suggest a system of hub and spoke to transfer people from the smaller centers to the big centers, and outline what therapies need to be done at what stage. And one of the things that we emphasize so much is called pharmaco-invasive therapy, where you give thrombolytic therapy if you cannot reach a PCI center in time, and then in the next three to 24 hours, you transport the patient to a center where they can do PCI. And this has been studied in a number of trials showing that it's a very effective strategy. And so these are the kinds of solutions that we try to emphasize.

Dr Greg Hundley: And how about the patients themselves and the doctors that would implement, in terms of education, does your document cover how to reach out to both patients and physicians in these countries to emphasize these new protocols that you and your group have developed?

Dr Chandrashekhar: Absolutely. That's the crucial issue, right? No matter how many guidelines we create, if we can't implement it, they're useless, right? And so we have two parts to this guideline. There's a section devoted to governmental agencies as well as NGOs interested in improving care, STEMI care in low and middle income countries, as well as a section for frontline clinicians, which includes very focused flashcards with definitions and what exactly each level of this center in the hub and spoke model should be doing and how do they transport patients and how do they ensure that adequate pharmacotherapy is instituted? And so we keep repeating this and we also provide some other options of how to communicate with the hub facilities, from the spoke facilities, including use of mobile and social media apps like WhatsApp.

Dr Greg Hundley: Do you have certain recommendations that physicians in the field and patients at home should be aware of, for example, administration of aspirin and things like that?

Dr Chandrashekhar: Absolutely. These are all codified in flashcards, which are going to be printed for distribution to the frontline physicians. And they are also created as wall posters and plastered in this peripheral health centers where essentially the only thing they may have is an old EKG machine and a few drugs like aspirin. And so we have tried to cater to each of this, both in the informational material and what basic pharmacotherapies and equipment these centers should be having. And that's where the governmental part comes. So when governments have to decide how they invest their scarce dollars, they can divide it appropriately based on these recommendations.

Dr Greg Hundley: I like that last statement, it sounds like in addition to physicians and patients that your document may even be useful for governments and organizations delivering the care in these countries, do you want to talk a little bit about where you think this document may go next in that regard?

Dr Chandrashekhar: The best use of this document would be for agencies in different parts of the countries to take this up. And at the last count, there are at least five or six governments which are actively looking at the blueprint that is provided from this document, and to see what parts of this are locally implementable within their environment. And eventually, if it appears that it's applicable to multiple jurisdictions, then perhaps something like WHO could take this and modify it suitably for different localities. We see a lot of potential in this.

Dr Greg Hundley: Well, we are very privileged to have the opportunity to publish this important work. And I wonder here, just in closing, on behalf of your entire author group, are there any words you'd like to leave us with regarding this just monumental effort?

Dr Chandrashekhar: The thing that we can say is we should thank Circulation and its editorial board for working with us. It went through, I think, three revisions and it really made the document much better. And we really thank all of you for allowing us this platform. As you know, this is going to reach a huge part of the medical establishment as an open access article. And hopefully it will help us implement some progressive changes in healthcare in the low- and middle-income countries. And so we really thank Circulation for providing us this platform.

Dr Greg Hundley: Well, listeners, we're going to wrap up here and we're most appreciative to Chandra from The University of Minnesota and his entire author group. On behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you next week. This program is copyright to The American Heart Association, 2020.

Circulation June 09, 2020 Issue

8 juni 2020 | 24 min

Dr Greg Hundley: And I'm Dr Greg Hundley associated editor from the Pauly Heart Center at VCU health in Richmond, Virginia. Well Carolyn, this week's feature investigates the compass trial and is going to examine the role of combination antiplatelet and anticoagulation therapy in patients with diabetes and cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and jump in and discuss some of the other papers in the issue?

Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and I'd like to start by talking about paclitaxel containing devices. You may already know this, but it was nice to revise that these significantly reduce re intervention in patients with symptomatic femoral, popliteal, peripheral artery disease, as we may expect. However, a recent aggregate data meta-analysis reported increase late mortality in pad patients treat it with these paclitaxel containing devices. Thus today's authors, Dr Rocha-Singh from Prairie Heart Institute of Illinois at St. John's hospital and their colleagues performed an individual patient data meta-analysis to evaluate mortality using data from eight randomized controlled trials of FDA approved paclitaxel coated devices using de identified data that was provided by manufacturers.

Dr Greg Hundley: Well, Carolyn, what did they find?

Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight paclitaxel coated device trials with a four year median follow-up, there was a 4.6% absolute risk of increased mortality associated with paclitaxel coated device use compared to balloon angioplasty at a median of four years follow up, significant loss to follow up and withdrawal rates of 24% and 23% in balloon angioplasty and paclitaxel cohorts respectively through five years were observed. Recovery of lost vital status data reduced the observed paclitaxel device associated mortality rate. And there was no paclitaxel drug dose mortality relationship identified.

Dr Greg Hundley: Oh, Carolyn, I think this is really an important finding, and we have a nice editorial, don't we? So what was the take home message?

Dr Carolyn Lam: Yeah. In fact, this was discussed in an important editorial by doctors Royce, Chakraborty and Dao from the USFDA. Now listen up. So based on the prior aggregate data meta-analysis and subsequent FDA review, FDA had already communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations. They had also implemented updated labeling for this device class to communicate the risk. So in this editorial, the FDA commended the authors of the current individual patient data meta-analysis for providing important information towards signal refinement, and also commend at their collaboration with device manufacturers to work together with a shared goal of patient safety. Now, there are still many unanswered questions, including the mechanism for the observed increase in late term mortality associated with these devices and how the benefit risk profile of these devices may shift across various patient populations.

Dr Greg Hundley: Well Carolyn, my paper comes from Professor Antje Beling from Charité – Universitätsmedizin Berlin in Berlin. And it investigates heart specific immune responses in an animal model of auto immune related Meyer carditis mitigated by an immuno proteasome inhibitor and a genetic ablation. So Carolyn, this study used mouse models to understand mechanisms involved in immune checkpoint inhibitor related Maya carditis, a phenomenon that we can observe in 5% to 10% of patients that are receiving these checkpoint inhibitors for treatment of their cancer.

Dr Carolyn Lam: So what did they find, Greg?

Dr Greg Hundley: Several things, Carolyn. All immuno proteasome deficient strains of mice showed mitigated auto-immune related cardiac pathology with less inflammation, lower pro-inflammatory and chemo tactic cytokines, less interleukin 17 production and reduced fibrosis formation. The auto-immune signature during experimental proponent I auto immune carditis with high immuno proteasome expression, immunoglobulin G deposition, interleukin 17 production in heart tissue, and troponin I directed humeral auto immune responses was also present in two cases of immune mediated related my carditis. Thus demonstrating the activation of heart specific autoimmune reactions by this checkpoint inhibitor related myocarditis therapy. So Carolyn, perhaps by reversing heart specific auto immune responses, immuno proteasome inhibitors applied to these mouse models demonstrated their potential to, in the future, aid in the management of auto-immune bio carditis in humans, possibly including cases with immune mediated myocarditis heart-related specific auto-immunity.

Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a quiz? Remember what desmoplakin is Greg?

Dr Greg Hundley: I think this is going to do something with right ventricular cardiomyopathy.

Dr Carolyn Lam: Very nice. Desmoplakin is the primary force transducer between cardiac desmosomes and intermediate filaments. And mutations in Desmoplakin indeed cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of desmoplakin cardiomyopathy have been limited to small case series. Today's paper, by Dr Helms from University of Michigan and colleagues is the largest series of desmoplakin mutation carriers reported to date.

Dr Greg Hundley: So Carolyn, what did they find here?

Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin mutations and 81 patients with pathogenic Plakophilin-2 mutations as a comparison cohort, they found compelling evidence that desmoplakin cardiomyopathy is a distinct form of cardiomyopathy marked by a high proclivity for left ventricular hypertrophy and arrhythmias and associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis. Furthermore they found that diagnostic and risk stratification variables that performed well for Plakophilin-2 associated ARVC exhibited poor accuracy for the diagnosis and risk assessment of desmoplakin mutation carriers. So these results strongly indicate that a genotype specific management approach is essential for desmoplakin cardiomyopathy.

Dr Greg Hundley: Wow, Carolyn. Lots of great science in this issue. Well, just like last week, we have got a lot of other papers in this issue. So let me tell you about a few that I've had a chance to preview. The first is a research letter by our own Dr Hesham Sadek from UT Southwestern Medical Center involving the homotypic fusion generates multi nucleated cardiomyocytes in the murine heart. Next is an ECG challenge. It's from Dr G. Neil Kay at the University of Alabama at Birmingham, and really reviews an ECG in a patient that presents with pulmonary embolism. Next, there's a case series from Dr Nil Uriel from Columbia University Medical Center regarding the variety of cardiovascular presentations of COVID-19. Next there's an on my mind piece that comes to us from Dr Ersilia DeFilippis from Columbia University College of and Physicians and Surgeons. And it involves cardiopulmonary resuscitation during this COVID-19 pandemic.

And it presents a view from trainees on the front lines. Next, Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic provides an informative white paper on the description and proposed management of acute COVID-19 cardiovascular syndromes. Next is a paper from Dr Francine Marquez from Monash University, and it's a perspective piece on the impact, strategies and opportunities for early and mid-career cardiovascular researchers during the COVID-19 pandemic. So many studies have been stopped and this very nice article highlights the new opportunities in this pandemic. Next, Dr Anabel Volgman from Rush University Medical Center has a piece on the seniors on the sidelines, and it's a call to action. And then finally, Dr Andrew Chapman from University of Edinburgh and professor Christian Mueller from the University Hospital of Basel exchange letters to the editor regarding a prior article of high sensitivity cardiac troponin, and the universal definition of myocardial infarction.

Dr Carolyn Lam: Nice. There's also a research letter by Dr Sandoval and colleagues who described the transition to using high sensitivity troponin T in a United States regional healthcare system, namely the Mayo Clinic enterprise. And they really showed that a small increase in MI diagnosis in part due to an increase in type two MI diagnosis occurred without an overall increase in hospital admissions or resource utilization using the high sensitivity cardiac troponin T implementation. And if I may mention, there is also a beautiful white paper by Dr Sana Al-Khatib, whom I was very lucky to coauthor with. And it's on the advancing research on the complex interrelations between atrial fibrillation and heart failure. This a report from the National Heart Lung and Blood Institute virtual workshop. Wow. A bonanza of an issue. Thanks so much, Greg. Let's move on to our feature discussion now.

Dr Greg Hundley: Look forward to it.

Dr Carolyn Lam: Today's feature discussion was in fact a late breaking clinical trial presentation at the American College of Cardiology meeting this year, 2020. And it's all about the compass trial, this time focusing on diabetes. I'm so, so pleased to have with us, the corresponding author Dr Deepak Bhatt from Brigham and Women's Hospital, as well as Dr Gregory Lip from University of Liverpool who was not only the guest editor, but also an editorialist for this paper. So welcome gentlemen. Deepak, could I start with you? This was an incredible presentation that was very well discussed. ACC not virtually, but I'm just so glad that we can have you on this podcast to tell us again, please, the rationale, the key findings and why this paper is just so important.

Dr Deepak Bhatt: So the background really is that prior studies and particular registry studies, the reach registry, for example, have shown that patients with concomitant CAD and/or PAD, that is coronary artery disease and/or peripheral artery disease, plus diabetes, are folks that are extremely high risk of future ischemic events. This is true even if they are apparently stable outpatients. At any rate in the compass trial, these sorts of patients with CAD or PAD, stable patients, both with and without diabetes who are enrolled 27,000 plus patients randomized. And there were three arms in this study, aspirin alone, rivaroxaban alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice a day.

And that was the winner, that combination sometimes referred to as dual pathway inhibition significantly reduced the schemic events versus aspirin alone, a significant reduction in cardiovascular death MI stroke, as well a lower rate significantly so of cardiovascular death, and even all-cause mortality was lower. So the overall trial was positive, but what we wanted to examine in this analysis was specifically how to patients with diabetes fare, knowing that they're a higher risk group in general across multiple registries and studies? And indeed we found that they were higher risk, those with diabetes versus those without diabetes and compass, and indeed, though their relative risk reductions were similar, those patients with diabetes had numerically larger, absolute risk reductions than those without diabetes with this regimen of low dose rivaroxaban plus aspirin versus aspirin alone.

Dr Carolyn Lam: Thanks Deepak. And I just have to refer the listeners to those beautiful figures in your paper. I mean, just one look at it really explains exactly what you were saying and really highlights that patients with diabetes are at higher risk of adverse events and also in one of the graphs of bleeding. Greg, could I bring you in here? You mentioned that in your editorial as well, that there has to be importantly acceptable bleeding risks. Could you expand on that?

Dr Gregory Lip: The compass crowd was a game changer and in this high-risk subgroup, as Deepak elegantly has described. These are diabetic patients, and then we also have the subgroups we call with or without PCI. And those would be so of course, being the higher risk group of patients. Nonetheless, the comparison was basically a dual pathway inhibition, but a combination rivaroxaban plus aspirin compared to aspirin alone. But a high cardiovascular risk and high bleeding risk tend to track each other.

So it was important that we certainly want to reduce the adverse outcomes of cardiovascular endpoints, we should certainly individualize our assessment of our patients and make sure that a patient is not an excessive high bleeding risk. I think overall, the study is very reassuring because there was no significant access in the overall population of the subgroup, at least in relation to fatal bleeding, critical organ bleeding or intracranial hemorrhage by dual path inhibition. But I think we, as physicians, just need to assess the patient in front of us just to make sure that particular patient is not at high risk particularly of bleeding, given that high risk of bleeding also generally is high cardiovascular risk as well.

Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some words from you about this sort of risk benefit ratio? How do you see it? How do we apply these results?

Dr Deepak Bhatt: I totally agree with everything Dr Lip said. Really, the key message when we're talking about antithrombotic numbers, something Dr Brunwald had said in this context, that is, there's no free lunch. When it comes to antithrombotics, there's always bleeding risks. There's just no way around that. In any trial that is adequately powered long enough, we'll find that, and that can include bad bleeding. Now, fortunately there was no significant excess and failure endocranial bleeding within the trial or within the subgroup of patients with diabetes. But nonetheless one needs to be cautious because these of course are carefully selected patients at low bleeding risk to get into the trial. There was a run in period. So when applying to real life, of course, there's the potential for bleeding. So we need to be really cautious about that. And it's also not a stat. So if we were talking about secondary prevention, either with or without diabetes, CAD, PAD, both of them together, of course, all those patients should be on Statin assuming they don't have a real type of contraindication.

So that's kind of a no brainer. That's a matter of implementation science. A lot of patients that should be on Statin aren't, but that's not an issue of science. We already know the answer there. Here, it's not the case of everyone that is like this who has diabetes, or even who doesn't, who has CAD or PAD should be on this regimen. It needs to be carefully selected patients, patients that are a low bleeding risk. And sometimes doctors ask, "Well, how do you tell that?" Well, it's not always easy, but for sure there's some things that predict future bleeding risks such as prior bleeding. So prior bleeding, anemia, those are powerful predictors of future bleeding. And one would want to be really cautious in these largely stable outpatients that we're talking about in the compass trial in intensifying their antithrombotic regimen. But in the right patients, I think it's a really effective way of reducing important future vascular risk, whether that's cardiovascular risk consisting of MI related end points, stroke, peripheral ischemic end points, including amputation, which was significantly reduced in the trial, and within the subgroup of those with diabetes.

So it's a matter of balancing those, but I do think with careful decision-making on the part of the physician, with discussion with the patient, with their understanding of the risks and benefits of intensifying the antithrombotic regimen beyond aspirin, there are a substantial number of patients who could benefit.

Dr Gregory Lip: I whole fully agree with Deepak's comments. And we do have to bear in mind also that risk is also a fairly dynamic process and we may well be assessing the patient as the one off initially while we are initiating treatment. But of course risk, whether from cardiovascular risk or whether from bleeding risk particularly, also is influenced by increasing age and by incident comorbidities, which really means that risk reassessment should be performed in every patient we contact. With bleeding risks in particular, there are modifiable bleeding risk factors that we can mitigate. So proactive assessment or rather reassessment of risks, whether both from cardiovascular events and/or bleeding, is necessary as we follow up these patients.

Dr Carolyn Lam: Thank you, both. Deepak, I'm just going to build a bit on your analogy of no free lunch. And maybe sort of a general question do you both, because it seems like we've got a bonanza of a buffet now when it comes to diabetes, especially with the new anti-diabetic drugs. So how do you think this fits in altogether? You talked about Statins. We now talk about low dose rivaroxaban in addition to aspirin, and you think diabetic patients should be treated with all? Maybe Deepak first, then Greg.

Dr Deepak Bhatt: What a terrific question. In fact, that was asked of me by the late-breaking clinical-trial panel clinical trial panel. They said, "Well, how does it fit in? Because these data look terrific, but there's also other new diabetes drugs and approaches." So for sure, I would say again, barring a real contraindication, I would say everyone that we're talking about here should be on a statin and preferably if they can tolerate it, a high intensity statin.

And if that doesn't do the trick in terms of LDL goal, I would say zetomyde. And potentially if they're in a region of the world where it's affordable a PCSK9 inhibitor. Then beyond that, I think we've got to pay attention to triglycerides these days, not just LDL cholesterol and if it's some patient that's sort of like REDUCE IT, well then, they should be on eicosapentaenoic. So we can modify LDL related and triglyceride related risks without too much effort or too much in the way of side effects. Then beyond that, I would say, we've got to think about blood pressure, inadequate control, especially in those with diabetes, but even those without that have cardiovascular disease. And then we have to think about glycemic control. And I don't mean the old-fashioned way, but I mean with some of the newer drugs. SGLT2 inhibitors in particular have been found to be useful for both.

That's just the glycemia control part of things, more importantly, cardiovascular outcomes. In particular, heart failure and renal related outcomes. And then GLP 1 agonist as well have been shown to be very useful once more modifying cardiovascular outcomes, including atherosclerotic outcomes. So there is, as you say, quite the buffet. And assuming a patient can tolerate that polypharmacy and afford it, I do think the majority of patients with diabetes should be treated that well. And that's of course on top of lifestyle modification, weight loss is particularly important, plant-based diet, et cetera.

But on top of that, then, with all those things that are being done and a patient is still at high ischemic risk but is at low bleeding risk, that's where I think, even in the deceptively stable appearing outpatient, it's worthwhile just running a mental checklist and saying, "Okay, are they on an SGLT2 inhibitor? Check. Did In someone measured their triglycerides? Check." And then on that checklist is, "Yeah, could they tolerate being on more than just aspirin alone in terms of bleeding risk? And if the answer to that is yes, might they benefit from adding this on?" And there are a lot of patients these results apply to, and I think a proportion of those patients who are otherwise optimally treated for their risk factors are the ones to target.

Dr Carolyn Lam: Beautifully put. And Greg?

Dr Gregory Lip: Deepak does raise an increasingly applied concept in how we approach our patients at high risk of cardiovascular events. That's the so called integrated or holistic approach to management. Because we have in the past tended to just focus on one strand of management. For example, we may well just be putting a lot of focus when on the analytic reduction and ignoring the rest. Well, we can't do that these days. We have to manage the whole patient and not just the bit of the patient. And this brings in this holistic approach, this integrated approach. And I think Deepak summarized that very nicely. It may require a number of medical approaches or medication-based approaches, but we have to practically look at the comorbidities like blood pressure reduction and also the lifestyle changes that Deepak's already summarized. So a holistic and integrated approach to our care of these patients. And in fact, some of the more recent studies showed nicely how this results in better outcomes in our patients at high cardiovascular risk.

Dr Carolyn Lam: And in fact, those were exactly the last words of your editorial. A holistic and integrated care approach. Beautifully done, thank you both so much for this excellent discussion. Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again. Next week.

Dr Greg Hundley: This program is copyright the American Heart Association 2020.

Circulation June 2, 2020 Issue

1 juni 2020 | 25 min

In today’s episode, Dr Carolyn Lam discusses the prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease with Dr Kausik Ray (KOSH) and Dr Amit Khera.

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg. I'm the associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia.

Dr Carolyn Lam: Greg, ever wondered what's the prevalence of familial hypercholesterolemia in the general population? It's an important question, but we're going to wait to discuss that with our feature discussion coming right up.

First, I want to tell you all about valvular heart disease. In a preclinical model, would you believe, but first let me just remind us all that primary valvular heart disease is a really prevalent cause of morbidity and mortality. And although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart disease has always centered around valve repair or replacement, rather than the prevention or reversal of myocardial dysfunction.

In fact, have you thought about this? We know very little about the mechanisms, the actual preclinical underlying mechanisms of left ventricular dysfunction and primary severe mitral regurgitation. Well, in the first paper I want to talk about today, Dr Li from First Affiliated Hospital, Sun Yat-sen, University Guangzhou, and Dr Sadek, from UT Southwestern Medical Center and their colleagues develop the first mouse model of severe mitral regurgitation. And they did this by severing the mitral valve leaflets and chords using iridectomy scissors.

Similar to the human condition, induction of mitral regurgitation was followed by gradual left ventricular dilatation and dysfunction resulting in severe systolic dysfunction. Further analysis revealed that severe mitral regurgitation resulted in a marked increase in cardiac mass, increased cardiomyocyte length, but not with, and electron microscopy evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe mitral regurgitation resulted in activation of multiple components of both the mTOR and Kelson urine pathways. Now intriguingly, inhibition of mTOR signaling even preserved sarcomeric structure and prevented left ventricular remodeling and systolic dysfunction.

Finally, immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator CRB2, along the longitudinal axis of cardiomyocytes and close to the intercalated discs, with a similar pattern of polysome localization. And all of this suggests a potential new mechanism of longitudinal cardiomyocyte growth.

Dr Greg Hundley: Well, Carolyn, there is a lot of basic science and a lot going on both histopathologically, but also mechanically with this model. What's our take home message?

Dr Carolyn Lam: Well, Greg, this mitral regurgitation mouse models suggest that cardiomyocyte hypertrophy in response to mitral regurgitation is a maladaptive process that may be pharmacologically targeted by mTOR inhibitors.

Dr Greg Hundley: Oh my, very nice Carolyn. Well, I'm going to bring you another kind of basic science paper as well. And it's from Dr Jin Li from the Institute of Biochemistry and Molecular Medicine at the University of Bern. And it really involves auto antibody signatures in cardiac arrests. So Carolyn, a quiz of what percentage of individuals sustaining out of hospital cardiac arrest have no known cause?

Dr Carolyn Lam: You said, “Oh oh!” I’m on the spot here, Greg. Okay. What about if I start with what I do know? Coronary artery disease is the most common cause. I think that may be, I don't know, large majority, 80% of it. And then we get inherited cardiomyopathy, channelopathies. So I'm going to guess less than 10%.

Dr Greg Hundley: Wow. That is why you're just the stellar extraordinaire. So it's exactly about 5% to 10%. So Carolyn this study sought to address the etiology for this out of hospital arrests in this 5% to 10% of individuals, using a peptide micro-ray designed to screen for IgG targeting epitopes from all known cardiac ion channels with extracellular domains.

So plasma samples from 23 patients with unexplained cardiac arrest were compared to 22 cardiac arrest cases of ischemic origin and a group of 29 age, sex, and BMI matched healthy subjects.

Dr Carolyn Lam: Wow. What did they find, Greg?

Dr Greg Hundley: The auto antibody against the poor domain of the L tight voltage gated calcium channel or Cav 1.2 was consistently identified as a biomarker of idiopathic cardiac arrest and functional studies on human induced pluripotent STEM cell derived cardiomyocytes demonstrated that the anti Cav 1.2 IgG purified from patients with idiopathic cardiac arrest is pro-arrhythmogenic by reducing the action potential duration through calcium channel inhibition.

Dr Carolyn Lam: Wow, that seems huge. Clinical implications?

Dr Greg Hundley: I thought you'd asked me that. So the present report addresses the concept of autoimmunity and cardiac arrest and hitherto unknown auto antibodies targeting extra cellular sequences of cardiac ion channels were detected. And so moreover, this study identifies an auto antibody signature to specific patients with cardiac arrest, thereby explaining perhaps a potential etiology for this 5% to 10% of individuals that here to for, we were uncertain of that particular ideology.

Dr Carolyn Lam: Wow. That clearly needs follow-up, but you know what? What also needs follow-up is a quiz question for you. What do you say to a young adult with stage one hypertension about his or her future health risks?

Dr Greg Hundley: Well, how about A, see a physician, B, listen to that physician and follow their recommendations?

Dr Carolyn Lam: Oh, you are brilliant. Well, guess what? I'm going to tell you a little bit more about this in the next paper from Dr Kim from Yonsei University College of Medicine and Colleagues who looked at almost six and a half million participants aged 20 to 39 years. So young, and without taking any antihypertensive medication in 2003 to 2007 in a nationwide health screening database.

Now participants were categorized according to the 2017 ACCAHA guidelines as having a normal blood pressure. That is an untreated systolic blood pressure, less than 120 and diastolic blood pressure less than 80. Or stage one, isolated diastolic hypertension. So that's when systolic is less than 130 and diastolic between 80 and 89. Or stage one isolated systolic hypertension. So that's when systolic blood pressure is between 130-139 and diastolic is less than 80. Or finally, stage one systolic and diastolic hypertension. So that's when systolic is between 130-139 and diastolic is between 80 and 89. And these were followed up for the primary outcome of composite cardiovascular disease events, including myocardial infarction, stroke, heart failure, and cardiovascular related death.

Dr Greg Hundley: Caroline, I am dying to hear what did they find?

Dr Carolyn Lam: So over a median follow-up of 13.2 years, more than 44,000 new cardiovascular disease events occurred. Among these young adults who had a median age of only 30 years stage one, isolated systolic hypertension, isolated diastolic hypertension, and systolic and diastolic hypertension were each associated with higher cardiovascular risks compared to normal blood pressure.

Cardiovascular risk of stage one systolic and diastolic hypertension was higher than the risks of stage one isolated systolic and isolated diastolic hypertension.

Dr Greg Hundley: Very good. That was an outstanding presentation and very pertinent to our younger listeners as well as young patients with hypertension. In the rest of this journal, we are jammed packed with more articles. Let me tell you about a few. First, I've got a research letter by Professor G. Kees Hovingh from Amsterdam UMC discussing Inclisiran and how that durably lowers LDLC and PCSK-9 expression in homozygous familial hypercholesterolemia. Next there's an ECG challenge from Dr Miguel Arías from Complejo Hospitalario Universitario de Toledo involving syncope and alternating QRS morphologies.

Next Professor Qing Yang from Tianjin Medical University General Hospital has a perspective piece regarding anti-platelet therapy following percutaneous coronary interventions in patients complicated by COVID-19.

One of our own associate editors, Dr Nicholas Mills, has a very nice on my mind piece related to the use of serum troponin and biomarkers, as well as their utility in managing patients with COVID-19. Next, Dr Courtney Campbell from Ohio State University and Wexner Medical Center has a perspective piece regarding will compliment inhibition be the new target in treating COVID-19 related systemic thrombosis.

And then finally, Carolyn, there's a nice exchange of research letters regarding Orai 1 channel inhibition, preserving left ventricular systolic function, and normal calcium handling after pressure overload. And the contributing authors that provided these letters are Dr Muddassir Mehmood from University of Tennessee Medical Center and Dr Jessica Sabourin from INSERM UMR S1180.

Dr Carolyn Lam: And that's not all, Greg. There's also an in-depth article on the implications of altered ketone metabolism and therapeutic ketosis in heart failure by Dr Salvaraj, Kelly, and Margulies. Now this review is a must read. It summarizes the current evidence supporting a role for ketones in heart failure and covers normal myocardial ketone utilization, alterations, and ketone metabolism in a failing heart and effects of therapeutic ketosis in both animals and humans with heart failure. There's also a research letter by Dr Susanna Larson who used the UK Biobank Cohort to perform a Mendalian Randomization investigation into the causal effects of circulating LPA levels on atherosclerotic, cerebral vascular thrombotic, and valvular disease.

There's another research letter by Dr Eliseo Guallar and that's on mitochondrial DNA copy number, which is an indirect biomarker of mitochondrial dysfunction and its association with incident heart failure in the Eric study.

Wow, such a full issue, but now let's go on to our feature discussion. Shall we, Greg?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: Today's feature discussion is all about familial hypercholesterolemia. Now, recent study suggests it is more frequent than previously reported. And in fact, increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Well, today's feature paper really represents one of the most comprehensive assessments of the prevalence of familial hypercholesterolemia.

More than 7.3 million individuals from 62 studies. So pleased to have with us the corresponding author of this beautiful paper, Dr Ray Kosh from Imperial College London, as well as our editor of digital strategies, Dr Amit Khera from UT Southwestern. Kosh, if I may call you that, congratulations again on another just really important paper. This systematic review and meta-analysis is really revealing. So could you tell us a little bit more of the details of what you did and just really tell us the take home messages.

Dr Kausik Ray: We've been getting signals that familial hypercholesterolemia... So this is where essentially individuals inherited an abnormality that results in lifelong elevations of LDL cholesterol birth, increases risk of cardiovascular disease. The previous prevalence was believed to be about one in 500 and suggestions... It's actually not just a suggestion, there's a lot of data suggesting that it's a lot more prevalent than that. And one of the queries that we often have, if you think about global health is does it affect all regions of the world? And if we don't go out looking for it, you're not going to find it. So this is really why this was done. And we basically synthesize the global data and there was basically over 7 million people approximately from general population primary care settings, if you will. And the global prevalence for FH is one in 311. Confidence interval is between about one and 250 to one in 397.

If you look at WHO regions of the world, it's equally prevalent across all regions of the world. And we know there are many regions of the world where they're not going out looking for this. So if you don't look for it, you won't find it. And we think that that should inform public health policies. The other key things about this or that because this is a condition that results in premature cardiovascular disease, there's been emerging data that actually in people with early myocardial infarction, for example, the possibility of FH may be higher.

So in proportion of studies where we had participants with established cardiovascular disease, the possibility of this being present is about one in 17. Now they're not all going to be FH, but it means that actually the coronary care unit where the vast majority of these patients arose from, that's a great starting place. If you see somebody with premature MI before the age of 55, high LDL cholesterol above 190, start thinking about it. If you find one, you can think about cascade testing and finding family members because each effected individual potentially the likelihood in a first degree relative is 50%, 1 in 2. So that becomes really important. And I think those are probably where I'd stop now and maybe take a few more questions, but I think that's the take home message.

Dr Carolyn Lam: Very, very important and practical take home messages. So thanks for that, Kosh. But could I just go back with one basic question? For those of us who don't think of it every day, what is the definition of familial hypercholesterolemia? There are so many definitions out there. Could you simplify it for us?

Dr Kausik Ray: Yeah, so basically all the definitions, the common ones that have been used in making an early diagnosis. So met that criteria, looking at family history, looking at elevated cholesterol levels. There's the Simon-Broome criteria with some clinical signs, as well as family history and genetic mutations. And then there's the Dutch lipid criteria. That's probably the most used in the world, looking at the physical signs, LDL cholesterol levels, and also family history.

And they give you essentially a score of the likelihood of this. And if you like, the gold standard really is probably genetic testing. That's not available in all regions of the world. There may be cost and other issues with that, but essentially that is giving you a diagnosis of a known variant of monogenic disorder and there's over 1,800 or so variants identified. So those are the ways that you can essentially do this.

Dr Carolyn Lam: Thanks, Kosh. Amit, I have to bring you in here. Thank you so much for managing this beautiful paper and recognizing how important it is. You invited an editorial as well. Could you share some of your thoughts?

Dr Amit Khera: Sure. The one thing, Kosh, as we look at this, which is so important to understand the prevalence worldwide and really glad that your group took on this project. But if you look at your figure, what's striking is how many areas are essentially white where there's no data. I mean, huge proportions of countries around the world. Why do you think that is? And how do we close that gap?

Dr Kausik Ray: That becomes really important. So what I would say is this was looking at prevalence and those are areas of the world where prevalence has not been reported. So if I were to overlap that with countries, for example, where we are starting to get definitive diagnosis through gene mutations, for example, there would be fewer gaps. We don't yet have enough data in terms of prevalence in those areas. But if you look, there's a huge gap, for example, in Africa. You've got a few countries that we know that haven't reported prevalent but have published on FH. So we do know it's there. And then you've got South Africa at the bottom and you've got Nigeria now also collecting data.

But part of it is, I guess, one important thing is misclassification. So if somebody dies in those regions of the world, often it's attributed to other causes. And because there is little public health information, because there hasn't been investments on thinking about cholesterol, for example, is it common in our population? If you were in sub Saharan Africa, maybe you think about infectious disease or other things, right? So it's not on the agenda. So there hasn't been that investment and therefore data is then lacking. We starting to see shifts in that, and hopefully this will move the needle a little bit more. And I think once that is done, what will then happen is we will get more reliable estimates from that part of the world. I think we've all got patients from that part of the world. And when I think about my clinical practice, I have patients from the middle of Africa, West, East, Sri Lanka, none of which is represented on that map.

Dr Amit Khera: I think that's a great point. And you know, there's no reason to think that the prevalence is much different. We just have a gap in knowledge there. And I guess the next part comes to implications. As you rightfully discussed many times in your paper, less than 1% of people are diagnosed. And even if someone publishes prevalence data, a diagnosis could involve genetic testing, it could involve broad limpid screening, a combination of both. What do you think is the next step?

Dr Kausik Ray: That's incredibly important. And I think you have to think about two different approaches. They're are the populations already out there living with this condition. So how do we picture those? It's going to be very difficult to think about universal screening in everybody 40-60, for example. So one way is to look at those people, the index case who comes in premature myocardial infarction in particular and use that as a source for cascade testing.

We know that that is cost-effective. There've been formal evaluations of that approach. I do think with the cost of genetic testing, for example, that will make life a lot easier. And I think that that point in CCU, the elevated LDL premature MI should be the start of that thought process. What we tend to do is we have a whole list of medications. We start people on that and it's an afterthought, depending upon the post-treatment cholesterol levels. It shouldn't be.

The other thing I think that you could do, there are lots of opportunities for screening. If you think about those people now, who are under the age of 10, 11, and you think about vaccination programs, you think about pre-college, pre-university health assessments that are often done in many parts of the world. Those offer opportunities to get a blood sample. David Wall did a lovely piece several years ago, looking at child parents screening, reverse cascade, if you will. And that showed that it could be cost effective. You don't need a small sample of blood. You can use DNA. And each of those interactions gives you an opportunity for screening.

What I'd love to see is we all think that there will be or there could be an update of the WHO recommendations for cholesterol management. And that might advocate, for example, universal screening for cholesterol before the age of 29. If that is done, then if you think of low middle-income countries, a lot of those white gap, we will start to see those things being or this condition being picked up and potentially huge numbers of lives being saved. And because this is a genetic condition which is ultimately dominant, you find one, you can either exclude or find other people early and early diagnosis changes prognosis as you well know.

Dr Amit Khera: Thank you for that, the implications and the potential profound if one could implement that broad screening. And as you pointed out early treatment, and I have one last question for you and it has to do with other part of the coin, which you touched on, which is the ASCBD. You know, your estimates of one and 17 were really helpful. I think many people aren't appreciative of how relatively common FH is in patients with coronary artery disease. And you talked about the implications being cascade screening of family members, but I know you work in therapeutics as well. There've been some data about maybe even earlier intervention or more aggressive intervention once someone's diagnosed with FH and after cardiovascular disease. What are your thoughts on that part of the investigation?

Dr Kausik Ray: Yeah, no, that's a really important question. So most of the studies that have actually looked at ACVD, they didn't utilize, for example, a genetic diagnosis. So it's largely the clinical phenotype. And remember, you have an A priority bias in terms of scoring on the Dutch Lipid Network Criteria, by virtue of the fact that you've had premature disease. Some of these people will probably have elevations in LP(a) and others it could be polygenic hypercholesterolemia, which does carry an increased risk, but not as much as FA.

If you could separate those three out the implications really are if you think about the ACVD patient population with true FA, you basically missed 40 years of unexposed exposure. And so in these people, I think those are people that we should be thinking about mainly more aggressive intervention with either lower LDL targets, because the absolute benefit is likely to be much, much greater. So I think that's the key implication I think of these findings.

Dr Carolyn Lam: Thanks so much, Amit. Thanks so much, Kosh. As someone living in an area where there is... It's white on that map as well, but no available data in Southeast Asia, I've learned a lot.

Thank you, listeners, for joining us this week. You've been listening to Circulation On the Run. Please tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association 2020.

Circulation May 26, 2020 Issue

25 maj 2020 | 25 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Today's feature discussion is the first huge look at the global, regional and national burden of calcific aortic valve disease and degenerative mitral valve disease over a huge period, from 1990 to 2017. Very important discussion coming right up after this coffee chat.

Greg, do you mind if I go first?

Dr Greg Hundley: Go ahead, Carolyn.

Dr Carolyn Lam: The first paper I want to talk about applies novel single cell transcriptomics to unveil new insights into pressure overload cardiac hypertrophy. Here's your quiz, Greg, ready?

Dr Greg Hundley: Well, I'm choking on my coffee here, but go ahead.

Dr Carolyn Lam: All right, I was thinking of asking you about single cell transcriptomics but let me just tell you the results. Single cell RNA sequencing is a new and rapidly advancing technique that can comprehensively characterize gene expression and relationships among individual cells.

Dr Wang from Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, and Peking Union Medical College and colleagues analyze the transcriptomes of 11,492 single cells and identified major cell types, including both cardiomyocytes and non-cardiomyocytes based on their molecular signatures. They did this at different stages during the progression of pressure overload induced cardiac hypertrophy in a mouse model.

Their findings not only illustrated dynamically changing cell type crosstalk doing pathological cardiac hypertrophy, but also shed light on strategies for cell type and stage specific interventions in cardiac disease. For example, subtype switching of macrophages was found to be a key event underlying the transition from normal to decline dejection fraction in cardiac hypertrophy.

Thus, targeting macrophages in hypertrophy for example, during the switch could attenuate disease progression. All of this is discussed in an editorial by doctors, Zhang and Zhou from University of Alabama in Birmingham.

Dr Greg Hundley: Oh wow. Carolyn very important macrophage infiltration and another role for those, that cell type. Well, my first paper gets at the topic of reversal of these factor Xa inhibitors.

In this particular patient population, it's the situation where we're dealing with intracranial hemorrhage. The article comes from Dr G Morgan Jones and colleagues from the University of Tennessee Health Sciences Center. Since the approval of oral factor Xa inhibitors, there have been few papers published really regarding the ability to neutralize the anti-coagulate effects of these agents, particularly after intercranial hemorrhage.

Dr Carolyn, this is a multi-center, retrospective, observational cohort study of 433 patients. Then it received apixaban, or rivaroxaban, and then developed an intercranial hemorrhage. They then subsequently received prothrombin complex concentrates in that period of time between 2015 and 2019.

Dr Carolyn Lam: Wow. How did these participants who had intracranial hemorrhage, how did they fare after receiving these prothrombin concentrates?

Dr Greg Hundley: Yeah, well, administration of the prothrombin complex concentrates after, apixaban or rivaroxaban in the setting of intracranial hemorrhage, provided a high rate of excellent or good hemostasis. That was in nearly 82%, coupled with an adverse consequence of 3.8% of those experiencing a thrombosis.

Thrombosis occurred in 25 patients who had a total of 26 thrombotic events of which 22 occurred in the first 14 days, following the prothrombin complex concentrate administration. One patient had documentation of an infusion related reaction. For the full cohort of patients, in the hospital mortality was 19% and the median ICU care and hospital length of stay were two and six days respectively.

Carolyn, these cohort analyses seemed to demonstrate the possibility of success and similar to other observational cohort studies. The results of this study suggest that future randomized control trials evaluating the clinical efficacy of these prothrombin complex concentrates in patients with factor Xa inhibitor related intercranial hemorrhage are needed.

Dr Carolyn Lam: Nice, Greg. You know what? I'm going to start with a quiz. True or false, heart failure with reduced ejection fraction is characterized by blunting of the positive relationship between heart rate and left ventricular contractility known as the force frequency relationship?

Dr Greg Hundley: Well, Carolyn, this is one of those where if I go 50/50, you'll knock out the wrong answer. Let's say, I'm going to go, true.

Dr Carolyn Lam: You're so right, Greg. This next paper really deals with this. It's from corresponding author, Dr Witt from Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds in UK and colleagues who previously described that, tailoring the rate responsive programming of cardiac implantable electronic devices in patients with HFrEF based upon individuals noninvasive force frequency relationship data, really improves exercise capacity. Addressing this reduce force frequency relationship and HFrEF.

Now in the current paper, they sought to examine whether using force frequency relationship data to tailor heart rate response in HFrEF with inpatients, with HFrEF and cardiac implantable electronic devices would favorably influence exercise capacity and left ventricular function six months later.

They conducted a single center, double blind, randomized parallel group trial in 83 patients with HFrEF. With a cardiac implantable electronic device and randomized to tailored rate response programming based on these individuals force frequency relationship versus conventional age guided rate response programming. The primary outcome measure was changed in walk time on a treadmill walk test.

Dr Greg Hundley: Wow, Carolyn. So this is a really detailed analysis. What did they find?

Dr Carolyn Lam: They found that rate adaptive cardiac implantable electronic device programming taking into account the at normal force frequency relationship in these patients, was associated with improved exercise time.

Force frequency relationship guided heart rate settings had no adverse effects on left ventricular structure and function. While conventional settings were associated with a reduction in left ventricular ejection fraction.

Out of the box age guided rate adaptive pacing, might be a sub optimal choice in patients with heart failure and an assessment of the force frequency relationship might be of clinical benefit in facilitating personalized rate adaptive programming.

Dr Greg Hundley: Very nice.

Dr Carolyn Lam: Thanks Greg, but there's other stuff I want to tell you about in this issue. There's a research letter by Dr Gambier on Molecular Imaging of Infective Endocarditis with Floral Multiple Trials PET-CT. This is the first time that a Florine 18 PET tracer has been used to specifically image bacterial infection of the heart valves with high sensitivity and specificity in an animal model.

Dr Greg Hundley: Oh, good job, Carolyn. Those flooring tracers, very interesting. Another application perhaps. Well, in a perspective piece, I have an article Carolyn from Dr Orly Vardeny from University of Minnesota Medical School in Minneapolis and remembers the prior cardiovascular complications from influenza. And how those experiences may be useful in anticipating some of the cardiovascular complications that we may see from SARS-CoV-2.

In a separate article, Dr Aatish Garg and collaborators from VCU Health, present an ECG case of syncope in an individual with severe aortic stenosis status post bioprosthetic aortic valve replacement and coronary artery bypass grassing. Who also has paroxysmal AV block?

Then finally, Carolyn, Professor Concepcion Peiró from Universidad Autónoma in Madrid. Has an on my mind pace discusses ACE inhibition and our abuse in relation to the SARS-CoV-2 to virus bonding to ACE two binding sites within the respiratory epithelium.

Well, Carolyn, how about we get on to that feature discussion? I can't wait to hear about aortic and mitral valve disease over nearly 30 years.

Dr Carolyn Lam: Let's go Greg. Nondramatic valvular heart disease is really common throughout the world. However, no studies have previously estimated their global or national burden, that is until today's feature paper. That's part of the Global Burden of Disease, or GBD, 2017 study. I am so pleased to have with us a corresponding author, Dr Greg Roth from University of Washington. As well as Victoria Delgado, our associate editor from Leighton University Medical Center.

What a great topic to discuss. Nondramatic valvular heart disease, meaning calcific aortic valve disease, degenerative module valve disease, all the stuff we see and have to deal with now. Greg, could you please tell us about this GBD effort and really what you found?

Dr Greg Roth: Let me tell you a little bit about the Global Burden of Disease Study and then why we wanted to explore this question and then what we found. I am the lead for cardiovascular research at the Institute for Health Metrics and Evaluation in Seattle at the University of Washington. We're the coordinating center for the Global Burden of Disease Study. It's now in its second decade, and it's a large-scale effort to quantify the lost health due to early death and disability for every country in the world.

This is a huge effort with over 5,000 people around the world working on it. We work closely with governments around the world, as well as the World Health Organization, as well as county, state, and other authorities in the US.

Our goal is really to bring together all of the evidence in the world to bear on important health policy questions. One of the areas that I've had a long interest in is valve disease.

I'm a practicing cardiologist at our county hospital here in Seattle, as well as an echocardiographer. I was really excited by the idea of bringing together my passion for taking care of patients with valve disease and looking at how to use diagnostic imaging to take better care of them and the disease modeling research that I do at the institute.

We decided a couple of years ago after exploring the global patterns of rheumatic heart disease, that we would turn our focus towards these really important questions of non-rheumatic valve disease. There's obviously a very large literature and lots of active research around the clinical pathways that we need to follow for patients with calcific valve disease and mitral valve disease that's not due to rheumatic causes. Obviously in recent years, we've got amazing technologies and interventions that we're using more and more frequently like percutaneous interventions.

However, we had not done the work to turn this really interesting tool, the Global Burden of Disease Study, towards looking at these important causes. We pulled together every data source we could find on the population level burden of nonrheumatic valve disease and then using a range of techniques, and we rely heavily on tools that come out of data science.

These include computer disease modeling tools that we've developed as well as ensemble models and other sort of big data approaches to pull all of this together into comparable, consistent estimates of death and prevalence. Then we're also really interested in using those to estimate what we call summary metrics of health, like disability adjusted life years. We do this for a very long time series. So we went back all the way to 1990 and we looked all the way to 2017.

Then we're able to get a really good sense of not only what the impact of these diseases are, but how they compare to the 350 other diseases that we estimated in exactly the same way for the Global Burden of Disease Study. Also, where is the burden of these particular conditions going up? Where is it going down?

We're really excited to be able to pull that together into this paper. In which we report the global, regional, and national burdens of calcific aortic valve disease and degenerative mitral valve disease. As well as a right sided valve disease that's not due to congenital endocarditis causes, which we estimate separately in the study.

Dr Carolyn Lam: Greg, you say, you're excited. I can definitely speak, I think on behalf of both Victoria and Augie, that we're the ones excited publishing this really great piece of work here in circulation. You know personally, I'm a great fan of your work in GBD. Tell us the results.

Dr Greg Roth: What we found was that in 2017, there was an estimated 12.6 million cases of calcific aortic valve disease in the world and 18.1 million cases of degenerative valve disease globally. With higher rates of calcific valve disease, among men and higher rates of degenerative valve disease among women. Now that is an aggregate.

We've produced estimates for every country in the world and for larger countries with more than 200 million people, we've gone down to what we call the first administrative level. So, US states, Chinese provinces, and we do this in the larger countries, but when you add it all up, you get those numbers.

We also found that there were just over a hundred thousand deaths globally each year due to calcific aortic valve disease and about 35,000 deaths reported due to degenerative mitral valve disease. I think this is really interesting because of course, as clinicians, we have a lot of experience with sources like cohort studies, and trials, and registries, but we have not actually looked at what's actually the world's largest public health reporting system, which is vital registration, meaning death certificates.

Now, most of us have filled out that certificates and we always wonder, how reliable are there? And there's clearly limitations. In fact, a huge amount of our work at the Global Burden of Disease Study is dealing with the limitations of death certificates, looking for bias, and adjusting that bias when we can, but these are death certificates where somebody's entered these causes as the underlying cause of death.

I think when that actually shows up on a death certificate, that's actually a real signal to us that there was a physician out there who felt pretty strongly that that was the sort of trigger that led to the patient's death.

We also found that aging and population growth are leading to about a hundred percent increase over this period of time over the last 25 years in the number of deaths due to these nonrheumatic valve diseases. If we age standardized, we see that the trend is flat, but if you're running a health system or a minister of health, you need to hear that message that with aging and population growth affecting almost every country in the world, you're going to see dramatic rises in the number of cases of both of these conditions showing up on the doorstep of all of your hospitals.

Dr Carolyn Lam: Fantastic Victoria, could you put these findings in context for us and maybe take us behind the scenes a little bit at what the editors thought?

Dr Victoria Delgado: These are very important data, because so far, for example, we have, as Greg said, registries and one of the most known registries was for example, in Europe, The Valvular Heart Survey that was done in 2001, if I remember well. Has been redone recently, it was last year published in circulation. The other one with a very large data is coming from counties. With similar data to the results that are publishing now.

For example, if you compare those two registries with much smaller populations, in US, they always report much, much frequently the genetic mitral valve regurgitation. While in Europe, aortic stenosis is the most frequent one, calcific aortic stenosis. Here, I was again surprised with in the global population that again, degenerative mitral valve regurgitation is much more prevalent than calcific aortic stenosis, but you can see that there was an increase of 124% in the prevalence of calcific aortic valve disease in 2017.

I wonder if this is related to the awareness of the risk associated with aortic stenosis and they invent of a new therapies, transcatheter therapies, with the TAVI for example, or transcatheter aortic valve replacement, which has opened the door for an effective treatment for many patients that before were simply denied for surgery. I don't know if you have further insights into that.

Dr Greg Roth: Yes. I think that's a really important point, that we see a lot of variation in the data. While we have millions of death certificates to look at all around the world. Really scores of millions, where we can look for trends and patterns. The population level data on nonrheumatic valve disease is actually quite limited compared to most diseases.

We did a very aggressive perspective review of the published and gray literature and found about 50 sources reporting prevalence for these conditions that were usable in our study. For the most part, those studies are not long time series. We have to estimate trends, piecing together data from different populations.

Now, there are a couple of places in the world where you can get a long trend of time where they've gone back repeatedly in the same population and looked with echo, which you obviously need here to make these diagnoses.

As far as we can tell, and these are just a handful of studies, the trend is flat. We don't see large increases. Now, the increases in our study were completely driven by aging and population growth and the age standardized rates. The epidemiologic pattern for this disease is that it's flat and for mitral valve disease, maybe trending down a little bit.

I think it's clear that in places where there's been a lot of attention paid either because of new therapies, like TAVR or new access to diagnostic screening with the growth of echo cardiography and other screening methods, that is a limitation of the study, for sure. I think what it really focuses me on is the idea that we need better data. We need to think about ways and probably more cost effective ways of surveilling for these conditions, but I'll tell you something that was really interesting, that we found is that, in the United States where we relied heavily on administratively coded data, because we have that in a uniform format for every state and we have a long time series for that, and we have complete vital registration.

We looked at the state level and we found that the all ages rate, was actually going up. Meaning it wasn't just population growth and aging, but in about a third of the states, the true epidemiologic rate of the disease was going up. Meaning it's becoming more common even if you control for the change in age structure of a country like the United States over time.

I think that given the fact that we're seeing this explosion of obesity around the world, and we know that atherosclerotic risk factors can be a major driver of let's say calcific aortic valve disease. I mean, an interesting question is, is valve disease going to be sort of a canary in the coal mine? Are we going to see more of it at younger ages?

Traditionally it's been the oldest patients who actually survived the longest and tend to be healthier, who we can actually find having the disease, but I wonder, are we going to see more of that as patients present with more obesity. Unfortunately we know that reversing or controlling those atherosclerotic risk factors hasn't paid off in big ways for preventing calcific aortic valve disease. It's complex and like mitral valve disease, clearly there's likely to be a very strong genetic component as well.

Dr Carolyn Lam: Greg, you mentioned a little bit more about the age effect, but you did mention some sex differences. Could you just clarify a little bit about that and maybe the interaction between the two?

Dr Greg Roth: What we've all been taught, or at least what I was always taught, was that there was more mitral valve disease in women. We actually did find that in the study and that was reassuring because when we went back to look for the source of that sort of common teaching, actually, it's pretty hard to find.

I think it actually comes, my guess is, from a lot of people's clinical practice. To see that match-up between what we thought was going to be true in terms of the relative prevalence by sex for these two major diseases, calcific aortic valve disease and degenerative mitral valve disease was reassuring. It suggested that the data we have is actually picking up on real patterns and patterns that match sort of our clinical experience as well.

One of the interesting things about the interaction between age and sex, is that women live much longer on average than men. As women age into those oldest years, what we actually see is a decline in the burden of disease. There's an increase in stroke, but for everything else, those women are truly survivors. Actually we see less bowel disease and cardiovascular disease in general, in the oldest old women.

What we do see is a massive rise in cognitive impairment and dementia. That's a very active area of research for us right now. The interaction between atherosclerotic risks, which can drive things like valve disease and of course, coronary disease and stroke and then the cognitive impact is a really important area of research. There are a couple of great papers that have come out even just in the last few weeks.

I think this question of how risk is going to impact people in those oldest age groups? Is really important. We know the population is aging. We know that in some places, life expectancy is increasing to the point where we really need to rethink what the disease patterns are going to be in the oldest old.

Dr Carolyn Lam: Indeed. So the feminization of aging is kind of what I like to call it, but yikes Victoria. Could I maybe ask you to please give the final words of advice and maybe the take home messages?

Dr Victoria Delgado: I think that this data are really welcomed because as Greg said, we need to understand better how we can modify the prognosis of these prevalent and how we can tackle it and for that we need data. I think that these are very welcomed data.

Now, how we are going to do it in the future? That's a great question. I don't have the answer right now, but I think that increasing the awareness that nonrheumatic valvular heart disease can impact as well on the outcomes of the population, is important to know. I think that people need to have access to diagnostics best particularly echo cardiography is very available imaging technique and very feasible. We can have right now developments where we can do the echo cardiography with our phone by adding one of the probes.

I think that in the future, we may see more and more valvular heart disease that probably was already there, but we just need to increase the awareness. From those data, learn how we can treat those individuals if they need and how we can improve the outcome of these individuals.

Dr Carolyn Lam: Thank you, Victoria. Thank you, Greg. More awareness and more good data needed.

Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation on the Run: Special COVID-19 Edition

21 maj 2020 | 25 min

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal

and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National

University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, the director of the Pauley Heart Center at VCU health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg. Today we have a special episode focused on COVID‐19 pandemic, something that has just

affected us so severely worldwide, it really needs no introduction. Why are we doing a special issue?

Well, I think it very quickly got recognized that patients with cardiovascular disease do seem

predisposed to severe COVID‐19 syndrome, and that these patients can have an acute COVID‐19

cardiovascular syndrome, in fact. We're going to be talking all about this in a series of interviews about

the syndrome, the clinical presentations, what this implies for management. Is the pulmonary embolism

involved in the pathophysiology of all of it? And what are ways that we should use to monitor or even

screen these patient?, For example, what's the role of troponins?

Dr. Greg Hundley:

Yes, Carolyn. I am excited, just as well as you, and our first paper today is from Dr. Leslie Cooper, from

the Mayo Clinic. He's really done a nice review describing the disease process and the management of

acute COVID‐19 and the cardiovascular syndromes.

Dr. Greg Hundley:

Leslie, we'd like to welcome you to Circulation on the Run and just to get started, I'm wondering, could

you tell us a little bit about the genesis of your paper and then also perhaps some of the mechanism,

how does this virus affect our systems and promote cardiovascular disease?

Dr. Leslie Cooper:

In mid‐March as the COVID, crisis was taking off in this country, I was on a telephone call with Dr.

[Biykem] Bozkurt and [Dr. Mark] Drazner, from Texas. We realized that there was a terrific need for

clinicians to have an overview of how to manage the COVID‐19 impact on the heart. There was also, at

that point, very little clinical data about the mechanisms and what the real pathogenesis was. We set

about and the rapidly put together the available world's literature. That is what was ultimately

published here in Circulation about two weeks ago.

Dr. Greg Hundley:

Tell us a little bit about that mechanism.

Dr. Leslie Cooper:

It became apparent that there is not one specific mechanism. We initially thought that like the Coxsackie

viruses, this could be a direct cardiac damage, but clinically as we reviewed the literature, it became

clear that it's more systemic. The older patients who have preexisting cardiac disease, hypertension,

coronary disease, other risk factors, such as diabetes or obesity have a much greater risk of cardiac

involvement and the consequences of that cardiac involvement are very substantial.

Dr. Leslie Cooper:

In addition, when you get a profound cytokine storm from the systemic infection, that can depress

cardiac function. A combination, in individuals, of cytokine mediated damage from systemic

inflammation, stress induced cardiomyopathy, as you would see in takotsubo, as well as hypoxia and

perhaps increased pressures in the lung from, as Carolyn mentioned, pulmonary emboli, and finally

direct viral damage. Viruses can infect macrophages in the heart. There is a growing body of literature

that there can be a direct effect independent of the systemic infection. The answer is there are multiple

factors each of which may have its own therapeutic target.

Dr. Carolyn Lam:

Oh, I love the way you explained that so clearly Leslie, and in fact, this is really bringing back sweet

memories of when I was training under you at Mayo Clinic. I won't say how many years ago, but there

comes the question, you know so much about myocarditis, in general, and a different viral myocarditis.

Could you maybe tell us a little bit about how this one may or may not differ and also how this impacts

management?

Dr. Leslie Cooper:

The coronaviruses have a very different mechanism of cell entry and propagation. It does not appear

that this particular infection in the heart is causing the kind of antigen specific immune reaction that you

see classically with a Coxsackie virus. We're not seeing necessarily a lot of auto‐antibody, molecular

mimicry. We're not seeing a lot of T‐cell infiltrate. We are seeing some infection of macrophages, and

it's not yet clear how many of those were infected peripherally and then migrated to the heart. The

histology is quite different and the acute damage is therefore, more subtle. You're not seeing sheets of

lymphocytes and the targeted therapies would not be necessarily directed at those cells.

Dr. Leslie Cooper:

Having said that, inflammation more broadly, for example, anti‐IL‐6, anti‐IL‐1 type, anti‐cytokine

mechanisms are currently under evaluation in clinical trials, and they may be quite meaningful. Quite

meaningful in the setting of the systemic inflammation. When you compare this to a SARS and other

coronavirus infections, I'd like to say, we have known that occasionally a coronavirus can cause

myocarditis, for 40 years. It's simply not very common. It predisposes the individual or makes the

particular virus more cardiovirulent at this point.

Dr. Carolyn Lam:

All listeners, you have to get ahold of this beautiful paper. As Greg was actually suggesting a little bit

earlier, they're this beautiful figure that you have to refer to that shows a management pathway and

considerations. Also, very lovely illustrations of potential mechanisms. Leslie, could you also let us know

then, in the overall management, not just treatment, where is the place then, for things like myocardial

biopsy?

Dr. Leslie Cooper:

I think you have to start with the clinical presentation. COVID‐19 as a syndrome, and SARS‐CoV‐2 as a

virus, can present with multiple cardiac syndromes. The first would be ST segment elevation, like

myocardial infarction with normal coronary arteries. In that setting, it may be microvascular obstruction,

or it could be myocarditis or stress cardiomyopathy, perhaps in a younger person who doesn't have risk

factors.

Dr. Leslie Cooper:

Can also present with a primary cardiomyopathy, a heart failure presentation, shortness of breath,

systolic dysfunction. And finally it can present as a pericardial effusion, not the most common

presentation, but it's important to realize that just like other viruses, this can cause an epicardial or

pericardial inflammation.

Dr. Leslie Cooper:

Management really depends on the clinical syndrome and I'd emphasize guideline‐directed medical

management. If it's an arrhythmia, a ventricular tachycardia or heart block, manage that per the current

guidelines. The same is true for systolic heart failure.

Dr. Leslie Cooper:

In addition, I would say that since most patients with COVID infection do not have cardiac involvement,

you should first treat the whole patient. First, see the clinical syndrome. What is the dominant problem?

Is it a lung problem? Is it kidneys? Then, if there is a cardiac manifestation, we recommend starting with

a troponin. If the troponin is elevated, proceed to a point of care echo.

Dr. Leslie Cooper:

We do want to minimize exposure of allied health staff and physicians to the virus. We do not

recommend multimodality imaging or heart biopsy upfront. Having said that, if the patient has

substantial left ventricular systolic dysfunction, and they're already in the cath lab, because you're

excluding coronary disease, our paper does recommend that you consider an endomyocardial biopsy to

find the mechanism of left ventricular dysfunction.

Dr. Greg Hundley:

Very good, Leslie.

Dr. Greg Hundley:

Could you close this out, a little bit about therapy when we have patients with this severe hypertension,

respiratory abnormalities requiring ventilation, and then also these devastating cardiovascular effects.

Are we looking at anti‐inflammation is primarily the target as opposed to antiviral therapy?

Dr. Leslie Cooper:

Right now, there are a couple of clinical pearls. Number one, as in all cardiogenic shock, you don't

have... Sinus tachycardia is not a therapeutic target. You may need that because of low stroke volume.

You want to allow when it's compensatory for the tachycardia. Once you've treated with guideline

directed therapy, the arrhythmias and the cardiomyopathy appropriately, specific mechanistic

interventions, such as antiviral therapy or anticytokine therapy should be given within the context of a

clinical trial, wherever possible.

Dr. Leslie Cooper:

Our article recommends that if you have access to a clinical trial and in this country, the convalescent

plasma trial, is up and running. Mayo is leading that for the country. It's available at approximately 600

sites. We would recommend, first of all, enrollment in a trial because we then will understand the

mechanisms and the best treatment. If you don't have access, it really depends on the clinical syndrome

and how sick the patient is. Patients who are less sick have been treated with things like

hydroxychloroquine. People who are more sick, we move on to a convalescent plasma and anticytokine

therapy such as tocilizumab.

Dr. Greg Hundley:

Very good. Well, Leslie, we want to thank you for sharing this wonderful review with us at Circulation.

We feel very privileged to have the opportunity to publish this and also to share it with our readership.

Again, thank you for all of your frontline work at the Mayo clinic and helping participate in trials and

things of this nature to combat this terrible disease.

Dr. Leslie Cooper:

Thank you so much.

Dr. Carolyn Lam:

Greg, from acute COVID‐19 cardiovascular syndrome to now, all about troponins. I am so, so thrilled that

Dr. Nicholas Mills is here with us, not only our associate editor, but also corresponding author of the

next paper. He's from University of Edinburgh in UK. Nick, I love the question that you asked in your

title, "Are troponins an ally or a foe in the fight against COVID?" Explain, please.

Dr. Nicholas Mills:

I strongly believe that they can be an ally, but I recognize amongst cardiologists and clinicians around

the world that are grappling with this new condition, that the use of biomarkers can be contentious.

We're still learning very much about this condition and how it affects the heart. Therefore, it's difficult

to provide very clear guidelines. It's how you interpret the cardiac biomarkers in this condition. The

reason I feel strongly that they can be an ally is, they're easy to measure, they're cheap, and you don't

require a direct patient contact to obtain the result of the test. It gives us some fundamental

information about whether the heart is involved or not.

Dr. Greg Hundley:

Nick, can you tell us which biomarkers do you favor and is it high sensitivity troponin? Is it regular

troponin? For our listeners in many different hospitals across the world, what would you suggest?

Dr. Nicholas Mills:

The evidence that has that merged very rapidly over the last few weeks and months suggests that our

range of cardiac markers have very, very high prediction for poor outcome. Whether that's predicting a

patient that might deteriorate and require admission to an intensive care unit for ventilation, or

develop complications such as acute kidney injury or death.

Dr. Nicholas Mills:

There are a number of biomarkers that look very useful for predicting the course of a patient. The

strongest, in most studies, is cardiac troponin. I think it's because we do have such sensitive assays now.

High sensitive assays are such a fabulous way of getting a barometer of your heart health. The heart of

course, is a fairly fundamental organ. If this condition is going to affect to any other organ out with the

lungs. If it's the heart, you're going to be in trouble. I think high sensitive troponins, in particular, give us

such exquisite information about the systemic complications of this virus that they are perhaps above all

other markers, the most useful for predicting outcomes. Now, that clinical question goes beyond that.

We need to understand how this virus is affecting the heart and whether we can intervene in any shape

or form in response to these results in order to try and improve the course for these patients. That is a

Circulation May 19, 2020 Issue

18 maj 2020 | 26 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: We've got a juicy, juicy feature discussion coming up. It's on a pre-specified analysis of the ODYSSEY OUTCOMES randomized clinical trial, this time to ascertain whether PCSK9 inhibition reduces the risk of peripheral arterial disease events or venous thromboembolism after acute coronary syndrome. And, also to answer, these effects are related to levels of lipoprotein(a) or LDL cholesterol. I'm going to keep everyone guessing, as we get on our coffee chat and talk about the other papers in this issue.

And I want to go first, because the first original paper I want to discuss is really quite related to the feature discussion too. And it asks the question, what is the relationship between cholesterol levels and risk of venous thromboembolism? And, what is the effect of PCSK9 inhibition on the risk of venous thromboembolism? So this is from Dr Marston from the TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts, and colleagues who performed a post hoc analysis of the FOURIER trial, testing whether evolocumab reduces the risk of venous thromboembolic events. That is, deep venous thrombosis, a pulmonary embolism. The authors then looked at data from FOURIER and the ODYSSEY OUTCOMES trial and combined them in a meta-analysis to assess whether there was a class effect of PCSK9 inhibition on the risk of venous thromboembolism. As a reminder, the ODYSSEY OUTCOMES trial tested alirocumab as the PCSK9 inhibitor.

Dr Greg Hundley: Well, Carolyn, what did they find?

Dr Carolyn Lam: Well, first Greg, remember, this is the first study to demonstrate a significant reduction in venous thromboembolism with PCSK9 inhibition. Interestingly, the reduction in venous thromboembolism was associated with the degree of lipoprotein(a) lowering and not LDL cholesterol lowering, suggesting that lipoprotein(a) may be the mediator of venous thromboembolic risk. More coming up in our feature discussion.

Dr Greg Hundley: Wow, Carolyn. Well, I'm going to go into the world of PCSKs, but talk about PCSK6. So this study involves a secretome analysis of cardiomyocytes as novel players in cardiac remodeling after myocardial infarction and the corresponding author is Dr Florian Leuschner from Heidelberg University. So Carolyn, we know that acute occlusion of coronary artery results in swift tissue necrosis and bordering areas of the infarcted myocardium may also experience impaired blood supply and reduced oxygen delivery leading to altered metabolic and mechanical processes. While transcriptional changes in hypoxic cardiomyocytes are well-studied, little is known about the proteins that are actively secreted from these bordering cells.

So in this study, the authors established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis.

Dr Carolyn Lam: Wow, sounds like very advanced methods and what did they find?

Dr Greg Hundley: Okay. Carolyn lots of results here. They found that PCSK6 expression was elevated in hearts of mice, following three days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements and human serum also indicated distinct kinetics for PCSK6 in patients suffering from acute myocardial infarction with a peak on day three post infarction.

One of these beautiful studies combining basic science and human subjects in the same paper. In addition, adeno-associated virus nine mediated cardiomyocyte specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis as well as decreased left ventricular function after MI. So Carolyn, this study demonstrates how novel mass spectrometry-based approach allows the investigation of the secretome of primary cardiomyocytes. That's a first for that technique. And then analysis of hypoxia-induced secretion led to the identification of PCSK6 to be crucially involved in cardiac remodeling after MI, demonstrating increased collagen expression and cardiac fibrosis in those border zones.

Dr Carolyn Lam: Wow, fascinating, Greg. Well, I want to switch tracks here. Maybe ask, when you're choosing between antithrombotic therapies for patients with atrial fibrillation and a recent acute coronary syndrome, have you ever wondered what is the tradeoff of risk? Risk of bleeding and benefit that would be in terms of prevention of ischemic events over time? Well, guess what, I'm not going to put you on the spot here because our next paper addresses this very question. And it's from corresponding author, Dr Alexander from Duke Clinical Research Institute and colleagues who performed a post hoc analysis of the AUGUSTUS trial.

Dr Greg Hundley: Okay, Carolyn. I'm going to digress for just a minute here. We have this wonderful producer, Augie Rivera, and he's just fantastic and we should give him accolades because he really helps put all these together. Now I'm not going to ask him this time, but maybe in one of our future discussions, we may need to bring him into one of these because of his expanded knowledge of all of science, but getting back, Carolyn, can you remind us what is the AUGUSTUS trial?

Dr Carolyn Lam: All right, so in the AUGUSTUS trial, patients with AF and a recent ACS and/or PCI taking a P2Y12 inhibitor had less bleeding and rehospitalization with apixaban, than vitamin K antagonists and less bleeding with placebo than aspirin. The composite of death or hospitalization was also reduced with placebo compared to aspirin. However, the risk of several recurrent ischemic events, including stent thrombosis, where numerically higher in patients assigned placebo. Further analysis of the stent thrombosis outcomes suggested that most of the increase in risk was early within 30 days of randomization.

And hence the objective of the current paper, which is a post hoc analysis to explore the balance of risk and benefit using a variety of composite outcomes between randomization and 30 days and between 30 days and six months over time comparing apixaban versus vitamin K antagonists and aspirin versus placebo. So, here's what they found. Apixaban caused fewer ischemic and bleeding events than warfarin in the first 30 days after ACS and/or PCI and similar or fewer ischemic and bleeding events from day 30 to six months. Use of aspirin acutely, and for up to 30 days, resulted in an equal tradeoff between an increase in severe bleeding and reduction in severe ischemic events. However, after 30 days aspirin continued to increase bleeding without significantly reducing the ischemic events. So these results really informed shared patient-centric decision making regarding the ideal duration of use of aspirin after an ACS and/or PCI in patients with AF already receiving oral anticoagulation.

Dr Greg Hundley: Very nice, Carolyn. You know, lots of data coming out about how we perform anticoagulation, the administration of aspirin, both an atrial fibrillation, ischemic events, those with stents and this is just another piece of important data that we're so fortunate to have published in circulation. Well in the rest of the issue Carolyn, there's a lot of information. I want to talk about a research letter from Dr Armand Killick from the University of Pittsburgh, and he describes the outcomes of the first 1300 adult heart transplants in the United States following a policy change in the U S related to allocation of hearts.

In an EKG challenge, Dr Nobuhiro Takasugi from Gifu University and colleagues reviewed the etiology of wide complexes. Are they aberrantly conducted supraventricular beats? Are they premature ventricular complexes or intermittent ventricular prereq citation in an individual 70 years old presenting with symptoms of palpitations? Then Carolyn, in one of our COVID-19 articles, there's an in-depth piece by Dr Kevin Clerkin and associates from Columbia University. And they review coronavirus disease that is caused by severe acute respiratory syndrome, coronavirus 2 or SARS-CoV-2, which invades cells through the angiotensin converting enzyme or ACE-2 receptor. Among those with COVID-19, they note there is a higher prevalence of cardiovascular disease and more than 7% of patients suffer myocardial injury as evidence from elevated cardiac troponin values from the infection and in 22% of those that were critically ill.

And despite ACE-2 serving as a portal for infection, the role of ACE inhibitors or angiotensin receptor blockers requires further investigation. And right now, as you know, in your field is a heart failure expert, they are not recommendations to consider discontinuation for those drugs. And then lastly, in a prospective piece, Professor Gianluigi Condorelli from Humanitas University in Milan, presents critical organizational issues for cardiologists in this COVID-19 outbreak, including prioritization of unstable patients with cardiovascular disorders by postponing visits, and in this situation they did so by 80%, reorganizing clinical activities in terms of ward, ICU beds and outpatient visits, using a hub-and-spoke model to prioritize management acute MI, and then finally rapidly acquiring and training physicians and staff in the correct use of PPE. All very valuable lessons from Italy that was so hard hit by this devastating disease.

Dr Carolyn Lam: Indeed, and you know what, Greg, I just want to tell everybody about our circulation YouTube channel, where we have frontline interviews with people dealing with this from all over the world. Thank you to Augie and his team for making all of this happen. Let's go on to our future discussion, shall we?

Dr Greg Hundley: Absolutely.

Dr Carolyn Lam: Patients with acute coronary syndrome are at risk of peripheral artery disease events and venous thromboembolic events. Now we've heard a lot about PCSK9 inhibitors in patients with acute coronary syndrome, but what is the effect of PCSK9 inhibition on the risk of PAD or venous thromboembolic events? Well, we're about to find out. The feature paper is a pre specified analysis of the ODYSSEY OUTCOMES trial. And I'm so pleased to have the first and corresponding author, Dr Greg Schwartz with us from the University of Colorado, School of Medicine, as well as our guest editor, Dr Erin Michos from Johns Hopkins School of Medicine. So welcome. And Greg, could I ask you to start us off. Tell us why you looked at this in ODYSSEY OUTCOMES and what you found.

Dr Gregory Schwartz: All of our patients or nearly all of our patients with acute coronary syndrome have had an atherothrombotic event and most of them also have a heightened inflammatory state. These factors are also thought to have a role in the pathogenesis of peripheral artery disease events, and perhaps also venous thromboembolism. We typically think of the risk factors for peripheral artery disease as being diabetes and smoking, and less so dyslipidemia, although dyslipidemia may play a role in PAD events as well. And although the association of LDL cholesterol levels with PAD events has been inconsistent in the literature, there's more consistency actually with levels of lipoprotein(a) and the risk of PAD events.

And that kind of makes sense because we think that Lp(a) has both atherogenic and pro-inflammatory and perhaps also prothrombotic properties. So elevated levels of that lipoprotein might promote the risk of PAD events. Now statins, which are obviously the mainstay of our treatment of patients with atherosclerosis, lower levels of LDL cholesterol, but they don't affect the levels of Lp(a). In contrast, inhibitors of PCSK9 lower the levels of both of those key lipoproteins. So we looked at the relationship of baseline and on treatment levels of both LDL cholesterol and lipoprotein(a) on the risk of PAD events and also venous thromboembolism, which has been associated with lipoprotein(a) in some observational studies.

Dr Carolyn Lam: Nice. So, could you tell us what were the results?

Dr Gregory Schwartz: So first, we used data from the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in nearly 19,000 patients with a recent acute coronary syndrome. And as you mentioned, Carolyn, those patients may be at elevated risk for other types of arterial and venous atherothrombotic or thrombotic events. We had three goals in our analysis. First, we looked at the relationship of PAD and venous thromboembolic events to the baseline levels of lipoprotein(a) and LDL in the trial cohort. Second, we looked at the effects of randomized treatment on both of those types of events, PAD events, and venous thromboembolism. And lastly, we determined the relationship of treatment effects on lipoproteins to the risk of those events in the alirocumab active treatment group. What we found are four principle findings. First, although this was an acute coronary syndrome cohort, and there were only four percent of the trial cohort who had a prior history of PAD, there was nonetheless a substantial risk of PAD events. About two percent of the placebo group suffered a PAD event during the trial and about one percent had a venous thromboembolic event.

In the placebo group. We found that there was a very strong association between baseline lipoprotein(a) concentration and the risk of PAD events. So to put that in a quantitative framework, if we compared the highest quartile of baseline lipoprotein(a) with patients in the lowest quartile of baseline lipoprotein(a), there was a more than twofold elevated risk of PAD events. And by that, I mean, critical limb ischemia, revascularization, or amputation for ischemia, more than a twofold elevated risk in the highest quartile of baseline lipoprotein(a). There was a non-significant relationship of venous thromboembolic events to the baseline concentration of lipoprotein(a). The patients who were treated with alirocumab, the PCSK9 inhibitor, achieved the expected approximately 50 percent reduction in LDL cholesterol and a median 23 percent reduction in lipoprotein(a) concentration.

And those effects were associated with significant reduction in PAD events, a hazard ratio of point six nine, and a nearly significant peak, well point zero six reduction in the risk of venous thromboembolic events with a hazard ratio of point six seven. And incidentally, in the same issue of circulation, there is a companion paper from the FOURIER study, which looked at the risk of venous thromboembolic events with another PCSK9 inhibitor, evolocumab. They found something very, very similar. And again, the results of that trial individually were kind of on the margins of statistical significance, but putting the two trials together in their analysis, there was a highly significant reduction in the risk of venous thromboembolic events with PCSK9 inhibition, compared with placebo. They also related those effects to lipoprotein(a), but not to LDL cholesterol levels.

So we found that the magnitude of the reduction in lipoprotein(a) was related to the reduced risk of PAD and VTE events, but a similar relationship between the magnitude of LDL cholesterol reduction and the risk of those events was not found. So to put it all together, lipoprotein(a) may be the stone that we haven't turned over, but should, when we encounter patients with PAD events or VTE events that we can't otherwise explain. And although these two trials were not purposed primarily to look at PAD events, the findings certainly suggest that treating elevated levels of lipoprotein(a) might be an effective strategy to reduce risk of PAD events and VTE.

Dr Carolyn Lam: Wow. Congratulations, Greg, that was beautifully summarized. A novel on at least two levels, right? One is the PCSK9 inhibition effects on these two outcomes that we never thought of before. And second, that role of lipoprotein(a). Erin, could I bring you into this discussion? You were guest editor when this paper came across your desk. Could you tell us what were the considerations and frame how novel these findings are for us?

Dr Erin Michos: Oh, Carolyn excited to be the associate editor for this paper. People who know me know; I love all things lipids. So as a preventive cardiologist, I'm very excited to have drugs like PCSK9 inhibitors in my toolbox. They are certainly known for their powerful LDL lowering effects, but also further lipoprotein little a reducing effect who these combined data show the PCSK9 inhibitors, not only reduced incident major adverse cardiovascular events and PAD events, but potentially can reduce VTE events as well in patients prescribed this therapy. So I thought it was really interesting and this new analysis from ODYSSEY, that it was the levels of lipoprotein little a, but not LDL cholesterol that predicted the risk of future PAD event and we saw a similar trend with VTE. And then furthermore, on treatment with alirocumab. It was the magnitude of Lp(a) little a reduction, but not LDL reduction that was associated with reduced PAD and VTE events.

And so this suggests that the reduction of PAD events is mediated by the lipoprotein little a lowering and not the LDL lowering. You know, lipoprotein(a) is a particularly risky type of LDL. It's strongly inheritable it's atherogenic similar to LDL, but prothrombotic, so it's this double whammy of badness due to its structural homology with plasminogen competes with berberine binding and inhibits tissue plasminogen activator and ultimately inhibits fibrinolysis. And so that's why lipoprotein(a) may be a mediator of this apparent effect of PCSK9 inhibitors with PAD and VTE incidents. So how do I put this in practice? Prior to PCSK9 inhibitors, we really didn't have any lipid modifying therapies to actually lower lipoprotein little a, except niacin, which we don't really use. This was mentioned by Greg, statins don't really lower lipoprotein(a) and they actually increase lipoprotein little as levels.

Although we do know that statins of course reduce ASCBD risk. So, I'm checking lipoprotein little a now in all my secondary prevention patients with established CVD and in high risk primary prevention with those with family history. While we're all anxiously awaiting outcome trials, such as the antisense oligonucleotides that can lower lipoprotein(a) by 80 percent, that therapy is not here now, we don't have that available in practice. But we do have PCSK9 inhibitors now, which can reduce lipoprotein little a by 20 to 25 percent and have meaningful outcome data like the alirocumab data we see here in this ODYSSEY OUTCOMES study.

With a 31 percent reduction of PAD, that is really meaningful. So I'm particularly excited about PCSK9 inhibitors and my patients with PAD who often have concomitant CAD, polyvascular disease, and then regarding the VTE effects, I think we should point out that the absolute risk reduction of VTE was pretty modest. We didn't really see significance until we combined it with the FOURIER data. So I think given the cost of the drug, it's not warranted to prescribe PCSK9 inhibitors to the general population, specifically for VTE prevention alone. But in patients with ASCBD, who would be recommended for a PCSK9 inhibitor to reduce incident CBD, you know, there may be this added special benefit of reducing risk of VTE as well.

Dr Gregory Schwartz: I just wanted to comment on a few things that Erin said, I think we’re really important. All of these patients were on intensive statin therapy in the background. So although we did not see a relationship between the further reduction in LDL cholesterol with alirocumab and the risk of these events, it doesn't mean that lowering LDL cholesterol has nothing to do with the risk of those events because everybody was on background statin therapy, 90 plus percent. So, I think that's important to point out. And I think the comment that was made about when to check a lipoprotein(a) level is very pertinent. And, in the European guidelines, they direct us to check lipoprotein(a) at least once in a lifetime for everyone, even if there's no other signs or risk factors for cardiovascular disease.

So I think as Erin indicated, with some tools in the toolbox now, and more tools, perhaps on the way with both the antisense, and also there are small interfering RNA approaches to lower lipoprotein(a), we should get more accustomed to looking at this, to turning over that stone. Even if we're not a hundred percent certain what to do with what we find underneath it, we should still look because there may be some things we can do in the interim.

Dr Carolyn Lam: Thanks, Greg. Erin, can I give you the last word? Any take home messages?

Dr Erin Michos: I definitely think that as we move forward with other therapies such as the small interfering RNA and the antisense oligonucleotides, we need really more phase three clinical trials specifically assessing VTE. And then I just want to mention, although I didn't write an editorial for this study, I did have the pleasure of writing an editorial for another ODYSSEY OUTCOMES analysis that was published in December. You know, my editorial was entitled, "Achievement, a Very Low LDL. Is it Time to Unlearn the Concern for Hemorrhagic Stroke?" And I mention this because one of the barriers I get in clinical practices, people get very worried about the very low LDL levels that we see with PCSK9 inhibitors and I think important to point out from ODYSSEY that, with the reduction in ischemic stroke, that there was no signal for increased hemorrhagic stroke and that provides additional reassurance.

So I think that's important to mention, I think this PCSK9 therapy is being under-utilized in clinical practice and ASCBD and PAD, these are really high-risk patients who have really high risk of recurrent events and our efforts to ward off these devastating consequences. We need to make sure that we're appropriately utilizing this important therapy.

Dr Carolyn Lam: Thank you so much, Erin. Thank you so much, Greg. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, The American Heart Association, 2020.

Circulation May 12, 2020 Issue

11 maj 2020 | 24 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Well, our feature article this week, Carolyn, is really interesting and evaluates management of patients that are suspected to have atrial fibrillation and how we should screen them, what kind of monitoring and the like, very interesting discussion that will be coming up.

But before we get to that, how about we start into the papers and would you like to go first?

Dr Carolyn Lam: I would love to. And the first one is a basic paper on regenerative therapy, very important topic. Now remember that mammalian adult hearts have limited regenerative capacity. However, a transient regenerative capacity is maintained in the neonatal heart.

So co-corresponding authors, Dr Wang and Dr Guo from Nanjing Medical University hypothesize that by analyzing systemic phosphorylation signaling in ischemic neonatal myocardium, they may unlock key pathways involved in heart regeneration.

They therefore used quantitative phosphorylation proteomics to analyze the kinase substrate network of regenerative myocardium post MI in neonatal mice. And they found that activated Chk1 kinase was responsible for neonatal regeneration and could enhance cardiac regeneration in adult hearts post MI via activating the mTORC1 P70-S6K axis.

Dr Greg Hundley: Wow, Carolyn. Sounds like this could have a lot of clinical application several years down the road. So what are your thoughts on that?

Dr Carolyn Lam: I thought you may ask. Well, potentiation of Chk1 kinase, therefore, may be a promising regenerative therapy and authors gave this example that Chk1 injection could for example, in the form of a hydrogel, be injected into the myocardial infarction region and surrounding areas and may even be a novel therapeutic option to promote cardiac regeneration post MI.

Dr Greg Hundley: Very good, Carolyn. Well, my paper comes from the PARTNER 3 trial and remember PARTNER 3 is a comparison of transcatheter versus surgical aortic-valve replacement in low risk patients.

The corresponding author is Dr Philippe Pibarot from Quebec. The placement of aortic transcatheter valve three or PARTNER 3 trial randomized a thousand patients with severe aortic stenosis and low surgical risk at 71 centers to undergo either transfemoral TAVR with the balloon expandable SAPIEN 3 valve versus undergoing SAVR or surgical aortic valve replacement.

Transthoracic echocardiograms were obtained at baseline and at 30 days and one-year post procedure and they were analyzed by a consortium of two echocardiography core labs.

The objective of this study is to compare echocardiographic findings in low risk patients with severe aortic stenosis following surgical or transcatheter aortic valve replacement.

Dr Carolyn Lam: Important topic, very hot. So what did they find?

Dr Greg Hundley: In patients with severe aortic stenosis and low surgical risk, TAVR with the SAPIEN 3 valve was associated with a similar percentage of moderate to severe AR compared with SAVR, but a higher percentage of mild AR with no association between any grade of AR and outcomes.

Trans-prosthetic gradients, valve areas and LV mass regression were similar in TAVR versus SAVR. And SAVR was associated with a significant deterioration of RV systolic function and greater tricuspid regurgitation, which persisted at one year.

So Carolyn, very interesting results. Another study from PARTNER 3 comparing TAVR versus SAVR for patients with severe aortic stenosis.

Dr Carolyn Lam: Nice. So going from PARTNER 3, I want to talk about MESA and this time focusing on coronary artery calcium. Now we know that the recent ACC/AHA primary prevention guidelines recommend considering low dose aspirin therapy only among adults who are at high atherosclerotic cardiovascular risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified.

So the current study aimed to assess the value of coronary artery calcium for guiding aspirin allocation in primary prevention using the 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk.

So corresponding author Dr Cainzos-Achirica from Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and colleagues studied 6,470 participants from MESA all of whom underwent coronary artery calcium scoring at baseline to assess benefit versus harm.

A 12% relative risk reduction in cardiovascular disease events was used for five-year number needed to treat calculations, while a 42% relative risk increase in major bleeding events was used for the five-year number needed to harm estimations.

And now here are the results. Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the ACC/AHA guidelines and using more than 20% estimated atherosclerotic cardiovascular disease risk to define higher risk.

Among the 3,540 aspirin naive participants less than 70 years old and not at high risk of bleeding, the overall number needed to treat in five years with aspirin to prevent one cardiovascular disease event was 476, while the number needed to harm in five years was 355.

The numbers needed to treat in five years was also greater than or similar to the numbers needed to harm among estimated ASCVD risk strata by pool cohort equations.

Conversely, with a coronary artery calcium score of more than a hundred or more than 400, both these cutoffs identified subgroups in which the number needed to treat in five years was lower than the number needed to harm in five years.

Also, coronary calcium score of zero identified subgroups in which the number needed to treat was much higher than the number needed to harm.

Dr Greg Hundley: Lots of data. So we're mixing aspirin and MESA coronary calcium scores. What do we take home from this?

Dr Carolyn Lam: So here's the take home message. Coronary artery calcium may be superior to the pool cohort equations to inform the allocation of aspirin in primary prevention.

Individuals with a coronary artery calcium score above hundred and particularly above 400 may be good candidates for aspirin therapy for primary prevention. Although the net expected benefit will likely be modest.

In the presence of zero coronary artery calcium, the risk of bleeding is greater than the potential benefit and aspirin therapy for primary prevention should probably be avoided.

Overall, implementation of the current 2019 ACC/AHA guideline recommendations together with the use of coronary artery calcium scoring for further risk assessment may result in a more personalized, safer allocation of aspirin for primary prevention. Although ,of course, confirmation and external settings are required.

Dr Greg Hundley: That was really interesting. Combining coronary calcium scores, if you happen to have it, if someone's considering primary prevention with aspirin, it looks like those calcium scores could really be helpful there.

Well, I've got a couple other papers to talk about in this week's issue. There's an ECG challenge from Abdulhamied Alfaddagh from Johns Hopkins reviewing the quote unquote de Winter EKG pattern in a truck driver presenting with chest pain.

Second, there's an in-depth article from Alexander Fletcher from Edinburgh in the United Kingdom who discusses the metabolic pathways involved in inherited aortopathies trying to move beyond just diameter assessments to predict risk above future dilation and rupture.

And then lastly, there's a research letter from Petra Frings-Meuthen from the German Aerospace Center, the reports on how weightlessness shifts intravascular volumes and concentration of natriuretic peptides in astronauts.

Dr Carolyn Lam: Huh. And I would like one on my mind by Dr Kowey and it talks about the relentless pursuit of new drugs to treat cardiac arrhythmias.

Wow. What a nice issue. Let's move on now to our feature discussion.

Dr Greg Hundley: Welcome everyone to our feature discussion. In this particular paper will focus on atrial fibrillation and we're delighted to have Dr Søren Diederichsen from Copenhagen presenting this work and Dr Changsheng Ma, one of our associate editors from Beijing, China to have nice discussion.

Søren, I was wondering if we could get started with you. Could you tell us a little bit about what was the background related to this study and perhaps even a little bit about the hypothesis that you wanted to test?

Dr Søren Diederichsen: The background for this study is that, as we all know, atrial fibrillation is actually big and it's a growing health problem throughout the world and we also know that AF is often asymptomatic. So many cases of atrial fibrillation go undetected until complications occur.

And, of course, one of the most feared complications from AFib is a disabling stroke. And there's more and more evidence growing that a large proportion of people with risk factors for stroke do have some subclinical atrial fibrillation when they investigated or when they are followed, for instance, with a pacemaker.

So there has been a recent meta-analysis that found that the at risk of stroke in patients with subclinical AFib was fairly large compared to the risk of stroke in patients without subclinical AFib.

So, in this study, we want to look at the subclinical AFib in patients from the general population using loop recorders to follow these patients. And we want to sort of look at how could we screen the patients to find those with subclinical AFib using different screening scenarios which are less intensive than using a loop recorder for everyone.

Dr Greg Hundley: Søren, could you tell us a little bit about your study population and your study design?

Dr Søren Diederichsen: First of all, this study is part of an ongoing randomized control trial called the loop study. And in the loop study we recruited study participants from the general population.

The participants had to be at least 70 years old. And besides age as a stroke risk factor, they also had to have at least one additional stroke risk factor, hypertension, diabetes, heart failure or previous stroke. And importantly, they could not have AFib.

And the included participants were then randomized to control or screening for AFib using implantable loop recorder with remote monitoring and adjudication of new onset AF episodes.

In this particular study, we looked at the first participants in the loop recorder group who had been monitored for the entirety of the device's battery life, which is approximately three and a half years. So for these persons, we know whether or not they actually have AFib and we know exactly when they were in AFib and when they were in sinus rhythm.

So we use this data from the loop recorders to reconstruct full heart rhythm histories for each person, including exact time of onset and termination of each episode after exclusion of any clinically detected AF in the patients.

And it's a bit complicated study design because we have these heart rhythm histories. Now you can imagine where we have a string of data which is approximately three and a half years long and we know exactly when is AFib present and when a sinus rhythm present in this patient.

So we could use that data to simulate that the persons had been invited to an AFib screening by the health care service and had undergone a different type of screening at a random time. And these screenings that we investigated were time-point screening using standard ten second ECG during office hours and intermittent screening using single list devices, for instance, and short term continuous screening using external devices such as Holter or event recorder.

So we simulated that the patients had undergone such screenings and we could also assimilate that the patients were screened several times on a monthly or annual basis such as, for instance, taking an ECG every year.

And this simulation was then used to evaluate the sensitivity and negative predictive value of various screening regiments using the loop recorders' gold standard.

Dr Greg Hundley: What were your study results?

Dr Søren Diederichsen: All of this data comprised, as I told you, the first participant in our trial that had been monitored for the full battery life of the device.

So that was 590 participants entering nearly 700,000 days of continuous monitoring. So that was our data. And one third of those participants actually had previously unknown AFib and the number of AF episodes in our data was more than 20,000 AF episodes.

The main results were that if we simulate the pseudo-random daytime ECG in those patients, we would have identified only 1.5% of those who had AFib while performing by daily 32nd ECGs during 14 days, we would have identified 8% of those with AFib.

And if we took a 72-hour Holter, we would have identified 15% or a longer, for instance, a 30-day event recorder, we would have identified about a third of all those with AFib.

So that was actually our main results. We were able to see how many would we have identified of those with AFib if we'd done anything from taking a daytime ECG to performing a rather long event recorder.

Dr Greg Hundley: Were you able to put together maybe a combination of other variables along with the more lengthy recordings that could forecast future atrial fibrillation?

Dr Søren Diederichsen: One of the things we wanted to do with this study was not only did we want to see what is actually the diagnostic performance of doing an ECG or screening patients at risk with different kinds of screening, we also want to look at specific subgroups of the population who were more likely to maybe benefit from the screening in terms of having their AFib diagnosed.

So we looked at some population characteristics, age, sex and NT-proBNP. And we saw that the sensitivity of the screening was consistently higher among those who were older with a cutoff at 75 years, and also among males and among those with a high NT-proBNP.

So we could see that if we had screened one of those risk factor groups, age, male sex or high NT-proBNP, we would have been more or less likely to identify if AF was actually present.

Dr Greg Hundley: Changsheng, I'd like to turn to you. Can you help us put this results into perspective? How should we use this information in managing patients with atrial fibrillation?

Dr Changsheng: The AI for screening is a very important clinical problem and a hot topic issue. The heart rate monitoring is a cornerstone for detecting suspected AF patients. And then emerging new technology make monitoring more convenient than before.

But however the best screening strategy for those at higher risk of future AF stroke. And probably the strategy for the general population screening remain undetermined.

On the contrary, they evaluated the performance of a large panel of AF screening strategy among the 600 persons with a stroke risk factor that was not known yet.

The study used as an implantable loop recorder as a gold standard to assess the detection or difference in simulating a screening model.

I've got to say, the method employed in this study is quite exquisite and there's a key finding our clients tried to forward.

The time-point screening or the short-term monitoring could only identify a very small fraction of AFIB as compared for long-term loop recording screening. And diagnostic yield increased with duration, number and the dispersion of screenings.

So this is done to provide important clinical implications that every relatively intense screening such as even now I knew 30-day monitoring would need more than four in ten with AF.

And about one in six which are underlying more than 24 hours episode of AF. So the authors also gave the practical dispersion concept that when screening for AF, three times 24 hour monitoring are superior to one time 72 hour monitoring.

So I think this is a very important study to understand the condition, to understand the screening of AF patient for the general population.

Dr Greg Hundley: So really, helping us put these results in perspective. Maybe I'll ask each of you Søren first and then Changsheng. What do you think is the next research that needs to be performed after taking your results into account?

Dr Søren Diederichsen: In terms of what we should do next, I agree with Changsheng that there's a lot of attention towards AF screening at the moment, but we still really don't know if widespread screening in the population is actually something that could prevent heart endpoints.

So the next thing we need to know is, first of all, if we screen, will we have fewer of those events or will we have more side effects from the screening such as anticoagulant-mediated bleedings? It's very important to keep in mind that we don't yet know if screening is something that would prevent heart endpoints.

Second of all, we want to know more about what is actually the relationship between AF burden or amount of AF and risk of stroke. There's some evidences coming up that it's growing.

Is it, for instance, from the CERT study that the amount of AF and the pattern of AF that you have might tell us a little bit about what is your risk of stroke? For instance, if you have long AF episodes, your risk of stroke is higher than if you have all the short AF episodes.

And so that would be two of the next things I would think we should look at.

Dr Greg Hundley: Very good. Changsheng, do you have something to add to that?

Dr Changsheng: Yes, I agree with Søren. Now, on the detection, it's important but as a burden, even more important. So in practice in future, wouldn't we need more advanced technology and the patients or the participants frontally the monitoring device, which has the same ability to loop record them.

But this is more easy to use because when we use frontal monitoring for the patients, the longer duration of your monitoring period. So worse complains to the patients, not as our study because we have a simulation methodology, that 100% of patient accomplishments.

So I think in future, the watch with a diagnostic function of AF differentiation based on not ECG, but only based on the pulse.

So, the watch diagnostic function, not by ECG that are by pulse, like a detection of pulse. And then depend on the artificial intelligence, the AI function, to make a diagnosis of atrial fibrillation, not by ECG. That would be the future.

Dr Søren Diederichsen: And if you don't mind, I would like to add to that because I think that Changsheng raises an excellent point here with the smartwatch and how could they contribute to our prevention of stroke and in society.

So the current smartwatches work by looking at the pulse by photoplethysmography. And they cannot look at the pulse continuously as we do with the loop recorder looking at the ECG continuously.

This like with the photoplethysmography turns on when the patient is at risk and builds up an algorithm to look at what is actually the likelihood that the patient is an AF at this moment or today.

So at this point it'll only detect fairly long AF episodes, but in this study, we also looked at the longer AF episodes and the AAF burden. How does that impact the likelihood of detecting AF and of course it's more easy to detect it in patients with long AF episodes.

And if we find out in the future that a larger AF burden or longer AF episodes are actually required to increase the risk of stroke, then I believe that technology such as smartwatches could be a very feasible way to screen or to detect that kind of AF in patients at risk.

Dr Greg Hundley: Well listeners we've had a wonderful discussion here with Dr Søren Diederichsen from Copenhagen and our associate editor, Changsheng Ma from Beijing, China.

And really reviewing some important results related to screening for atrial fibrillation and the three 24-hour monitoring sessions combined with risk factors really help us identify who may be experiencing atrial fibrillation in our patients.

And then also, very interesting projections for the future, both using technology to try to identify atrial fibrillation perhaps through watches.

And then also how we could incorporate the duration, the time, et cetera of atrial fibrillation occurrences and how they may relate to adverse events.

Thank you so much Søren. Thank you Changsheng. And to all our listeners, we wish you a very safe week and look forward to meeting with you next week. Take care.

This program is copyright the American Heart Association 2020.

Circulation May 05, 2020 Issue

4 maj 2020 | 19 min

Dr Carolyn Lam: Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia. Well Carolyn, our feature this week really examines long-term efficacy of drug eluting stents versus coronary artery bypass grafting in those patients with left main disease. Really looking at long-term extended follow up from the PRECOMBAT trial but before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And I'll start off. My first article is a basic science paper looking at catecholamine sensitive and ventricular tachycardia in ARVC. And it comes from Dr Long-Sheng Song from the University of Iowa Carver College of Medicine.

So, the study from Dr Song used protein mass spectrometry analyses and that identified integrin beta one is downregulated in those patients with arrhythmogenic right ventricular cardiomyopathy hearts without changes to calcium handling proteins as adult cardiomyocytes express only the beta-1 D isoform, they generated a cardiac specific beta-1 D knockout mouse model and perform functional imaging and biochemical analyses to determine the consequences from integrin beta-1 D loss of function in hearts in vivo and in vitro.

Dr Carolyn Lam: Nice, very elegant design. So what were the results Greg?

Dr Greg Hundley: Well Carolyn, the authors found that integrin beta- 1D deficiency and RyR2 serine 2030 hyper phosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. And in the mouse experiments, beta-1 D negative or knockout mice exhibited normal cardiac function and morphology, but presented with catacholamines sensitive polymorphic ventricular tachycardia consistent with increased RyR2 serine 2030 phosphorylation and apparent calcium handling in beta-1 D knockout cardiomyocytes.

So Carolyn, in conclusion, the authors found their data suggest that integrin beta-1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.

Dr Carolyn Lam: Okay. You told us about integrin beta-1 D and I'm going to tell you about apolipoprotein M. So Greg, what do you know about apolipoprotein M?

Dr Greg Hundley: Well, Carolyn, at seven o'clock the morning, I seem to have forgotten a little bit about that. Can you remind me what apolipoprotein M is?

Dr Carolyn Lam: Sure Greg, very happy to. So apolipoprotein M or apoM mediates the physical interaction between high density lipoprotein particles and sphingosine 1-phosphate and exerts an anti-inflammatory and cardio-protective effects in animal models. Now listen on, listen on. So authors, Dr Chirinos from Perelman Center for Advanced Medicine, University of Pennsylvania and Dr Javaheri from Washington University School of Medicine and co-authors hypothesized that reduced levels of apoM would be associated with worse outcomes in human heart failure.

Specifically, they tested the hypothesis that reduced circulating apoM would be associated with the risk of death, a composite of death, ventricular assist, device implantation or heart transplantation and a composite of death, heart failure related hospitalization among adults with heart failure and rolled in a large multicenter Penn heart failure study. They did stratified analysis in patients with heart failure with reduced and preserved ejection fraction and even replicated these findings in two independent cohorts, the Washington University heart failure registry and a subset of the TOPCAT trial. What they found was that reduced apoM plasma protein levels indeed were associated with adverse outcomes in heart failure including both HFpF and HFrF. The relationship between reduced apoM and outcomes and heart failure was particularly pronounced when concentrations of its binding partner sphingosine 1-phosphate were also reduced. ApoM protein levels were associated with inflammation in human heart failure and thus the conclusion being that apoM represents a risk marker in human heart failure.

Further studies are of course needed to assess whether it could be a therapeutic target as well.

Dr Greg Hundley: Very good. Carolyn. So more information for the world of heart failure isn't it. I'm going to sort of switch over to coronary artery disease and talk about low attenuation non-calcified plaques that are sometimes appreciated on cardiac computed tomography scans. And in this study, Dr Michelle Williams from the University of Edinburg evaluated the results from the multi-center SCOT-HEART trial or the Scottish computed tomography of the heart. So Carolyn, the future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score or coronary artery stenosis severity and the authors assessed in 1,769 patients about 56% men and the average age 58 years and they followed them up for a median of 4.7 years and looked at whether noncalcified low attenuation plaque burden on coronary CT angiography might be a better predictor of the future risk of myocardial infarction.

Dr Carolyn Lam: Interesting. So what did they find?

Dr Greg Hundley: Well, low attenuation plaque burden was the strongest predictor of myocardial infarction irrespective of cardiovascular risk score, coronary artery calcium score or coronary artery area stenosis. And patients with low attenuation plaque burden greater than 4% were nearly five times more likely to have subsequent myocardial infarction and the hazard ratio was 4.65 with a confidence interval of two to more than 10 and a half. So in conclusion, Carolyn in patients presenting with stable chest pain, low attenuation plaque burden is the strongest predictor of fatal or nonfatal myocardial infarction and these findings may add to classical risk predictors of myocardial infarction.

Dr Carolyn Lam: Wow. Important findings. Okay, let's go onto what else is in this week's journal issue. There's an online mind by Dr Jaffe. It's on the universal definition of myocardial infarction. It talks about both present and future considerations. There's an ECG challenge by Dr Arias and what's described as spontaneous wide QRS complex rhythm in a patient with wide QRS complex tachycardia.

Dr Greg Hundley: Very good, Carolyn. Well, I've got two other articles. Another on my mind piece from Professor Peter Nagele from the University of Chicago Medicine and it discusses a simplified proposal to redefine acute MI versus acute myocardial injury. Looking at that troponin question. And then finally Dr Fabian Hoffman from the Heart Center and University of Cologne has a research letter on providing new data regarding the evolution of pulmonary hypertension during severe sustained hypoxia.

Well Carolyn, how about we get onto that feature discussion looking at left main disease and whether we should place an intercoronary stent or undergo coronary artery bypass grafting.

Dr Carolyn Lam: Important question. Let's go, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion today that really pertains to interventional cardiology and we're very fortunate to have Duk-Woo Park from Asian Medical Center in Seoul, South Korea and our own associate editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Well Duk-Woo, we'd like to get started with you and could you tell us a little bit about the background data and the hypothesis related to your research study?

Dr Duk-Woo Park: Our research, it was the 10-year report of the PRECOMBAT trial. If I'm going to first introduce the background over the last half of a century bypass surgery, it was a mainstream, the number one choice of on protecting the main disease. Yeah. Did you know unprotected left main disease, the one were very high risk of coronary artery disease and owing two and the supply, the large burden of myocardium. But the last two decades, 20 years. Their remarkable evolution in PCI field including development adaption of a drug eluting stent and the adaption of intravascular ultrasound as well as experience of intervention or catalyst expertise. So on the basis of such evolution, many interventional cardiologists think about that, a PCI with a drug eluting stent. Will it be non-inferior to a standard type A surgery? Sometime for single region PCI could be very nice alternative option for unprotected left main disease that the reason why we're going to start quick on the trial. This trial already done 15 years ago at the time. We designed this PRECOMBAT trial on the basis of that background.

Dr Greg Hundley: Very good. Well can you tell us a little bit about the study population of this trial and what was your study design?

Dr Duk-Woo Park: This is a open library trial design and we at first time we evaluated the noble unprotected left main disease and the for considerable for clinical and ethic eligibility, initially assessed by intervention or cardiologists as you as a cardiac surgeon and the reason why we try to pick up the post treatment eligible population and then at the screening initial re-screen the nearly 1,400 patient and then finally 600 of patient who was our individuation one arm is drug eluting stent, first-generation ciphers 10 versus another arm is convention or a coronary artery bypass stent grafting.

Dr Greg Hundley: What were you looking for your outcome measures and how long did you follow these patients?

Dr Duk-Woo Park: Initially and the BDN two year follow and are published in England, the journal of medicine nearly eight years ago. And then we did five year follow-up at the publish the JAG in five years ago and the this time is a, we did complete that 10 year follow up all the render mutation population and the median follow-up duration is nearly more than 11 years and we complete 10 year follow-up and the key outcome was PCI is a comparable apart from surgery for treatment of left main disease.

Dr Greg Hundley: And were there other outcomes that you were looking for?

Dr Duk-Woo Park: We evaluated several important clinical outcomes. We primary end the point we select competent outcome compass of all cause of mortality by myocardial infarction, stroke, or ischemia-driven target vessel revascularization. Secondary outcome was each component of a primary outcome all-cause mortality as you raise the harder clinical and the point like compost outcome like this am I sure. So finally we did not any statistical difference with the regard to primary composite outcome as well as a hard clinical compost outcome as death or stroke. Finally, we did not detect all-cause mortality. One exception or difference was a target vascularization as well as a repeat rebase collateralization was a much higher after PCI than after bypass surgery.

Dr Greg Hundley: So overall, in this more lengthy follow up of 10 years. The primary outcomes were similar between the two interventional arms, but there was a difference in target vessel revascularization. With that being more frequent after PCI as compared to bypass, were there any other subgroups that tended to have distinctions or discrepancies between your primary outcome?

Dr Duk-Woo Park: As the sensitive to analysis, in circulation we supply the subgroup analysis or more, we did not find any differential treatment. IPEC according to subgroup in age group, diabetes and clean-cut presentation or in environmental coronary embolism shock versus application. We didn't find any interaction effect, just the except the extent of disease vessel, left or main. We the three best three digit bypass surgery was better than PCI. However we did not do any P value. Adjust them on. So interpretation is should it be cautious.

Dr Greg Hundley: Well you know as an interventional cardiologist, what new information does this bring and how do you interpret the results of this study relative to other studies that have been published in the past?

Dr Emmanouil Brilakis: I think this is a very timely study, especially since about a year ago we did have the five-year outcomes from two other similar trials, the Excel file and the Nobel trial which say randomized patients with unprotected left main disease to either PCI or bypass. And actually those studies had some differences which are also relevant to the present study. So for example, Excel overall the outcomes were similar. There was a higher all-cause mortality in the PCI where normal had better outcomes in terms of death, MIT VR, but there was no difference in mortality. So I think the natural question that comes up from the studies was whether mortality is different with PCI versus coronary bypass and you know the PRECOMBAT, the 10 years. It's really suiting in that respect because it doesn't show any difference in the overall mortality. So I think this comes very timely and the answers a lot of questions. Of course there's limitations with the sample size and the number of patients treated, but I think although it's a very timely result.

Dr Greg Hundley: Maybe I'll start first with you, Manos and then I'll circle back to you. Duk-Woo. Manos what do you see is the next important study to perform in this field?

Dr Emmanouil Brilakis: I think the natural question here is these outcomes which are similar but use first generation drug eluting stents, which we no longer use. He did use high proportion of five which is an excellent feature in, again congratulate Duk-Woo and the other co-investigators for doing such a high rate of follow-up. But we now know that the techniques, for example, for bifurcations, maybe the DK crush or double DK crush might be a better technique to do. So in my mind, the next question would be if who use the current, a much improved the drug eluting stent and state of the art bifurcation techniques. For example, DK crush where the double-kiss crush bifurcation would, the outcomes have been different and perhaps PCI will be similar, even better than bypass in long-term outcomes. So for me this next study will be state of the art techniques, state of the art materials and long-term for follow-up as in frequently.

Dr Greg Hundley: Duk-Woo. How about from your perspective?

Dr Duk-Woo Park: You know, a future perspective is a very difficult to expect. Our trial is the longest to follow-up trial. We have the nation are insurance support and we nearly a hundred percent pop picked up fighters status, but I think most of them interventional cardiologists as well as a cardiac surgeon. One true additional longest follow-up Excel and Noble trial. The reason why we didn't do additional random trial using additional second generation drug eluting stent. We already do exit trial approximately 2000 and noble trial and more than thousand patients we already do and the two trial a complete five-year follow and most of the trial is as well as the clinician want to extend the follow-up of Excel and Noble trial but I don't know how much that extended of a follow-up would be possible.

Dr Duk-Woo Park: The next step as you know the intervention or cardiac surgeon still debate about the long-term mortality issue after release of exited five-year-old research and the data peak issue, European association cardiac thoracic group. We did draw the endorsement of a guideline so I think an additional stem we require the individual patient level data analysis involving, Excel, Nobel, Syntech and PRECOMBAT trial would be required to provide the more definite compelling evidence for mortality difference as well as the have the end point and including or so some end point to repeat revascularization. We do allow individual patient data analysis. That would be next. The short step, next the long step, we definitely require extended follow-up, Excel and Noble trial.

Dr Greg Hundley: Very good. Well listeners, this has been another very informative feature discussion where we've compared PCI and coronary artery bypass grafting in those with left main disease. And now from this PRECOMBAT trial, 10 years of follow up showing very similar outcomes related to death, myocardial infarction and stroke in the two randomized arms. We want to thank Dr Duk-Woo Park and Dr Manos Brilakis for presenting this information and as we move forward, their insights as to next studies with newer technologies and different examinations of stents. More long-term follow-up from ongoing trials and then individualized patient assessments.

Listeners, we hope you have a great week and hope everyone is staying safe in this COVID crisis. Take care.

This program is copyright of the American Heart Association 2020.

Circulation April 28, 2020 Issue

27 april 2020 | 18 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today looks at the use of Apixaban versus Warfarin, so a trial between the two in patients with atrial fibrillation and advanced kidney disease. But before we get to that, how about if we break away, grab a cup of coffee and go through some of the other important papers in this issue?

Dr Carolyn Lam: Yeah, and why not start with talking about our gut and fiber in the diet. Now, we know that a diet poor in fiber is associated with the prevalence of hypertension, but what are the underlying mechanisms? Well, this first paper I want to talk about is from Dr Marques from Baker Heart and Diabetes Institute in Australia and colleagues who basically performed a nice series of mouse experiments and found that a diet lacking prebiotic fiber led to a gut microbiome that was pro hypertenenogenic facilitated the development of cardiac hypertrophy in germ free mice.

Even in the absence of fiber, gut metabolites called short chain fatty acids usually produce from the fermentation of prebiotic fiber by the gut microbiota, but they were able to protect against the development of hypertension, cardiac hypertrophy and fibrosis in a preclinical model. This cardioprotection involved short chain fatty acid receptors, and a decrease in the ratio of sodium to potassium excretion and changes in genome white methylation that supported higher levels of T regulatory cells.

Dr Greg Hundley: Oh my goodness, Carolyn. So I need to know what I eat for lunch? What's the take home message here?

Dr Carolyn Lam: Lots of fiber and definitely not the low fiber westernized diet, which may underlie hypertension. And how? Through deficient short chain fatty acid production and thus the take home is maintaining a healthy, short chain fatty acid producing microbiome is important for the cardiovascular health.

Dr Greg Hundley: Wow, Carolyn. I love that article because it really helps provide some perspective on all the diet information that we've been receiving lately. Well, my paper is from doctor ... another Carolyn, but this is Carolyn Ho from Brigham and Women's Hospital-

Dr Carolyn Lam: I love her.

Dr Greg Hundley: ... And it involves hypertrophic cardiomyopathy and left ventricular systolic dysfunction. So Carolyn, the term end-stage has been used to describe hypertrophic cardiomyopathy with left ventricular systolic dysfunction. And that's defined when someone has hypertrophic cardiomyopathy and the LVEF is less than 50%. The prognosis of patients with this condition has been reportedly poor, but it's very rare in occurrence and therefore, the natural history really remains incompletely characterized. So what did the authors do in this study? They evaluated more than 500 patients from 11 high volume hypertrophic cardiomyopathy specialty centers comprising the international Sarcomeric Human Cardiomyopathy Registry or SHaRe registry. And they were used to describe the natural history of patients with hypertrophic cardiomyopathy and left ventricular systolic dysfunction.

Dr Carolyn Lam: Interesting. So what did they find, Greg?

Dr Greg Hundley: Number one, first overall, this group of patients, hypertrophic cardiomyopathy with left ventricular systolic dysfunction occurs in about 8% of those with hypertrophic cardiomyopathy. Although the natural history of left ventricular systolic function and hypertrophic cardiomyopathy is variable, 75% of those that have this condition experience adverse events including 35% experiencing a death equivalent at a medium of 8.4 years after developing their systolic dysfunction. In addition to clinical features, the genetic substrate appears to play a role in both prognosis, so there are multiple sarcomeric variants, and in the risk for incident development of left ventricular systolic function with hypertrophic cardiomyopathy due to variance in the thin filaments within those myocytes.

Dr Carolyn Lam: Nice. Thanks for that Greg. My next paper is a really interesting secondary analysis if you may, of the EXSCEL study. As a reminder, the Exenatide Study of Cardiovascular Event Lowering or EXSCEL assessed the impact of once weekly exenatide versus placebo in patients with type two diabetes and showed non-inferiority but not superiority for the primary MACE outcome.

Now, during this trial, while aiming for glycemic echo-poise, a greater drop-in of open label glucose lowering medications occurred in the placebo group, thus prompting the current authors, which is Dr Rury Holman from University of Oxford and their colleagues to really explore the possible impact of unbalanced open labeled drop-in of glucose lowering medication on EXSCEL outcomes. To our modern diabetes trial, they used three methodologies. One, drop-in visit, right censoring. Two, inverse probability for treatment waiting. And three, applying drug class risk reductions. Now, Greg, I could either quiz you on these methods or summarize the results, which would you prefer?

Dr Greg Hundley: Well, Carolyn, this calls for the infamous phone a friend. So one of the nice things we have at Circulation is a wonderful group of statisticians that really help us go through all the papers. But I sure would like to pick up the phone and call one of those folks now. But I think what I'm going to do ... maybe just give me the results of this study. That's what I prefer.

Dr Carolyn Lam: I thought you might say that. So the EXSCEL observed has its ratios for MACE remained robust after right censoring or application of the literature derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by the inverse probability treatment waiting approach. So I think the take home is that effects of open label drop in cardioprotective medications do need to be considered carefully when designing, conducting and analyzing cardiovascular outcome trials of glucose lowering agents. Do we have the perfect solution? Perhaps not, but this was a really important paper to just look at and study. So Greg, I can see that you are stats out, so I'm going to tell you a little bit more about other papers in this week's issue.

There's a research letter by Dr Zhang on transcription factor Kruppel-like factor 15 and how it regulates the circadian susceptibility to ischemia-reperfusion injury in the heart.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple of other papers. There's a nice in-depth piece from Dr Gregory Marcus from the University of California, San Francisco on how we evaluate and manage patients that have premature ventricular contractions. Dr Mori Krantz from Denver Health and Hospital Authority gives us an EKG challenge in someone that's had a needle stick. And then finally, there's a nice perspective piece from Dr Paul Armstrong from the Canadian VIGOUR Centre, department of medicine cardiology at the University of Alberta. And he really goes over nicely how we're going to do global collaboration to enhance cardiovascular care. What a great issue. And now onto that feature where we're going to hear a little bit about Apixaban and Warfarin in those individuals with atrial fibrillation and chronic kidney disease.

Dr Carolyn Lam: Let's go, Greg.

Today's feature paper really represents the first randomized data on NOAC versus warfarin in a very important group of patients, that is those with atrial fibrillation and advanced chronic kidney disease. So happy to have with us the corresponding author, Dr John Stanifer from Munson Healthcare, Traverse, Michigan. As well as our associate editor, Dr Chang-Sheng Ma from Beijing Anzhen Hospital in China. Welcome, welcome. So John, could you tell us the inspiration if you may, or the rationale, for doing this study?

Dr John Stanifer: This is a population that's near and dear to my heart as a practicing nephrologist. We care for so many patients with atrial fibrillation, particularly those on dialysis or those with advanced kidney disease. And as other practitioners and people taking care of this population will tell you, this is just such a confusing and challenging clinical problem to try to deal with. And then really this stems from that important clinical need that we recognize almost on a daily basis.

Dr Carolyn Lam: I just love that you shared that John, because coming from a nephrologist, and we're usually talking to cardiologists where we think about this all the time and have no idea what to do. So tell us about your study and what you found.

Dr John Stanifer: As you know, these were data that were taken from the Aristotle trial that was finished in 2011, that was really a landmark study that established the real superiority of Apixaban compared with Warfarin and the general population.

And it happened that within the study, there were several patients, 269 that had a creatinine clearance of between 25 and 30 milliliters per minute. We then took those data from those patients and compared really in this study, the safety of Apixaban compared with Warfarin within that subpopulation, and then compared that as an interaction with the safety of Apixaban versus Warfarin in patients with creatinine clearance of greater than 30.

Dr Carolyn Lam: And what did you find?

Dr John Stanifer: Well, in conclusion, we really found that among these patients with a creatine clearance of 25 to 30 MLs per minute in atrial fibrillation that Apixaban did cause less bleeding than Warfarin. And it appeared to be an even greater relative risk reduction when you compare that with the safety of Apixaban versus Warfarin and those with a less severe kidney disease.

Dr Carolyn Lam: It's truly the first time I've seen data like this. So congratulations John and thank you so much for publishing this paper with us at Circulation. Chang-Sheng, Circulation seems to be publishing a lot in the space of combined renal and cardiac disease, which is very interesting. Why was this paper so important to us as well?

Dr Changsheng Ma: It's a very important question for a clinical practice. The anticoagulation therapy in patient with advanced CKD. And observation or analysis have demonstrated inconsistent of findings regarding the net clinical benefit of warfarin in reducing the risk for stroke in patients with advanced CKD. The problem of Warfarin treatments in this patient group is dramatically higher bleeding risk. The current study also show that the bleeding risk was three- to four-fold higher in patient with advanced CKD compared to that in patient with creatinine clearance more than 30 milliliters per minute when treated with a Warfarin.

So these studies are our first randomized data for NOAC compared with warfarin in patients with advanced CKD. The results provide important information as to the safety of Apixaban in this special patient group with high risk of bleeding. With reduced risk of bleeding, we may expect net clinical benefits of Apixaban in preventing stroke in patients with advanced CKD.

Dr Carolyn Lam: Indeed. John, did you demonstrate that net clinical benefit or could you perhaps explain if future steps are needed to look at that a bit better?

Dr John Stanifer: Well, I think absolutely future studies are needed. You have to keep in mind that these were pre-specified groups within Aristotle. These are still post-trial data from this study and that absolutely we need studies that are powered to really compare the safety. I would add not just apixaban with warfarin, but I would also add placebo to that.

Dr Carolyn Lam: Interesting. Changsheng, you had some questions for John as well.

Dr Changsheng Ma: Yes. John, I had questions for you. If you take a randomized trial for the answer for this question, how many cases do you think?

Dr Carolyn Lam: How many cases of?

Dr Changsheng Ma: How many cases should there be for a sample size for a trial?

Dr John Stanifer: Well, you're really putting me on the spot here. I'll have to go back to my statistical days. Well, I think the easy part in the design of a trial for a question like this is that the event rates are so high. Whether that be for both safety outcomes related to hemorrhage and bleeding risks or primary benefit outcomes. So that would be very beneficial with that respect. But I think the key to designing a study ... and I know that there are several ongoing RENAL-AF and several others that are trying to examine this very question, but I think as a nephrologist, what we would kind of push back on a little bit is that there's no placebo arm to these trials. And I actually think that that would be a step forward even though that would be a very challenging thing, I think at this point to push for ... I think the nephrologist has kind of continued to push for that a little bit.

Dr Carolyn Lam: So John, that was beautifully answered. If I could ask you then, have these results influenced your practice even now?

Dr John Stanifer: Well, prior to this, we've been a little bit nervous with Apixaban, even though observational data may suggest that it would be safer or potentially usable in patients with advanced kidney disease. But part of the real conundrum and some of the challenges that come up are really around dosing of Apixaban. And they say, "Well, gosh, if they're in stage renal disease, yeah, maybe it's too bad. Maybe the kidney function is way too low and we need to kind of reduce it based just on that one criterion as opposed to the three criteria laid out in Aristotle." So I think that was some of the challenges. but I think after seeing these data and seeing the safety relative to Warfarin was really there in this patient group, yeah, it has influenced me a little bit. I am a little more adamant about switching patients.

Dr Carolyn Lam: Yep. Chang-Sheng, do you agree with that? What do you think are next steps here?

Dr Changsheng Ma: Because clinical practice is different, apparently, more evidence is badly needed to guide the future clinical practice because the patients with creatinine clearance even less than 25 milliliters per minute. And those in dialysis were not included in any of the pivotal studies of NOAC.

Dr John Stanifer: Absolutely.

Dr Changsheng Ma: It is still uncertain whether this patient will benefit from Apixaban or other NOACs. So in this study, even the significant less measured bleeding events were observed. I think the all-cause mortality was not different between the two groups. So the next step we should design a new trial to confirm whether Apixaban will really improve the prognosis of the patient with advanced CKD and AF.

Dr John Stanifer: I will second that. For sure we want to answer that very important efficacy question related to this class of medications.

Dr Carolyn Lam: Efficacy and patients on hemodialysis. Wow. This really just opens up a lot, but you're right. It's such tantalizing information that you see in ... so thank you so much John, for publishing this paper with us. Chang-Sheng, it's such a great paper. I remember the discussions we had during our editors’ discussions and it's so nice to see it out in print. I'm telling you, audience, you have to get hold of this paper. It will change this field I think and will lead to further trials exactly like you've heard here, and that we've put John on the spot to describe.

Dr Carolyn Lam: Thank you very much gentlemen for a wonderful discussion. Thank you, audience, for joining us. You've been listening to Circulation On The Run. Join us again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.

Circulation April 21, 2020 Issue

20 april 2020 | 21 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. But I am running to hide today, because I am going to get quizzed by the master in the feature discussion. And listeners, it's really interesting. It involves quantitative myocardial perfusion using magnetic resonance imaging, but also adding the twist that artificial intelligence computer algorithms are being used to read the stress test images without any physician interference. Oh, my goodness. I don't know what she's going to quiz me about.

Dr Carolyn Lam: Absolutely about all the AI algorithms and exactly how you derive them. But why don't you tell us what you want to describe first and the rest of the issue.

Dr Greg Hundley: Carolyn, I'm going to start with a paper on peroxynitrite and as you know, that's a very short-lived free radical produced in cells, part of the both oxidative and nitrosative stress pathways. And this article comes from Dr Swapnil Sonkusare from the University of Virginia School of Medicine. Well, Carolyn, this study is involving mouse models, and the investigators evaluated the relationship between peroxynitrite, that powerful oxidative nitrosative stress molecule, and obesity and hypertension.

Dr Carolyn Lam: Nice. And before you ask me anything more about peroxynitrite, because I think you just summarize everything I know. What did the authors find, Greg?

Dr Greg Hundley: What that found is that obesity induced impairment of endothelial AKAP150-TRPV4 channel signaling contributes to the loss of endothelial function and elevated blood pressure. And lowering the levels of this oxidant molecule of peroxynitrite reduces endothelial AKAP150-TRPV4 channel signaling, vasodilation and blood pressure and obesity.

Dr Carolyn Lam: And what are the implications?

Dr Greg Hundley: Well, endothelial TRPV4 channels are essential regulators of resting blood pressure and impairment of endothelial TRPV4 channel activity contributes to obesity induced hypertension. And therefore, therapeutic strategies, perhaps in the future, that lower peroxynitrite levels can be used to rescue endothelial TRPV4 channel activity, endothelial function and blood pressure in obese individuals.

Dr Carolyn Lam: Nice, Greg. Well, I want to tell you a little bit more about plain old hypertension. Now, we know that blood pressure is regulated by the function of the kidney vasculature and sympathetic nervous system, but do immune cells play a role?

Well, Dr Guzik from University Medical College, Krakow, Poland, and University of Glasgow and his colleagues, studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and employed a Mendelian randomization analysis to examine which leukocyte populations maybe causally linked to blood pressure.

Dr Greg Hundley: So we've got another blood pressure article. What did they find?

Dr Carolyn Lam: They found potentially causal positive effects of total blood lymphocyte count with blood pressure. Among the mechanisms that might mediate this relationship, they found evidence that blood lymphocyte count might influence albuminuria. The study may additionally support a reverse, potentially causal positive effect of blood pressure indices on blood neutrophil monocyte and you sit a full count. So fairly interesting.

Dr Greg Hundley: Very nice. So I'm going to switch over and talk a little bit about lifestyle interventions. I know you're a big fitness buff. So this paper is about fitness, body mass index and the risk of heart failure in overweight, obese individuals with type two diabetes mellitus. It's an analysis from The Look AHEAD Trial. The corresponding author is Dr Ambarish Pandey from the University of Texas Southwestern Medical Center. And a little bit of background Carolyn. Type two diabetes is associated with a higher risk of heart failure and the impact of a lifestyle intervention and changes in cardiorespiratory fitness and body mass index on the risk of heart failure in this population is not well established.

So what are the authors do? They had 5,109 participants from The Look AHEAD or The Action for Health in Diabetes Trial, without prevalent heart failure at the time of their inclusion. They implemented time to event analysis to compare the risk of incident heart failure between an intensive lifestyle intervention versus a diabetes support and education group. The association of baseline measures of cardiorespiratory fitness estimated from a maximal treadmill test. The participants, BMI and longitudinal changes in these parameters with the risk of heart failure were evaluated using multi variable models.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Carolyn, very surprising. Among participants with type two diabetes mellitus. In The Look AHEAD Trial, the intensive lifestyle intervention did not, did not appear to modify the risk of heart failure. What they also found is that higher baseline cardiorespiratory fitness and sustained improvements in cardiorespiratory fitness and weight loss were associated with a lower risk of heart failure.

So even that education group where patients started doing things more, had more cardiorespiratory fitness and baseline and sustain that with weight loss, those were the ones that had lower risk of heart failure.

Dr Carolyn Lam: Nice summary. Well let's go through what else is in today's issue. There's a research letter by Dr Eitel on the impact of morphine treatment within without metoclopramide co-administration on ticagrelor-inducted platelet inhibition in AMI and that's the randomized MonAMI trial. There's also an in-depth paper by Dr Eijsvogels on exercise and coronary atherosclerosis. So, this interesting review describes the effects of physical activity and exercise training on coronary atherosclerosis in middle aged and older athletes and really aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries. Very interesting.

Dr Greg Hundley: And Carolyn, I've got a perspective piece and it comes from Dr Robert Stravitz, as well as Dr George Vetrovec from VCU, and it evaluates the risk of invasive cardiac procedures in patients that have liver cirrhosis.

Then finally there's a very nice ECG challenge. It's the anterior STEMI without S T elevation in lead one and it comes from Dr Yun-Tao Zhao from the Peking University Aerospace School of Clinical Medicine. Oh no. Oh, I've got to run.

Dr Carolyn Lam: Now, we're going straight into the prolonged Dr Hundley quiz.

Dr Greg Hundley: Very good.

Dr Carolyn Lam: Oh boy. Today's feature paper is really a biggie. It talks about AI and its approach in quantitative myocardial perfusion by cardiac magnetic resonance imaging. Now, I know we've been building up to this discussion already right from the start because I've got my beloved cohost, Greg Hundley talking about this, but wearing the hat as the editor who managed this paper and also so pleased to have with us the corresponding author, Dr James Moon from University College, London and Barts Heart Centre in UK, as well as from across the other side of the world. We have Dr Peter Kellman from the National Heart, Lung and Blood Institute of NIH. So welcome gentlemen, what a great paper. I think in Greg's words he said earlier just really landmark. I'm almost paradigm shifting in this area. So let's dive straight into it. And so maybe James, could you start by telling us how does CMR quantitative myocardial perfusion usually work in today's world without the AI and perhaps you know what the study showed that it can do. What can AI help us do?

Dr James Moon: If we want to understand where chest pain comes from, we can sometimes use cardiac CT, or we can use a functional test and a different function test. But a particular test with bandages is chronic MRI. And what we do is we give a dye into a vein and track that through the heart. And the upslope can tell us about a fusion. And if you do that during vasodilators stress, you can see regional differences visually. Now, the interesting thing is that if you take those signals and using a team such as Peter Kamina, NIH, you can make that constative and, in fact, do that inline on the scanner, so you get color maps where the pixels of valid in mils per gram per minute. So you can see exactly how much facilitation there is. And what we share in here is that if you quantify that, literally, automatically on the scanner using artificial intelligence approaches from the NIH, those values are incrementally prognostic predicting outcomes for patients.

Dr Carolyn Lam: Wow. Okay. So give us a little bit more here, James. What do you mean by incrementally prognostic? Did you compare it with the best human readers and perhaps have a subset and I think you did, of course, who the human readers can see something, and AI did, right? Could you tell us a little bit more about that?

Dr James Moon: We've been doing a lot of the sort of technical development papers after the common initiatives from the NIH. So we've been doing the correlations across a number of sensors with, for example, pets and animal models. And really what we did here was we overlaid our clinical service with the AI and in more than a thousand patients actually at two sites, we were able to follow up patients and a number of those of course, and sadly underwent an event, death, or mace. And what we are able to see is that the stress flow and the ratio stress to rest flow, were independently associated by death and base and mace. So for each mil decrease in stress flow that has a great share went up. And that was as you say, something that you just can't do viscerally because you can't get that global background change.

Dr Carolyn Lam: Oh this is scary. So AI beating out humans, I suppose is what you're saying, not quite maybe. Or is it right?

Dr Greg Hundley: You know, we have to do a number of things in health care and we're often drawing circles, drawing consoles, identifying regions of interest and these are quite mundane tasks and if you can train your AI correctly, then that can do that for you, leaving you and freeing you up to higher executive functions, like discussing the results with patients. And I wouldn't be scared of the AI here because the way PISA implemented this, the contours are all drawn, so it's completely explicable.

Dr Carolyn Lam: I really liked that explanation. And so what most people fear when AI comes about is, they fear this black box approach that they cannot understand. And what you're saying here is it something understandable and it will facilitate efficiency, which is beautifully done, and what you've shown as well. So Peter, it sounds to me that it took a long time to develop this. Could you describe what it takes to get an algorithm and AI algorithms like this?

Dr Peter Kellman: This is quantitative perfusion and perfusion in general using cardiac mechanisms has been in development by a lot of labs around the world over the past 20 years. And the specific objectives we had were to get it out of the laboratory into the hands of the clinicians and do that, we chose to implement everything fully, automatically and integrated onto a clinical scanner so that the clinicians would get the answers on the fly.

That is to say they would perform a scan and it would be transparent. They'd run the scan the way they normally do today, and the results of the myocardial blood flow would appear on the scanner within a minute. So, we probably worked on this, myself and Dr Wie Wzei at NIH, for the past five years. Gradually building this up to the state where it is now at sites like The Barts Heart Centre can use it.

Dr Carolyn Lam: Just really hats off. This is amazing because you've summarized it in a few sentences, but you know I kind of personally know what it takes. Just getting an algorithm is one thing but making it clinically usable and then James demonstrating it clinically are all huge achievements. So congratulations. I don't think anyone can say it better than Greg. Greg, tell us why is this paper so important? And see that was an easy question.

Dr Greg Hundley: This is really dramatic in the field of cardiovascular magnetic resonance, but also for stress testing related to patients with cardiovascular disease. As many of our listeners know today, the majority of studies are interpreted visually and while the spatial and temporal resolution is just beautiful like high definition television of the inside of our bodies, the artifacts that sometimes occur and then some of the interobserver variability remains problematic. What I love about this, is this is now a quantitative. It's not a visual interpretation of signal intensity. What both Dr's. Kellman and Moon have developed is something that measures the blood flow in mls per minute, per gram of tissue regionally throughout the heart and then color codes that so that all of us can interpret it readily. I think another big piece of this is that they have created the artificial intelligence that helps interpret that for us and just think now we'll be able standardize readings across medical centers.

That's an enormous advance for this field and combining this information and putting it into, both national as well as international registries, could be very important for identifying abnormalities that would forecast prognosis. And these gentlemen have laid the framework for that because they have a large number of subjects, two centers, and they had comprehensive follow up that looked at heart events and this technology was able to forecast that on the backdrop of all the other parameters, demographic variables, risk factors, etc., that we find in patients that present to us with cardiovascular disease and are symptomatic with chest pain syndromes. So boy, what an outstanding imaging paper and feel so fortunate to actually have this in circulation.

Dr Carolyn Lam: Greg, no one can say it better than you. I would like to emphasize that this just doesn't hold the implications for MR imaging. I think it holds implications for many forms of cardiac imaging if we have AI to assist us. So James, how do you see this helping the patients? These are prospectively performed cardiac MR scans, but you know, what about surveillance of MR databases? What are the implications for perhaps detecting microvascular abnormalities? Another pet topic on my own. If you don't mind, you know, tell us, what do you think are the clinical implications?

Dr James Moon: Quite a lot of clinical implications. We're really starting a journey here. So, one of the things I'm interested in is that we have been in an era of thinking about the epicardial cone use only. We were seeing significance between patient differences in peak hyperemia related to, for example, age and presence of diabetes, but must be reflecting the microvasculature and of course, that may be a key biomarker for the future and understanding what happens to patients. So naturally, of course, when we're assessing the epicardial arteries, we're going to have to understand that those assessments, especially if it's measuring wall flow, will be influenced by the microvasculature because it's a circulation. So, this may just bring that microvasculature into the mainstream as potentially therapeutic target.

If you think about this AI and observe a variation. So what we do is measure things clinically and that sounds like boring old science, but metrology and accuracy and precision translate into something that cascades down. So that key dots the patient relationship where we're making the decisions on what therapies together might influence outcome. And if you can rely on those results and if the results that scanner one in one place and another scan at another place always read the same, then your healthcare system just gets a boost because everything is more reliable.

Dr Carolyn Lam: That's beautifully put. And Peter, thank you to you and your group for developing such AI and James for demonstrating this. Now if I may, this is an amazing collaboration. I understand the British Heart Foundation had a role in supporting this. How did you get together to decide to work across regions and so on, on this? Could you just give us a little bit about that?

Dr Peter Kellman: Our working together was an outgrowth of prior collaborations in areas such as T one map and for tissue characterization and Barts Heart Centre represents the largest cardiac MR site in the world, in terms of volume. And when you have a quantitative method, it was the perfect place to evaluate this kind of ischemic heart disease. And furthermore, when you talk about AI, you need to train the algorithms and develop the models. You need a large volume of data. So, right now we're probably doing on the order of 150 stress tests a week. And so, after a year we had a large volume of data to train the algorithms for segmenting the myocardium. So the collaboration has been ongoing for about five years.

Dr Carolyn Lam: That's great. Greg, you know what, because I adore you, I'm going to ask you to give us the final words. Tell us your thoughts on where this is all heading.

Dr Greg Hundley: I think Peter astutely identified that Barts Heart Centre and you're seeing really in the United Kingdom the primary use of magnetic resonance imaging for cardiovascular stress testing with its accuracy. And now, adding to this these quantitative assessments that can reflect, not only epicardial disease, but as we've heard, have the potential to identify micro circulatory disease. I see this growing and extending worldwide. And I think the next studies will involve the use of this type of technology and multiple different manufacturers of scanners and across different field strengths, 1.5 and three T, and multi-center initiatives using this technology to try to forecast cardiovascular prognosis in patients that present with chest pain syndromes as well as other disease processes that involve both epicardial coronary arteries and micro circulation.

Dr Carolyn Lam: Wow. And we're so pleased and proud to be publishing then this paper here in circulation this week. Thank you so much, gentleman. It's been awesome discussing this with you.

And thank you, audience for joining us this week. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, The American Heart Association 2020.

Circulation April 14, 2020 Issue

13 april 2020 | 21 min

Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Greg, amyloid cardiomyopathy is the rage. I cannot tell you the number of discussions I've had on the topic. Of course, it was tafamidis, the amazing results with that trial that really made us realize we need to pick this up. But have you ever thought about the cost effectiveness of tafamidis for amyloid cardiomyopathy? Well, guess what? We're going to have a whole feature discussion just about that. But first let's go to our summary, shall we?

Dr Greg Hundley: You bet, Carolyn. Well, let me get started. I'm going to talk about regulation of cell cycle growth as well as division in regard to cardiac regeneration. My first paper comes from Dr Lior Zangi from the Mount Sinai School of Medicine. Well, Carolyn, have you ever wondered why the adult mammalian heart has limited regenerative capacity?

Dr Carolyn Lam: All the time, Greg.

Dr Greg Hundley: Well, of course you have. It's mostly due to postnatal cardiomyocyte cell cycle arrest. In this study the investigators evaluated the effect of pyruvate kinase muscle isozyme 2 and cardiomyocytes through models of loss, that is cardiomyocyte specific PKM2 deletion during cardiac development or gain using cardiomyocytes specific PKM to modified mRNA to evaluate PKM to function and regenerative effects post-acute or chronic MI in mice.

Dr Carolyn Lam: Nicely described. What did they find, Greg?

Dr Greg Hundley: What they found is that PKM2 is expressed in cardiomyocytes during development and immediately after birth, but not during adulthood. Using cardiomyocytes PKM to modified RNA, they found that cardiomyocyte targeted strategy following acute or chronic MI resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. They found that PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and beta-catenin.

Dr Carolyn Lam: Cool, Greg. Man, this cardiac regeneration really, really is a hot area.

Dr Greg Hundley: Carolyn, that is so insightful because these results really impact research toward unlocking pathways that could be involved in induction of myocyte cell division and regeneration in those sustaining MI or conditions like MI.

Dr Carolyn Lam: Nice. Well, Greg, I'm going to change tones here and ask you, can we prevent atrial fibrillation with treatments for diabetes? Well, guess what? We have a paper next. It's from Dr Wiviott from the TIMI Study Group and his colleagues who really reason that since atrial fibrillation is associated with hypertension, obesity and heart failure in patients with diabetes and SGLT2 inhibitors have been shown to lower blood pressure, reduce weight, and reduce hospitalization for heart failure in these patients, perhaps SGLT2 inhibitors may also reduce the risk of atrial fibrillation. They explored the effect of Dapagliflozin on the first and total number of atrial fibrillation and atrial flutter events in patients from the DECLARE-TIMI 58. As a reminder, they had type two diabetes with either multiple risk factors for or known atherosclerotic cardiovascular disease.

Now importantly, atrial fibrillation events were identified by a search of the safety database using these MedDAR preferred terms. Now what they found was Dapagliflozin reduced the risk of atrial fibrillation events during follow-up as well as the total number of atrial fibrillation events in patients with type two diabetes. These reductions were consistent across major subgroups including sex, presence of atherosclerotic cardiovascular disease, history of atrial fibrillation, history of heart failure, history of ischemic stroke, HBA1C groups, body mass index groups, blood pressure or EGFR. They looked at all these subgroups because these are all clinical factors, well established, with associations with the risk of atrial fibrillation.

Dr Greg Hundley: Wow, Carolyn. Another sort of feather in the cap for the SGLT2 inhibitors. What does this mean for clinical practice?

Dr Carolyn Lam: Ah. I'm not going to answer it here. I am going to say everybody has to read the excellent editorial by Dr Granger from Duke University and Dr Mahaffey from Stanford University School of Medicine. But what I will tell you is their concluding sentences. They said, "This report provides evidence that Dapagliflozin appears to reduce atrial fibrillation events in patients with diabetes and coronary disease and multiple risk factors. It also raises the issue of how to determine when effects on a secondary outcome, particularly one collected without the rigor of systematic collection using perspective definitions and case report forms, whether or not these are reliable." So must read.

Dr Greg Hundley: Absolutely. Carolyn, my next study comes and evaluates arrhythmogenic right ventricular cardiomyopathy and is really investigating the concept of auto immunity, looking at associations of circulating anti heart and anti intercalated disc auto antibodies with disease severity and family history. The paper comes from Professor Alida Caforio from the University of Padova. Again, looking at the role of auto antibodies in patients with ARVC. An interesting topic.

Dr Carolyn Lam: Yeah, that's really novel. What did they find?

Dr Greg Hundley: They investigated ARVC pro bands, so those that sort of started with the disease process in a family and noted an increased frequency of serum organ specific anti heart autoantibodies and anti-intercalated disc autoantibodies in a sizeable arrhythmogenic RVC cohort as compared to controls. They found that positive AHA status.

Dr Carolyn Lam: Anti-heart antibodies.

Dr Greg Hundley: Yep. Was associated with lower left ventricular ejection fraction, a higher frequency of cardiac symptoms and implantable cardioverter defibrillator implantation. Positive AIDA was associated with lower ejection fractions in both the right and the left ventricle.

Dr Carolyn Lam: AIDA being the anti-intercalated disc auto antibodies. Wow. That is interesting. But what are the clinical implications?

Dr Greg Hundley: Well, the presence of both these organ specific AHA and AIDA antibodies provides evidence of autoimmunity in the majority, so 85% of familiar, and almost half, 45%, of sporadic ARVC. In programs and in effective relatives, these antibodies were associated with the disease severity features. So really a link with this auto immunity and ARVC.

Dr Carolyn Lam: Yeah. I never thought of ARVC as an autoimmune disease. Very interesting. But let me also tell you what else is in this week's issue. There are letters to the editors, one from Dr Kaski regarding the mag STEMI randomized control trial questioning whether improving coronary vasal motion can be equated to restoring patient's cardiovascular health. Interestingly with a letter in response from Dr Sabatine. There's also a research letter by Dr Alahmad on the cardiovascular mortality and exposure to heat in an inherently hot region and where they were was Kuwait. They also drew some implications for climate change. Very interesting piece. There's also an ECG challenged by Dr Verma describing conduction abnormalities and ischemic cardiomyopathy in an 84-year-old man.

Dr Greg Hundley: Very nice. Carolyn, in the mailbag, there's a nice research letter from Dr Nicholas Leeper from Stanford University School of Medicine. It's entitled “The 9p21 locus promotes calcific atherosclerosis.” Our own Josh Beckman has an on my mind piece regarding “The Big Mac Attack on Peripheral Arterial Disease.”

Dr Carolyn Lam: I love that. I just love the titles Josh comes up with.

Dr Greg Hundley: Then finally Bridget Kuehn has a very nice sort of correspondence on Cardiovascular News regarding cardiac imaging on the cusp of artificial intelligence. What a revolution we have ahead, Carolyn, and I know that's a topic that's true to your heart.

Dr Carolyn Lam: It is. I loved her paper.

Dr Greg Hundley: Okay. Carolyn, how about we get onto that feature article? I'm waiting to hear about the cost effectiveness of tafamidis.

Dr Carolyn Lam: Me too.

Dr Greg Hundley: Well listeners, we have got a great discussion for our feature publication today and we have Dr Dhruv Kazi from Beth Israel Deaconess in Boston and our own associate editor, Dr Justin Ezekowitz from University of Alberta. Well, as we get started, Kazi, can you tell us a little bit what was the hypothesis that you wanted to test with this study and maybe even before that a little bit of background with transthyretin amyloid and tafamidis?

Dr Dhruv Kazi: Yeah. Transthyretin amyloidosis is a subgroup of patients who present with heart failure with preserved ejection fraction, which we know is a heterogeneous condition that has been pretty resilient to effective guideline directed therapies over the past decade. It's a subgroup of patients generally presenting in their 70s with slowly declining quality of life and a median survival of about three years. It hadn't had an effective therapy before and so when tafamidis, which is a stabilizer of transthyretin and prevents its deposition in the myocardium, was developed and tested in a randomized clinical trial that showed an improvement in survival, a reduction in heart failure hospitalizations and a slowing of decline and quality of life. It was viewed as a really big win for the heart failure community.

What came as a surprise though is the pricing. It was launched in 2019 at $225,000 a year. We set out to ask, given that this is a severe disease without alternative treatments, is this price tag generating enough value? Is this a cost-effective therapy? The background here again is that oncologic therapies have had a long history of very high prices for rare diseases and severe diseases. But this is the first time we're seeing this in cardiology. Can we think more broadly about how we're going to tackle this issue? Not just for tafamidis but also for other drugs that come down the pipe.

Dr Greg Hundley: Wow. $225,000 per year. Tell us what was your study design, and how did you go about evaluating this issue?

Dr Dhruv Kazi: We started off with the one phase three trial of the drug that has been published and simulated in a mathematical model the population that would be eligible for this therapy, reproduced the events, heart failure hospitalizations, debts, quality of life that were seen in the trial for the first three years, and then extrapolated beyond the trial based on what we know about HFpEF and what we know about transthyretin amyloidosis. It's a mathematical model that first reproduces what was seen in the trial and then extrapolates beyond what we think is the best guess of what happens to these patients. We tested a variety of scenarios whether the drug continues to be effective, whether the effectiveness declines over time or the effectiveness ceases immediately after three years.

Dr Greg Hundley: What did you find?

Dr Dhruv Kazi: What we found was interesting and it surprised us a little bit, which is that in the base case, which is assuming that the drug stays effective beyond three years, the drug is actually very effective in the traditional sense. It added 1.3 quality adjusted life years. For context here, this is about twice the effect size you expect to see with Entresto, and the HFpEF patients. So here's a drug that we've accepted and HFpEF has part of guideline directed medical therapy. Tafamidis in that best-case scenario is about twice as effective, but it is not cost effective. Because you're paying $225,000 for every year that the patient is on the medication, its incremental cost effectiveness ratio compared with usual care was $880,000, so well above what we would consider value for money. That's the best-case scenario assuming that the drug is permanently effective, if the drug's effect wanes over time, which is very likely as these patients get older and sicker, then the drug gets even less economically attractive.

Dr Greg Hundley: You've pointed out in your article, if you had 120,000 transthyretin patients in the United States, that would translate to how many dollars?

Dr Dhruv Kazi: We estimate that if all of those 120,000 patients received tafamidis, the healthcare spending would go up by $32 billion a year and most of it is towards the drug. But the caveat is that we think 120,000 patients in the US is a very conservative number because the diagnostic technology for amyloid cardiomyopathy has improved substantially over the last five years so that we no longer need biopsies. We can use nuclear scans to diagnose the disease and we have pretty good to genetic testing to identify the genetic variant of the disease. We think that number is probably closer to 200,000 or even higher because the healthcare expenditure is almost entirely driven by drug costs. The more patients we diagnosed, the bigger the budget's impact on healthcare spending.

Dr Greg Hundley: Oh my. Well Justin, for our listeners, Justin resides in Canada. Justin, what do we do with these results? I mean this is quite a sticker shock for probably an important therapy for this patient population.

Dr Justin Ezekowitz: Greg, it's a great issue and Kazi, thank you very much for this terrific, easily understandable manuscript that I think everybody should read as it's very well written and easy to understand for us non-health economists. The sticker shock is a bit of a tricky one because we always want to do what's best for our patients. When we look at that budget impact analysis, the challenge is what do we think internationally? The US is critical in terms of understanding this, but then for the rest of the world, there's certainly almost no willingness to pay at this threshold and with an uncertain incidence of amyloidosis globally, but also within the US and Canada and the difficult in diagnosis already, I think we're going to have to realize what can we do for our patients and who benefits the most with this drug given its importance and its efficacy?

Kazi, you mentioned another thing which I think is critical is what happens after 30 months if the effect wanes and where does that take us for the impact on cost and effectiveness over time but also the budget impact analysis? Because the second drug or third drug may very well come along that may fill that niche.

Dr Dhruv Kazi: Justin, that's a really good question. I mean the study only goes to 30 months and that's the only one randomized trial for tafamidis that we're working off of. So there's substantial uncertainty about what happens to this drug beyond 30 months. It's reasonable to assume that some of the effect persists, that as patients get older, get sicker, that effectiveness will wane over time. Which ties very closely to the cost effectiveness. So if the patients continue to take the drug but it's not as effective as you can imagine, it becomes less cost effective.

This also has implications for other drugs coming down the pike, which may or may not be more effective than tafamidis. They may or may not be tested head to head with tafamidis. Physicians are going to be left with the question, very clinically relevant question, of which drug to start with, how do you switch on them the next generation or more expensive drugs that come down the pike? We'll have to rely on both real-world evidence and to some extent mathematical modeling to use our best judgment on developing a treatment strategy for these patients. But rest assured that our current regulatory framework means that the drugs coming down in the future will be more expensive than tafamidis and hence, this is a good time to have the conversation about cost effectiveness and our willingness to pay for innovation.

Dr Greg Hundley: What needs to happen next to help either lower cost or develop some sort of competition in the treatment of this disease to lower the cost?

Dr Dhruv Kazi: I can take a stab at that. Greg, I think the findings of this particular drug in transthyretin amyloidosis is illustrative of the challenges that lie ahead. I think there are clinical research and policy implications. As clinicians, it's really important for us to know that this high cost of the drug is not a theoretical challenge. It's a practical challenge for our patients. The majority of these patients are going to be on Medicare part D. We estimate that the out of pocket costs is going to be in the range of $8,000 to $9,000 a year even with Medicare part D, which is a big amount of money for our fixed income seniors. I encourage our clinicians to have this conversation about out-of-pocket costs with patients, not just when you start the therapy but throughout the year. We know that the Medicare part D copays change over the course of the year based on where they are in the insurance plan.

Having this conversation may help preclude costs related non-adherence. We might be able to identify patients early or at risk, put them into patient support programs or switch them to alternate therapies that may not be as effective but at least are likely to offer the patient some support.

From a research perspective, we really need to figure out what subgroup of patients are more likely to benefit. Let's say we have 200,000 patients with transthyretin amyloidosis in the US. We need more research, and the company is not going to be vested in doing this research, it's going to have to be NIH funded research to identify subgroups of patients who benefit most from this drug, both in the short term and over the long term.

From a policy perspective, what this drug pricing issue is telling us is that we provided incentives for companies to innovate in the rare disease orphan drug program. These incentives are working. More than half of the drugs that are coming out now or have in the past year are under this rare disease umbrella. But these drugs, once they're approved, are super expensive.

We need to figure out a regulatory framework where we continue to incentivize innovation for rare diseases for orphan drugs, but at the same time tie those incentives to the final pricing to ensure that the patients get access to the drug and not just the wealthy patients who can afford the copays, but all patients who would benefit from the drug.

One of the things that comes to mind as clinicians and researchers is that particularly in cardiology, we are obsessed with innovating, with regards to new molecules and new technology. I would like us as a community to focus not just on molecules but also on markets because the innovation is not meaningful if our patients cannot have access to them. This year being the presidential election year, we're going to hear a lot about drug pricing. What I hope that this example shines a light on is that drug pricing is complicated and trying to figure out the right framework to incentivize innovation while it's still ensuring access is going to take thoughtful interventions, regulatory interventions, and clinicians should very much be a part of that process.

Dr Greg Hundley: Well listeners, we've heard a wonderful discussion here highlighting a new therapy for a disease process that's being increasingly diagnosed with our aging population and new technologies, magnetic resonance, echocardiography that identify this condition. But then how are we going to afford some of the therapies that are moving forward and design a system that emphasizes not only scientific discovery, but cost effectiveness?

We want to thank Dr Dhruv Kazi from Beth Israel Deaconess and also Justin Ezekowitz from the University of Alberta. We hope you have a great week and look forward to speaking with you next week. This program is copyright the American Heart Association 2020.

Circulation April 07, 2020 Issue

6 april 2020 | 22 min

Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Greg today's speaker paper is all about soy products and whether or not there is a benefit with them with regards to risk of coronary heart disease. Now, this has been extremely controversial and today's speech or paper is really important in its findings. Ha ha, I bet you want to get to it right now but I'm going to say, hold on let's get to some other really interesting papers in this series first. Can I start off? You got your coffee?

Dr Greg Hundley: Yes. Let's get going Carolyn.

Dr Carolyn Lam: So the first paper I want to highlight really talks about myocardial energetics in obesity, and you're going to love this one Greg it's got some really cool MRI techniques. We know that obesity is strongly associated with exercise intolerance and the development of heart failure particularly HFpEF. Well Dr Rayner from University of Oxford and colleagues looked at this carefully in 80 volunteers, which included 35 controls with an average BMI of 24 and 45 obese individuals with an average BMI of 35, who did not have coexisting cardiovascular disease. Now, these participants underwent body composition analysis and MRI of the abdominal liver and myocardial fat content, left ventricular function and 31 Phosphorus Magnetic Resonance Spectroscopy to assess Phosphocreatine ATP and Creatine Kinase Kinetics at rest and during Dobutamine Stress.

Dr Greg Hundley: Oh, wow Carolyn, this is right up my alley. You've got MRI imaging for body composition coupled with MR spectroscopy for metabolism, so what did they find?

Dr Carolyn Lam: Thanks for putting that simply for us Greg. They found that in the obese resting heart, the myocardial creatine kinase reaction rate is increase, maintaining ATP delivery despite reduced energy stores during increased workload. While the non obese heart increases ATP delivery through creatine kinase the obese heart does not, and this is associated with reduced systolic augmentation and exercise tolerance. Weight Loss reversed these energetic changes, so these findings really highlight myocardial energy delivery via creatine kinase as a potential therapeutic strategy to improve symptoms in obesity related heart disease, as well as a fascinating modifiable pathway involved in the progression to heart failure. Now with this paper the central illustration is so critical, everybody has to pick up that issue and have a look. Furthermore, you must read the elegant editorial by Barry Borlaug and Craig Malloy.

Dr Greg Hundley: Oh, you bet Carolyn. Craig always puts these MR spectroscopy papers in such fantastic perspective, really looking forward to that read and such an elegant study. Now, we haven't had Carolyn's quiz in weeks and we're going to get into one. This paper comes from Professor Nina Wettschureck, from the Max-Planck-Institute for Heart and Lung research, and it pertains to the infamous G-protein coupled receptors. Now, Carolyn here's your quiz and guess what, it's just multiple choice. All you have to do is fill in the blank.

Dr Carolyn Lam: On G-protein coupled receptors?

Dr Greg Hundley: Yeah, I know it's... we know a lot about these, but we're going to learn. So, G-protein coupled receptors are the largest family of transmembrane receptors in eukaryotes. They transduce signals of numerous physio-chemical stimuli including... and Carolyn you have to complete this sentence. So it's neurotransmitters, hormones, local mediators, metabolic or olfactory cues and got to complete the sentence. Is it air resistance? Time? Or light?

Dr Carolyn Lam: Space.

Dr Greg Hundley: That's not a choice.

Dr Carolyn Lam: All right, all right let me guess light.

Dr Greg Hundley: That's awesome. Fantastic, great job Carolyn. So in the vascular system the contract alternative vessels is crucially regulated by these GPCRs, including basic constrictors such as Angiotensin two and Endothelin one. In this study the investigators studied the role of GPRC5B, and the regulation of contractility and differentiation in human and murine smooth muscle cells in vitro, as well as in tamoxifen inducible smooth muscle cells Pacific knockout mice under conditions of arterial hypertension and atherosclerosis, and these experiments were done in vivo.

Dr Carolyn Lam: Okay, so what were the results?

Dr Greg Hundley: They found that GPRC5B regulates vascular smooth muscle tone and differentiation by negatively regulating prostate cycling receptor signaling. Thus, Carolyn inhibition of the interaction between GPRC5B and the prostacyclin receptor might be beneficial in human arterial hypertension and vascular remodeling. What a great new insight into basic science. Well, let me get on I have a clinical paper, and this is on the infamous topic from the COMPASS-PCI trial, Rivaroxaban plus Aspirin versus Aspirin alone in patients with Prior Percutaneous Coronary Intervention from Dr Kevin Bainey at the Canadian VIGOUR Center in University of Alberta.

So Carolyn, the cardiovascular outcomes for people using anticoagulation strategies or COMPASS trial demonstrated dual pathway intervention with Rivaroxaban 2.5 milligrams twice daily plus aspirin, and 100 milligrams once daily versus aspirin 100 milligrams once daily, reduced the primary major adverse cardiovascular event outcome of cardiovascular death, MI or stroke as well as mortality in patients with chronic coronary syndromes or peripheral arterial disease. Now, whether this remains true in patients with a history of PCI is unknown.

Dr Carolyn Lam: Oh, Greg I'm so disappointed. Why didn't you give me a quiz here? I know about the COMPASS trial. Okay, so what did the author's find?

Dr Greg Hundley: So Carolyn of the 27,000 plus patients in COMPASS 16,500 plus patients had chronic coronary syndrome, were randomized to DPI or aspirin and of these 9,862 had prior PCI. So here are the results, DPI compared with aspirin produce consistent reductions in MACE mortality, but with increased major bleeding with or without prior PCI. So among those with prior PCI one year and beyond, the effects on MACE and mortality were consistent irrespective of time since the last PCI.

Dr Carolyn Lam: Mm-hmm (affirmative) Interesting implications on dual platelet inhibition. Well, let me tell you a little bit about what's in the mailbag in the rest of this issue. There's a research letter by Dr Joseph Wu on molecular signatures of beneficial class effects of statins on human induced pluripotent stem cell derived cardiomyocytes. We have global rounds by Dr Annika Rosengren and Dr Lars Wallentin on the cardiovascular medicine in Sweden. We have a White Paper by Dr Abhinav Saxena and colleagues on the value of hemodynamic monitoring in patients with cardiogenic shock undergoing mechanical circulatory support. And we also have paired perspective pieces, one by Dr Salim Virani and colleagues on secondary prevention of atherosclerotic cardiovascular disease comparing recent United States and European guidelines on dyslipidemia, and another by Dr Neil Stone and colleagues on comparing primary prevention recommendations with the focus look at the US versus European guidelines on dyslipidemia.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a research letter Professor Do-Young Kwon from the Korea University of Ansan Hospital, Korea University College of Medicine and discusses the association of Parkinson's disease with the risk of cardiovascular disease and all-cause mortality, and a nationwide population-based cohort study. In addition, different series of letters Dr Seung-Jung Park from Asan Medical Center at the University of Ulsan College of Medicine, and Professor Lang Li of The First Affiliated Hospital of Guangxi Medical University exchanged letters regarding the article, Clinically Significant Bleeding With Ticagrelor versus Clopidogrel in Korean patients with Acute Coronary Syndromes Intended for Invasive Management, that previously published randomized clinical trial. Then finally one of those great ECG investigations from Dr Miguel Arias, and they have an ECG quiz entitled The Hidden Reveals the Hidden, but really, it's referring to a Brugada ECG pattern and a patient with Wolff-Parkinson-White. I can't wait to get onto that feature article discussing the potential benefits or harms of soy in men and women as it relates to cardiovascular disease.

Dr Carolyn Lam: Yeah, you and I Greg let's go. Oh, boy today's feature paper really literally cuts close to the heart for me talking about soy products, and whether or not there's a relationship with cardiovascular health. This remains controversial but thankfully we've got really great data just published in this week's issue, so proud to have the first author with us Dr Qi Sun from Brigham and Women's Hospital, as well as our associate editor who's also an editorialist for this paper and that's Dr Mercedes Carnethon from Northwestern University Feinberg School of Medicine. So welcome both I cannot wait to just jump right into it. Please, Qi, tell us what you found about soy products.

Dr Qi Sun: First off this is a prospective cohort study that included three cohort studies, the Nurses’ Health Study and the Nurses’ Health Study II and Health Professionals Follow-Up Study. So those three big prospective cohort follow up studies. Now over the years we have collected much data of diet which has been repeated, reviewed, and assessed over the years, and we have accumulated many cases of cardinal heart disease the numbers are a solid. Now what we found is that the intake isoflavones which are the big family are flavonoids, the higher intake of isoflavones were associated with a lower risk of developing coronary heart disease in those three cohorts of men and women. And in addition because tofu and soy milk are the primary contributor in our guide of isoflavones, we also examine the tofu and soy milk in relation to the risk of cardinal heart disease What we found is that tofu intake is significantly associated with lower risk of developing heart disease, and soy milk is also associated with lower risk of developing heart disease. It's just the association for soy milk, soy milk is not significant. And I think very interestingly we also found that the menopausal status and the postmenopausal hormone use somewhat also modulated association primarily for coffee intake with heart disease risk, in that we found younger women who were before their menopause and also postmenopausal women who did not use hormone will benefit more from tofu intake.

In contrast, for postmenopausal women who are using hormone the association was not significant. I think those are the primary findings of our prospective cohort study.

Dr Carolyn Lam: Oh my goodness, hallelujah. That's really marvelous and beautifully summarized, Mercedes please explain why was this such a controversial area before? And what does this paper add? Love your editorial by the way.

Mercedes Carnethon: We hear a lot about nutritional epidemiology studies, and we have a lot of debates about what we should believe, whether we should change our behavior based on these observational studies and quite often we have discussions about what's new. And I lean on that final point about why I like this particular paper so much, and that's because I found the topic of isoflavones, tofu intake and soy to be extremely relevant to a large proportion of the world's population, whose primary protein intake may be something made from a soybean, heavy and isoflavones. Within the United States it's also relevant even though a smaller proportion of our population relies primarily on vegetarian diet, there is a very large and interested group wondering whether soy intake is safe. There have been discussions about whether there's harm associated with it, and the possibility that it could have beneficial influence on our leading causes of death of coronary heart disease.

So I was most thrilled about the innovation of this particular topic, and its methodological rigor. When we think about what we lean on, we lean on large studies, we lean on multiple events and the size of the study allowed the investigators to explore numerous subtleties. Subtleties such as that reported related to the moderation by menopausal status, and that was the point I was most curious about and why I'm really excited to have an opportunity to talk to you today Chi. Can you tell me a little more about the menopausal status finding?

Dr Qi Sun: So first off as I mentioned tofu intake was more strongly associated with lower risk of developing heart disease among younger pre-menopausal women, or postmenopausal women who did not use ham. Before that I want to also mention for isoflavones intake where I also found a similar pattern in that isoflavones are more. Appear to be more strongly associated with lower risk also in those two groups of women, although the past by interaction was non-significant. Now in terms of why I think there are a couple reasons why is that, among postmenopausal female or in our use hormone, the isoflavone can function as estrogen and provide at least partially the estrogenic effects that were calculated in postmenopausal women who do not use hormone, and for premenopausal women we think that's probably because before menopausal, the activity of estrogen receptor may be higher than the estrogen receptor after menopausal. So, in reality, the other variables of isoflavones may provide estrogen effects after menopausal. So those are the hypotheses although I have to mention that those hypotheses, we need more evidence to really shed light on the mechanisms underlying those interactions between menopausal status, postmenopausal hormonal use, where's the intake of isoflavones and tofu.

Dr Carolyn Lam: So Chi I love that explanation and giving it some biological possibility, although as you said it's a postulation. But may I ask so what's the implication for men? I lived with a man who thinks if he takes soy he's going to grow boobs. So what... did you see any sex differences and do studies like this and able looking for the downsides of eating soy?

Dr Qi Sun: As a scientist I'm open to any kind of new findings as long as the findings are from well conducted, rigorously designed study. But having said that I couldn't exclude the possibility that maybe soy intake is associated with certain adverse health outcomes, but so far based on my experience I didn't see any such evidence. But having said this I always say I wouldn't risk any possibility, but coming... circling back to the coronary heart disease we really didn't see much difference between men and women. It's true for the younger women we saw a stronger association but for men I also see a lower risk of heart disease. So there's a kind of interesting image on soy intake or isoflavones intake in the United States that people believe they are estrogen so a man shouldn't take it, but if you look at the group of vegetarians, the vegans. There are a lot of guys they practice vegetarian, they practice vegan diets and we also publish on plant-based diet in relation to coronary heart disease and lot of men eat very healthy. And we found those people who practice those kinds of healthy diets, soy is often mouthful of primary sources of proteins and if you look at their risk of developing heart disease, type two diabetes is quite low. Something lower than other normal women who practice otherwise omnivore diet.

Dr Carolyn Lam: It's true Qi soy intake could also be a marker of a healthier lifestyle in general, by extension of what you just said. But Mercedes I love that you discuss quite a number of these issues in your editorial and at the end of the day you asked the most important question, what does this mean for us? Should we all be increasing our intake of soy products? Could you give us your synthesis of that?

Mercedes Carnethon: Yes, a point that I've definitely tried to make here, and this is really in response to what I expect to be the media fear surrounding new dietary findings. One of the first questions that I know that she and his colleagues will be asked is, should I change my diet? Can I extend my life? And that's because the media is really looking for a lot of sensational headlines in this topic, and I think we have to focus on what we learn from these observational studies. They're a very important step in the scientific process that helps us provide a justification for later clinical trials, that helps us think about the multiple components that work together to promote overall excellent health. And the point you were making right before this about the individuals who eat plant based diets that are heavily based in soy. In the paper it also describes that those individuals exercise more, they may have lower intakes of saturated fat, and so I think ultimately what I take from this at least for myself and for people who would ask is that an overall healthy diet seems to stand up very well in these well done observational studies. And that soy in particular may be a part of an overall healthy diet given what we're seeing here in this very well done study.

Dr Carolyn Lam: Oh, that's beautifully put Mercedes and Chi perhaps I can give you the last word. What would you say is the take home message and what are next steps?

Dr Qi Sun: I think the core message is this as Mercedes very well discussed, I think soy and especially tofu can be really good components of the overall healthy plant based diet, and by practicing that I think we can significantly reduce the risk of developing coronary heart disease for both men and the women. I think moving forward we would like to see evidence from clinical trials that target cardiometabolic risk factors as outcome, and to see whether increased consumption of tofu and isoflavones can really reduce those risk markers so that they have ample evidence to support the mechanisms. As you mentioned Carolyn that this is an initial study, and it could be soy, intake could be just macro how is it, through clinical trials, we can really control those confounding factors and really provide good evidence to support our findings.

Dr Carolyn Lam: Well, in the meantime I just have to say you made my day this is coming from a soy eating vegetarian, so thank you so, so much. Thank you, listeners for joining us today.

Dr Greg Hundley: This program is copyright the American Heart Association 2020.

Circulation March 31, 2020 Issue

30 mars 2020 | 24 min

Dr Greg Hundley: And I'm Dr Greg Hundley from the VCU Health Pauley Heart Center in Richmond, Virginia. Well, Carolyn, we've got a great feature article this week, evaluating do we wait or do we do now ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and implantable defibrillators? But before we get to that, how about if we grab our coffee or whatever it may be and jump into the other articles?

Dr Carolyn Lam: Sure. Well, Greg, have you ever wondered what the outcomes are of transcatheter aortic valve replacement, or TAVR, in patients with bicuspid aortic valve stenosis? Now, remember, patients with bicuspid aortic valve stenosis were excluded from the pivotal evaluations of TAVR.

Dr Greg Hundley: I wondered that yesterday, Carolyn.

Dr Carolyn Lam: Well, guess what, Greg, it's your lucky day because we're going to get answers now from corresponding author Dr Brennan from DCRI and coauthors who use data from the Society of Thoracic Surgeons, American College of Cardiology, TAVR registry from 2011 to 2018 to determine the device success procedural outcomes, post-TAVR valve performance and in-hospital clinical outcomes in almost 171,000 eligible procedures, of which 5,412 TAVR procedures were performed in bicuspid aortic valve patients, including 3,705 with current generation devices.

Dr Greg Hundley: Wow. Carolyn, this sounds to me like probably one of the largest collections of patients that have had TAVR and bicuspid valves. What did they find?

Dr Carolyn Lam: Well, compared to patients with tricuspid aortic valves, bicuspid aortic valve patients were younger and had a lower STS predicted risk of operative mortality score, so you have to bear that in mind first. With the current generation TAVR devices, the incidence of device success was only slightly lower for bicuspid versus tricuspid aortic valve patients and residual two-plus aortic insufficiency remains slightly higher, though, for bicuspid versus tricuspid aortic valve patients.

There was no difference in adjusted one-year hazard of stroke in patients with bicuspid versus tricuspid valves, but the adjusted one-year hazard of mortality was lower among bicuspid aortic valve patients. Thus, using current generation technology, TAVR appears both safe and effective for the treatment of bicuspid aortic valve stenosis, although there remains a low incidence of moderate or greater aortic insufficiency among both bicuspid and tricuspid aortic valve patients.

Dr Greg Hundley: Very nice. Well, Carolyn, do you ever wonder how white cells are recruited into areas of the heart that have sustained a myocardial infarction?

Dr Carolyn Lam: Every day, Greg. Every day I think about that.

Dr Greg Hundley: You know, we've got so much wondering on your side of the world and on my side of the world, but if we connect that we will solve a lot of things. Well, this paper is from Dr Prabhakara Nagareddy from Ohio State University. This group of investigators used a mouse model involving ligation of the LAD and flow cytometry to characterize the temporal and spatial effects of myocardial infarction on different myeloid cell types, a process termed myelopoiesis, that results in heightened production of neutrophils.

The investigators sought to understand the mechanisms that sustain white blood cell production in recruitment to the injured heart using global transcriptome analysis of different cardiac cell types within the infarct. In addition, just as these clever circulation papers do, also a human subject study was performed utilizing a combination of genetic and pharmacologic strategies. The authors identified the sequela of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography and the association of early indices of neutrophilia with major cardiac events, or MACE, was studied in those patients sustaining an MI.

Dr Carolyn Lam: Wow, that's a huge amount of work. What was the bottom line results?

Dr Greg Hundley: So, first, in the patients with acute coronary syndromes, a higher neutrophil count on admission and post-revascularization correlated positively with major adverse cardiovascular disease outcomes. And then, second, from the basic science component, the study identified novel evidence for the primary role of neutrophil-derived alarmins and, in particular in this study, S100A8-A9 in dictating the nature of the ensuing inflammatory response following myocardial injury.

Therapeutic strategies aimed at disruption of this S100A8-A9 signaling, or its downstream mediators in neutrophils, were shown to suppress granulopoiesis and therefore, perhaps in the future, could improve cardiac function in those patients sustaining an acute coronary syndrome. Really elegant work. That combination of the basic science in the animal model and then the translational work in the human subject model.

Dr Carolyn Lam: Exactly what I was going to say. Translational work. Well, hold onto your seat because this next one is super cool, too. It is the first time a pre-clinical development and first in human proof-of-concept of peritoneal direct sodium removal using a zero-sodium solution as a candidate therapy for volume overload. So, as a background, remember that loop diuretics have been well described to have toxicities and that loss of response to these agents are common when we try to treat volume overload. So alternative strategies are clearly needed for the maintenance of euvolemia in heart failure.

These authors, led by Dr Testani from Yale University hypothesized that non-renal removal of sodium directly across the peritoneal membrane, that is called direct sodium removal, using a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal. So what they did is they performed porcine experiments followed by a human study in which participants with end-stage renal failure on peritoneal dialysis underwent randomization and crossover to either a two-hour dwell with one liter of this direct sodium removal solution or a standard peritoneal dialysis solution. Sodium-free 10% dextrose, by the way, was utilized as the direct sodium removal solution.

Dr Greg Hundley: Boy, Carolyn, this is really another one of these elegant translational studies. So we have the animal model, we have the human subjects and then we have different concentrations of these peritoneal fluid that are injected and then extracted for dialysis. I can't wait to hear. So what did they find?

Dr Carolyn Lam: First, cycling a sodium-free osmotic solution that's a 10% dextrose across the peritoneal cavity of swine resulted in substantial sodium removal. So, proof of principle there. The sodium removal increased proportionately as the volume of 10% dextrose cycled across the peritoneum increased. Experimental elevation of right-sided cardiac filling pressures also resulted in substantial increased sodium removal with this technique. Now, in the humans, a single dose of sodium-free 10% dextrose was well tolerated in human subjects and resulted in over four-fold greater sodium removal than the strongest commercially available peritoneal dialysis solution.

So, direct sodium removal with a sodium-free osmotic peritoneum solution represents a new potential therapy for non-renal sodium and fluid removal in edematous disorders such as heart failure. However, there is a long way to go in deploying such a procedure in the heart failure population. And this is really highlighted and discussed in an accompanying editorial by Dr Robert Toto from UT Southwestern.

Dr Greg Hundley: Fantastic. Carolyn. Bob Toto always puts things really in perspective. That'll be a great read. Well, let me tell you about a couple other articles in this issue. Dr Bina Ahmed from Santa Barbara Cardiovascular Group has a very nice on-my-mind piece getting at this issue of how we should, as physicians, be reacting to the healthcare issues. Also, particularly in cardiovascular disease, as they occur in the face of climate crisis. A great read. Then there's a beautiful adult learning excerpt put together by Dr Daniel Kramer from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center.

It involves a patient that presents with some symptomatology associated with their thoracic spine. They have to undergo an MRI. They've got an implanted device. How do you work through that? What do we need to do with anticoagulation? It turns out the patient also may need a Watchman device. Who is a candidate for that? Boy, it's just a great educational read.

Carolyn, there is a lot in the mailbag this week. Professor John Madias from the Icahn School of Medicine at Mount Sinai and Dr Adaya Weissler-Snir from the Hartford Hospital and University of Connecticut exchanged some letters regarding the article previously published on hypertrophic cardiomyopathy-related sudden cardiac death in young people in Ontario.

Robin Woods from Monash University has a research letter involving no modulation of aspirins effect by body weight in healthy older men and women. And then Myra Lipes from the Joslin Diabetes Center Harvard Medical School has a research letter entitled the Cardiac Autoimmunity is Associated with Subclinical Myocardial Dysfunction in Patients with Type 1 Diabetes.

Dr Carolyn Lam: And I'll add one more research letter by Dr Dempsey on prospective associations of accelerometer-measured physical activity and sedentary time with incident cardiovascular disease, cancer and all-cause mortality. So something that's really a hot topic now. Man, that has been a great issue. But let's move on to our feature discussion, shall we?

Dr Greg Hundley: You bet. Well, listeners, welcome to this feature discussion where we're going to understand a little bit more about ICDs and ventricular tachycardia and we have Dr Karl-Heinz Kuck from the University Hospital of Lübeck. We have Francis Marchlinski from the University of Pennsylvania and we have Dr Sammy Viskin, our own associate editor from the Tel Aviv Medical Center. What a great study. So, Karl, I'd like to start with you. Can you give us a little bit of background about why you wanted to perform the study and what was your hypothesis?

Dr Karl-Heinz Kuck: There is an ongoing debate in clinical electrophysiology, what would be the optimal timing of catheter ablation in patients with ventricular tachycardia and ventricular fibrillation. Now, until today, most patients come to catheter ablation at a very late stage of the disease, mostly after multiple ICD shocks. So the patients are in a very bad condition and our strong feeling is the patients should undergo, much early, a successful catheter ablation.

The study was initiated with the background that we, and others, have shown that a very catheter ablation, which is before any ICTD shock, a so-called preventative ablation, is superior with respect to clinical endpoints as compared to optimal medical treatment. That's number one. And number two is that we know from retrospective analysis of multiple ICD studies that ICD shocks increase mortality as compared to patients with ICDs that have no shocks.

So, on one side we have the benefit of a preventive ablation which has been shown in three randomized trials, and on the other side we know that ICD shocks increase mortality. So somewhere in between multiple ICD shocks and no shock should be the benefit of catheter ablation and this, exactly, was the background of the BERLIN-VT Trial to investigate whether a very only catheter ablation study, which is after the first episode of VT/VF, before any ICD shock, would be superior as compared to having an ICD implanted and follow the patients and then ablate the patients after an arbitrary taken number that we set to three ICD shocks. We were looking then for a combined clinical endpoint to see whether there is any benefit of prophylactic, or preventative, ablation versus what we call deferred catheter ablation.

Dr Greg Hundley: Can you tell us about the BERLIN-VT? What was your study population? A little bit about the design.

Dr Karl-Heinz Kuck: Yeah. The patients that we investigated were patients only with ischemic cardiomyopathy who would had a previous myocardial infarct, to reduce the number of interventions that would require an epicardial access in that patient population. That's number one. And number two, the patients should have an ejection fraction above 35 because a previous study that we have done, the VTACH Study showed that there was no benefit of catheter ablation in patients with a very low ejection fraction, so this was the patient population that we were looking. And then patients had to have had at least one episode of VT/VF before they were randomized either into preventive ablation or into deferred ablation.

Dr Greg Hundley: How many participants were in your study? And then tell us a little bit about the study results.

Dr Karl-Heinz Kuck: We randomized the 76 patients to preventive ablation, and 83 patients do differed ablation. The number, we originally thought to be higher, but we had redesigned interim analysis and after the second interim analysis at the DSMV, we commanded to terminate the trial for futility. And at that point in time when the study was terminated, these numbers were included, which was almost two thirds of the patients which were originally included in to the front.

Dr Greg Hundley: What were your results?

Dr Karl-Heinz Kuck: Now, which respect to the endpoint of the trial, which was the primary endpoint, which was a composite endpoint of all-cause mortality and unplanned re-hospitalizations for worsening of heart failure or ventricular arrhythmias, we did not find any significant difference between the preventive and the deferred ablation group. Actually, after 12 months, there were 21% of patients in the differed, and 27% in the preventive ablation group, and these numbers almost doubled over two years but didn't show any difference.

So with respect to the components of the combined endpoint, we also didn't see any significant difference with respect to overall mortality, hospitalization for worsening of heart failure and hospitalization for worsening of ventricular tachycardia or ventricular fibrillation, despite the fact that there was a strong trend to a reduction of hospitalization for VT/VF in the preventive group as compared to the deferred group.

But this was fully compensated for the primary endpoint by an increase of hospitalizations, early hospitalizations after ablation for worsening of heart failure and a somewhat higher mortality rate in the preventive group as compared to the deferred group, which I believe was really bad luck because almost none of the six [inaudible 00:17:12] in the preventive group died due to cardiovascular reasons. Whereas most patients in the deferred group died because of ventricular tachycardia, ventricular fibrillation.

Now, what is interesting to mention is that with respect to the secondary endpoint, which is sustained VT and VF and appropriate ICD therapy, there was a significant benefit of preventive catheter ablation as compared to deferred catheter ablation but, as I mentioned before, this could not be translated into a benefit with respect to clinical outcome in the trial.

Dr Greg Hundley: Thank you, Dr Kuck. Dr Marchlinski, could you help us put this in perspective as we're thinking about patients with ischemic heart disease that we are considering implantation of an ICD?

Dr Frank Marchlinski: Yes, definitely. First, I like to congratulate the investigators. This is a real tour de force, a lot of effort, multiple centers involved. Dr Willems, Dr Kuck, congratulations because this is an important effort. I think that one needs to realize, of course, that it is our goal to try to eliminate VT with the hope that we're going to improve mortality outcome in addition to improving quality of life. It's a worthwhile goal. I hope someday we will achieve it and that we'll be able to use ablative therapy very early in the course, even in advance of ICD implantation and potentially even to prevent ICDs. That's a worthwhile goal and something that we all need to target as investigators in this area.

But Dr Kuck's study demonstrated that we're not there yet to use it as very early in the course of a disease before patients manifest a lot of arrhythmia recurrences. One thing is for certain, though. This study, although important in suggesting that we need to take our time in terms of planning to do the ablation procedure, we don't want to delay. There's enough evidence to say that repeated shocks can increase mortality, as Dr Kuck pointed out, and enhance a bad outcome.

It certainly provides a very poor quality of life for the patient to experience these shocks, so we need to consider the timing of when it's appropriate, when patients begin to experience ICD shocks after receiving a defibrillator and not wait for repeated shocks, not wait for excessive dosing with Amiodarone, but rather to intervene in a timely fashion after a patient begins to get the shock therapy. It was clear that even the BERLIN-VT investigators didn't wait for multiple additional shocks. As soon as patients received one or two shocks, they got enrolled in this study, this is the deferred limb, and took advantage of the effectiveness of ablation to reduce the number of VT episodes.

Dr Greg Hundley: Sammy, now back to you. What study do we need to perform next in this field? How do you think the results here guide us moving forward with research in this area?

Sammy Viskin: As Frank said, in [inaudible 00:20:25], it is very important that patients are not referred too late for ablation when they arrive after many shocks and they're already, sometimes even encouraged to getting shocks. The present study shows that perhaps they should not be referred for ablation too early at this point, at least not until we get better with our ablation techniques. So we need studies on how to improve our ablation techniques. They keep getting better, but they still have a long way to go. And then we should be able to define the optimal time when it's not too early and when it's not too late to perform the ablation procedure.

Dr Karl-Heinz Kuck: I agree with all of what had been said. I just would like to mention that the study, the BERLIN-VT Study compared, actually, very early catheter ablation versus early catheter ablation. We just wanted to know whether very early ablation is better than early because I think that all the three physicians here, the three electrophysiologists, would agree that we would be happy if most of the patients would even be sent after the second or third shock. Many patients having multiple more shocks before they are sent for catheter ablation.

So, in this sense, the BERLIN-VT Study was an aggressive study because they did not allow patients to be sent after the 10th shock, after the 15th shock, after an electrical storm. So we are comparing very early versus early ablation and I'm not giving up, like Frank Marchlinski was saying. I'm not giving up on the idea.

Sammy is saying we are not yet there, but we should continue to prove that an early ablation is superior to a late ablation. But BERLIN-VT did not look at the very late ablation component of the strategy here. I think what this study shows and what all the other studies also show how difficult it is, in the field of VT/VF and severely diseased patients, to do such a randomized trial. We have a lot of problems to enroll these patients and therefore, I was glad that we could at least get some information out of the trial.

I'm still supporting the idea that the international community should work closer together in the field of catheter ablation of ventricular tachycardia and ventricular fibrillation so that we could increase the number of patients within a rather short period of time that should be included in these VT ablation trials. That's, I think, another learning that I've done from this trial but also from some of the other trials that we and others have done in the field.

Dr Greg Hundley: Well, listeners, we want to thank Dr Karl Kuck from University of Lübeck in Germany, Dr Frank Marchlinski from University of Pennsylvania, and Dr Sammy Viskin from Tel Aviv Medical Center. We've really heard some insightful results related to ICD placement and those with ischemic heart disease from the BERLIN-VT Study. It really emphasizes the importance of, as we move forward, international collaborations when we're trying to study this patient population.

Well, on behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you and grabbing a cup of coffee next week. Take care. Of this program is copyright of the American Heart Association 2020.

Circulation March 24, 2020

23 mars 2020 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast soiree and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor for the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week we're going to talk about carotid stenosis, and you remember how we measure those a lot with ultrasound, and what that thickness is, and IMT? Well, we're going to talk about getting some thresholds and an update in that with our feature discussion today. But before we get there, how about grab a cup of coffee and we get started with other papers.

Dr Carolyn Lam: All right. Well, I've got my coffee and I'm ready to tell you about two papers. They're both on left ventricular hypertrophy. One is basic and one is clinical. I will start with the basic paper because it is a super cool one that uncovers a novel mechanism underlying myocardial hypertrophy. And this involves S-nitrosylation, a prototypic, redux-based post-translational modification, S-nitrosylation.

So this is from co-corresponding authors, Drs Xie, Han, and Ji from Nanjing Medical University, who performed a series of elegant experiments using myocardial samples from patients and animal models exhibiting myocardial hypertrophy, and they demonstrated that S-nitrosylation of muscle limb protein plays a crucial role in myocardial hypertrophy.

This muscle limb protein modification enhanced binding to toll-like receptor 3 and receptor interacting protein kinase 3, which stimulated NOD-like receptor pyrin domain containing 3 or NLRP3 inflammasome activation and consequent caspace-1 and interleukin 1 beta activation, ultimately promoting myocardial hypertrophy. They further showed that the deficiency of S-nitrosylated muscle limb protein governed toll-like receptor 3 really alleviates pathological myocardial hypertrophy.

Okay Greg, I can see the look on your face. You're like what? That was a lot. What are the clinical implications, right?

Dr Greg Hundley: Yeah, Carolyn, you are taking me back to molecular biology course 410, that I would take as a senior in college. Wow. So tell me what are the clinical implications?

Dr Carolyn Lam: All right, here's a take-home. The data really identify that S-nitrosylated muscle limb protein is a key regulator, which together with toll-like receptor 3 made therefore serve as putative therapeutic targets in treating pathological myocardial hypertrophy in heart failure. That's the take-home. Before any further comments, let's go to the clinical study.

Now, this one focuses on a malignant subphenotype of left ventricular hypertrophy in which minimal elevations of cardiac biomarkers identify individuals with left ventricular hypertrophy at high risk for developing heart failure. And this is from corresponding author Dr James de Lemos from UT Southwestern. He and his colleagues tested the hypothesis that a higher prevalence of the malignant left ventricular hypertrophy phenotype among blacks may contribute to racial disparities in heart failure risk. So they pooled data from three large multi-ethnic cohorts, that is Eric, Dallas Heart Study, and MESA, totaling more than 15,700 participants. These participants were then classified into three groups: One, those without ECG left ventricular hypertrophy; two, those with ECG left ventricular hypertrophy but normal biomarkers; and three, those with ECG left ventricular hypertrophy and at normal levels of two biomarkers, high sensitivity troponin T above six nanogram per liters, or NT-proBNP above 100 picograms per milliliter. And that last group were the malignant left ventricular hypertrophy group.

They found that the prevalence of malignant left ventricular hypertrophy was threefold higher among black men and women versus white men and women. Compared to participants without left ventricular hypertrophy, the adjusted hazard ratio for heart failure was 2.8 in those with malignant ventricular hypertrophy and only 0.9 in those with left ventricular hypertrophy and normal biomarkers. And these were similar findings in each race and sex subgroups.

Mediation analysis indicated that 33% of the access hazard of heart failure among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant left ventricular hypertrophy in blacks.

Dr Greg Hundley: So Carolyn, race could be a really important issue in left ventricular hypertrophy. What did the authors conclude? I mean, how should this help us perhaps manage these patients? What was the take-home?

Dr Carolyn Lam: So this really shows that a higher prevalence of the malignant hypertrophy phenotype may in part, explain the higher risk of heart failure among blacks compared to whites. And what it means too is that when left ventricle hypertrophy is detected by ECG or cardiac imaging, perhaps we should consider measuring high sensitive troponin T or NT-proBNP, which will help distinguish those in whom risk for heart failure is favorable from those at a much higher risk.

Dr Greg Hundley: Very, very interesting. Well Carolyn, I'm going to switch. I've got a basic paper and it's going to focus on dysfunctional adipocytes and how they might talk to cardiomyocytes in the situation of ischemia reperfusion injury. And the corresponding author is Xin-Liang Ma, from Thomas Jefferson University in Pennsylvania.

So Carolyn, do you have any thoughts regarding how patients with diabetes might experience a greater degree of myocardial ischemia reperfusion injury in the setting of an MI?

Dr Carolyn Lam: Oh my goodness, you're really putting me on this spot here. Well, I know things that come to mind would be oxidative stress, microvascular disease.

Dr Greg Hundley: Very good. Open-ended questions for Carolyn's quiz. I'm going to give you a 90. That was very good. So Carolyn, this current study attempted to clarify whether and how small extracellular vesicles may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating myocardial ischemia reperfusion injury. And to do this, adult male mice were fed a normal or high fat diet for 12 weeks.

The small extracellular vesicles from diabetic serum, diabetic adipocytes, high glucose, high lipid-challenged, non-diabetic adipocytes were injected then, intramyocardially, distal of the site of a coronary ligation.

Dr Carolyn Lam: Okay. So Greg, I would not have guessed it was about extracellular vesicles, but very interesting. What did they find?

Dr Greg Hundley: Intramyocardial injection of diabetic serum small extracellular vesicles or these SEVs, in the nondiabetic heart, significantly exacerbated myocardial ischemia reperfusion injury, as evidenced by poor cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. And administration of small extracellular vesicles, biogenesis inhibitors, significantly mitigated the myocardial ischemia reperfusion injury in diabetic mice. And mechanistic investigations in these studies identified that MIR 130B3P is a common molecule, significantly increased in diabetic serum of small extracellular vesicles and mediated the pathological communication between the dysfunctional adipocytes and the cardiomyocytes. Therefore, if in the future, we could interfere with this molecule, that could perhaps be a novel strategy for attenuating diabetic exacerbation of myocardial ischemia reperfusion injury. Really, a clever study, I think. What else did you find in this issue of the journal?

Dr Carolyn Lam: Yeah, Greg, this week's issue is packed with other papers too. For example, there's the research priorities for HFpEF by NHLBI working group summary by Dr Shah, et al. There's a research letter by Dr Kaltman on the disparities in congenital heart disease mortality based on proximity to a specialized pediatric cardiac center. There's also another research letter by Dr Irisawa, on the impact of low-flow duration on favorable neurological outcomes of extracorporeal CPR, after out-of-hospital cardiac arrest, and this is a multicenter prospective study.

Dr Greg Hundley: It sounds like a lot's in the mailbag. In the couple of things that I wanted to talk about, Dr Giulia Rivasi from the University of Florence, and William White from University of Connecticut, exchange a series of letters back and forth regarding a previous publication on the effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older individuals.

I have another research letter entitled, The Cardiac Cell Therapy Rejuvenates the Infarcted Rodent Heart via Direct Injection, but not by Vascular Infusions. And that is from Dr Jeffrey Molkentin from Cincinnati Children's Hospital Medical Center.

Finally, though Carolyn, there's a very interesting piece from Dr Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of Chicago, discussing are we now in a time, in the United States, where congenital heart surgery should be coalesced or regionalized? And that really comes on the back of a discussion of there have been several high-profile articles in the national media, reporting on US congenital heart surgery programs. And that's led to, the author describes, some closure of several centers and at least in five programs. So a great discussion on, should this be regionalized? But we've got a great feature article coming ahead and how about if we head to that.

Dr Carolyn Lam: Let's go, Greg.

Dr Greg Hundley: Welcome everyone, to this feature discussion where we are going to discuss the use of diagnostic ultrasound in the carotid arteries and how that pertains to selection of patients for vascular surgery. And with us today, we have Dr Jesse Columbo from the Geisel School of Medicine at Dartmouth University in Hanover, New Hampshire. We also have Dr Bob Zwolak, from the Manchester VA at the Dartmouth School of Medicine and we have our own Josh Beckman from Vanderbilt University, one of our associate editors at Circulation. And Bob, let's get started with you. Could you tell us a little bit, what was the background of this study and what hypothesis were you looking to test?

Dr Robert Zwolak: It goes without saying that stroke is still a huge health problem in the United States. If there is any good news, it's that stroke incidence is falling slightly, but there are still over 100,000 deaths from stroke each year in United States and as many as 700,000 new strokes each year, and a significant proportion of those derive from atherosclerotic plaque in the carotid bifurcations.

Carotid duplex ultrasound is a fantastic way to assess the presence of plaque in the carotid bifurcations because it does not use any ionizing radiation, does not require any contrast. Ultrasound is a relatively less expensive technology than CT or MR, and the study can be repeated so we can follow people over time, who are found to have significant atherosclerotic plaque in their bifurcations.

The hypothesis of our study though, was that there is variation in the diagnostic thresholds used by various carotid ultrasound testing laboratories, such that it may impact the healthcare and the treatment plans of people who undergo the studies. Jesse will tell you the details, but specifically, we hypothesized that people who undergo this carotid ultrasound test may or may not be inducted into a surveillance program and intensive therapy based on the diagnostic criteria that were used by the individuals conducting their ultrasound study. And even more substantially, we hypothesized that individuals who undergo carotid endarterectomy or potentially carotid stenting, could also have their procedure influenced, whether or not they undergo surgery or stenting based on the carotid ultrasound results. It might vary from one facility to another. So it potentially could be that an individual would be inducted into ultrasound surveillance or even undergo carotid surgery, depending on the vascular laboratory in which they were tested.

Dr Greg Hundley: Jesse, could you tell us a little bit, what was your study population and how did you design this to address the hypothesis that Bob just stated?

Dr Jesse Columbo: Sure. A review of the published literature really shows a variability in that ultrasound criteria that's used for diagnosing carotid stenosis. And so our first objective was to see if we could obtain as many in-use criteria as possible. Our first step was to partner with the Intersocietal Accreditation Commission, the commission that accredits vascular labs. We partnered with them and obtained a 25% random sample of ultrasound criteria in use across the US. And so that kind of gave us the starting point for the criteria upon which to look at.

We then wanted to apply those to a couple of different groups. As Dr Zwolak mentioned, there's really two primary breakpoints here. One, you either have mild stenosis, where you get medical therapy, but no further surveillance, or moderate stenosis, at which point you then are dedicated to long-term surveillance per the AAJ recommendations, or then, the break point between moderate and severe stenosis where surgery is considered.

What we wanted to do is examine the impact of moderate and severe stenosis thresholds. For the severe stenosis thresholds, we use the Vascular Quality Initiative Registry, which collects information on patients who underwent carotid endarterectomy. When we studied patients specifically that we thought the percent stenosis would be the major deciding factor in who got surgery, those are the asymptomatic stenosis and we applied the range of severe stenosis criteria from the IAC to those patients. We then wanted to study other individuals who might be committed to long-term surveillance based on the criteria used. And so for that, we used participants in the Cardiovascular Health Study, which had their induction into the study, had baseline data on carotid stenosis collected. And so that kind of formed our basis of the study, applying the criteria to those two different groups of individuals.

Dr Greg Hundley: And so how many subjects did you have in the two cohorts? And then tell us what were your study results?

Dr Jesse Columbo: Sure. Once we narrowed down that patients in the vascular quality initiative to those who underwent surgery for asymptomatic carotid stenosis, we had about 28,000 patients. And then when we examined the Cardiovascular Health Study, we had about 4,800 or 5,000 patients in that group. What we found was pretty interesting.

If you look at individuals who underwent surgery, and you take the carotid threshold criteria and apply it to them, and if you say, "Well, we're going to take criteria in the fifth percentile versus criteria in the 95th percentile," what you'll find is that 10% of patients who got surgery, fall between that range. And what that means is that there are patients, approximately 10% of patients, who are undergoing surgery that may not have been offered surgery if they had gone to a different institution, which we thought a pretty important finding.

The second part was studying patients who maybe committed to long-term surveillance. And if we took centers that were in the fifth percentile versus those in the 95th percentile for their carotid stenosis thresholds, we found a twofold difference in the number of patients that would be committed to long-term surveillance. And remember, this is the difference between getting aspirin and a statin and medical therapy, but no longer surveillance and getting carotid ultrasound every six months to a year for a long period of time. That twofold difference really could have a meaningful impact on patients.

Dr Greg Hundley: It sounds like we've got a variance issue here and that could really impact clinical care. So while ultrasound's very portable and advantageous, how do we use these results to more effectively select how we're going to implement ultrasound to monitor these patients?

Dr Joshua Beckman: I have to say the results of this study, when I read them the first time were eye opening. One point that doesn't come out clearly to those folks who aren't necessarily in the field, is that these are the labs that have been accredited and they are the top labs in the United States. This doesn't include at least half of the rest of the labs in the United States and suggest that if there's variation in the very best of labs, you know that there's even more variation that's being practiced routinely around the United States. So when I read this, I thought that there was a huge problem that they were uncovering. There are many, many millions of patients with atherosclerosis.

And so what we have to figure out now is how to standardize the measurement and reading of these studies so that ultrasound can be deployed routinely, without a fear of your treatment varying based on which doctor you decide to see and where you decided to go. And I think the fact that these guys highlighted that in such a nice and clear way, really raises the alarm and raises the flag that attention needs to be paid here quite soon because it's quite important.

Dr Greg Hundley: So what study could we perform next? And maybe I'll ask, Bob, you just start off. What study could we perform next to help clarify and guide us to the better use of ultrasound in this situation?

Dr Robert Zwolak: Well, I think there are two issues. The first issue that this manuscript points out is the one of variation and it's real and the results speak for themselves. The second issue is the one of accuracy, and the question of what are the best thresholds? And there are several ways that this can be standardized. I'm pleased to say that the Intersocietal Accreditation Commission, the IAC, that Jesse mentioned, is actually tackling this problem.

Dr Robert Zwolak: But what's the gold standard? 40 years ago when ultrasound was developed, these thresholds that people are discussing, were related to measurements on contrast arteriograms. And the catheter-based contrast arteriogram, a relatively invasive study, was the source and we compared ultrasound velocities to the measurements on the contrast arteriograms to determine these thresholds that Jesse has investigated. That resulted in substantial variation depending on the individual authors. The question is, over time, have the machines changed? Is there really a central focus that we can look at? Most of these studies were very small and so it accounts for the variation in recommendations.

Dr Robert Zwolak: The IAC now, is going back and collecting contemporary contrast arteriograms, not so many of which are done anymore and so, it's taken a very substantial multicenter effort. But trying to look again, to see if there are more accurate results that could be published, studied in a way such that they would be universally accepted and potentially promulgated by professional societies within guidelines. And standardized such that various specialties, whether it's vascular surgeons who run the labs, or a cardiologist, or radiologist, would agree on a set of both accurate and reproducible and constant velocity thresholds to standardize this technology, which is otherwise a very, very good technology and eliminate this variation that we've seen.

Dr Greg Hundley: Well, this has been a phenomenal discussion in a very interesting piece of research. Jesse, can you give us sort of a point forward from here, how do we move forward with some of these results and what you anticipate seeing going forward?

Dr Jesse Columbo: Well, a duplex ultrasound for carotid stenosis is really important. There are lots of studies done. It's a great way to follow patients over time, in a noninvasive manner. And I might hope that this paper would open the eyes of some of the listeners as to what the carotid ultrasound really means. Instead of just looking at the percent stenosis on the report, to perhaps look at the raw velocities and interpret them in the context of the patient, because I think that has really important impact on how we might manage some of these individuals, for each person that you see.

Dr Greg Hundley: Well, listeners, we want to thank Dr Jesse Columbo, Dr Bob Zwolak, also Dr Josh Beckman, for discussing this very informative research related to the use of ultrasound for assessing carotid stenosis.

Dr Greg Hundley: On behalf of both Carolyn and myself, we wish you a great week and see you next week. This program is copyright, the American Heart Association 2020.

Circulation March 17, 2020 Issue

16 mars 2020 | 22 min

Dr Greg Hundley: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start.

Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients?

Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial.

They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival.

Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study?

Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt.

Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation.

Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find?

Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality.

Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus.

Dr Greg Hundley: Coated, remember, coated stents.

Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction.

Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights?

Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational?

Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI.

Dr Carolyn Lam: Whoa, so what did they find?

Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal.

Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy.

Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania.

I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute.

Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG?

Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone?

Dr Carolyn Lam: Let's go.

Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population.

I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find?

Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population.

At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population.

Dr Carolyn Lam: What did you find?

Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy.

Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important?

Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects.

While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting.

Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study.

Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study.

In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results.

That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion.

Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population?

Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country.

Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country.

Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there.

Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience?

Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah.

Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but most of them, the vast majority of them, so of course they are not so well prepared and that may have an impact on the follow-up. We try to talk to the family; we try to talk to the general practitioner.

Dr Mark Drazner: Of the 10 patients, it's very interesting that patients are being implanted and not knowing they're being implanted in and say waking up with an LVAD. I don't know if you have the granular detail, but do you know, of these 10 patients, how many of them were in that situation?

Dr Vincent Galand: The patients were implanted in cardiogenic shock, so I think it's four patients, but six patients were implanted without cardiogenic shock. They received this kind of information before the LVAD implantation, so it's not a big part of the population, but it's some patients.

Dr Mark Drazner: Could you, just for our readers, it's a little goory, I will admit, but in terms of how these patients attempted or actually committed suicide, just to explain in terms of, it was oftentimes related to a mechanism through the LVAD. If you could just summarize that and how they tried to commit suicide or commit suicide.

Dr Vincent Galand: That was the case. The suicide was with drive line disconnection or drive line section. In two patients, it was drug suicides, but in most of the patients the drive line is the main way for suicide.

Dr Mark Drazner: It's interesting that the mechanism that these patients tried to commit suicide was directly through the LVAD.

Dr Erwan Flécher: Of course it's the easiest way to terminate their life and they just cut off it. Just don't plug the battery and they are alone and that was the main way to practice their suicide.

Dr Mark Drazner: I know we don't have the initial report, we probably don't have all those, but in terms of you postulating in the paper why patients might get to the state where they would try or commit suicide with the LVAD. If you just want to throw out some of your hypotheses so that our listeners can hear those as well.

Dr Erwan Flécher: I've got in mind two or three points in order to improve our results. First of all, we should implant maybe earlier patients in France in order to have a better way to prepare and to invest the VAD implantation.

The second point would be to have a better organization of care and I think we should develop that VAD nurse coordinators program like in many countries. We still have some but not in all the hospitals implanting that.

The third point would be also to get the better LVADs. I mean, probably the drive line in sections, batteries, the controller, this of course it's much better than it was 10 years ago. There is no noise. It's less big than it was, but still, I think if we can improve the device itself, I think we may observe maybe the decrease in the risk of a system in society, especially the drive line, if there is no drive line, the quality of life should be better. We may suggest that the risk of suicide would decrease.

Dr Carolyn Lam: A very somber topic, but those last take home messages, leaving hope for improvement, were really important. Thank you everyone for sharing with us today, and thank you, audience, for joining us today.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.

Circulation March 10, 2020 Issue

9 mars 2020 | 20 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, the feature article today is really interesting. It's evaluating the evolution of cardiovascular disease associated adverse events in developing countries and It's really fascinating looking at differences between Russia, China, India, and Brazil, but more to come. Don't want to spoil all that. How about we get started with a cup of coffee and discussing some of the articles in the Journal.

Dr Carolyn Lam: You bet, Greg. Well, I want to start off with this paper that provides really novel insights into the pathogenesis of hypertrophic cardiomyopathy.

Dr Greg Hundley: Carolyn, you're one of the cardiomyopathy experts. Can you give us a little background before we get started?

Dr Carolyn Lam: Not sure about expert, but I can sure give you a background. So. Hypertrophic cardiomyopathy remember, is caused by pathogenic variants in the sarcomere protein genes, and that evokes hypercontractility, poor relaxation, and increased energy consumption by the heart and increases the patient's risk for arrhythmias and heart failure. Recent studies show that the pathogenic missense variants in myosin are clustered in residues that participate in dynamic confirmational states of the sarcomere proteins.

In today's paper from co-corresponding authors Dr Seidman and Toepfer from Harvard Medical School, authors hypothesized that these confirmations were essential to adapt contractile output for energy conservation and that pathophysiology of hypertrophic cardiomyopathy resulted from destabilization of these confirmations.

So they assayed myosin ATP binding to define the proportions of myosin in two confirmational states called SRX or DRX. This was done in healthy rodent and human hearts at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic hypertrophic cardiomyopathy variants.

They found that hypertrophic cardiomyopathy mutations that disrupted the physiologic balance of SRX and DRX altered cardiomyocyte contraction, relaxation and metabolism, and conveyed increased risk for heart failure and atrial fibrillation. In fact, a small molecule could restore the physiologic balance of SRX and DRX and improve functional energetic and cellular abnormalities that occurred in hypertrophic cardiomyopathy.

Dr Greg Hundley: Very interesting, Carolyn. Well, let me tell you about my paper. It's called The OUTSMART Heart Failure. It's a randomized controlled trial of routine versus selective use of cardiovascular magnetic resonance for patients with non-ischemic heart failure. And it's from Dr David Ian Paterson at the University of Alberta.

This is a study from Canada randomizing 500 patients with suspected non-ischemic heart failure to either having a cardiac MRI as the first imaging study or have an echo, and then based on the echo, order an MRI if the physician so indicates. It was an older version of MRIs, so it's a SUNY assessment of function, including the EF, and then delayed enhancement, a technique that again has been available for the past 20 years and incorporates gadolinium contrast.

Dr Carolyn Lam: Greg, this is so unfair. I'm an echo person, you're an MRI person, but you get to tell us the results and inject your thoughts.

Dr Greg Hundley: No bias. So, Clinical outcomes, Carolyn, you'll be very appreciative, were similar for the two groups of subjects, although the heart failure etiology was more frequently derived in those that received an MRI, whether you're randomized to an MRI first or if you had an echo and they said, "Oh, go get an MRI." The patients with specific heart failure etiologies from imaging had worse outcomes, whereas the heart failure etiologies defined clinically did not.

So, if you didn't take the imaging into account, it didn't discriminate. Importantly, the authors note that more modern techniques, involving mapping with or without contrast, were not employed. It's an older form of the MRI imaging, but the results would suggest that physician decisions regarding the potential use of MRI are important. Bringing us in to decide when to get it is a good idea based on these results.

Dr Carolyn Lam: That was very balanced. Thank you, Greg. But I've got a question for you now. What do you think of coconut oil? Do you take it?

Dr Greg Hundley: Well, I love coconut cake. Does that count?

Dr Carolyn Lam: Well, I have to tell you, I cannot even begin to name the number of people, it's friends and relatives and patients, who take coconut oil because they believe it's good for them. They literally spoon it into their mouths. The truth is coconut oil has been accorded much attention in the popular media as a potential beneficial food product. In fact, a survey in 2016 found that 72% of Americans viewed coconut oil as a healthy food. This represents a remarkable success in marketing by coconut oil and related industries calling coconut oil a natural healthful product despite its known action to increase LDL cholesterol. Of course, we know that, that's an established cause of atherosclerosis and cardiovascular events.

This paper in our journal really deserves attention. It's from corresponding author Dr Rob van Dam from Saw Swee Hock School of Public Health and the National University of Singapore. He and his colleagues conducted a systematic review of the effect of coconut oil consumption on blood lipids and other cardiovascular risk factors compared with other cooking oils using data from clinical trials. In a meta-analysis of 16 trials, they found that coconut oil consumption significantly increased LDL cholesterol concentrations as compared with non-vegetable oils. Although coconut oil consumption also increased HDL cholesterol concentrations, we need to remember that efforts to reduce cardiovascular risk by increasing HDL, have not really been successful in the past.

Anyway, there was no evidence of benefits of coconut oil over non-tropical vegetable oils for adiposity or glycemic or inflammatory markers. Now, this is discussed in an editorial by Dr Frank Sacks at Harvard T.H. Chan School of Public Health and it's entitled: “Coconut Oil and Heart Health. Fact or Fiction?”

Dr Greg Hundley: Very nice, Carolyn. Well, I guess I can't use my coconut cake to lower my LDL. How about we get on to what else is in the journal? You want to go first?

Dr Carolyn Lam: Yeah. We have an important white paper by Dr Sharma on the impact of regulatory guidance on evaluating cardiovascular risk of new glucose lowering therapies, to treat type two diabetes. It talks about lessons learned and future directions. All of this was occurring in February 2018 when a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of findings of the completed CV outcome trials. Very, very important read. We also have a research letter from Dr Wanken entitled, “Characterization of Endovascular Abdominal Aortic Aneurysm Repair Surveillance in the Vascular Quality Initiative.” You got to read about that.

Dr Greg Hundley: Well, Paul Ridker writes a very nice perspective piece. Will all atherosclerosis patients soon be treated with combination lipid lowering and inflammatory inhibitors? Very interesting read. In a separate article, there's a nice ECG challenge from Dr Andrei Margulescu, An Irregular Tachycardia that's not Responsive to Medical Treatment: What is the Diagnosis? A great read for those in training.

Got a couple letters to tell you about. One is the research letter on filamin-C and it's essential for heart function from Professor Ju Chen University of California, San Diego. Then, there's a letter to the editor regarding the article, Stroke Risk as a Function of Atrial Fibrillation Duration in CHA2DS2-VASc Scores from Dr Ming-Wu Xia from Hefei Affiliated Hospital and Anhui Medical University. Then there's a response letter from Rod Passman from the Feinberg School of Medicine at Northwestern University. Well, Carolyn, how about we go to learn about the evolution of cardiovascular events and how they're evolving in Russia, China, India, and Brazil.

Dr Carolyn Lam: Super excited about this one. Let's go, Greg. Our feature paper today focuses on cardiovascular disease burden in the BRICS, and that stands for Brazil, Russia, India, China, and South Africa, B. R. I. C. S. Which is a grouping of upper and lower middle-income countries constituting almost half the world's population and contributing almost a third of the world's GDP. A really, really important paper here. I'm so pleased to have with us the corresponding author of this paper, Dr Zhiyong Zou from Peking University School of Public Health.

Dr Jo, can you please start by telling us a little bit about how you did this study? I thought the methods were amazing.

Dr Zhiyong Zou: There was little study on cardiovascular disease in breaks. So most of the studies have focused just fatality across year, and then reported change in different age groups. However, this fails to distinguish cohort from period effects. So our study aims to examine the time change and also the relative contribution of period and cohort facts.

Dr Carolyn Lam: Wow. So that's big and an acute area. So could you tell us a little bit more about how you did this? Like the databases and then some of the very interesting methodology such as net drift, age curves, period, relative effects. Could you maybe describe those?

Dr Zhiyong Zou: The data was derived from global burden disease 2017 which was as estimate by the university of Washington. This data was estimate for the whole population in each country from many original data sources. Our study used a new method, age period, cohort model.

We can use this model to estimate first cohort from period effects so we can compare different post cohort population and the different period population. They have different effects. And also, we can estimate the net drift, net drift is the overall annual percentage change. It is different from other study. Just to calculate the average percentage change. It is different. It was adjusted for period effects.

Dr Carolyn Lam: Audience, I really have to refer you to the figures of this paper. They're beautiful and that really... Pictures say a thousand words, but Dr Zou, could you now tell us what were the key findings?

Dr Zhiyong Zou: First, although there have been reductions in the breaks of the CVD mortality, they have lagged behind North American by over 15%. Yes, it is very decreased slowly but there is a notable exception of Brazil and the second, there was striking difference between countries. Russia consistently has the highest CVD mortality and Brazil have the lowest. Brazil and China have had continuing vitality improvements since 1992 but there has been little decry in India for middle age Indian males. CVD mortality has increased.

The last one is China has a high rate of out of hospital ischemia heart disease test reflecting poor pre-hospital care. Only 11% of the out of hospital desks received a basic cardiopulmonary citation. And the yes in China, this situation is very serious.

Dr Carolyn Lam: So really fascinating results. And maybe I could just add that you observed over a 25-year period from 1992 to 2016 the general picture is at least there's a decline in these areas, but definitely not as much as that observed during the same time in North America. But I absolutely agree that the striking country differences, so you know, maybe we should start with something positive. Dr Zou, what lessons do you think we could learn from Brazil's strikingly exceptional example?

Dr Zhiyong Zou: Brazil stands out for successful epidemiological transition. Yes, they with a rapid reduction. There are two important factors: The first one is Brazil investment in health with a decrease in smoking from 13.5% in 1999 to 17% in 2009 it decreased by 15%. Another factor is Brazil reform of primary health care focus on the family health program and the prevention and the care for the management of SADs.

Dr Carolyn Lam: I like that. From this paper we could get very, very important public health messages that may inform countries on how this burden can be tackled better like that. Good example of Brazil, but now maybe the tougher topic of in China, what do you think is the reason for the continuing problem with ischemic heart disease

Dr Zhiyong Zou: In China? The real mortality of ischemia heart disease increased very quickly, around 13.5% Increase. Compare that with other countries or declined. So in China with that, there were about 300 million more smokers in China. It was the biggest number in the world? Yes. So it's a big challenge for the government to control the smoking rate. And also, we mentioned that only 11% of the outside hospital Does received a cardiopulmonary citation.

Dr Carolyn Lam: Yeah. And so the point about the low CPR rates may point to more systematic issues in a primary care and public setting, isn't it? And it must be so difficult in a place as huge as China with such diversity in rural communities versus urban and so on. So very important points. I mean, do you have any insights for the issues that are seen in, for example, South Africa, Russia and India?

Dr Zhiyong Zou: We don't have data from the other countries.

Dr Carolyn Lam: Sure. One postulation I suppose thinking about things could be just very rapid transition from the era of infectious disease, communicable diseases to noncommunicable diseases. But you know, the diversity even among those is really, really astounding.

And I think everyone really just has to pick up your paper and have a good read. So could I ask, what are some of the take home messages and next steps that you may have in further research?

Dr Zhiyong Zou: The take home message is, Brazil's success suggest that the prevention policies can both reduce the risk for younger both cohorts and also, the greater risk for all age groups indicating greater progress in achieving CVD health is possible in rapid three in merging economics, which provide example for China and for India. And also a failure to investigate CVD prevention in countries undergoing rapid economic change will exert huge human and economic costs. So that's the take home message.

Dr Carolyn Lam: And those are great, great summaries. And do you have personal plans for further research in this area?

Dr Zhiyong Zou: Yes. In future, we will forecast on the risk factors because in this paper we find many priority age groups in different countries like example, in China those aged over 15 years old, is the prime priority age groups. But in India, 35-60 years old is the most priority age group because in these people, they are most of the productive age, but the mortality increased very quickly.

Dr Carolyn Lam: Yeah, a very good point. And investigating those risk factors would be so informative. Well, thank you so much, Dr Zou for sharing your incredible work with us. We're so proud to be publishing this important work.

Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Please tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.

Circulation March 03, 2020 Issue

2 mars 2020 | 24 min

Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. You know that problem we have with the development of calcification of the aortic valve, the aorta, etcetera with hemodialysis? Well, our feature is going to talk about the results of a randomized phase 2B study to address this. But first, how about if you get us started with a couple of your papers?

Dr Carolyn Lam: In fact, it is a couple of papers and they're both related to hypertension. So in the first one, we know that exercise is associated with a lower incidence of hypertension, but what's the association of excessive levels of exercise in the incidence of hypertension? This question was examined by Dr Andersen from Uppsala University Hospital and colleagues, who compared the incidence of hypertension among almost 207,000 participants in a long-distance cross-country skiing event and more than 505,500 persons randomly sampled from the general population who are matched to the skiers on age, sex, and place of residence.

Dr Greg Hundley: I love skiing! I want to be in the match group. Tell me, now, how long was this distance that they had to cover?

Dr Carolyn Lam: Ah ha. Now the long distance event was really long. It was the Vasaloppet. I hope I pronounced that right, but it's a 45 to 90 kilometer skiing race. So participation, I'm sure you want to hear this, participation was associated with a 41% lower incidence of hypertension over the next eight years, compared to non-participation. And the better the performance in terms of percent of winning time, the lower the incidence of hypertension. If the observed associations are causal, it really adds to the list of beneficial effects of high, or even very high physical fitness. I can see you smiling, Greg.

Dr Greg Hundley: This is your confirmation that the AHA wants to send us to Norway to do one of these recordings.

Dr Carolyn Lam: Well, this next paper asked the question, what is the association of cumulated blood pressure exposure from young adulthood to midlife with gait and cognitive function in midlife. This is from Dr Mahinrad from Northwestern University Feinberg School of Medicine and colleagues who included 191 participants from the coronary artery risk development in young adults’ study, which is a community-based cohort of young individuals followed over 30 years. Cumulated blood pressure was calculated as the area under the curve for baseline up to year 30 exam and gait and cognition were assessed at the year 30 exam. Cerebral white matter hyperintensity was available at year 30 in a subset of participants who underwent MRI.

Dr Greg Hundley: I heard that MRI word. So what did they find Carolyn?

Dr Carolyn Lam: They found cumulative exposure to higher blood pressures from young adulthood to midlife, even at levels below the clinical definition of hypertension, was associated with worse gait and worse cognitive function in midlife. The impact of cumulative levels of blood pressure exposure was independent of other vascular risk factors during a follow-up period of over 30 years, and the higher burden of midlife cerebral white matter hyperintensity on MRI, Greg, moderated the association of cumulated blood pressure exposure with gait but not with cognitive function.

Dr Greg Hundley: You've got me convinced we now have to go to Norway. But what did the authors think were the clinical implications of their study?

Dr Carolyn Lam: Well, here it is. The deleterious effect of elevated blood pressure on brain structure and function may begin during early adulthood and this really emphasizes the need for all primordial, if you may, prevention of high blood pressure. But also reconsidering individual levels of blood pressure for the diagnosis of hypertension. Furthermore, gait may be an earlier measure of hypertensive brain injury than cognition. Now these issues are discussed an editorial by Angela Jefferson from Vanderbilt University Medical Center.

Dr Greg Hundley: Very nice, Carolyn. Well, I'm going to take another sort of twist on hypertension. My paper is from Dr Thomas Thum from the Hanover Medical School and is really looking at the relationship between cardiac fibrosis and diastolic dysfunction. So the study sought to identify anti-fibrotic drug candidates by functional screening of 480 chemically diverse natural compounds found in human cardiac fibroblasts.

Dr Carolyn Lam: Ooh, interesting. And what did they find?

Dr Greg Hundley: What they found is using multiple in vitro fibrosis assays and stringent selection algorithms, the authors identified the steroid bufalin, also seen in Chinese toad venom, and the alkaloid lycorine, from the Amaryllidaceae species, to be effective anti-fibrotic molecules, both in vitro and in vivo, leading to improvement in diastolic function in two hypertension dependent rodent models of cardiac fibrosis. In addition, administration of these agents at effective doses did not change plasma damage markers, nor the morphology of the kidney and liver. And therefore, it's kind of an early first toxicological safety study.

Dr Carolyn Lam: Fascinating. Not just in the findings and the methods, and who knew we'd be talking about Chinese toad venom on this podcast, Greg? Okay. But let me tell you about what's more in this issue. So, there is a research letter by Dr Djoussé, and it is entitled Supplementation with Vitamin D and/or Omega-3 Fatty Acids and the Incidence of Heart Failure Hospitalization. And this one is a letter from the VITAL-Heart Failure ancillary study of the parent VITAL trial. I'm sure I've got everyone's attention. (You) Got to read that letter.

The next is an On My Mind, by Dr Joe Hill, and is entitled, very intriguingly, Can HFpEF and HFrEF Co-exist? Basically accumulating evidence has revealed that the pathophysiologic mechanisms driving HFrEF and HFpEF are distinct, but this On My Mind paper asks can they coexist? Is it possible to identify subjects who harbor pathophysiological elements of both syndromes simultaneously, and if so, we may find that targeting specific pathways is beneficial and in depth characterization of specific subsets of patients might help overcome the limitations of an ejection fraction driven approach.

Dr Greg Hundley: Very interesting, Carolyn. I've got some letters from the mailbox, and the first letter is regarding SGLT2 inhibitors in cardiac hypertrophy and the corresponding author is Professor Kazushi Tsuda from Kansai University of Health Sciences. Another letter, from the corresponding author Dr Renato Lopes from Duke University Medical Center in Durham, evaluates stent thrombosis in patients with atrial fibrillation undergoing coronary stenting from the AUGUSTUS trial. And our own Tracy Hampton provides an update on cardiology news features. And John Warner, from UT Southwestern, the prior American Heart Association president, discusses his journey through healthcare reform. And then finally, our own Sarah O'Brian provides highlights from other journals in the Circulation family related to high points in cardiovascular disease. Well, Carolyn, how about on to dialysis and calcification?

Dr Carolyn Lam: Can't wait. Let's go.

Our feature discussion today, we will be focusing on patients with end-stage kidney disease. And we know that in these patients, the high cardiovascular morbidity and mortality could partially be due to extensive cardiovascular calcification. Well, our feature paper today is the first double blind placebo-controlled phase 2B trial that tests intravenous myo-inositol hexaphosphate, a novel strategy to inhibit the formation and growth of hydroxyapatite and therefore reduce calcification in these patients. I won't tell you more. I'll leave that to the corresponding author, Professor Paolo Raggi, from University of Alberta, and I'm also so pleased to have with us our editor for digital strategies and associate editor Dr Amit Khera from UT Southwestern. So Paolo, please tell us about SNF472 and your very novel trial.

Prof Paolo Raggi: As you correctly stated, patients with end stage renal disease have phenomenally high morbidity and mortality, particularly cardiovascular, and they also manifest extreme calcification on the cardiovascular system. Both the valves and the vessels are very heavily calcified. There's a very clear impression throughout the literature that calcification contributes, no doubt, to the high morbidity mortality with these patients. SNF472 is a derivative of a natural product that is only present in nature in sub molecular quantities and essentially is administered intravenously and the mechanism of action is quite simple. It keeps calcium and phosphorous molecules separate. In other words, it doesn't allow crystallization of calcium and phosphate into what we call hydroxyapatite, or amorphous calcium crystals. This, hopefully, was developed, this product was developed, to inhibit the final step of calcification. Everything comes down, no matter what the promoting event is, to crystallization of calcium and phosphorus. Therefore, if we were able to stop the final event, hopefully you will be able to inhibit further calcification, and that's what we tested in this particular article, in this particular study.

Dr Carolyn Lam: Oh Paolo, I just love the way you described that. Very, very crystal clear, if you don't mind the pun. But could you please let us know, so a phase 2B trial, does that mean a surrogate outcome, duration of treatment, number of patients? How about telling us a little bit about the trial?

Prof Paolo Raggi: So, the trial involved recruiting three different groups of patients. One would be treated with placebo and two other cohorts would be treated with either 300 milligrams of SNF472 three times a week or 600 milligrams of SNF472 three times a week. The product is injected intravenously into the dialysis line. Therefore, the patients do not have to remember to take a pill or inject themselves. Actually, it's perfect, if you will, compliance because all they have to do is come to their dialysis session and they receive it during dialysis.

The study therefore, it was a relatively small study, but enough to prove our point. Three groups were recruited, about 90 patients each, and the two treatment arms at 300 milligrams and the 600 milligrams, were combined as a single group for the purpose of reporting the primary results. The follow up was at one year, so these patients were submitted to CT scanning of the chest without contrast for measurement of calcification only at baseline and then again at 52 weeks. In the intention to treat group, patients were included if they had a baseline scan and at least one follow-up scan at some point during the study. These are very sick patients and sometimes are referred for transplant. Sometimes they withdraw from studies. So, we asked everybody to have a second scan if they needed or wanted to withdraw before the 12 month mark was reached. That's for the intention to treat analysis. And then we need some confirmatory analysis on patients who actually did have the baseline in an actual 12 months scan and received the entire year treatment with these two drugs, with a drug or placebo.

Dr Carolyn Lam: That's great and please tell us the results.

Prof Paolo Raggi: The results were, in our minds, very exciting. And let me first say, that in all the literature that looked at what is the average progression of calcification in the general population, it's anywhere between 10 to 15% per year. For the person with calcium in the coronary arteries, there's an expected progression about 10 to 15%. All the publications in patients with renal failure and undergoing dialysis, show the progression of anywhere between 25 and 35%, so these people are not only more calcified, these patients also progressing very fast. In the particular trial that we reported in Circulation, we demonstrated on average, a progression of 20% in the group receiving placebo and about 11% in the group receiving SNF472. So, there was about a 45% slowing of progression in the treated group compared to the placebo group.

Interestingly enough, we saw a slower progression unusual in the placebo group. As of today, many more treatments are available to patients with end stage renal disease that were not available when the original studies that I mentioned earlier were conducted. So, the 25 to 35% progression that we saw 15 years ago, it's now slowed, you notice, to a 20% progression in these patients, but SNF472 was even more effective at further slowing that progression.

Dr Carolyn Lam: Well, congratulations first and foremost on a very successful and really striking and novel results. Well, Amit there's so much to discuss I don't even know where to start. But first, maybe can I bring you in by saying, so what, is Circulation now publishing renal papers?

Dr Amit Khera: The answer is absolutely yes. So first I want to congratulate Dr Raggi on a fantastic paper. This was a concomitant late breaking science at the American Heart Association Sessions; so, we always try to think of timely and exciting topics and appreciate working so closely with this group to bring this across the finish line. At Circulation, one thing we've been working on is something called Bridging Disciplines, where purposefully we appreciate the heart is not in isolation and not in a box by itself, but within a larger system, a body system. So, we really enjoy these types of papers that cross disciplines and there's an outstanding editorial by Susan Hedayati, from UT Southwestern who's a nephrologist, who weighed in here as well. So we certainly really value these types of papers in Circulation.

Prof Paolo Raggi: I have to say, working with Circulation was amazing. You know, you get a great job and so fast. It was an incredible, actually.

Dr Amit Khera: Obviously, the results speak for themselves that the study was positive, and we certainly see this diminishing the vascular classification and certainly you've been, for decades now, an expert in vascular calcification and coronary imaging. And you know, the question that always comes up is, what are the implications here? Now, on one side, especially with the coronaries, you think this would be favorable, you get less obstructive disease, perhaps less ischemic heart disease. But there's always been this debate if calcium's a good or bad thing in terms of plaque stabilization, so what are your thoughts on what ends up being the clinical ramifications of this down the road?

Prof Paolo Raggi: Well of course, as we clearly stated in the paper, this has to be followed by some sort of clinical outcome study. So, it is only speculating at this point as to what the benefit might be. But more specifically about your question, I think that there is a misinterpretation of what calcification means in general. And honestly, I would prefer not to have calcification in my cardiovascular system if I had the choice. Many believe, and it's possibly true to a degree, that calcification comes in to repair the plaque and there's some sort of repair mechanism, but we have shown very clearly that the greater the calcification burden, the higher the probability of cardiovascular morbidity mortality. And therefore, it is not benign to have cardiovascular calcification in general.

In the case of the patients with end stage renal disease, calcification is not limited to the atherosclerotic plaque. It extends to the thickness of the entire vessel wall and it's well known that patients with end stage renal disease have severe calcification of the media as well as the intima. This obviously causes a series of other problems, such as stiffening of the vessels and therefore reduce compliance and in the long run, many profusion issues to multiple organs, even in the absence of luminal stenosis. A stiff vessel does not comply with what it's supposed to be doing. It is not allowing proper profusion of an end organ and many have demonstrated that also increases the work of the heart, pumping against very rigid plumbing, if you want to put it that way and simply, and therefore may induce left ventricular dysfunction in the long run, arrhythmias if a patient develops left ventricular hypertrophy and fibrosis. So, I think that there's a cascade of events that goes beyond and above just the single plaque, atherosclerosis, calcification. I think that calcification in general, and especially in patients with end stage renal disease, is a whole marker, very high risk of complications.

Dr Amit Khera: Thanks for that clarification. I think first and foremost, it's so helpful to think beyond just isolated luminal stenosis and sort of all the maladaptive aspects of vascular calcification in patients with end stage renal disease. And that leads to the next thing in your paper, which I thought was also really interesting, which was the aortic valve calcification. We certainly appreciate that focus on aortic stenosis as of late with the new therapies, but you know particularly in patients with end stage renal disease, it becomes a very complex issue. And you saw some abating of this vascular calcification in the aorta as well. Tell us a little bit about what you think the implications of that would be.

Prof Paolo Raggi: So first, a word of caution that the trial was not powered to demonstrate specifically an effect on aortic valve. However, we did demonstrate a beautiful effect on the slowing of the aortic valve calcification as well. It's exciting! I think that it's something that needs to be pursued further and I hope future studies, and definitely is the first time that anything has demonstrated an effect on aortic valve calcification. I'm very well aware of other studies that have attempted, for example, use of statins to slow the progression of valvular calcification and in essence, were completely negative. Patients with end stage renal disease, very severe valvular abnormalities, very, very severe, very important valvular dysfunction as a consequence of massive calcification on the annulus and the leaflets more so of the aortic valve, but also the mitral valve. So this could definitely be a signal for an excellent potential and unexpected if you will, a secondary outcome of this treatment. I believe that in affecting valvular calcification in patients with end stage renal disease would be, could have potentially a massive effect from the point of view of lowering the cardiovascular event rate.

Dr Carolyn Lam: May I chime in with a quick question? What were adverse effects like?

Prof Paolo Raggi: This particular drug actually was associated with the same exact rate of adverse effect as placebo. In other words, we didn't see anything at all that was alarming. There was one patient that had been reported by the investigator as potential side effect of the drug. They reported something, I think it was like acute hepatic failure, but when the case was clearly analyzed by the DMV, we actually assessed dictation as being a case of cholecystitis had been incorrectly labeled, we believe. And except for that one case, there essentially were no side effects, no adverse effects from treatment. In fact, although it was not powered for those outcomes, there was a lower morbidity and mortality with the SNF472 and then with placebo.

Dr Carolyn Lam: I really like that and was really struck by your pointing out a little bit earlier, the ease of administration as part of hemodialysis. That was very nice. Amit, I'm going to give you the final words and questions if I may.

Dr Amit Khera: As expected, this has been an exciting podcast and as much as I've read this paper and looked at it in detail, I learned a lot more as I had anticipated. My question for you, Paolo, now, is what's the next step? This is a phase 2B study. What's the next step in the development or evaluation of this compound and where are you going with this?

Prof Paolo Raggi: There are a few sub analysis that we haven't yet looked at in this particular study that we just reported. One of the things that we are definitely interested in is to evaluate the effect on bone. As you can imagine, it is true that this particular drug has a wonderful effect on vascular calcification, but the next question is, did it do anything adverse to the bone? It's a logical question but I feel that most likely the answer is going to be a resounding no.

But, besides that, the further development of this drug is obvious in my mind. It will have to be addressed in a proper, randomized clinical trial to address some of the clinical questions that we all have. Is this reducing the cardiovascular events? Be it when we need, we will decide together what those cardiovascular events would look like. But obviously myocardial infarction, congestive heart failure, admission for unstable angina, cardiovascular deaths in general, those are going to be very important questions to be answered in a further step. Before we get there, there are a few other questions that we have for the drug itself from this particular 2B study that we can still look at.

Dr Amit Khera: Excellent. Looking forward to those subsequent analyses.

Dr Carolyn Lam: Thank you and we look forward to the next publication on Circulation.

Dr Amit Khera: Absolutely.

Dr Carolyn Lam: I'm sure the audience is actually looking forward to more such discussions as these. Remember, you've been listening to Circulation on the Run.

Dr Greg Hundley: This program is Copyright The American Heart Association 2020.

Circulation February 25, 2020 Issue

24 februari 2020 | 22 min

Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at BCU Health in Richmond, Virginia.

Dr Carolyn Lam: So Greg, guess what? We are going to be discussing predicting the benefit of evolocumab therapy in patients with atherosclerotic disease using a genetic risk score. That's our featured paper this week coming from the results of the FOURIER trial. I bet you can't wait to discuss it, but I'm not going to let us until we talk about some of the papers in today's issue. Do you have one?

Dr Greg Hundley: Yes, Carolyn, but first I'm going to get a cup of coffee because there's a lot of data in this one. This study is from the ODYSSEY trial and it involves alirocumab and it's from Dr Charles Paulding. Remember Carolyn, the ODYSSEY trial was a randomized double-blind placebo-controlled trial comparing alirocumab, a PCSK9 inhibitor or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. And the primary endpoint of this trial comprise death from coronary artery disease, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization. Now Carolyn, this is a sub-study and it was performed an A genome wide polygenic risk score for coronary artery disease comprising 6,579,025 genetic variants. And they were evaluated in 11,953 patients with available DNA samples. Analysis of the MACE risks, all those outcomes together, was performed in placebo treated patients while treatment benefit analysis was performed across all the patients.

Dr Carolyn Lam: Ooh, so what did they find?

Dr Greg Hundley: Well, Carolyn, both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. Those genetic, polygenetic risk scores combined in the patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6% and 1.5% respectively, and relative risk reduction in the alirocumab of 37% in the high PRS group versus 13% in the low PRS group. And so Carolyn, these results suggest the possibility of an independent tool for risk stratification using sort of precision medicine by selecting those using these genetic constructs, who may be more likely to benefit from this form of therapy.

Dr Carolyn Lam: Wow Greg, that is really interesting. I genuinely think that our world is moving towards precision medicine and this really, really speaks to remember that feature paper also talking about genetic risk scores, but from the FOURIER trial. But before we get to that, I've got a basic science paper. Now this one provides insights into the mechanisms underlying age related hypertension. And it's from Dr Ying Yu and colleagues from Tianjin Medical University who hypothesize that since proinflammatory cytokines increase in T lymphocytes with aging and prostaglandin D2 suppresses T helper 1 cytokines through the D-prostanoid receptor 1, that this axis in T cells may play a role in age related hypertension.

Dr Greg Hundley: Ah, Carolyn. What did they find in this study?

Dr Carolyn Lam: Prostaglandin D2 biosynthesis and D-prostanoid receptor 1 expression, were both markedly decline in CD4 positive T cells from older humans and aged mice. D-prostanoid receptor 1 depletion in these CD4 positive T cells, exaggerated age dependent blood pressure elevation in mice by increasing tumor necrosis factor alpha and interferon gamma secretion. Whereas its over expression showed the opposite effect and its activation suppressed TH1 cytokines. These results really indicate that D-prostanoid receptor 1 and its downstream pathway may serve as an attractive immuno-therapeutic target for age dependent hypertension.

Dr Greg Hundley: Oh wow. Very insightful Carolyn. Well, I've got a basic science paper to go over and it's from professor Kinya Otsu from Kings College London. This study addresses the mechanism of ongoing inflammation within the hearts of patients with cardiomyopathy. The study involves the assessment of Regnase-1 and RNAs involved in the degradation of a set of pro inflammatory cytokine messenger RNAs in immune cells. And the study involves the role of Regnase-1 in non-immune cells such as cardiomyocytes.

Dr Carolyn Lam: Wow.

Dr Greg Hundley: The degradation of cytokine messenger RNA by Regnase-1 and cardiomyocytes plays an important role in restraining sterile information in failing heart. Once the inflammatory cascade gets going, this is that constant inflammation that's ongoing. In addition, the Regnase-1 mediated pathway might be a therapeutic target to treat patients with heart failure as adeno-associated virus 9 mediated cardiomyocyte targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody, attenuated the development cardiomyopathy induced by severe pressure overload in wild type mice.

Dr Carolyn Lam: Wow, that's really interesting. I find this whole field of inflammation in heart failure of course, of key interest, but I'm going to next tell you about the results of the FUEL trial, which is the Fontan Udenafil Exercise Longitudinal trial.

Dr Greg Hundley: Tell us about the Fontan operation.

Dr Carolyn Lam: Aha, I thought you may ask, Greg. Well, the Fontan operation to remind us all, really creates a total cavopulmonary connection and a circulation in which the importance of pulmonary vascular resistance is therefore magnified. Over time, the circulation needs to deterioration of cardiovascular efficiency associated with a decline in exercise performance. This FUEL trial and reported this time by David Goldberg and colleagues from the Children's Hospital of Philadelphia was a phase 3 clinical trial, which randomized 400 patients with Fontan physiology from 30 sites in North America and the Republic of Korea. The participants were randomly assigned to Udenafil at 87.5 milligrams twice daily or placebo. And the primary outcome was the between group difference in change in oxygen consumption with peak exercise.

Dr Greg Hundley: Hmmm, very large important trial it seems like Carolyn. What did they find?

Dr Carolyn Lam: Treatment with Udenafil did not result in a significant increase in peak oxygen consumption, which was the primary outcome, but did result in improvements in measures of exercise performance at the anaerobic threshold, which was a secondary outcome. Udenafil was well tolerated with side effects limited to those previously known to be associated with phosphodiesterase type 5 inhibitors.

These results and future perspectives are discussed an editorial called FUELing the Search for Medical Therapies in Late Fontan Failure, by Doctors Gewillig and De Bruaene.

Dr Greg Hundley: Very nice, Carolyn. Now how about the rest of the journal?

Dr Carolyn Lam: Oh well I want to tell you about this in-depth review by Dr Rosenkranz and it's entitled, Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Very intriguingly, talking about non-cardiac features, as well as cardiac, of right heart failure, a real, real must read with beautiful figures.

In the cardiovascular case series we discuss a case of left ventricular non-compaction and cardiogenic shock by Dr Shenoy. There are also two research letters I want to tell you about one by Dr Gillinov on the accuracy of the Apple watch for detection of atrial fibrillation. And this time looking at the Apple watch series 4, which interestingly employs electrodes to generate a single lead ECG and provides two mechanisms for rhythm assessment. Won't tell you more. You got to pick up this beautiful letter.

The next is by Dr Mazer on the effect of empagliflozin on erythropoietin levels IN stores and red blood cell morphology in patients with type II diabetes and coronary artery disease. And this really provides evidence to suggest that SGLT 2 inhibition with empagliflozin may stimulate erythropoiesis via an early increase in erythropoietin production in people with diabetes.

Dr Greg Hundley: You know Carolyn, we just keep hearing more about EMPA and DAPA and they are just going to really pave the way I think for a whole new class of agents that we're going to be using frequently.

I've got a couple letters in the mailbox and one is by Sugimoto and Taniguchi regarding the article, Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients with Implantable Cardio Defibrillators, a randomized clinical trial. And then also there's another research letter by Dr Hiroshi Sugimoto from Kobe Red Cross Hospital with a response by Jakob Lüker from University of Cologne.

What a great issue. How about we proceed to that feature article?

Dr Carolyn Lam: You bet.

Can a genetic risk score identify individuals who will derive greater benefit from PC SK9 inhibition? Well guess what? We're going to find out now in our feature discussion. So pleased to have with us the first and the corresponding authors of our feature paper, Dr Nicholas Marston and Dr Christian Ruff, both from the TIMI study group in Brigham and Women's Hospital and Harvard Medical School and also to have our lovely associate editor, Dr Svati Shah from Duke University in Durham, North Carolina. Welcome everyone.

Nick, could I get you started with telling us about this exciting analysis that you did from the FOURIER trial?

Dr Nicholas Marston: The FOURIER trial was a 27,000 patient cardiovascular outcomes trial that studied the PC SK9 inhibitor, evolocumab and it demonstrated a significant reduction in major adverse cardiovascular events in patients who had established atherosclerotic disease. And in the study, there was a 15% relative risk reduction and a 2% absolute risk reduction, which earned it a class 2 recommendation for very high-risk patients with atherosclerosis in the recent cholesterol management guidelines. And what we've done in previous lipid trials is we studied the interactions between genetic risk and treatment benefit. For example, in 2015 we showed that patients with high genetic risk, those in the top 20% of genetic risk, had the greatest benefit from statin therapy in terms of both absolute and relative risk reductions. And so now we have the opportunity with evolocumab and data from the FOURIER trial to ask the same question of PC SK9 inhibitor. That is, could a genetic risk score identify patients who will drive a greater treatment benefit and we hypothesize that like statins, there would in fact be a significant interaction between genetic risk and therapeutic benefit.

Dr Carolyn Lam: That's so cool Nick. But could I ask, the question always comes, is it nature versus nurture? And so I really love the way that you dealt with the clinical risk factors as well. Could you maybe walk us through that and then tell us the results?

Dr Nicholas Marston: Yes, absolutely. We for this study, kind of had two objectives. One was to look at risk prediction and then the other look at treatment benefit and using a genetic risk score for both. However, we wanted to go further than just use the genetic risk score. We wanted to incorporate clinical risk factors since that's how we would do it as physicians in the clinic. We would have not just genetic risk data in front of us but also clinical data. And so when we were grading a patient's risk using genetic risk, we also factored in if they had multiple clinical risk factors. And what we found by combining both genetic and clinical risk was that there was a significant gradient of risk across these risk categories.

That is patients who were without high genetic risk and without multiple clinical risk factors actually had no benefit from evolocumab over the 2.2-year follow-up period. However, those without high genetic risk, but who did have multiple clinical risk factors, derived an intermediate benefit. About a 13% relative risk reduction and 1.4% absolute risk reduction. And then it was the high genetic risk group, independent of whether or not they had multiple clinical risk factors that had the largest benefit from evolocumab with a relative risk reduction of 31%, absolute risk reduction of 4% and the number needed to treat of 25. And that's actually a twofold greater benefit than was seen in the overall FOURIER trial population.

Dr Carolyn Lam: That's really stunning results. Now I know Svati's going to have questions for us, so maybe I should invite you Svati, just put these results into context and let the audience know what we were thinking as editors when we saw this brilliant paper.

Dr Svati Shah: Yeah, thanks Carolyn. And I think Nick has done a fantastic job of describing the exciting results from this paper and just kind of taking a step back to help the audience understand what we're talking about when we're talking about genetics. For decades, we've been trying to figure out the genetics of heart disease and we're not talking about the genetics of things that are really rare like long QT syndrome, but the genetics of just common complex heart diseases. And amongst the scientific community, we've tried all different ways of sort of analyzing these data and so I want to make sure that everybody who's listening understands the novelty of really looking at these polygenic risk scores. Where we have now come to understand that it's not a single gene, it's not even two genes, that it's multiple variants and multiple genes and when they're combined, that's when you really have the power to understand how it might be useful in terms of how we take care of patients.

Really important with how Nick and Christian have laid out this really nice paper as well as their prior work in statins, is that not only did they show that these polygenic risk scores are associated with cardiovascular outcomes or even different amongst whether you get treated with the drug or whether you don't, but really importantly they're getting it clinical utility, not only with regards to showing that they compare it to a clinical risk score, but really showing that if you use these polygenic risk scores, you can identify patients who may derive the greatest benefit from PC SK9 inhibitors. And importantly in their paper, they show that if you have low polygenic risk score and low clinical risk score, you may not derive benefit from PC SK9 inhibitors. With all the caveats that this is a secondary prevention population, so I really applaud Christian and Nick and his team for the nice work that was done.

Dr Carolyn Lam: Oh, couldn't agree more, Svati. You know what I was very struck with too, because some people go, I may have a genetic risk. Maybe I could undo it or somehow overcome it with my clinical risk factors. And that's why I really appreciated that they showed that it was additive, and genetics still matter even if you have risk factors and vice versa. That was really cool. Christian, could I ask you to maybe describe a bit, what kind of genetic risk score this was and maybe perhaps point out some of the limitations therefore of what you studied.

Dr Christian Ruff: As Svati mentioned, this is really a quickly evolving field. We now have the ability to either genotype or sequence all of the variation that makes us different from one another. Our susceptibility to disease as well as our potential benefit for treatment. We had for this study, looked at several different risk scores. The one we focused on was a coronary artery disease genetic risk score that had 27 different variants that had been shown to predict having a cardiac event, both in primary and secondary populations. And we have previously identified patients who may have been at a higher risk who received greater benefit from statin therapy. And in this study, we actually compared this 27 variant genetic risk score with actually a much larger score of over six million variants. And interestingly, the two scores performed fairly similar with respect for risk prediction. One of the big questions going forward is, we have lots of ways to develop genetic risk scores, how many different variants do we need? What more information do we have with more complicated scores?

And I think Svati really hit on a really critical point is that really this study is really layering in genetic risk on top of clinical risk factors, which we can easily assess at the bedside. And I think what's reassuring to patients is that not only is genetic risk able to give us much more information for prognosis, but that this risk is modifiable. People think that their genetic risk, they're sort of born with it and there's nothing that they can do about it. But in this study, as Nick pointed out, even over a very short period of time with powerful lipid lowering therapy with a PC SK9 inhibitor, we essentially reduced these patients at high genetic risk to the risk of the very low risk patients on placebo. I think this is a reassuring message that genetics plays an important role for risk prediction and it identifies patients who we might target for more intensive therapy and that we can potentially reduce that risk even though that risk is based on the DNA that they're born with.

Dr Carolyn Lam: Indeed. That's a great point. And Svati, I'm sure you were thinking along those lines when you invited that beautiful editorial by Doctors Daniel Raider and Michael Levin. But Svati, would you like to comment on your thoughts on, is this ready for prime time?

Dr Svati Shah: I think that's the key question. What Christian and Nick and his team have done is take us a big step forward in how we use these polygenic risk scores. I think there still are many skeptics amongst the genetic scientific community about, well great, you can look at 27 variants and some of these polygenic risk scores, you're looking at a million things. How do we actually use that to take care of patients?

I actually want to turn this back, that question back around Carolyn, and I'd like to ask Christian next, what are the next steps? There are a lot of cardiologists who if you're listening to this podcast, should we all run out and get our patient's genotype to order this genetic chip so that we can figure out what their polygenic risk score is?

Dr Christian Ruff: Yeah, that's a great question and I could start off and then hand off to Nick, but I think one of the key questions is obviously there are a lot of genetic risk scores and I don't think as a field that we've come up with which one we really should implement in clinical practice. There's still a lot of fine tuning and figuring out which score gives us the most amount of useful information.

And then I think as something that you had mentioned that these scores are generated in both a healthy cohort population and now, we're looking at it in clinical trials and there's no sort of reference. Like when we have a blood test and we say, "If your hemoglobin A1C is above or below this number that means that you have diabetes." And we haven't figured out, what are the actual thresholds that you use for these genetic risk scores that you can implement broadly across different patient populations. There's still a lot of work that needs to be done to make these scores ready for prime time. This is really setting the stage. Is this something that we should be doing? And I think these studies and others say that the data looks great that we should be doing this, but we haven't yet figured out the logistics of which score and how do we actually reference to population.

Dr Nicholas Marston: Yeah, I agree with Christian definitely that we need to figure out what's the optimal genetic risk tool and for which population and what the cut points are. And then I think another piece that's going to be very important moving forward is doing a lot of this work and studying in non-European ancestry and cohorts and populations. Because most of the work done so far in discovery has been in databases such as the UK Biobank. And that limits us in our analyses to European ancestry patients. And so, I think for this to go to prime time, we want to be able to offer it to all of our patients. And so that means making sure we have scores that fit all populations, not just primary and secondary, but also all different types of ancestry.

Dr Carolyn Lam: Oh, I'm so glad you mentioned that, Nick. That was exactly on my mind coming from Asia. And the other thing of course, would be cost effectiveness of these approaches. Oh my goodness. I wish we had all the time in the world to talk about this more. The implications are enormous, but just let me thank you on behalf of all of us for publishing this remarkable paper in Circulation.

Audience, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.

Circulation February 18, 2020 Issue

17 februari 2020 | 30 min

Dr Biykem Bozkurt: I am Biykem Bozkurt, Professor of Medicine from Baylor College of Medicine, Senior Associate Editor for Circulation and today, I'm joined with Sana Al-Khatib, Professor of Medicine from Duke University, Senior Associate Editor of Circulation, for the podcast for the fourth annual Go Red for Women issue for Circulation. As all our listeners are aware, cardiovascular disease is a leading cause of death among women, but we have significant gaps in our awareness and treatments, and with a recognition of these disparities for cardiovascular care in women, AHA has launched a Go Red for Women campaign back in 2004. We have made great strides, and despite the improvement in awareness, significant gaps persist and adverse trends are emerging for cardiovascular disease in women.

With such recognition, in 2017, Circulation launched the annual Go Red for Women issue, dedicated to cover transformative science, exciting new treatment strategies, recent epidemiological trends, and with an intent to close the gaps and eliminate the disparities for cardiovascular care in women. This is the fourth Go Red for Women issue and we have an exciting portfolio that we'd like to share with our readers and listeners. In this issue, we have quite a few important papers. The first two that we would like to start with are going over the epidemiologic trends. Sana, do you want to walk us through the two papers that we have on myocardial infarction and sudden cardiac death?

Dr Sana Al-Khatib: I would love to start with the paper on sudden cardiac death, which is very fitting. That's what I focus most of my work on. This particular paper actually looked at sudden cardiac death as the first manifestation of heart disease in women, and it was focused on the Oregon sudden unexpected death study, the timeframe for which was between 2004 and 2016 and what they really wanted to do is to assess sex specific trends in sudden cardiac death incidence. And so they focused on out of hospital, sudden cardiac death cases among adults during that time period.

And they divided that 12-year period from February 2004 to January 2016 into three four-year intervals, 2004 to 2007, 2008 to 2011 and 2012 to 2015. And they really looked at these trends among women and men and they found that there were 2,938 sudden cardiac deaths, 37% of who were women. And they found an interesting U-shaped pattern of risk of sudden cardiac death with Anader in 2011. An increase in the years that followed 2011 so regarding that rebound, the rates really increased in 2013 and 2015. And when they specifically looked at women, they found that the rates of sudden cardiac death declined by 30% between the first and second four year time period and increased by 27% between the second and third period.

Interestingly, the subsets with sudden cardiac death as the first manifestation of heart disease, accounted for 58% of the total rebound in sudden cardiac death incidence from period two to three but there was no change in the incidence over time for sudden cardiac death occurring among people with preexisting heart disease. For men actually sudden cardiac death also declined from the first to the second period, but not as much as in women and also increased between the second and third periods. Again, not as much as we saw in women. Subsets of sudden cardiac death occurring in the setting of identifiable heart disease was responsible for 55% of the rebound in overall sudden cardiac deaths incidence. Certainly some significant differences between men and women. Very exciting findings.

Then if we actually turn our attention to the second study looking at sex specific trends in acute myocardial infarction, this particular analysis, Biykem, was done within an integrated healthcare network between 2000 and 2014 and they picked the Kaiser Permanente Southern California network. They were able to identify 45,000 plus acute MI hospitalizations between 2000 and 2014 and they found that age and sex standardized incident rates of AMI declined from 2000 to 2014. And they found that a decline for women was actually more so than in men. And in fact for men it was pretty much stable. And they found that the incidence of hospitalized MI had declined, however, declines are slowing among women compared with men in recent years.

That's actually identified some unmet care needs among women that hopefully can meet people and investigators to tailor their approaches to try to close those gaps and disparities in care. With that, let me actually turn it back to you to potentially talk about to cardiovascular risk assessments in women.

Dr Biykem Bozkurt: With the recognition of the disparities and the recent emerging trends of adverse outcomes, especially in younger women, there has been a focused attention in how to assess risk, cardiovascular risk in women. There is a very comprehensive review by Salim Virani and colleagues who's addressing the cardiovascular risk assessment for women. As our listeners will recall in 2018, ACC/AHA cholesterol professional guidelines specified risk enhancing factors such as premature menopause or preeclampsia for women. And if present, in borderline or intermediate risk patients, would elevate the 10 year risk to a higher category. But now with a recognition of many more risk factors, Virani and colleagues are proposing a more comprehensive cardiovascular risk assessment for women. And these include the risk factors that are not only identified in the 2018 ACC/AHA cholesterol guidelines, but additional such as gestational hypertension and diabetes or adverse pregnancy outcomes such as preterm delivery, small birth for gestational age or placental abruption or infarct or premature menarche or premature menopause, primary ovarian failure or pregnancy loss and additionally inflammatory disorders such as lupus, rheumatoid arthritis, psoriasis and history of cancer and cancer related therapies.

And they formulate this in a nice and well tabulated fashion. And all these risk factors are summarized table one which I think most of our listeners and readers will refer to. And they also come up with a nice approach. What shall we do? And how shall we detect that risk? First recommendation they have is that we should obtain a comprehensive obstetric and gynecological history from all women. And if these risk factors are present, then we should then screen for other traditional risk factors early and frequently and then treat for modifiable risk factors such as hypertension, hyperlipidemia, diabetes, metabolic syndrome, and also implement aggressive lifestyle modification with strategies such as management of blood pressure control, reduction of blood sugars, remaining active eating, healthy, losing weight, and not smoking. Which is summarized as life's simple seven which is an AHA initiative that summarizes healthy lifestyle as life's simple seven.

And very complimentary to Virani’s review paper, we had another wonderful paper that is titled Life's Simple Seven and health by Jacqueline Kulinski who reminds us that not only these seven factors but breastfeeding for postpartum mothers is an important approach to reduce cardiovascular risk. Breastfeeding is not only beneficial for the newborn infants but for the mother as it's been associated with reduction in risk of myocardial infarction, stroke, cardiovascular disease hospitalization rates, future development of diabetes, hypertension, and even mortality. And this paper elaborates on potential mechanisms such as increases in metabolic expenditure, enhancement of insulin sensitivity, reduction in cholesterol, greater mobilization of fat stores and reversal of elevated triglycerides and cholesterol that's seen during pregnancy.

It also emphasizes the importance of recognition and education of women because currently only about 25% of women are exclusively breastfeeding at six months and US has one of the lowest breastfeeding rates among industrialized countries. And we do have disparities according to race and income and black infants and infants living in rural areas in Southeast USA are less likely to be breastfed. And there is definitely increased recognition for importance and but it's also important to be able to accommodate and facilitate breastfeeding for mothers. Currently the paper emphasize that all 50 states now have laws allowing women to be able to breastfeed in public or private locations. But again, there definitely is a necessity for increased awareness and education.

On that end, there is also a great paper covering the news release announcing the partnership between American Heart Association and American College of Gynecology and Obstetricians in promoting risk identification and reduction of cardiovascular disease in women through collaboration between obstetricians and gynecologists. In 2018, AHA and American College of Gynecology issued a call for action for both specialists to team up and increase screening for cardiovascular disease by obstetricians and provide education and appropriate referrals. And I think this initiative is going to increase the opportunities for young women whose primary care provider solely could be an obstetrician, who potentially will get screened for cardiovascular disease and if they have these risk factors, will potentially be able to be offered lifestyle modification, message and intervention strategies.

These, I think, three very complimentary papers are enhancing our recognition for the new risk profile that needs to entail getting a comprehensive obstetric and gynecological history in all women. And in the event we recognize either of these risk factors including the traditional risk factors or obstetric and gynecological risk factors such as pregnancy related complications or preeclampsia or other additional special risk factors such as autoimmune disorders and cancer, then we will need to heighten our awareness for lifestyle modification, risk management, and earlier treatment and closer monitoring.

That brings us to another important risk profile, which is cancer for women. And Sana, I know we do have two great papers related to cancer topic. If you could elaborate on those.

Dr Sana Al-Khatib: I'm really excited about these papers. As you pointed out, Biykem, that cardio oncology is a field that is really expanding and so it was really very gratifying to get these two papers. The first paper had to do with a comparison between aromatase inhibitors and Tamoxifen in women with breast cancer in terms of their association with the risk of cardiovascular outcome. And this particular study was done in the United Kingdom and they studied women though with newly diagnosed breast cancer initiating hormonal therapy, either with everyone at aromatase inhibitors or Tamoxifen between 1998 and 2016. And the study outcomes that they were interested in included myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality.

And they actually had a sizable patient population with 23,000 plus patients included in this analysis of whom close to 18,000 initiated treatment with either an aromatase inhibitor or Tamoxifen. And they found that the use of aromatase inhibitors was associated with a significantly increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that aromatase inhibitors seemed to have a trend towards increased risk of myocardial infarction, ischemic stroke. Although those differences were not statistically significant. They actually concluded that aromatase inhibitors were associated with an increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that there were trends toward increased risks also of MI and ischemic stroke. And so they really want clinicians and patients to be aware of these findings when they are trying to make decisions about treatment for breast cancer.

We have another really interesting study, Biykem, that was actually a randomized control trial that studied the effect of exercise therapy dosing schedule on impaired cardiorespiratory fitness in patients with primary breast cancer. And so this randomized trial enrolled 174 post-menopausal patients who were randomly allocated to one of two supervised exercise training interventions, delivered either using a standard linear test or nonlinear test. And they had a control group of just stretching. They did some stretching. And they did the trial over at periods of 16 consecutive weeks and the primary endpoint was change in the VO2 level, PCO2 level from baseline to post intervention.

They had a couple of other secondary endpoints and their results were interesting. They found no serious adverse events during the trial, but they actually found that 40% of patients in both exercise dosing regimens were classified as responders. And they concluded that short term exercise training independent of dosing schedule was associated with modest improvements in cardiorespiratory fitness in patients previously treated for early stage breast cancer. Really interesting, a smaller study, not really looking at hard endpoints yet. It's still important because I believe that it is going to form the basis for more studies and more research in this important field, Biykem.

With this, I'd like to turn it over to you to talk about elevated body mass index in young women.

Dr Biykem Bozkurt: And this is another fascinating study, a large study from Sweden. It involved more than 1.3 million young women. Average age was 27. It was a national prospective cohort. The recruitment was between 1982 and 2014. What they did was they measured the baseline of weight of women in early pregnancy in the first trimester, actually the first antenatal visit before they could gain any weight related to the pregnancy. With their BMI measurement at baseline, then they followed these patients for approximately 30 years and associated this baseline BMI with future developments or dilated cardiomyopathy or any cardiomyopathy. They looked at that dilated cardiomyopathies, hypertrophic cardiomyopathies, these other cardiomyopathies such as alcoholic cardiomyopathy and others.

Interestingly, elevated body mass was associated with future development of dilated cardiomyopathy. A very similar finding was reported in former studies for adolescent men, but we didn't have this finding for young women. This study provides evidence that elevated BMI, even if it is only in the overweight range, is associated with future development of dilated cardiomyopathy. In the past we had numerous studies demonstrating overweight or obesity status being associated with future development of clinical heart failure, clinical symptoms of heart failure, but this is one of the largest scale population based cohorts demonstrating the association with dilated cardiomyopathy.

And interestingly, these women at baseline did not have the usual other confounders or comorbidities associated with future development of cardiomyopathy. The risk of diabetes and hypertension was less than 1% at baseline. Very interestingly, BMI by itself, independent of all these other variables was associated with future risk. And of course the higher the BMI was, the higher the risk was. The highest risk was for those with morbid obesity or BMI over 35 and in those patients the risk was increased by about five fold.

Sana, we talked about the disparities for women. Where are we with women participation in cardiovascular trials? And how do we looked globally overall regarding the disparity of cardiovascular diseases in woman?

Dr Sana Al-Khatib: These are really important questions, Biykem. Let me first start with a study that will be in the Go Red for Women issue on women's participation in cardiovascular clinical trials. They looked at that. Between 2010 and 2017, which is a very important topic as you know, Biykem. And so what they did here is they actually assessed the participation of women in completed cardiovascular trials that were registered in clinical trials between 2010 and 2017. And they parked calculated the female to male ratio for each trial to determine the prevalence adjusted estimates for participation of women. And so they kind of defined it as participation prevalence ratio. And so they said that they were able to identify 740 completed cardiovascular trials including more than 860,000 adults of whom 38% were women. And they talked about how the median female to male ratio of each trial was 0.501 overall and varied by age group and type of intervention and region and trial size and funding sponsors.

Actually, these are really interesting findings. In the interest of time, I'm not going to delve into all those details, but I think it would be really interesting for people to read that and look at this more carefully. But they found that relative to their presence in the disease population, the participation prevalence ratio of women versus men actually was a higher than 0.8 for hypertension, pulmonary arterial hypertension and lower for arrhythmia, coronary artery disease, acute coronary syndromes and heart failure trials. And they found that in the most recent time period, that they defined between 2013 and 2017, they saw a significant increase in the participation and prevalence ratios for stroke and heart failure trials compared to other periods. They concluded, not surprisingly, that among cardiovascular trials in the current decade, men still predominate overall, but that the representation of women actually is improving, especially when it comes to studies related to stroke and heart failure. That's what's really interesting, Biykem.

The other point that you were very nicely raised had to do with sex differences in primary and secondary prevention of cardiovascular disease. And the one study that we have in our issue, Biykem, was actually done in China. I really like this global reach of our issue. I presented a study that was done in the UK. You presented a study done in Sweden. This particular one was done in China and they conducted a community based survey of adults in seven geographic regions of China between 2014 and 2016. They really wanted to determine sex differences in the primary and secondary prevention of cardiovascular disease. And they looked at different factors in terms of age, education level, area of residence. And they had more than 47,000 participants of whom 61% were women. And they found that 5,454 had established cardiovascular disease, 57% of whom were women and 9,532 had a high estimated 10 year cardiovascular disease risk. And of those, 71% were women. And they found that only about 49% of women versus 39%, 60% of men were on any kind of blood pressure lowering medications, lipid lowering medications, antiplatelet therapy for primary and secondary prevention.

And they found that women with established cardiovascular disease were significantly less likely than men to receive blood pressure lowering medications, lipid lowering medications, antiplatelet therapy, so on, so forth. And that woman with established cardiovascular disease had better blood pressure control but less well controlled NVM cholesterol, were less likely to smoke and achieve physical activity targets. Conversely, women at high risk of cardiovascular disease were less likely than men to have their blood pressure LDL cholesterol, body weight controlled, despite the higher use of blood pressure lowering medication. Really interesting gaps in care that this study highlights that hopefully can form the basis for interventions to try to address those disparities.

And then as you know, we actually have a couple of research letters on the representation of women in editorial boards of major general and subspecialty cardiology journals, publishing clinical research. In this particular study, they actually found significant disparities where women were less represented among deputy associate editors and more so in European journals compared with US journals, general cardiology journals. Although editorial board membership was actually similar between Europe and the US, and they found that over 20 years, women deputy associate editors representation increased significantly for our journal, Biykem, Circulation. That was really very encouraging to see. And women editorial board membership increased for Circulation and for JACC without a significant change for the American Journal of Cardiology. That was really nice to see.

The one thing that was notable was in terms of women serving as editors-in-chief, we're still lagging behind in a big way, but I'm hoping that this particular study and several other studies that may get published in the future, will highlight these gaps and hopefully will lead to increased representation of women on editorial boards.

And finally we have an interesting study looking at the representation of women and men among training programs where they looked at the AAMC data and they were interested in looking at training in general cardiovascular disease medicine as well as for adult cardiology sub-specialties. And they also looked at pediatric cardiology by the way. And they found that in 2017 to 2018, among all adult cardiology trainees, only 21% were women. 79% were men. And among trainees in the different adult cardiology subspecialties, the representation was actually pretty poor in interventional cardiology, where only 10% of the trainees were women. And for electrophysiology, my own sub specialty, were only 11.6% of the trainees were women. Really interesting findings, the representation for advanced heart failure and transplant like your specialty, Biykem, women constituted 31% of the trainees and women did better when it came to adult congenital heart disease representing 47% of the training.

Really interesting trends and they concluded that in this review of ACG and the accredited training program, they found that cardiology ranked second for the most under representation of women, preceded as only by orthopedic surgery. And the sub specialty trends that I shared with you were really interesting. Hopefully as we see more of these publications, we'll be able to as a community come together and think about what are the barriers to more representation of women in these training programs? And how can we overcome these failures to encourage more women to go into this wonderful specialty of cardiology and the different sub-specialties, including procedural sub-specialties? Back to you, Biykem.

Dr Biykem Bozkurt: Thank you Sana. Very interesting findings indeed. Another fascinating study that we have in our issue is a study that provides us some insights on peripartive cardiomyopathy and potentially the role of natriuretic peptides during pregnancy.

This is an experimental study that involved natriuretic peptide receptor knockout in mice in which natriuretic peptides would not work. And the investigators demonstrated that these mice, during the postpartum lactation period, had elevated aldosterone levels, evidence of expression of pro inflammatory mediators such as IL-6, cardiac hypertrophy, fibrosis, left ventricular dysfunction, and even increased mortality. And interestingly, they were able to abrogate the effects of the lactation by use of mineralocorticoid receptor antagonists. With MRA use, there was evidence of reduction in LVH and reduction in inflammatory mediators.

There is a great editorial by Denise Hilfiker-Kleiner, who addresses the potential hypothesis of the role of unbalanced oxidative stress with prolactin in peripartum cardiomyopathy. And that the natriuretic peptides can be protected. And raises the question whether there could be a role for augmenting the natriuretic peptides further by use of sacubitril/valsartan. Or as was demonstrated in this study by you as a mineralocorticoid receptor antagonists in the postpartum period. And she also questions why in this experimental model, the detrimental effects were not seen during pregnancy but only in the postpartum lactation period.

Overall, very interesting papers. And finally we have an inspiring piece in our past or discovery section. It's an interview with Barbara Casadei, the President of European Society of Cardiology. She goes in a very detailed fashion over her career path, what she considers as the critical reasons for her success and how she envisions to shape the future of women in cardiology.

Dr Sana Al-Khatib: We would like to thank everyone who submitted their research and their work for this issue and congratulate the authors and investigators who were successful in getting their work published. Thank you very much.

Dr Biykem Bozkurt: We thank you for tuning in to our podcast. We hope that you'll enjoy our fourth issue for the Go Red for Women as we continue to highlight some of the best science for cardiovascular disease in women. Thank you.

This program is copyright, the American Heart Association 2020.

Circulation February 11, 2020 Issue

10 februari 2020 | 22 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week relates to an international multi-center evidence-based reappraisal of genes reported to cause congenital long QT syndrome. But, before we get to that, how about if we grab a cup of coffee and start on our other papers? Do you have one you'd like to discuss?

Dr Carolyn Lam: Yes. My favorite part of the week. So this first paper really asks the question, "What's the association between HDL functional characteristics, as opposed to HDL cholesterol levels, and acute coronary syndrome?" The paper comes from Dr Hernáez from IDIBAPS in Barcelona, Spain and colleagues who conducted a case control study nested within the PREDIMED cohort.

Originally a randomized trial where participants followed a Mediterranean or low-fat diet. Cases of incident acute coronary syndrome were individually matched one is to two to controls by sex, age, intervention group, body mass index, and follow-up time. The authors measure it the following functional characteristics, which were HDL cholesterol concentration, cholesterol efflux capacity, antioxidant ability, phospholipase A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and A4, serum amyloid A and complement 3 protein.

Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they find?

Dr Carolyn Lam: They found that low values of cholesterol efflux capacity, and levels of sphingosine-1-phosphate and apolipoprotein A1 in HDL or all associated with a higher risk of acute coronary syndrome in high cardiovascular risk individuals, irrespective of HDL cholesterol levels and other cardiovascular risk factors. Low cholesterol efflux capacity values and sphingo-1-phosphate levels were particularly associated with an increased risk of myocardial infarction, whereas HDL antioxidant or anti-inflammatory capacity was inversely related to unstable angina.

Now this is significant because it's the first longitudinal study to comprehensively examine the association of several HDL function related biomarkers with incident acute coronary syndrome beyond HDL cholesterol levels in a high-risk cardiovascular risk population.

Greg Hundley: Very nice. Carolyn. It sounds like function over just the levels is important.

Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've got another paper and I want to pick your brain first. Is it your impression that type 2 myocardial infarction, the type that occurs due to acute imbalance in myocardial oxygen supply versus demand in the absence of atherothrombosis, do you think that this type of MI is on the rise? It seems more and more common in my country.

Dr Greg Hundley: Do we want to say it's on the rise? Certainly by measuring all these high sensitivity troponins, et cetera, we're finding, I think, more evidence of type 2 MI. So, all in all, yeah it probably is on the rise, but likely related to some of our measurement techniques.

Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper that I'm about to tell you about really addresses some of these issues and it's from corresponding author Dr Gulati from Mayo Clinic in Rochester, Minnesota. And they really start by acknowledging that despite being frequently encountered in clinical practice, the population base incidents and trends of type 2 myocardial infarction is unknown and long-term outcomes are incompletely characterized. So they prospectively recruited 5,640 residents of Olmsted County, Minnesota who experienced an event associated with cardiac troponin T greater than 99th percentile of a normal reference population, which is greater than or equal to 0.01 nanograms per milliliter. And this was between 2003 and 2012, so very careful to talk about which Troponin T assay exactly to the point you discussed earlier, Greg. The events were retrospectively classified into type 1 versus type 2 MI using the universal definition.

Dr Greg Hundley: So Carolyn, what did they find?

Dr Carolyn Lam: They found that there was an evolution in the types of MI occurring in the community over a decade with the incidence of type 2 MI now being similar to type 1 MI. Adjusted long-term mortality following type 2 MI is markedly higher than after type 1 MI and that's driven by early and non-cardiovascular deaths. Mortality of type 2 MI is associated with a provoking factor and is more favorable when the principle provoking mechanism was an arrhythmia compared with postoperative status, hypotension, anemia or hypoxia. And these findings really underscore the healthcare burden of type 2 MI and provide benchmarks for clinical trial design.

Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from type 5 long QT syndromes and an analysis. And it's from Dr Jason Roberts from Western University. Through an international, multi-center collaboration, improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in long QT 5 was sought across 22 genetic arrhythmia clinics and four registries from nine countries that included 229 subjects with autosomal dominant long QT five. So there were 229 of those subjects. And then 19 individuals with the recessive type 2 Jervell and Lang-Nielsen syndrome. The authors compared the effects of clinical and genetic predictors on a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter defibrillators shocks, aborted cardiac arrest, and sudden cardiac death.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Well, several things, Carolyn. First, rare loss of function KCNE1 variants are weakly penetrant and do not manifest with a long QT syndrome phenotype in a majority of individuals. That's a little bit of a surprise. Second, QT prolongation and arrhythmic risk associated with type 2 Jervell and Lang-Nielsen syndrome is mild in comparison with the more malignant phenotype observed for type 1 Jervell and Lang-Nielsen syndrome. And then number three, all individuals possessing a rare loss of function KCNE1 variant should be counseled to avoid QT prolonging medications and should undergo a meticulous clinical evaluation to screen for long QTS phenotype.

And then finally, Carolyn, the last finding, in the absence of a long QTS phenotype, more intensive measures, such as beta blockade and exercise restriction, may not be merited.

Dr Carolyn Lam: Oh, very interesting. Well, I've got one more original paper and in this, authors describe a new cellular mechanism linking ischemia-reperfusion injury to the development of donor specific antibody, a pathologic feature of chronic antibody-mediated rejection, which mediates late graph loss. This paper is from corresponding author Dr Jane Witt from Yale University School of Medicine and colleagues who use humanized models and patient specimens to show that ischemia-reperfusion injury promoted elaboration of interleukin 18 from endothelial cells to selectively expand alloreactive interleukin 18 receptor 1 positive T peripheral helper cells in allograph tissues and this promoted donor specific antibody formation.

Dr Greg Hundley: Carolyn, here's the famous question. What does that mean clinically for us?

Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against endothelial cell derived factors like interleukin 18 may therefore block late complications of ischemia-reperfusion injury.

Dr Greg Hundley: Very nice. Sounds like more research to come. Well, how about other articles in the issue?

Dr Carolyn Lam: Well, I'd love to talk about a white paper from Dr Al-Khatib, and it's about the research needs and priorities for catheter ablation of atrial fibrillation and this is a report from the National Heart, Lung, and Blood Institute Virtual Workshop.

Dr Greg Hundley: Well, I've got another arrhythmia paper, so this is from Professor Michael Ackerman at the Mayo Clinic and its minor long QT gene disease associations by coupling the genome aggregation database. It's a harmonized database of 140,000 or more exomes and genome derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large long QT syndrome registry to reassess the strength of these minor long QT syndrome gene disease associations. Next, Carolyn, in an on my mind piece, Professor Gerd Heusch from University of Essen Medical School discusses, how can the many positive preclinical and clinical proof of concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes.

The author discusses the important differences between animal models that have been used a lot in this ischemia reperfusion and infarct size reduction science, and then the clinical scenarios of STEMI in humans as well as the many aspects of coronary reperfusion. How is that affecting the myocytes? How is that affecting the microcirculation, et cetera, that must be addressed? And then finally Carolyn, there is a series of letters, one from Professor Oliver Weingärtner from Universitätsklinikum Jena and another from Professor Yasuyoshi Ouchi from Toranomon Hospital. They're exchanging letters debating the utility of lipid lowering with Ezetimibe in individuals over the age of 75 years.

Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now move to our future discussion.

Dr Greg Hundley: You bet.

Well, welcome everyone. This is our feature discussion and today we're going to hear more about long QT syndrome. We have Dr Michael Gollob from University of Toronto and our own associate editor, Dr Sami Viskin from Tel Aviv Medical Center. Good morning. Good afternoon, gentlemen. Before we get started with a discussion of some of the study findings and results, Michael, could you tell us a little bit about why you performed the study and what were some of the hypotheses you wanted to test?

Dr Michael Gollob: As you know, long QT syndrome is probably the most recognized channelopathy associated with sudden cardiac death in young individuals and adults. And at the present time, there are 17 genes available for clinical genetic testing in cases of suspected long QT syndrome. We simply ask the question, "Is there sufficient scientific evidence to support that each of these genes are single gene causes of long QT syndrome based on our contemporary knowledge of genetics and the human genome?

Dr Greg Hundley: Great, Michael. So, can you tell us a little bit about your study population? How did you go about this and what was your study design?

Dr Michael Gollob: We designed a methods approach that would assure that any conclusions that were made from our working group were not based on the opinions of one or two individuals. We wanted to ensure that this was a consensus conclusion with multiple experts in the field including genomic scientists, genetic counselors, inherited arrhythmia experts, and researchers in the field. We created three independent teams of genetic experts to curate the genetic evidence reported in the medical literature for each of these 17 reported causes of long QT syndrome. This was essentially an evidence-based approach using a pre-specified evidence-based matrix or scoring system depending on the level of evidence, genetic primarily, in the reported literature for each gene.

Each of these curation teams worked independently of each other and they were blinded to each other's work and they were tasked with concluding whether a gene, based on the medical literature and the resource methodologies, had sufficient evidence for disease causation. Their classifications would be one of disputed evidence, limited evidence, moderate evidence, strong or definitive evidence for claims towards disease causation. Remarkably, independently, all of these teams reached the same conclusion. In the end, their summary data was reviewed by a clinical domain expert panel with individuals with expertise, particularly in long QT syndrome and other channelopathies. So in total 19 individuals reviewed all of the literature and the data presented and came to unanimous conclusions for each gene.

Dr Greg Hundley: Out of the 17, were there some that were more important than others or was it uniformly all 17 were relevant?

Dr Michael Gollob: Well, I think the most relevant conclusions of our study are that nine of these genes, more than half of these genes, were felt not to have sufficient evidence to support their causation as a single gene cause for typical long QT syndrome. So nine genes that are currently tested by clinical genetic testing providers do not have enough evidence to support their testing in patients with suspected long QT. And to us, that is the most relevant observation because testing genes that do not have sufficient evidence for disease causation poses a significant risk to patient harm and family harm. We concluded that only three genes had very definitive evidence for causation of long QT syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There were another four genes that were concluded to have strong or definitive evidence for unusual presentations of long QT syndrome. And by that, I mean presentations that typically occur in the neonatal period and are associated with heart block seizures or developmental delay or in the case of one of these genes, Triadin, an autosomal recessive form of the disease.

Dr Greg Hundley: So helping us perhaps what types of genes to screen for when we have someone with this condition or suspected. So Sami, can you help us put this into perspective? How does this study help us in management of this clinical situation.

Dr Sami Viskin: In Circulation, we immediately recognize the importance of the manuscript, the importance of the study because unfortunately, there are too many physicians all over who will accept the results of genetic testing essentially like gospel. Now it's in the DNA, it's in the genes, so whatever you find must be true. And too often, clinical decisions on treatment including ICD implantation have been undertaken based on results of genetic testing’s; thus are wrongly interpreted. So we recognize immediately the importance of this paper. We already had a different study by Dr Gollob and his associates. Again, reassessing the role of genes in Brugada syndrome. So we were familiar with this type of analysis.

We recognize the importance and we moved ahead to accept this paper, it went fairly easily, I think only one revision. At the same time, we were getting additional paper by other groups. So in the same issue, we have two more papers, one from Jason Roberts with the International Long QT Registry of long QT 5, reaching similar conclusions that this is a gene with very limited penetrants and another study by the Mayo clinic also showing that many of the genes who are not the major genes are overrepresented in the healthy population. So we put all these three papers together with a very nice editorial by Chris Semsarian in the same issue. So everything is put in the right perspective of how we should be looking at all the genes of these disease in a different way.

Dr Greg Hundley: So as a clinician quickly, how can I use this information in the issue, perhaps this paper and all three, in management of patients with either suspected or long QT syndrome?

Dr Michael Gollob: First off, I would emphasize that the diagnosis of long QT syndrome or any genetic base disease for that matter, should be based on clinical phenotype and not the observation of a genetic change, particularly if genes are being tested that do not have strong evidence for disease causation, as is the case for the nine genes that we've pointed out in this manuscript.

So I think clinicians need to be wary of the genetic testing panels that they are requesting be screened or used in the assessment of their patients and be knowledgeable that at this point in time, we really only have three genes with very strong evidence to support disease causation of the typical form of long QT syndrome. And that for the most part, these other genes should not be tested or should only remain in the realm of research.

I think that responsibility extends further than just the clinician taking care of the patient, but also clinical genetic testing providers, companies that offer these genetic testing services. I think they should assume a responsibility to ensure that they are only offering services for genes that have strong evidence for disease causation because when they report results in genes that are not valid for the disease, that only confuses the care of the patient and that creates a risk of harm to them if that information is misinterpreted by a physician.

As Dr Viskin or Sami pointed out, we do see patients who are inappropriately diagnosed. We remove the diagnosis of roughly 10 to 20% of cases in our own clinic. And unfortunately, many of these patients and their families have suffered undue anxiety. Some of them have ICDs in place that should not have been there. So I think overall, the field needs to be aware of what genes are relevant and what genes still are within the realm of research.

Dr Greg Hundley: Can you tell us just quickly Michael and then also Sami, what do you see as the next study in this field?

Dr Michael Gollob: We're taking a step back now. The first decade of this century saw an exponential growth in reported gene disease associations. And now in the last five or six years, we've learned a lot about human genetic variation, which has provided us an opportunity to reflect back on some of these previous and reported genes as causes for long QT and other diseases.

So I think many individuals in our field may say, "Well, you know, this is disappointing. We believed in these genes. We really thought these genes were causes of long QT." And to that point I would say, we need more research. If you believe in some of these genes that have now been considered to have limited or disputed evidence, research should continue if these remain plausible candidates for the disease.

So I think future research has to continue. There are probably still a few other genes that have not yet been discovered. I think we've got the vast majority. I think in most cases, at least in our experience, 90 to 95% of cases are explained by the top three genes. But there are probably other genes out there and it's always fascinating to learn or discover new genes, but those sorts of studies have to be done with the correct methodologies and rigid protocols. Lastly, I think in the future us clinicians and geneticists and genetic counselors need to work closely with genetic testing providers to ensure that they are offering responsible genetic testing services.

Dr Greg Hundley: Sami, do you have anything to add?

Dr Sami Viskin: Just congratulate the authors. I think they did a very great service to the medical community by pointing out the limitations of the genetic testing and the way we interpret the results, and they deserve to be applauded for reminding us that we have to be careful when we read papers about genetic results or when we get genetic testing results ourselves.

Dr Greg Hundley: I want to thank Michael from University of Toronto and Sami from Tel Aviv Medical Center for participating. And on behalf of both Carolyn and myself, wish you all a great week and look forward to chatting with you next week.

This program is copyright, the American Heart Association 2020.

Circulation February 04, 2020 Issue

3 februari 2020 | 27 min

Dr Carolyn Lam: Welcome to Circulation on the Run, Your Weekly Podcast Summary and Backstage Pass to The Journal and its Editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial.

So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States.

So, Greg, do you remember what the REDUCE-IT trial was about?

Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah!

Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer.

Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find?

Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo.

Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy.

Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find?

Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy.

Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers?

Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented.

Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues.

Dr Greg Hundley: Ah, so I'm interested. What was this interaction?

Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding.

Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women.

Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg?

Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis.

Dr Carolyn Lam: Ah, so are there any possible solutions to this?

Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy.

Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find?

Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions.

Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association.

There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association.

Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response.

Well, Carolyn, how about onto that feature?

Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well.

Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper?

Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same.

In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction.

Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found?

Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study.

Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum.

Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this?

Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction.

Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction.

And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies.

Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott.

Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women.

And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction.

Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it.

But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper.

Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read.

Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF.

And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women.

So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men.

Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating.

Scott, I'm going to give you the last word.

Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients.

Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright The American Heart Association 2020.

Circulation January 28, 2020 Issue

27 januari 2020 | 23 min

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Dr Greg Hundley, also Associate Editor, the Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Say, Greg, you know the feature paper this week talks about the perennially hot topic now and that is transcatheter aortic valve replacement or TAVR or TAVI. It's actually data from the France TAVI Registry comparing balloon expandable versus self-expanding transcatheter aortic valve replacement.

I'm sure you want to hear more about it, but first I'm going to tell you about another paper in the same issue, this time also comparing a balloon expandable versus a self-expanding transcatheter aortic valve implantation, but data from a nationwide analysis and from corresponding author Dr Fauchier from Centre Hospitalier Universitaire Trousseau. He and his colleagues basically did a head to head comparison of the two competing transcatheter aortic valve replacement technologies that have been published but have not really been followed for long-term clinical outcomes. This was comparing balloon expandable versus self-expanding technology.

They collected information from more than 31,000 consecutive patients treated with Tavern in France between 2014 and 2018 and based this on the French administrative hospital discharge database. They did propensity score matching, which was used for the analysis of outcomes according to the Sapien 3 balloon expandable versus the Evolut R self-expanding TAVR technology and studied this as nationwide level in France.

Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really large study. What did they find?

Dr Carolyn Lam: They basically found that balloon expandable TAVR was associated with lower mortality rehospitalization heart failure and pacemaker implantation compared with the self-expanding TAVR. Now, that's of course a pretty big finding and this is discussed along with the feature paper that we're going to hear about in an editorial by Drs. Abdel-Wahab and Thiele from Heart Center Leipzig.

I want to tell you about another paper before I let you tell you about yours, okay?

Dr Greg Hundley: Sounds great, Carolyn.

Dr Carolyn Lam: Greg, what is your clinical impression of Impella use in the United States among patients undergoing PCI? Do you think it's increasing or decreasing over time? As a reminder, Impella was approved for mechanical circulatory support in 2008, so from then, what do you think?

Dr Greg Hundley: You know, Carolyn, I really think it's increasing, especially used more frequently rather than an intra-aortic balloon pump. How about you? What's going on in your area of the world?

Dr Carolyn Lam: My impression too, but you know, you're lucky because we now have data looking at the trends in Impella use, but in the United States, and this comes from the corresponding author, Dr Amit Amin from Washington University School of Medicine and colleagues who describe clinical outcomes and costs across U.S. hospitals in PCI patients treated with mechanical circulatory support, which is either the Impella or the intra-aortic balloon pump.

They found that among more than 48,300 real world patients undergoing PCI with mechanical circulatory support at 432 hospitals between 2004 and 2016 in the Premier Healthcare Database, Impella use was indeed found to be rapidly increasing with marked variability across hospitals and not only its use, but also in its associated adverse outcomes. When analyzed by time periods or at the level of the hospitals or at the level of the patients, Impella use was associated with higher rates of adverse events and higher hospital costs.

Dr Greg Hundley: You know, I wasn't thinking about the higher rate of adverse events. You wonder sometimes, are we using a technology in a sicker group of patients? Did this study shine any light on that?

Dr Carolyn Lam: Those are great, great thoughts. The authors concluded that the variability in Impella use, the variability in its associated outcomes, and the association of Impella use with higher adverse events and costs really, really underscore the need for better defining of the appropriate use of mechanical circulatory devices and that was what you indicated as well, Greg, and what we need there is adequately powered randomized clinical trials and prospective real world evidence, which we don't quite have yet. Until then, perhaps a more measured approach is needed in clinical practice that balances risks versus benefits in complex patients undergoing PCI who require mechanical circulatory support.

Dr Greg Hundley: That's going to be really needed, I think in this era, especially with the results from this study. Well, Carolyn, I'm going to switch over to the world of basic science and the first study I'm going to talk about is from Dr Richard Lee from Harvard University and it's a very interesting study. Just as some background, current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells are capable of generating highly pure cardiomyocyte populations, but these cardiomyocytes remain immature and they really more closely resemble the fetal state.

As a result, they have a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared to adult cardiomyocytes. Also, they're prone to ventricular arrhythmias. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of Rapamycin mTOR signaling pathway plays a key role in nutrient sensing and growth, and Dr Lee and colleagues hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation.

Dr Carolyn Lam: Wow Greg, I really love the way you explained that. That's so interesting. What did they find?

Dr Greg Hundley: Among human induced pluripotent stem cell lines, transient treatment with Torin 1, an inhibitor of the mTOR pathway, shifted cells to a quiescent state and enhanced their cardiomyocyte maturity. Also, the investigative team suggests that further testing will be necessary to evaluate whether delivery of Torin 1 treated cardiomyocytes could reduce the risk of ventricular arrhythmias in newly differentiated myocytes derived from pluripotent stem cells. Really an important advance in this whole area of developing mature cardiomyocytes from our own pluripotent stem cells.

Well, Carolyn, my second basic science paper comes from Dr Calum MacRae from Brigham And Women's Hospital, also at the Harvard Medical School. Carolyn, this study used both highly purified human pluripotent stem cell derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells with human MYL4 mutations in a zebrafish MYL4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations associated with definitive genetic causes of atrial fibrillation.

Dr Carolyn Lam: Oh, that's really interesting. Is this new genetic predispositions that they discovered?

Dr Greg Hundley: I think the answer's yes. They found there was evidence of increased retinoic acid signaling in both human pluripotent stem cell derived cardiomyocytes and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins and loss of intracellular NAD and NADH, and thereby established a mechanistic link between the transcriptional, metabolic, and electrical pathways previously implicated in the atrial fibrillation substrate of MYL4. In the future, these data could lead to novel therapies for some patients with atrial fibrillation.

Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let me round up by telling you about some of the other things in the issue. There is a research letter by Dr Parish on the effects of Omega-3 fatty acid supplements on arrhythmias and here, these authors reported more comprehensively on atrial fibrillation and other arrhythmias using additional data extracted from linked electronic health records in the ASCEND trial, remember, which was 1 gram of Omega-3 fatty acid supplementation daily in people with diabetes but without known atherosclerotic cardiovascular disease.

Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a couple other really interesting articles in the issue. First there's an In Depth review from Dr Yvan Devaux from Luxembourg Institute of Health, and he discusses regulatory RNAs in heart failure. In a perspective piece, Dr Alejandro Lucia from Universidad European de Madrid discusses the role of aerobic and resistance training as a therapy in addition to prescribed medications in patients with resistant hypertension. Really interesting.

Then finally, Dr Ify Mordi from University of Dundee examines metformin use and clinical outcomes among patients with diabetes, with or without heart failure, kidney dysfunction observations from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues found that metformin use was associated with a reduction in all-cause mortality and cardiovascular death, but not due to myocardial infarction or stroke, particularly in patients without a prior history of heart failure.

What could the mechanism be, if not related to presumed atherosclerosis? Dr Mordi and colleagues proposed possibilities, and Dr Brian Bergmark from the TIMI study group and the cardiovascular division of Brigham and Women's hospital at Harvard Medical School and colleagues, they write a very nice response. It's really interesting listening to how could metformin reduce events but not related to atherosclerosis? How about onto our feature article?

Dr Carolyn Lam: You bet.

Dr Amit Khera: This is Amit Khera, digital strategies editor for Circulation from UT Southwestern Medical Center joined by my colleague, Dr Dharam Kumbhani who's also an associated editor at Circulation and we're pleased to have Dr Eric Van Belle, Professor Van Belle, from Lille University Hospital to discuss the featured article today, "Transcatheter Aortic Valve Replacement Propensity Match Comparison From the France TAVI Registry." Welcome to you both.

Dr Van Belle, I'm going to start with you and we always like to hear a little bit. Perhaps you can tell us some of the background, what led up to this investigation, what led to your group pursuing this manuscript?

Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR procedure, is becoming very prominent kind of way of treating patients without stenosis, and basically we have two different type of devices that are available to treat the patients. Once series is based on the balloon expandable concept and the other one on the self-expandable concept. These two type of devices are considered to be used primarily in every kind of patient. Theoretically, we can use any of these two devices, any kind of patient, if we follow the recommendation of the manufacturer and I'll just say that that'd been done.

These two devices are being validated against surgery, so basically, we could potentially use any kind of them. In today, there is no direct and there was no direct comparison between the two different kinds of concept, although they are very different. Again, the device is different. The way we implant the device is different. The major question that we had behind was to say, okay, what is the outcome? If it's a mean patient get one of the devices or can we expect or should we expect a different outcome? That was the main question behind it.

Dr Amit Khera: Okay, so essentially there's two valves, they're both being used fairly regularly and without any kind of direct comparisons. Tell us a little bit about the study design and what you found in this project.

Dr Eric Van Belle: For methodology, we used what is called a French study registry, basically nationwide registry with almost all patients treated in France included, and we used it as a database of patients between 2013 and 2015 with an overall group of 12,000 patients treated with either of these two kinds of devices. This is one of the aspect of this registry. The other very important aspect of this registry, and that's the mortality data survival that was obtained in all the patients in 2008 through 2016, so we have a set of 12,000 patients. It was a cool kind of device with complete mortality data by April 2016 so basically, this is the main methodological aspect. On top of this, we did the best to do some matching on the older clinical variables and all the matching valuables that we had to create pairs of patients that could be matched to one to one. We had, at the end, a group of almost 4,000 patients.

Dr Amit Khera: Okay and tell us a little bit about some of your main findings of this study.

Dr Eric Van Belle: The two main findings were those differences between the two groups of patients, that is a patient treated with self-expandable devices at a higher risk of valvular regurgitation. This was mainly a confirmation because this finding was already reported previously in previous studies trying to compare the two devices, but what was more striking was the difference in mortality. It was a difference mostly in hospital mortality but also in mortality after two years. That was significant with an absolute difference in mortality around 3% by two years.

Dr Amit Khera: Well, obviously important, as you mentioned that paravalvular leak had been seen before and this now a long-term mortality difference. Certainly an important finding and one of the main findings of your study. One of the concerns about comparative effectiveness research, essentially you're using observational data such as this is that there still could be residual confounding. There still may be patient characteristics or decisions made by interventionalists that aren't fully accounted for. How did you all really try to account for some of these components, this residual confounding to try to get the best answer that you could?

Dr Eric Van Belle: That's going to be a major comment, and everything you can do, every best way to try to control for this, there is no better answer than to do a randomized study, and probably we'll discuss on this. Let's see, indeed, we try to do our best to minimize as much as we could, all these potential confounders, so we did it in a different way, indeed.

The first way to do it was to adjust all the potential differences among group but what was very also interesting to remind is that, when you look at the 25 clinical and imaging variables and creating the aortic annulus diameter that was incorporated in the matching, that actually 21 of the 25 variables were already there. We were balanced between the two groups, existing that indeed most of the case, the operators, we are not so much directing or at least if there was selecting it was not captured but all of these valuables because again, out of 25, the correction needed to do the matching was only affecting 4 variables, mainly. Those variables were already pretty well-matched between the two populations.

The other way we did it was to look at what is called falsification endpoint, that it is endpoints that are supposed to be unrelated to the devices to verify that indeed, we have not selected a population that will have issues that are not related to the device itself. We look at, let's say, mortality by infection, mortality by cancer, to verify that, indeed, this kind of event where it did well balanced between the two groups suggesting that the mortality effects that we observed was not related to this kind of unbalance related to something else that was not captured by analysis.

Dr Amit Khera: Yeah, I think that was quite an important observation you mentioned. The first that these two groups are generally well-balanced to begin with, even before with all the matching parameters and then certainly the falsification endpoint helped to add validity to the findings.

Dharam, I'm going to turn it over to you. Maybe you can show this from an associate editor's perspective. What are some of the observations you found interesting about this study and what are some of the considerations we had in some of the discussions about it?

Dr Dharam Kumbhani: I'll just remind our listeners that this was also a late breaker at AHA last year in 2019, so this is really a very important finding. As Eric briefly pointed out, there haven't really been head to head comparisons between, the two dominant valves in the market even though TAVR has pretty much become the dominant strategy for treatment of aortic stenosis.

At the end of the day, it's an observational analysis. We have to take the findings with that in mind. At a minimum, it's first a lot of debate and discussion about the need to have randomized trials and our belief that, perhaps, TAVR is a class effect may not always be true. I think that hypothesis would certainly need to be tested and that's what this paper really sparks as far as discussion going forward.

Dr Amit Khera: Maybe I'll ask both of you. One of the challenges of any type of observational research is time period. First there was a hint towards even maybe a greater effect in the more recent time period than the distant time period. Also, there's always commonly changes in technology, especially interventional field where a study comes out and it's already obsolete because there's some new technology. There are some newer generations of valves that have come out. Do you think that it would affect these findings in any way? Maybe we'll start with you, Eric.

Dr Eric Van Belle: That's always an issue. Again, because it's a very rapidly evolving field and if you want to have strong data, you need to have really long-term follow-up. You need to have mortality data. There is some kind of contradiction between both that the field is evolving very quickly but then to have solid data, you need to have some time.

What we could say, indeed, as a study period was 2013 and 2015, but the device that we are using at that time were already really well matured and also the devices that were used at that time was usually the ones that were used for the comparison with the surgical techniques. Again, these devices are not so much obsolete since they were accepted and used again, when you need this one device study to compare with surgery.

Of course these devices have still had some evolution and change, and it is for the good of the patient, but again, as mentioned there, I'm seeing what is very, very important is that this finding is, in my view, intriguing enough to say, okay, even if it's difficult to conduct this kind of randomized study, it has to be done now because we need to really know. Let's say 80% of the patients could indeed be treated with any of the two device in this large margin of patients. Do we have to choose one or the other one to start with? This has already been well answered in a larger randomized trial.

Dr Amit Khera: Dharam, maybe I'll ask you, do you think this large randomized trial, are you optimistic that that would happen? Certainly it sounds like it's something that would be very helpful for the field. What are your thoughts on whether that's actually going to occur?

Dr Dharam Kumbhani: I know that there are some head to head trials ongoing. I don't know if they will have the sample size to really drill down, as far as hard endpoints, mortality, for example. I think the field clearly needs it. The question is, who's going to sponsor a trial like that? There's probably not much incentive for industry to sponsor something like that. Really it would fall down to whether there's a way for government agencies to partner with industry or other ways to run this. I do agree with Eric that that's really very important and hopefully we'll see that in the field going forward.

I did want to comment on the next iteration of devices as far as what we may see now. The mortality signal, I know we've talked about it. It's an observation study. It's hard to know if there's confounding, and even with all the sophisticated statistical analyses that the team did, there's always a possibility that somehow there was sicker patients that received self-expanding valves.

The signal for paravalvular regurgitation is not just in this study. We've observed it in many other studies and for other self-expanding platforms as well. Both the SCOPE trial and the St. Jude trial last year, both came around the same time. They were self-expanding platforms and both of them showed a higher paravalvular regurgitation rate compared to the balloon expandable rate. That may be a real thing, and I don't know if that is an inherent design flaw in the self-expanding platform or if there are ways that that could be mitigated going forward. Again, I think the trials, for it to be meaningful, it would be obviously important to collect and have short term and imaging markers. Really, what the field needs is long-term evaluation of these two strategies.

Dr Amit Khera: I want to take both Dharam Kumbhani and Dr Eric Van Belle l from Lille University Hospital. Thank you both for joining today.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.

Circulation January 21, 2020 Issue

20 januari 2020 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, Associate Editor from National Heart Center at Duke National University of Singapore.

Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia.

Dr. Carolyn Lam: Greg, it is so good to be back. I just love doing these podcasts with you and what more when we get to feature a paper like the one that we have this week. It's all about high sensitivity, cardiac troponin and the universal definition of myocardial infarction, one of these evergreen topics that we truly need to understand better. But before we go onto that, I want to share my first paper. It's a preclinical paper and it provides an important breakthrough discovery that could protect the heart against progressive left ventricular systolic dysfunction following injury. Want to hear about it?

Dr. Greg Hundley: Absolutely.

Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs Sabourin and Benitah from INSERM University, Paris, as well as Doctors Foster and Beech from University of Leeds.

Dr. Carolyn Lam: Now, whereas store operated calcium entry has recently gained attention in cardiac pathophysiology, the role of the prototypic store operated channel known as Orai1 remains elusive. So these authors used a novel genetically modified mouse that specifically disrupts the Orai1 channel in cardiomyocytes and showed that functional inhibition of Orai1 preserved alterations of calcium homeostasis, fibrosis and systolic function without affecting hypertrophy. A novel in vivo small molecule Orai1 channel inhibitor, in fact, markedly improve left ventricular systolic function and calcium handling after pressure overload without causing adverse effects.

Dr. Greg Hundley: Tell me, how does this help me as a clinician?

Dr. Carolyn Lam: All right, you always ask the tough questions. Well, these results really suggest that Orai1 inhibition has the potential for favorable hemodynamic value in the protection of the heart from maladaptive hypotrophy, and therefore might represent a new way to provide inotropic support to help relieve systolic dysfunction.

Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from Dr Peter Kudenchuk from University of Washington Medical Center and this study evaluates the overall survivor after out of hospital cardiac arrest from shock refractory ventricular fibrillation or pulseless ventricular tachycardia related to the route of accessory drug administration. So to accomplish this, the investigators had 2,358 individuals that had received Amiodarone, lidocaine or placebo study drugs and randomized to an IV route.

Dr. Greg Hundley: And then they also included 661 patients that received the same medications, but they were randomized to an intraosseous route.

Dr. Carolyn Lam: So what were the results, Greg?

Dr. Greg Hundley: Well, Carolyn, while no significant effect modification by drug administration route was observed point estimates for the effects of both drugs, both the lidocaine and the Amiodarone, compared to placebo were greater for the IV, as opposed to the intraosseous route and that was across all outcomes. And they had significant increases in survival to hospital admission and discharge and favored improved neurological outcomes with the IV administration.

Dr. Greg Hundley: Unfortunately, however, the study was underpowered to examine for an interaction between the route of vascular access and drug effectiveness and thus additional studies are needed to determine whether Amiodarone in lidocaine may be lifesaving drugs in patients with shock refractory out of hospital cardiac arrest when given IV, but not necessarily intraosseous.

Dr. Carolyn Lam: Very interesting. Well, my next paper is really focused on HIV infection and asks the question, is HIV infection associated with abnormal cardiac repolarization that may contribute to a greater risk for sudden arrhythmic death? Well, corresponding author Wendy Post, our very own from Johns Hopkins University School of Medicine and her colleagues studied 1,123 men, 589 of whom were HIV positive and they were from the multicenter AIDS cohort study and they were studied using the ZioXT ambulatory ECG patch.

Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the largest study of QT variability in HIV today.

Dr. Greg Hundley: Is that right? And what did the authors find?

Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they found that HIV positive men had greater beat to beat variability in the QT interval compared to HIV negative men, especially in the setting of HIV viremia and heightened inflammation.

Dr. Carolyn Lam: Among HIV positive men, a higher QT interval variability suggests ventricular repolarization lability which could increase susceptibility to arrhythmias. However, lower heart rate variability also may signal a component of autonomic dysfunction.

Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the world of basic science and it's from Dr. Chen Yan from University of Rochester. And in this study, Dr. Yon and colleagues examine the role of cyclic nucleotide phosphodiesterase in isolated adult mouse cardiomyocytes and fibroblasts as well as in preclinical mouse models of hypertrophy and/or heart failure. And they found that phosphodiesterase 10A expression is significantly induced in mouse and human failing hearts.

Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic growth as well as cardio fiber-blast activation, proliferation, migration and extracellular matrix production. In addition, phosphodiesterase 10A deficiency, so not as much of it, ameliorates cardiac hypertrophy fibrosis and/or dysfunction in different preclinical mouse cardiac disease models. And finally inhibiting phosphodiesterase 10A activity with a compound labeled T P 10 effectively antagonizes the pathological cardiac remodeling in LVH.

Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask you, so what are the clinical implications?

Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have been evaluated in phase two clinical trials for treatment of schizophrenia, suggesting that these agents are safe, druggable, if you will, targets. And therefore the results with TP 10 suggests a potential therapeutic effect of targeting phosphodiesterase 10A on antagonizing the development of pathological cardiac remodeling. Perhaps as suggested by Dr. Ezekowitz last week, this could represent another new agent in the treatment of the adverse effects of heart failure syndromes, more pharmacological agents coming to treat heart failure.

Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk about what else is in this issue. So let me tell you about an online mine by Dr. Kalra and it's called the Cardiovascular Science India Tour. And what this talks about is a multi-pronged initiative bringing together professionals and diverse expertise to allow better understanding of the issues driving the ever-rising cardiovascular disease burden in South Asia.

Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a research letter, Carolyn from Dr. Julian Luetkens from the University of Bond, who investigates a surrogate of frailty by examining the fat fraction within skeletal muscle at the L three L four level. So it's from an axial CT that's acquired at the time of CT scanning for TAVR pre-evaluation and uses the fat muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's a great wrap up. How about we get onto our feature article?

Dr. Carolyn Lam: You bet.

Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies editor for circulation and today with our featured podcast we have Dr. Andrew Chapman from the university of Edinburgh, UK who is the first author of a study entitled high sensitivity cardiac proponent and the universal definition of myocardial infarction. Welcome Dr. Chapman. Thanks for joining us.

Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you.

Dr. Amit Khera: This is obviously a very interesting study and timely and on the backs of the prior work that your group has published. Maybe we can start by you telling us a little bit about the impetus, the background which led to this work.

Dr. Andrew Chapman: We've been using high sensitivity cardiac troponin in Europe now for some years, and the way that we diagnose myocardial infarction has, of course changed. We now recognize that myocardial infarction can occur in the context of an occluded coronary artery, be that a STEMI or an NSTEMI, also known as a type one myocardial infarction.

Dr. Andrew Chapman: But increasingly with the use of more sensitive cardiac troponin, we're recognizing myocardial infarction can occur in other conditions. So for example, after arrhythmia or after severe infection with hypoxia. So the real rationale and background for this study is trying to understand better the different subtypes of myocardial infarction. As proposed in the universal definition.

Dr. Andrew Chapman: And we were in quite a unique position to evaluate this as, when we implemented high sensitivity cardiac troponin testing in Scotland as part of a randomized controlled trial. We did so across different hospitals and two of our major cities, Edinburgh and Glasgow, and the trial which formed the basis for this study was called the high States trial and we enrolled 48,000 patients of who we initially used a contemporary sensitive cardiac troponin on an IRC and we then implemented a high sensitivity cardiac troponin IRC.

Dr. Andrew Chapman: And that allowed us to evaluate what impact implementing this high sensitivity test hard firstly on the prevalence of different subtypes in myocardial infarction, but also on the investigations and the treatments received. And finally of course the clinical outcomes of these patients.

Dr. Amit Khera: So obviously at a really sizable study and good forethought on your group to implement this as this step wedge type study design. As you pointed out, the goal here was to understand the different subgroups of myocardial infarction, the prevalence and implications. Tell us a little bit about what you found in this study.

Dr. Andrew Chapman: As I mentioned, we had over 48,000 consecutive patients and that was the real benefit of this step wedge design is that rather than recruiting patients between say nine and five where we had research nurses available, we enrolled all consecutive patients. So we think this is quite a representative population for our area. So of those patients, we found around 10,000 had elevation in the high sensitivity cardiac troponin concentration, and we adjudicated these diagnoses in parallel. So two independent clinicians look through every case, all the clinical information. And we had a consensus from a third when there was disagreement. So in short we found that around half of all elevations in cardiac troponin in this study were to take one myocardial infarction, that is that the blocked artery phenotype and the type two myocardial infarctions or an acute or chronic myocardial injury and myocardial injury being elevation and cardiac troponin, either acute with a rise or fall or chronic with a stable concentration with no evidence of myocardial ischemia and occurred in the other 50% of patients.

Dr. Andrew Chapman: So looking between the phases of the study, we found introducing high sensitivity troponin disproportionately increased the diagnosis of Type II MI or acute or chronic myocardial injury. So there's just an 11% increase in the diagnosis of Type I MI, and I think again that's highlighting that these more sensitive tests are finding myocardial damage in areas that previously it might not have been recognized.

Dr. Andrew Chapman: So moving forward from that, we evaluated the primary outcome of the trial, which was future myocardial infarction or cardiovascular death by subgroup. And we also evaluated unimportant non-cardiovascular death. If I may for just 30 seconds, I'll just discuss why this is important.

Dr. Andrew Chapman: So evaluating future cardiovascular events is very important and in different subgroups of myocardial infarction. However, we know patients with Type II MI and acute or chronic myocardial injury are different. So they tend to be older, they're more commonly female, they have more comorbidities, they're on more medications to start with.

Dr. Andrew Chapman: And these patients are ar increased risk of a competing events to cardiovascular death or a myocardial infarction. And that is that these patients can go on and die, will primarily from their primary illness, be an infection or a pulmonary embolism or what have you. But also they are at increased risk of death from other non-cardiovascular causes.

Dr. Andrew Chapman: So in this study we were able to evaluate future cardiovascular risks using quite advanced competing risks modeling. And I was very grateful for the input of a number of experts and we managed to find that actually, Type I myocardial infarction patients with occlusion or partial occlusion of the coronary artery were at the highest risk of cardiovascular events going forward.

Dr. Andrew Chapman: But interestingly, even despite the vast excess in non-cardiovascular death, patients with Type II MI, and acute or chronic injury also had quite a high cardiovascular risk over three folds out of patients without myocardial injury. And we noticed that these patients did not stand to receive increases in investigations or treatments for coronary heart disease and we speculate and we hypothesize that actually in a proportion of these patients there is some clinical coronary artery disease which has manifested itself during this physiological stress test of an alternative illness. We wonder and we hope that moving forward this might be an opportunity for better targeting it in an investigation and perhaps even improving clinical outcomes.

Dr. Amit Khera: Well, you just shared a ton of important findings there and I'm going to unpackage a few of them. I guess the first is this sort of type I versus type II MI, and I think one of the fears with implementing these high sensitivity troponin would be perhaps an explosion in these type II MIs. And I think, if you look, although you mentioned proportionally, the absolute numbers of increase in type I and type II MI was relatively small so it didn't seem we had this explosion that I think people had feared was implementation.

Dr. Andrew Chapman: Yes, that's a fair point. And also need to bear in mind this is a population of patients from Scotland and our high sensitivity troponin testing is quite selective. You would find differences in the impact of high sensitivity if you're testing practices were different and I know there's prior work from the United States showing that less selective testing or to put it in a different way, testing troponin in more patients. Perhaps some of them may not have symptoms of chest pain or symptoms suggestive of myocardial infarction, is likely to change the prevalence of these different groups and you are likely to pick up more secondary injury or type II MI, but I think we don't need to panic. There's no need for alarm. I don't think there is going to be an explosion in recognition of these patients. If you check a temperature, you'll find a fever, but provided we're sensible and who we're testing, then I don't think practice needs to change dramatically.

Dr. Amit Khera: That was a great way to say it. Unfortunately, we're always looking for fevers in the U.S. So as you pointed out, the prevalence increase may increase a bit, but definitely reassuring from what you're finding in your population was more judicious testing.

Dr. Amit Khera: The second point that you brought up was the event rates, type I versus type II MI. I guess this does remind us again that patients with type II have almost comparable cardiovascular deaths and MI rates as type I, so certainly a higher risk group. As you pointed out, there's many comorbidities there and this gets to your point about treatments. I guess the question is now the event rates are higher, these are higher risk group or what to do about it I think is one of the vexing problems. As you pointed out, there's, there's not a lot of secondary prevention treatments, but what should those treatments be and where do we go from here in terms of these type II MI?

Dr. Andrew Chapman: That's the million dollar question I suppose and something that we've explored in another recent circulation review under the [00:17:07] lead author is what we do for these patients. When we've looked at different strategies, it seems the most reasonable initial approach is determining, does my patient with type II MI or myocardial injury actually have a cardiac problem?

Dr. Andrew Chapman: Now I don't think we have the evidence to support routine and baited testing in this population yet and indeed that might expose patients to harm and that's one of the tensions with this diagnosis.

Dr. Andrew Chapman: For example, consider the patient with gastrointestinal hemorrhage and could it have gone forward for an angiogram. Giving them heparin might not be the best thing to do in their acute illness. However, whether or not these patients would benefit from noninvasive tests such as a CT scan to delineate the coronary anatomy and identify those that might benefit from an iron platelet agent or a statin or indeed an echocardiogram to determine which patients have left ventricular impairment and could benefit from the many number of treatments we have now for LV impairment and that would be my initial thinking is that we need to firstly risk profile these patients.

Dr. Andrew Chapman: What is their pretest probability or likelihood of coronary artery disease? It's not intermediate or high. Let's have a think about investigating their coronary arteries. In the first instance, I think a noninvasive test is going to be most appropriate for the majority of people, but we need a personalized approach. It may be that someone's just had a very brief run of an arrhythmia and that's resulted in a disproportionate level of ischemia and a very high cardiac troponin.

Dr. Andrew Chapman: Your index of suspicion for that patient having coronary disease is going to be significantly higher. So a personalized approach, I think, is where we're heading. And there are trials which are coming in this area. So yeah, two trial is being led by Derek Chu of Melbourne in Australia and they're evaluating the use of CT or invasive angiography to identify coronary disease and target treatment to see if that can improve outcomes.

Dr. Andrew Chapman: And certainly here in Scotland, we're hoping to evaluate the use of a personalized approach to target treatment in patients with type II MI and again, try and improve cardiovascular outcomes. So things are coming.

Dr. Amit Khera: Well, I appreciate that and I think as you pointed out, as we wait for these additional data and additional studies, sort of a thoughtful. algorithmic approach would be helpful and we certainly will make sure the readers and listeners look out for that paper that you mentioned in circulation.

Dr. Amit Khera: I should also point out that your paper here is an excellent editorial by David Morrow, which has a nice figure and illustration of your central findings. So we appreciate that. As we wrap up here, maybe you can tell us what are the main take homes? What should they take away from this study?

Dr. Andrew Chapman: What we've shown is that high sensitivity troponin are useful and we've shown that they increase recognition of patients who have myocardial jury or type II myocardial infarction, where in the past this may not have been found and we've shown quite clearly that these are prognostic. Not only predicting non-cardiovascular disease, but also going on to identify patients at increased risk of myocardial infarction, cardiovascular death.

Dr. Andrew Chapman: So I think moving forward, clinicians using these tests and identifying these patients should be considering investigations to identify coronary or structural heart disease. And until we have that high quality randomized controlled trial data, we need to be pragmatic and we need to evaluate secondary prevention on an individual patient basis, be that an antiplatelet agent or be that a statin as the primary ones. This may even go on to include an ACE inhibitor or a beta blocker if there's LV impairment, but our aim ultimately has to be to try and reduce the cardiovascular event rates in this population who, to date, have been under investigated and undertreated.

Dr. Amit Khera: That summarizes it quite well. And I want to thank Dr. Andrew Chapman for his excellent discussion today and that's why we do these backstage passes to get an inside look as to what the authors were thinking and some behind the scenes on their papers.

Dr. Amit Khera: Again, I'm Omnicare digital strategies editor for circulation, and thank you for joining us on this circulation on the run podcast.

Dr. Greg Hundley: This program is copyright, the American heart association 2020.

Circulation January 14, 2020 Issue

13 januari 2020 | 24 min

Dr Greg Hundley: Welcome listeners. This is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond, who is in the second of his two-week stint without his dear friend, Dr Carolyn Lam who will be returning in a week or two. Our feature article this week is from Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and the Georgia Institute for Global Health, and University of New South Wales. And we'll review the effects of dapagliflozin on quality of life and other metrics in patients with heart failure and reduced ejection fraction. But first, let's have a look at the other articles in this issue and just like last week we've got four other original manuscripts. The first two are sort of clinically related and that very first article comes from Dr Ben Levine from University of Texas Southwestern and he serves as the corresponding author and he's examining future predictors of the development of heart failure and preserved ejection fraction or HFpEF.

His team tested the hypothesis as to whether patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF. The team recruited 46 patients with LVH. The LV septum was greater than 11 millimeters and elevated cardiac biomarkers, so the NTproBNP was greater than 40 or the cardiac troponin T was greater than 0.6. And they were recruited along with 61 age and sex-matched cohort of healthy controls. To define LV pressure volume relationships, right heart catheterization and 3D echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. They found that the left ventricle was less distensible in the LVH patients relative to the controls, that is they had a smaller volume for the same filling pressure. When preload was expressed as transmural filling pressure or wedge pressure minus right atrial pressure left ventricular myocardial stiffness was nearly 30% greater in the LVH group compared to the controls.

The author's note that although LV myocardial stiffness of LVH patients was greater than that of the healthy controls at this relatively early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals.

Well, the second paper comes from Professor John McMurry of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in the United Kingdom. And the paper is somewhat similar to our feature article because it emanates from the DAPA Heart Failure dataset that we will hear about later. So in this paper, the authors examined the effects of Dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly in the prior trial. A clinical trial that as we know, demonstrated that a reduced risk of mortality and heart failure hospitalizations occurred in patients with HFrEF.

So in this current study, a total of 4,744 patients that were 22 to 94 years of age were randomized. 636 were less than 55 years of age, 1,242 we're 55 to 64 years of age 1,717 were 65 to 74, and finally 1,149 were greater than 75 years of age. Consistent benefits were observed for the components of the primary outcome of all-cause mortality and symptoms across all the age groups. Although the adverse events and the study drug discontinuation increased with age, neither was significantly more common with Dapagliflozin across any of the age groups. There was no significant imbalance and tolerability or safety events between Dapagliflozin and placebo, even in the very old population group. So we'll have more to discuss later in the feature discussion with a second paper that really looks also at the DAPA-HF study.

The next original article comes from our world of Basic Science and it reports that the deficiency of circulating monocytes ameliorates the progression of myxomatous valve degeneration in the Marfan syndrome. And this paper comes from Dr Katherine Yutzey from Cincinnati Children's Medical Center. Well, first is some background, leukocytes comprised primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in myxomatous mitral valve degeneration is not known. So the authors found in this study that Marfan syndrome mice recapitulated the histopathologic features of myxomatous valve disease by two months of age, including mitral valve thickening, increased leaflet cellularity and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation.

Concurrently, disease mitral valves of the Marfan syndrome mice exhibited a marked increase of infiltrating and resident macrophages along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited Marfan syndrome pigs as well as human subjects exhibited increased monocytes and macrophages detected by immunofluorescence. So remarkably deficiency of monocytes was protected against mitral valve disease progression resulting in a significant reduction of macrophages, had minimal leaflet thickening and preserved mitral valve integrity. So the authors identify for the first time in this interesting study from the world of basic science that monocytes are a viable candidate for targeted therapy in myxomatous valve degeneration.

The second basic science original article in this issue is entitled "Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis" and the corresponding there is Pradeep Natarajan from the Mass. General is background clonal hematopoiesis of indeterminate potential or CHIP is a term that refers to clonal expansion of hematopoietic STEM cells due to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice CHIP accelerates atherosclerosis and increases IL-6 and IL-1 beta expression raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease risk.

So in this study, the authors observed some really exciting results. They analyzed over 34,000 samples from the UK Biobank and identified 1,079 individuals with CHIP, including 432 with large clones an LV fraction greater than 10%. During a 6.9-year median follow-up CHIP presence was associated with increased incidents, cardiovascular disease event risk with greater risk from large CHIP clones. IL6R attenuated cardiovascular event risk among participants with large CHIP clones but not in individuals without CHIP. This really exciting research results suggest that CHIP is associated with increased risk of incident cardiovascular disease. And among carriers of large CHIP clones, genetically reduced IL-6 signaling abdicated this risk. Really exciting results in an emerging area of science.

So what else is in the issue? Well, in our in depth review feature, Professor Stephan Rosencrantz from the University of Cologne Heart Center reviews the systemic consequences of pulmonary hypertension with right side heart failure. And then an On My Mind piece, our own associate editor, Dr Vlad Zaha coupled with doctors Walter Myers and Javid Moslehi from Vanderbilt discuss the impact of evolving immunotherapies for cancer and their impact on the cardiovascular system. In our mailbag, Dr Xiayan Shen from the Medical Classification Center of the Singapore Armed Forces discusses in a research letter the prevalence of Brugada Syndrome in a large Singaporean young male population. In letters to the editor, Dr Muddassir Mehmood from University of Tennessee Medical Center in one letter and Dr Goodarz Danaei from Boston in a response letter discuss the importance of diet relative to the development of HFpEF and how heart failure may be coded in by the World Health Organization when assessing global cardiovascular outcomes.

Bridget Kuhn in our cardiology news feature reports on preliminary results from the International Childhood Cardiovascular Cohort or i3C Consortium that was presented at the 2019 European Society of cardiology Congress. The i3C Consortium used data on 40,000 patients who participated in seven major longitudinal cohort studies that evaluated childhood cardiovascular risk factors from repeated measures during childhood and adolescence. And finally, our own Molly Klemarczyk at Circulation gathered and combined a very nice serial update that highlights important articles from our circulation family of journals, including electrophysiology, imaging, heart failure, and others.

Well, listeners, that's a summary of what's in the journal. But let's now proceed to our feature discussion to learn more about the rapidly emerging field of SGLT2 inhibition.

Well listeners, we are very excited for this feature discussion we have today, Dr Mikhail Kosiborod from Saint Luke's Mid America heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada. And we're going to be discussing the paper related to the effects of Dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction. They're going to be presenting results from the DAPA Heart Failure trial. Well Mikhail, I was wondering could you orient us a little bit to the DAPA heart failure trial. And then what was the hypothesis that you were trying to address in the current study?

Dr Mikhail Kosiborod: DAPA-HF was the first heart failure outcome trial trying to answer two critical questions about the effects of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction. We knew from prior trials, outcome trials in patients with diabetes SGLT2 agents can effectively prevent heart failure inpatients, overwhelming majority of which did not have heart failure and baseline. But what we didn't know was whether these agents can also be used as therapies for patients with established heart failure, and specifically heart failure with reduced ejection fraction. And they reduce death or worsening heart failure in the patient population. And the second question was whether that effect, if in fact this medications can significantly improve outcomes in patients with heart failure reduced ejection fraction. Can they do that even in patients who do not have type 2 diabetes? Because, in a diabetes trial it appears that that heart failure protective effect may be completely independent on the hemoglobin AONC.

And so DAPA-HF was specifically designed to test those two hypotheses. It enrolled about 4,800 patients with heart failure and reduced ejection fraction about 45% of which had types 2 diabetes. And there's a majority of us, 55% did not. And the main trial results that were published prior to risk analysis showed that in fact dapagliflozin significantly reduced the risk of the composite endpoint of cardiovascular death and worsening heart failure. It was a 26% relative risk reduction and the effects were identical in patients with or without type two diabetes. So both of those hypothesis were proven to be correct. It was effective therapies for established heart failure and reduced ejection fraction, and it was equally effective regardless of diabetes status. Now what we did in this study is really trying to understand the effects not just on cardiovascular deaths and hospitalization for heart failure, but on health status, which is symptoms, physical limitations, and quality of life.

He knows that heart failure is a debilitating disease, causes high burden of symptoms, and physical limitations, has adverse impact on quality of lives. We know that two key goals of managing heart failure are to; one, reduce deaths and hospitalizations for heart failure and two to reduce the burden of symptoms and physical limitations and improve the quality of life. So, that was really the focus of this specific analysis that we're talking about today.

Dr Greg Hundley: Excellent. So I understand you use the KCCQ-12, maybe help us understand what that test is and then tell us a little bit about your methods and your study population. Did you use the whole study population?

Dr Mikhail Kosiborod: KCCQ stands for Kansas City Cardiomyopathy Questionnaire and we actually in the study we use KCCQ-23 which is the full Kansas City Cardiomyopathy Questionnaire, consists of 23 items. And it a disease-specific tools for evaluating health status and heart failure.

So it essentially assesses four key domains, which are the symptom burden, physical implementations, quality of life, and social limitations. In this particular study is a primary endpoint as a primary part of the KCCQ as KCCQ total symptom score, which is a domain that focuses on symptoms. And the idea behind KCCQ is that you have a debilitating disease, which is heart failure. That disease has impact on the patient by causing symptoms, the symptoms then translate to physical limitations. And the combination of the symptom burden physical limitations has an impact on quality of life and social limitation. So that's why are this four different domains assessing these four components of the adverse effects of the heart failure compared to health status. And just very briefly, to mention that KCCQ has been proven to be responsive to clinical change. It's highly for data predictive of death and hospitalizations from heart failure. It has been extensively validated both of them hearts failure was reduced enters and the ejection fraction.

And so we essentially focused, or the primary focus of the paper was really to evaluate the effect of dapagliflozin versus placebo on a Kansas City Cardiomyopathy Questionnaire or KCCQ level symptom score. But we also looked at other domains as well. We looked at the clinical summary score, which includes both symptoms and physical limitations and we looked at the overall summary score, which includes all of the four domains that I mentioned before.

Dr Greg Hundley: What did you find?

Dr Mikhail Kosiborod: The patients treated with dapagliflozin had a greater improvement in health status as assessed by a KCCQ total symptom score or for that matter KCCQ clinical summary overall summary score as compared to patients treated with placebo. So if you look at the mean effect, there is some improvement in the patients taking placebo. That's what we call a placebo effect. And it's very commonly seen in clinical trials. We assessed health status, but there was a greater improvement with dapagliflozin as compared with the placebo, it was statistically significant even in four months. But as the effects were further amplified to eight months and this differences were, I would say favorable when you kind of compare the effect of Dapagliflozin versus other established heart failure therapies when you look at the effects on health status.

What I think was even more important than analysis from a clinician standpoint, and then they think it's actually much more meaningful clinically is what we call a responder analysis. And that's where we look as the proportion of patients that have a clinically meaningful improvement with one type of therapy versus other in this case Dapagliflozin versus placebo.

So it's been previously established that at five-point difference or a five-point change rising KCCQ is what's considered to be clinically meaningful or minimal clinically meaningful difference. So a 5.2 grade deterioration KCCQ means it's a clinically important deterioration. And a five-point or greater improvement is a clinically important improvement. And then we also looked at the proportion of patients with moderate and large improvements in health status as well defined as STEM point of grade of two, or two point a great improvement. And essentially what we found was that significantly fewer patients treated with dapagliflozin and as compared with placebo had a clinical importance deterioration. And significantly greater proportion of patients treated with dapagliflozin has small, moderate, large improvements in health status. And the numbers needed to treat to see those differences, as the small moderate large improvements was very favorable ranging typically between 12 and 18 and over eight-months-treatment period.

Dr Greg Hundley: Outstanding. So both clinically relevant as well as statistically significant findings. Now we're going to bring in Justin, our associate editor. Justin, help us put these results into the just our perspective in looking at SGLT2 inhibitors, particularly for treatment for heart failure.

Dr Justin Ezekowitz: This is an exciting class of medications and we're eagerly awaiting these results because we saw the DAPA-HF Overall results. The majority of us treat patients with a pretty symptomatic disease and as such this quality of life is quite an important change. There's ongoing trials we're eagerly awaiting which are also going to be using other medications in the same class, but I think one question that remained was, are these simply improving symptoms by one meaning, so the total symptom score? Or the overall quality of life? And I think you nicely, elegantly portrayed that in the figures and you have. The one other part maybe Mikhail, you could expand upon, which is when you think about DAPA-HF, and the quality of life gains and across all the three different ways of looking at quality of life, where do you see this in terms of its relationship to other things that we know improve quality of life? Where we send patients, for example, CRT or put them on an RNE. Where does this fit on top of those types of changes?

Dr Mikhail Kosiborod: Thanks Justin. I think it's a really important question because it says think critical from a clinical standpoint to put it in the context of other therapies that had been previously shown to improve health status, which means again, reduced symptoms, improve physical and patient quality of life. And there are a number of perhaps the types of therapies on heart failure and LVCF that have been evaluated particularly on side this one there also have been studies with exercise training in heart failure or and the ones that you brought up, which is cardiac resynchronization therapy in patients with heart failure reduced ejection fraction and left bundle branch block. And as that perhaps, if you kind of think about it. What are some of the most effective treatments to improve the health status? That is ones that we typically would consider as such, which is CRT in patients with half RAF and a left bundle branch block.

And in fact, if you look at the mean effects dapagliflozin compares very favorably even with highly effective therapies such as TRT. Relatively few studies have previously reported to this responder in analysis. But if you look at Digoxin comparing those to dapagliflozin, one of the recent ones that I can think of is [inaudible 00:20:23], again dapagliflozin compares very favorably when you look at this types of responder analysis where again you look at proportion of patients, it was a clinically meaningful change.

So I think the beautiful thing about putting the study in the context of further studies looking at health status and also in the original main results that were published from a DAPA-HF early this year is that it's really kind of a full house if you will. So as the agent reduced deaths, reduced hospitalizations and made patients feel better and all of that, with very favorable safety profile. So, if you kind of think about risk benefit analysis and you look at numbers need to treat both for clinical outcomes such as CVS and hospitalizations for heart failure for example, where health status, it looks really impactful from a clinical standpoint.

Dr Greg Hundley: So relevance to other therapeutic interventions for heart failure is what this whole class of agents seems to be showing? So briefly, what do you see is the next important study in the field?

Dr Mikhail Kosiborod: I will waffle on this question a little bit and say there was more than one, but my views are there kind of two key components to this. One is that there are additional trials going on and heart failure with reduced ejection fraction with other agents. And so seeing what happens with those other agents in the class in a similar patient population and whether is this a class effect or not? Now the diabetes trials would suggest that these may well be class effects but I think it's nice to have validation of that. I would say that is one real important questions that hopefully we will have additional answers to in the coming year or so.

And the second and perhaps I would argue even more important question is whether these agents can also be effective in improving outcomes in patients with heart failure and preserved ejection fraction. That's a patient population that has also very high debilitating burden of symptoms that has poor prognosis and for which unlike them, half rubs, there are very few, if any medications that have been proven to be disease-modifying and actually have shown outcomes and benefit. So I would say those in my mind, are the two critical developments that we'll be seeing. And the good news is, there are the trials going on with more than one agent in a class and half to half as well. Great.

Dr Greg Hundley: And Justin?

Dr Justin Ezekowitz: Yeah, I think that there's been an explosion of therapies and Mikhail is bang on with this is the one class where we're excited about. I think the other groups of medications include Omecamtiv Mecarbil we'll know in a year or two. We'll hear more details in the spring and then there's a few other medications that Mikhail mentioned. I think this is a real good message though, that both HFrEF and HFpEF, it's the rise of medications again. Because we were on a device track for a while, but I think the medications have such more potent effect on the underlying structure and function that it's great to see that there's been such a development and explosion of medications that may obviate the need for implanted devices or advanced therapies, so we're very excited about that.

Dr Greg Hundley: Outstanding. Well, listeners, we've had the opportunity to hear from Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada, and learn more about SGLT2 inhibition and its importance in improving clinically symptomatology both in those with diabetes and heart failure, but also those with heart failure alone.

On behalf of Carolyn and myself, we wish you a great week and we look forward to running and having a coffee chat next week. Take care of. This program is copyright the American Heart Association, 2020

Circulation January 7, 2020 Issue

30 december 2019 | 24 min

Dr Greg Hundley: Well listeners, this is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond this week, who is sadly missing his dear friend, Dr Carolyn Lam, who is away for just a week or two. I hope you've experienced a wonderful holiday season and are able to embrace the new year with joy and hope.

In our feature article this week, Dr Marcelo Di Carli and colleagues are going to discuss the role of coronary microvascular dysfunction assessed with cardiac stress during PET, as well as left ventricular remodeling assessed with echocardiography and how both of those relate to clinical outcomes in patients with chronic kidney impairment. But first, let's have a coffee and chat about other articles in this issue.

We have four original manuscripts, two or more clinical papers, and two from the world of basic science. So let's go to the clinical papers first. And the first emanates from our own associate editor, Dr Sana Al-Khatib from Duke University. Her paper comes from the ARISTOTLE trial, a randomized study of 18,201 participants that compared apixaban with warfarin in patients with atrial fibrillation at increased risk of stroke. And so this sub study included 17,423 patients in ARISTOTLE without severe renal or liver disease. And the authors evaluated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking either NSAIDs with therapixaban or warfarin. The authors found that those with NSAID use at baseline, so before starting into the study or incident NSAID use, that is they began an NSAID after initiating this study were more likely, both groups were more likely to have a history of bleeding, nearly a quarter of the patients to a fifth of the patients versus only 15% that had never used NSAIDs either before or after entering the study.

In addition, the safety and efficacy of apixaban versus warfarin appeared not to significantly be altered by NSAID use. That is whether you were taking apixaban or whether you're taking warfarin, the impact of NSAID use was not different between either of those anticoagulants.

The second original clinical article comes from Dr Audrey Blewer, also from Duke University, and evaluates the variation in bystander cardiopulmonary resuscitation delivery and subsequent survival from out of hospital cardiac arrest based on neighborhood level ethnic characteristics.

As background for this research, bystander cardiopulmonary resuscitation delivery and survival from out of hospital cardiac arrest varies at the neighborhood level, was generally lower survival seen in neighborhoods predominantly with individuals from black race. Despite Hispanics being the fastest growing minority population in the United States, few studies have assessed whether the proportion of Hispanics in a neighborhood is also associated with delivery of bystander CPR or subsequent survival for an out of hospital cardiac arrest. Accordingly, the authors in this study assessed whether bystander CPR rates and survival buried by neighborhood level ethnicity. And they hypothesized that neighborhoods with a higher proportion of Hispanics would have lower bystander CPR rates and overall lower survival.

This study was a retrospective cohort and use data from the Resuscitations Outcome Consortium, or ROC Epistry across the United States. So in this study, the authors identified 18,900 cardiac arrests. And they excluded pediatric arrests, EMS witnessed arrests, or arrest occurring in a healthcare or an institutional facility. And they found overall that bystander CPR was administered in 37% of these out-of-hospital arrests. Among neighborhoods with less than 25% Hispanic residents, bystander CPR was administered in 39% of the events, while it was administered in only 27% of the events in those neighborhoods with greater than 75% Hispanic residents. Also, lower rates of survival occurred in neighborhoods with greater than 75% Hispanic residents. And so the authors conclude that these findings suggest there's an important need to understand the underlying disparities in CPR delivery and an unmet CPR training need among Hispanic communities.

Well now let's shift to our two original articles that come from the world of basic science. And the first is from Dr Ying Shen from Baylor College of Medicine and reports on the critical role of cytosolic DNA and its sensing adapters sting in aortic degeneration, dissection and rupture. So as some background for this study, recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing it after sting, a stimulator of interferon genes, plays a critical role in vascular inflammation and destruction. And so in this paper, the authors examine the involvement of this mechanism in aortic degeneration and sporadic aortic aneurysm and dissections. Just like with our other basic science papers, the authors perform both studies in a small animal model, mice, and also in human subjects. So what did they find?

The authors found that in human sporadic aortic dissection tissues, they observe the presence of cytosolic DNA in smooth muscle cells and macrophages. And they had significant activation of this sting pathway. In a mouse model, sting deficient mice showed significant reduction in challenged induced aortic enlargement, dissection and rupture in both the thoracic and abdominal aortic regions. Additional single cell transcriptome analyses were performed and provided some mechanistic understanding for the author's findings.

So in summary, for this very interesting paper from the world of basic science, the author's findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing it after, or sting signaling, is a key mechanism in aortic degeneration. And therefore future studies, perhaps targeting sting, may be performed to see if they could prevent sporadic aortic aneurysm dissection development.

The second basic original article in this issue is entitled In Vivo CRISPR CAS9-mediated gene editing and how that ameliorates atherosclerosis in familial hypercholesterolemia. It comes to us from Dr Bin Zhou from the Chinese Academy of Sciences.

So as background for this study, mutations in the low-density lipoprotein receptor are one of the main causes of familial hypercholesterolemia. The clustered regularly interspace short palindromic repeats of CRISPR and caspase-9 system is an effective tool for gene editing to correct gene mutations and thus ameliorate the disease.

So these authors tested whether in vivo sematic cell gene editing through the CRISPR CAS based nine system delivered by adeno associated virus could treat familial hypercholesterolemia caused by the LDLr mutant in a mouse model. Well, the authors ... As Carolyn would ask, so what did they find, Greg? Well, the authors observed some really exciting results. They found that the LDLr mutation was corrected in a subset of hepatocytes after the CRISPR CAS based nine treatment with LDLr protein expression partially restored. Compared with control animals, the CRISPR CAS based nine targeted SGRNA group had significant reductions in total cholesterol, total triglyceride, and LDL cholesterol in the serum while the aorta had smaller atherosclerotic plaques and a lower degree of macrophage infiltration. So this study really implicates perhaps not only a mechanism of disease, but a potential treatment. But with the relatively small numbers in this study, more research is needed to confirm and substantiate the findings from this group.

So great original articles in this issue. What else is in the issue? And let's move to those. We have a global rounds feature. Remember, global rounds are investigating how cardiovascular disease is assessed and managed in countries from all over the world. Well, in this global rounds feature Professor Ali Oto from Memorial and Cairo Hospital provides a quick reference to the control and management of cardiovascular disease in Turkey. And the next article, an on my mind piece, Dr Milton Packer explorers whether the conditions of atrial fibrillation and heart failure with preserved ejection fraction are two separate diseases that occur frequently together in patients or alternatively, whether these two adverse clinical syndromes may be parallel manifestations of the same underlying myocardial disease with atrial fibrillation affecting the left atrium and heart failure preserved ejection fraction afflicting the left ventricle.

In our what's in the mailbag series, Professor Nicholas Mills from the University of Edinburgh shares in a research letter the relationship between exercise intensity and duration on cardiac troponin release in 10 physically active healthy volunteers averaging 34 years in age. A great read for our readership that is actively exercising. And it looks like in this letter, intensity of exercise matters when evaluating post-exercise serum troponin values. I really encourage everyone to take a look at that letter.

And then finally, there's a letter to the editors from Dr Abdallah Fayssoil from the Raymond Poincare Hospital in Garches, France regarding a prior publication related to nutrition and functional tricuspid regurgitation.

Well, listeners, that sums up our summary. And I hope you had a great coffee or if you're running on your treadmill, a great run. And let's now move on to our feature discussion with Dr Di Carli. Welcome everyone to our feature discussion and we have Dr Marcelo Di Carli from Brigham and Women's Hospital who's going to be discussing with us a manuscript relating to the measurements of coronary micro circulatory function and how they may impact patients with chronic kidney disease. Also discussing today, we have our own associate editor, Dr Victoria Delgado from Leiden in the Netherlands. Well, welcome Marcelo and Victoria. We're so glad to have the opportunity to speak with you. And Marcelo, could you tell us a little bit about what was the hypothesis and some of the background of why you wanted to perform this study?

Dr Marcelo Di Carli: Chronic kidney disease represents a relatively large segment of the population. In the US alone, it's estimated that around 50 million people have the diagnosis of chronic kidney disease. And it's a disease that we all know is associated with a high risk of cardiovascular events. Even in the absence of obstructive coronary disease, it's been shown that the incidents of cardiomyopathy and the absence of obstructive disease, of coronary disease, is pretty high and that associates with a high risk of heart failure and death.

The mechanisms related to cardiomyopathy in patients with chronic kidney disease have been debated for a long time. This has been associated with LVH incidents of non-transmittal or non-ST-elevation MIs, also with microvascular disease as a measure of ischemic heart disease, but there's no clear association with how do these features of chronic kidney disease link to each other. And so our objective was to look at the associations between LV remodeling, coronary microvascular disease and adverse events. And we hypothesized that coronary microvascular dysfunction as a more integrative marker of myocardial ischemia and injury would associate with changes in cardiac structure and function and with increased risk of adverse cardiovascular events.

Dr Greg Hundley: Very nice. So tell us a little bit, Marcelo, about your study population and your study design.

Dr Marcelo Di Carli: Well, this is a cross sectional analysis of a cohort that is well-characterized in our registries. And so it consisted of a consecutive group of patients who underwent both PET scanning for measuring coronary vascular function and echocardiography within 90 days of each other. Could it not have evidence of overt obstructive coronary disease as defined by a history of prior revascularization, prior AMI or an abnormal PET scan indicating presence of obstructive disease.

We also excluded patients with severe valvular disease, cancer, severe LV disfunction to try to avoid confounding elements in the associations where we're trying to study. We used echocardiography to assess quantitatively the changes in LV geometry, diastolic function and subclinical systolic dysfunction. Most of our patients have relatively preserved LV function, LV ejection fraction. And so we looked at peak longitudinal strain, global radial strain and circumferential strain as indicators of systolic dysfunction. And of course we also looked at changes in LV mass. Patients were followed a little over four years for the occurrence of death, hospitalization for heart failure or myocardial infarction. And all of these myocardial infarctions were non-ST-elevation MIs, or people might call it type two MIs.

Dr Greg Hundley: Tell us a little bit about the results. But before you get to that, how old were these patients and what was their breakdown in terms of race and gender?

Dr Marcelo Di Carli: Yeah, so we had a population of 352 patients. The mean age was mid-sixties. not surprisingly, 60% of the patients were female. And this is because we obviously excluded obstructive coronary disease that would be more prevalent in male. They have about a 40% incidence of diabetes, a high percentage of them had hypertension. These are all the features that would typically be associated with chronic kidney disease. The rate of obesity was actually lower in patients with CKD. And we call CKD here as a GFR less than 60. That's the population we're targeting here. And so that's essentially the cohort.

Dr Greg Hundley: And what did you find?

Dr Marcelo Di Carli: Well, there were essentially three or four main findings. Number one and not very surprisingly, patients with CKD had worse myocardial mechanics that is worse diastolic function and worse systolic strain. In multi-variable models, fully adjusted for a number of clinical covariates as well as ejection fraction, we found that these abnormalities in myocardial mechanics were relatively strongly associated with abnormal coronary microvascular function as defined by PET. So this sort of suggests that the variability that we see in diastolic and systolic function are explained largely by microvascular disease, but not necessarily directly linked to GFR as a mediator.

The second finding was that patients with CKD, again, not surprisingly, it showed a higher incidence of MACE, including especially death and heart failure, more than triple the rate of death and doubled the rate of heart failure compared to those without CKD. And in multi-variable analysis, again, MACE was associated with coronary flow reserve as a measure of microvascular dysfunction but not glomerular filtration rate. And there was no interaction between coronary flow reserve and GFR. Interestingly, when we looked at the adverse events subgroup by measures of LV remodeling and we picked three measures. One is changes in LV geometry, diastolic dysfunction, and impaired global longitudinal strain, we found that the incidence of both mace as well as heart failure and myocardial infarction were significantly higher when both abnormal LV mechanics or remodeling were present and the patients also had microvascular disease. So in the absence of either one, the rate of mace was relatively low, indicating that there is a clear interaction between abnormalities in cardiac structure and function and microvascular disease.

And then lastly, we looked at mediation analysis to try to investigate a plausible pathway between impaired renal function and events and we hypothesized that coronary microvascular dysfunction might actually mediate at least part of that relationship. And indeed we found that about a third of the relationship was explained by the presence of microvascular disease. Very nice,

Dr Greg Hundley: Very nice. Very important work. So now we'll turn to our own associate editor, Victoria Delgado. Victoria, help us put this into perspective for what we know about patients with chronic kidney disease. How does the results of this study really move the field forward?

Dr Victoria Delgado: I think that this article brings new evidence on phenotyping of these patients and the factors that influence the cardiac abnormalities that we may see. There are not many studies including patients with chronic kidney disease. These patients are usually underrepresented in randomized control trials. And we know that these patients are associated with an increased mortality and morbidity and mainly heart failure hospitalizations. And I think that this study is showing another piece in the person that can help us understand why these patients are associated with much higher cardiovascular morbidity and mortality. I think that relating the coronary microvascular dysfunction is an important piece and important knowledge because then we may think how to improve the microvascular dysfunction on these patients and see if by improving these microvascular dysfunction, these abnormalities that have been described in terms of a structure and function can be reversed and see how these impacts on the outcome of these patients.

Dr Greg Hundley: So Marcelo, just briefly, what do you think is the next study that needs to be performed in this area of science?

Dr Marcelo Di Carli: I think that obviously our study has some limitations and the causation. Cause and effect cannot be inferred from our study. So I think the next steps will be to try to demonstrate whether indeed modifying microvascular dysfunction leads to improved outcomes. And I think this will be best done by intervention studies that can be targeted towards improving microvascular dysfunction. We can think of novel therapies as well that have been initially associated with improved renal outcomes. I'm talking about for example, SGLT2 inhibitors that can be potentially of benefit not only on renal outcomes but potentially on cardiovascular outcomes as has been shown in populations largely without CKD.

Dr Greg Hundley: Victoria, anything to add in terms of how noninvasive imaging could play a role in some of those next future studies?

Dr Victoria Delgado: I think that the point that Marcelo raise on the use of SGLT2 inhibitors is very timely and very appealing because we know that for patients with diabetes who have renal dysfunction and you have EGFR below 35, they may not be eligible for these therapies. But as you can see in this study, the mean EGFR of the patients with renal dysfunction was 41. So there is a wide range of patients that could be eligible for these therapies. How imaging can help to see or to detect the patients that may benefit from these therapies and see how these therapies may improve the structure and the function of the heart.

Dr Greg Hundley: Well, listeners, we've had a great discussion today with Dr Marcelo Di Carli from Brigham and Women's Hospital and Dr Victoria Delgado from Leiden. And really trying to understand some noninvasive markers of both micro circulatory dysfunction as well as abnormal echocardiographic assessments of both diastolic function as well as systolic dysfunction and how they forecast adverse events in patients with chronic kidney disease.

I want to wish you all a great week and on behalf of Carolyn and myself, I hope to see you next week. Take care now.

This program is copyright the American Heart Association 2020.

Circulation on the Run and Discover CircRes Dual Podcast with Dr Joseph Hill, Dr. Jane Freedman, and Dr. Amit Khera

23 december 2019 | 10 min

Dr Amit Khera: I'm Amit Khera, I'm digital strategies editor for Circulation and I'm standing in this week for Carolyn Lam and Greg Hunley. And I'm also doing the Circulation on the Run podcast, as well as Discover CircRes podcast with our two editors in chief. This is Jane Freedman, who recently took over as editor-in-chief of Circulation Research, and Joseph Hill, who is the editor-in-chief of Circulation. So, welcome you both. We're excited to do this. Dr Joseph Hill: Thank you. Dr Jane Freedman: Thank you. Dr Amit Khera: The idea behind this, there's this session here at sessions where we're learning a little bit about Circulation Research and Circulation, pulling back the cover, if you will, and seeing behind the cloak, as what happens in the Journal. So, Dr Freedman, I'll start with you. Tell me a little bit about, as the incoming editor of Circulation Research, some of your vision for the Journal, which you're excited about. Dr Jane Freedman: Mm-hmm (affirmative). Well, I'm thrilled to be the new editor of Circulation Research. And I've assembled a fabulous team of associate editors, deputy editors and other staff and support, that are going to continue to grow what's already a wonderful journal, to be the preeminent and primary journal for basic and translational cardiovascular sciences. And also support and interact with the other HA family of Journals. Dr Amit Khera: So obviously that starts with a great team. And it sounds like you've assembled that. Anything new that you're thinking about, and sort of the redesign of Circ Research in your term? Dr Jane Freedman: Sure. So, we're hoping to expand the original scientific content, so we can have a larger number of articles in original science. And we can have the pages to be able to handle other areas of basic cardiovascular science to include new areas, emerging areas, things like that. We're also increasing some of our early career initiatives, so that's very important to us as well. Dr Amit Khera: Fantastic. Fantastic. Can you talk about expanding for science? And Joe, that leads to you. I'm going to, in this session tomorrow, one of the goals is when people submit their science, it really goes into a black box and people don't know what happens on the editorial level. Can you maybe enlighten us a little, what happened? Dr Joseph Hill: Jane and I have been friends for 20 or more years and we now have established a bi-directional, mutually synergistic collaboration where we send papers each way. We have distinct missions, but yet with significant overlap. And I think it's an incredibly exciting time for the entire portfolio of AHA Journals. So as you say, most people that you hit send and you wait four to six weeks, and you either get a happy note or an unhappy note. And, what happens at both our Journals is we have a strategy of multiple touches on every paper. The paper that first comes in, is first touched by a senior editor, either myself or James de Lemos, and two or three others. And we will reject without review, about 50% of the papers at that point. We publish six papers a week, but we get 110 a week. So we don't need to review 50 of them to pick the top six. Out of respect to our authors to save them time, out of respect to our reviewers who devote tremendous effort to reviewing papers, we don't send them papers that we don't think have a shot. That said, if a paper makes it past that first stage, there's about a 50% chance it'll get published either in our Journal, or in one of the subspecialty journals. Probably a 50-50 chance it'll be published somewhere in an AHA family Journal. So if it makes it past that stage, we send it to an associate editor, of which you are one. And we have about 50 of them. A third are in Dallas, another third are in the U.S. outside of Dallas, and another third are in countries around the world, 17 different countries. And that person will probably reject without review, another five or 10% maybe. But he or she will dig into that paper, and in parallel send it out to two or sometimes three reviewers, who are trusted and valued advisors. They help that associate editor make a strong recommendation. He or she makes a decision to bring to the larger group, that is informed by those reviewers. So already that paper has been touched by five different investigators. Typically, that associate editor will reach out electronically within his or her affinity group. We have an affinity group in epidemiology, heart failure, intervention, basic science. Asking other AEs, "Could you take a look at this paper? One reviewer said this, one said that, I'm sort of thinking this." And then we'll have a conversation on our weekly video conference, and then a decision goes out to the authors. So every paper is touched by at least five, and sometimes 10 different editors and reviewers, which we have found has been a powerful way to really dig into and identify things that one or two people might have missed. Dr Amit Khera: One thing I note here is, if you realize how many people touch these articles, yet how efficient and how fast this process is, then that's a testament to sort of, the goals of the Journal, to be really responsive and rapid for our authors. One big part of that, and come back to Dr Freedman is peer review, right? So, associate editors have a lot of work, and were affinity groups and so forth, but really critical are these peer reviewers. And in the modern era, we're all so busy. Tell us a little bit about the value of peer review, and how we enhance the value to the peer reviewers themselves. Dr Jane Freedman: Mm-hmm (affirmative). Well, just as you said, the peer reviewers are absolutely central, valued and vital parts of making the Journal run correctly. And we, like Circulation, our associate editors send them out to three different peer reviewers, and they have a very fixed amount of time to review the articles, and they provide these wonderful comments. We also very heavily rely on our editorial board. They know the drill, that it needs to be back within a fixed amount of time. And for the most part, they do it. It's an interesting question, "What's the value to them?" I've been a reviewer too. It's part of your pay back. It's part of educating yourself about what's new and interesting. There's a lot of reasons for doing it. People enjoy being on the editorial board and interacting with the Journal. But fundamentally, as an editor, you're incredibly grateful to your reviewers. They are the unsung heroes of making a Journal work. Dr Amit Khera: You mentioned sending out to three, when you have sort of disparate reviews. It's amazing when some people love it and some people hate it. Dr Jane Freedman: Yeah. Dr Amit Khera: How do you handle that? Dr Jane Freedman: Yeah, well, sometimes it's apparent from the reviews why that happened. Someone may have focused on something, that the editorial group thinks is less important. Or they have focused on something that's addressable. The other thing we do, similar to Joe, is we have a video conference call every single week on Wednesdays, and that's a period where people can vet any concerns or questions. And then my editors, my associate and deputy editors know we have an open communication at all times. So I very frequently, when they have questions about reviews and how to reconcile disparate reviews, we'll have an ongoing conversation about that. Dr Amit Khera: It sounds like, of course you're actively engaged in how this is a dynamic process. I'll mention one thing, is digital strategies editor and I know both at Circ Research and Circulation. We're always thinking, "How do we bring these articles to life? How do we have the most people read them or engage with them?" And one is traditional social media. So Twitter and Facebook, which is incredibly important. Podcast, you have a monthly podcast. Dr Jane Freedman: Mm-hmm (affirmative). Dr Amit Khera: We have a weekly podcast and really hope that people listen to them because they're really full of important information. And finally, I think what people don't appreciate is the media. So we work with the AHA media. Some of our top stories get over a million media impressions, go all around the world and there's Professional Heart Daily. So, there's so many ways that we're bringing articles to life. Joe, I'm going to finish with you. This is a Circ family. The value of having a family of Journals and how we keep cohesion, and for authors when they're submitting to sort of a family of Journals, what's the value and how does that add? Dr Joseph Hill: Well, there has been complete turnover of all the editors in chief in the entire family of Journals, of which there are 12. And we are all quite similar in our personalities, and in our perspectives on the importance, the ultimate importance of validity. The first question we ask, "Is this true?" If it's not, it's gone. It doesn't get referred. We reject it. Even if it's going to be on the front page of the New York Times and cited 10,000 times. And all of us hold ourselves to that same standard. So our vectors are all pointed in the same direction. We also care about impact, not impact factor. But does it change the way you think? Does it matter? Is it incremental, or does it really move the needle? So we are now in a situation, I think a wonderful situation where we all sink or swim together. We send papers all around, as you know very well. We send papers to the subspecialty journals. We send 20 or 30 a week, on an extraordinarily regular basis. And we send papers horizontally to Circ Research, or Hypertension, or Stroke and so forth. So, it is a syncytium now I would say, of a family of journals where we are all looking out for each other. Jane cares about our Journal and we care about her Journal. And that's really a wonderful situation to be in. Dr Amit Khera: Well thanks. That family and how this fluidity of articles and thought and exchanges, is really part of the value. And ultimately the goal is for a great paper to find a great home. And I think in this Circ family we do that. Thank you very much. It's been a wonderful podcast. Again, I'm Amit Khera, digital strategies editor sitting in for Carolyn Lam and Greg Hundley for Circulation on the Run, as well as for Discover CircRes. Thank you. Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation December 17, 2019 Issue

16 december 2019 | 20 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart center and Duke National University of Singapore.

Dr Greg Hundley: And I'm associate editor, Dr Greg Hundley, from VCU Health, the Pauley Heart Center, in Richmond, Virginia.

Well Carolyn, our feature discussion, are results from the Odyssey study and they're presented by Professor Wouter Jukema from Leiden University Medical Center, regarding the relationship between ultra-low LDL levels in both ischemic and hemorrhagic stroke. The study really seeks to answer the question related to concerns that ultra-low LDL levels, less than 15 milligrams per deciliter, in patients treated for ischemic heart disease could increase the risk of hemorrhagic stroke, but more to come on that intriguing question. Carolyn, how about your first paper?

Dr Carolyn Lam: It's from doctors Condorelli and Kallikourdis from Humanitas Clinical and Research Center and Institute of Genetic and Biomedical Research respectively in Rozzano Milan in Italy. Now, these authors used single cell RNA sequencing to map the cardiac immune composition in the standard Murine non ischemic pressure overload heart failure model. They then integrated their findings using multi parameter flow cytometry, immunohistochemistry and tissue clarification immunofluorescence in both the mouse and the human. And they found that despite the absence of infectious agents or an autoimmune trigger, induction of disease led to immune activation that involved far more cell types than previously thought. And that included neutrophils, B cells, natural killer cells, and mast cells. And this really opens up the field of cardio immunology to further investigation using toolkits that have already been developed to study these immune subsets.

Dr Greg Hundley: Ah, so Carolyn, do they have any specific examples?

Dr Carolyn Lam: Hmm, indeed they did. They found that activation lead to up regulation of key subset specific molecules such as pro inflammatory cytokine onco statin M in pro-inflammatory macrophages, and PD1 in T regulatory cells. Now these are significant because they may help to explain clinical findings such as the refractivity of heart failure patients to anti TNF therapy and cardio toxicity during anti PD1 cancer immunotherapy respectively, for the more these subset specific molecules may become useful targets for the diagnosis or therapy of heart failure.

Dr Greg Hundley: Oh, beautiful. Well Carolyn, my next article is from Ambarish Pandey from University of Texas Southwestern Medical Center and it's entitled Incorporation of Biomarkers into Risk Assessment for Allocation of any Hypertensive Medication, According to the 2017 ACC, AHA High Blood Pressure Guidelines, a Pooled Cohort Analysis.

Dr Carolyn Lam: So I suppose asking does consideration of troponin or BNP inform cardiovascular risk in those with hypertension?

Dr Greg Hundley: Great question Carolyn. So in this study, the authors included participant level data from 12,987 participants across three cohort studies, ERIC, the Dallas Heart Study and MESA. And they were pooled excluding individuals with prevalent cardiovascular disease and those taking antihypertension medications at baseline. Participants were analyzed according to blood pressure treatment group from the 2017 ACC AHA Blood Pressure Guideline and those with high blood pressure, 120 to 159 millimeters of mercury, were further stratified by biomarker status.

Dr Carolyn Lam: Okay. So what did they find Greg?

Dr Greg Hundley: Participants with elevated blood pressure or hypertension, not recommended for any hypertensive medication with versus without either elevated high sensitivity, cardiac troponin T or N terminal pro BNP, had a 10-year cardiovascular incidence rate of 11% and 4.6%, with a 10-year number needed to treat to prevent one event for intensive blood pressure lowering of 36 and 85 individuals respectively.

In addition, among participants with stage one or stage two hypertension recommended for antihypertensive medication with a blood pressure less than 160 over a hundred millimeters of mercury, those with versus without an elevated biomarker had a 10-year cardiovascular incidence rate of 15.1% and 7.9% with a 10-year number needed to treat, to prevent one event of 26 individuals and 49 individuals respectively.

Dr Carolyn Lam: Wow, Greg, those are impressive numbers. So does this mean we should be checking biomarkers in everyone?

Dr Greg Hundley: Great question again Carolyn. These results suggest that a biomarker based approach to cardiovascular risk assessment may help identify high risk individuals with elevated blood pressure or stage one hypertension who are currently not recommended for any hypertensive medication, according to the 2017 ACC AHA Blood Pressure Guideline, but who may benefit from blood pressure lowering therapy. And it seems the more we research blood pressure measures, the more we learn regarding individualizing targets for blood pressure lowering.

Dr Carolyn Lam: Very interesting Greg. Thanks. So my next paper sought to understand to what extent do drug costs, which are potentially actionable factors, contribute to medication non-adherence? A very interesting and relevant question, and this is from Dr Nasir from Yale New Haven Health System and colleagues who identified more than 14,000 US adults with a reported history of atherosclerotic cardiovascular disease in the national health interview survey from 2013 to 2017. Now participants were considered to have experienced cost related non-adherence if in the preceding 12 months they reported either skipping doses to save money or taking less medication to save money or delaying filling a prescription to save money. And they used survey analysis to obtain national estimates.

Dr Greg Hundley: Okay, Carolyn. So what did they find?

Dr Carolyn Lam: Listen to this. So they found that one in eight patients with atherosclerotic cardiovascular disease reported non-adherence with medications due to cost, representing nearly 1.5 million estimated patients missing doses, 1.6 million taking lower than prescribed doses and 1.9 million intentionally delaying a medication fill to save costs, all in the United States. Patients less than 65 years of age, had a three fold higher rate of medication noncompliance due to cost, with significantly higher rates in women and among patients from low income families and those without health insurance. Now the take home message I think is that the removal of financial barriers to accessing medications, particularly among vulnerable patient groups, may help improve adherence to essential therapies to reduce atherosclerotic cardiovascular disease, morbidity and mortality.

Dr Greg Hundley: Great paper, Carolyn. We've got a couple other articles in this issue. Let's just run through so our listeners get a synopsis. So Dr Javed Butler from University of Mississippi Medical Center has a nice white paper regarding heart failure endpoints in cardiovascular outcome trials of SGLT2 inhibitors in patients with type two diabetes. Dr Brahmajee Nallamothu in a perspective piece, discusses issues related to the legal prosecution of stent cases and the 70/30 rule. Remember Carolyn, the 70/30 rule, the operator may say a stenosis is 70% of an intracoronary luminal narrowing, but in review, others seem to think it's less than 30% and often these cases are prosecuted for performing coronary artery interventions on these lesions, but what Dr Nallamothu argues is perhaps, these definitions are really related to how that stenosis was measured. Are you taking approximately dilated segment or a distantly dilating segment as your reference point? Really interesting perspective piece.

The next article is from Dr Prateeti Khazanie at the University of Colorado in Denver and provides an on my mind piece with Dr Mark Drazner regarding ethical issues that arise during cardiac transplant allocation process. They review some of the pitfalls associated with current physician subjective assessments used for heart transplants in the United States. Dr Neil Kay presents another EKG challenge related to T, a new wave alternans and consumption of alcohol in association with combinations of antiarrhythmic drugs. Dr Dipan Shah from Houston Methodist provides new data in a letter, a research letter, regarding the association of extracellular volume fraction and MRI measure of interstitial fibrosis in the setting of chronic mitral regurgitation.

And finally, Carolyn, Dr Nirvik Pal and colleagues write a letter referring to an earlier publication related to LVAD adverse outcomes and cardiac transplantation. Well, shall we move on to that feature discussion?

Dr Carolyn Lam: Yeah, let's do that, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and we're very excited today to have Dr Wouter Jukema from Leiden University Medical Center who's going to tell us about the utility of PCSK9 inhibitors on the impact of both ischemic and hemorrhagic stroke. A large study that comes from the Odyssey study. Welter, we are so glad that you're with us this morning, afternoon, evening, wherever you may be in the world. Could you tell us, what were the thoughts behind putting this study together?

Dr Wouter Jukema: As we all know that patients with acute coronary syndromes, ACS, are at an increased risk for a subsequent stroke. And we also do know that lowering of atherogenic lipoproteins, including LDL cholesterol of course, reduces the risk of ischemic stroke in chronic atherosclerotic cardiovascular disease or recent ACS.

However, concerns have been raised about very low LDL cholesterol levels and the potential risk and increased risk of hemorrhagic stroke.

So the effect of lipid lowering by PCSK9 inhibition, both ischemic and hemorrhagic stroke is actually not fully determined. So what we therefore did to better investigate this is that in the obviously outcomes trial, the main publication was of course in New England Journal of Medicine already, we did a pre-specified analysis. We was designed to assess the effect of LRO come up on the ischemic as well as on the hemorrhagic stroke in patients with a recent ACS in obviously outcomes, all patients had a recent ACS and we have hypothesized that for patients treated with LRO come up that would be one, A, a reduction in risk of ischemic stroke, B, without an increase in hemorrhagic stroke. And we also hypothesize that the results would be irrespective of baseline LDL cholesterol and the history of cerebral vascular disease.

So that was our background and objectives and we investigated this in urology outcomes trial a huge, huge trial. If you may all recall post ACS patients one to 12 months post ACS, they all had a run in period two to 16 weeks of high intensity or maximum tolerated dose of atorvastatin or rosuvastatin, and then you had to meet certain lipids criteria and then you were randomized to LRO come up circuitously every two weeks or placebo. And of course all the patients and investigators were blinded to lipid levels and treatment location. So this was a design.

Dr Greg Hundley: Wouter that was a fantastic description of why we're studying this particular series of issues as both ischemic and hemorrhagic strokes.

Tell us a little bit about your study results?

Dr Wouter Jukema: We looked at the entire population of the Odyssey outcomes trial. This is almost 19000 patients and then we looked if they had a history of prior cerebral vascular disease or we have no history of cerebral vascular disease. The majority, almost 18000 did not have a history of cerebral vascular disease and over 900 did have a history of cerebral vascular disease. And we've also looked at our baseline LDL cholesterol levels. Well, if you can of course, be sure we appreciate people with history of cerebral vascular disease or way out, there are a different study population. So that's of course what you may expect anyway. And that's what we saw.

But regardless if you have the history of a vascular disease or you didn't have that, we saw a reduction of any stroke and actually it was 28% reduction of any stroke, which is quite impressive, in my opinion, as highly significant with a P value of point 0.05 and then afterwards of course, we tried to split it in ischemic stroke and hemorrhagic strokes.

So as I told you, any stroke was reduced with 28% and if you then look at ischemic stroke, it was 27%. Also significant at the P value of 0.01. And then of course, the big question, what would happen with hemorrhagic stroke. And actually this was numerically less also in the LRO come up group. So there was not only a reduction in any stroke, but also in ischemic stroke. But also in hemorrhagic stroke, but this was 17% and then of course you are in the low numbers. So the ischemic ratio for hemorrhagic stroke was 0.83 in favor of LRO come up. And of course that by itself is not significant to the low numbers, but numerically there were less hemorrhagic strokes on top of that, there were less ischemic strokes and that was, I think a very reassuring finding. And the interesting part is that these results were more or less independent.

If you have a history of cerebral vascular disease are not, so people without a price were benefiting and with a price were benefiting. And it was also statistically independent of your baseline LDL cholesterol level. So the results were basically the same. If you had a baseline LDL starting below 80 between 80 and 100 and over 100 the results were the same. LRO come up was always better than placebo. If you look at the data, you could see that it was perhaps doing slightly even better if you had a slightly higher cholesterol from the start, which is conceivable. But the formal test returned 80 did not say show any difference. So you could say the beneficial effect of other LRO come up on stroke in post ACA patients is independent of your history of cerebral vascular disease, is independent of your baseline LDL. LRO come up is just better for ischemic strokes as well as for hemorrhagic strokes at least there was no sign.

Never mind add to that, we did even go one step further and we looked at the risk of hemorrhagic stroke in relation to the HG LDL cholesterol level. So not your baseline LDL cholesterol level, but the achieved LDL cholesterol level in the LRO come up group because there you find the, of course very low numbers and we divided them and below 25 milligrams per deciliter, which we could continue really low between 25 to 15, 15 to 17 over 17 and the numbers of hemorrhagic strokes were exactly the same, always 0.1, 0.2, 0.3%. So very low. And it was certainly not the case that they do very low numbers. We saw more hemorrhagic strokes. So this is again very reassuring data. So even at very low levels of LDL during the trial. Of course we should realize that this trial is of course only a medium duration of two per date, but we didn't see more erratic strokes.

So in my opinion, this is very reassuring data.

Dr Greg Hundley: Very good. I loved all that analysis of subgroups. I want to ask you one quick subgroup question. Was there any difference in outcomes related to gender or age?

Dr Wouter Jukema: As far as we could see there was no differential effect in gender nor in age. Of course you should realize that in very advanced age, of course the numbers get small and if you then start dividing them again in the history of stroke or not, then of course the numbers will get low. But in general there is no age or gender difference.

Dr Greg Hundley: Fantastic. So where do you think, does this field progress from here and what do you think will be the next study that we need related to PCSK9 inhibitors and adverse effects?

Dr Wouter Jukema: I think we have shown now that patients with a recent ACS and dyslipidemia, despite incentive therapy, they do benefit from the PCSK9 LRO Come up, which is reflected by a decrease in the risk of stroke. You should of course realize that this is a post ACS population, so it was not targeted in a post stroke population. This is a atherosclerotic disease population, so the results are applying for an atherosclerotic population of course, many people that have a stroke in the past may have and also from embolic processes from a FIP or whatsoever, and those results may be the same but may of course they may also be different. So that situation was not tested here. This is a atherosclerotic post ACS population. Of course you may be interested in what would happen with strokes in an embolic population with a FIP and that would of course be a very nice trial to do as well. But then you have to do an entirely new trial. And some of these trials are of course underway, but I cannot, with my publication circulation, I cannot provide you with the answer.

Dr Greg Hundley: Well listeners, we've had a great discussion on our feature article today from Dr Wouter Jukema from Leiden university medical center and really some important insights related to PCSK9 inhibitors and the fact in this study, a large study, a sub study from Odyssey that indicates really no increase incidents of both hemorrhagic or ischemic stroke in patients that receive these agents and had previously sustained acute coronary syndromes.

I want to wish you all a great week and on the half of Carolyn and myself. Hope to see you next week. Take care now.

This program is copyright American heart association 2019.

Circulation December 10, 2019 Issue

9 december 2019 | 22 min

Dr Greg Hundley: And this is Dr Greg Hundley from VCU health, the Poly Heart Center in Richmond, Virginia. Well, Carolyn, this week's feature analyzed a pool cohort of all patients in partner one and partner two, both the trials and registries. Patients had severe aortic stenosis and were treated with TAVR or SAVR and then were analyzed with respect to the development of prosthetic valve endocarditis. But more to come on that later.

Dr Carolyn Lam: Let me start by telling you about my picks from this week's journal. So the first one is a really interesting natural experiment. First, do you think that a short term visit to a location with severe air pollution increases the risk of cardiovascular disease?

Dr Greg Hundley: Well, Carolyn, I would say yes.

Dr Carolyn Lam: Greg, you're too smart. But let me tell you what these investigators did. So their co-corresponding authors, Dr Araujo from David Geffen School of Medicine and UCLA, Dr Zhu from UCLA Fielding School of Public Health, and Dr Qiu from College of Environmental Sciences and Engineering in Peking University. These co-corresponding authors and their colleagues did a natural experiment by collecting urine and blood samples from 26 healthy adult residents of Los Angeles before, during, and after they spent 10 weeks in Beijing during the summer of 2014 and 2015.

Dr Greg Hundley: I am really excited to hear this. Carolyn, what did they find?

Dr Carolyn Lam: So traveling from less polluted Los Angeles to more polluted Beijing induced pro oxidative and pro inflammatory effects, which reversed after returning to Los Angeles. This is also the first human study associating exposures to polycyclic aromatic hydrocarbons with changes in paraoxonase 1, enzymatic activity, and circulating levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids. Cool, huh?

Dr Greg Hundley: Absolutely. Carolyn, you did an awesome job. Very nice. Well, my article comes from the world of basic science and it's from Dr Philip Shaul at the University of Texas Southwestern medical Center. So Carolyn, in recent studies of obesity induced insulin resistance in mice with corroborating findings in human type 2 diabetics, this group, Shaul’s group, previously made the surprising discovery that the insulin resistance is driven by an altered post-translational modification in IgG that leads to enhanced activation of FCYR2B in endothelial cells. And as a result, there is an attenuation of insulin transcytosis across endothelial cells and delivery to skeletal muscle myocytes where up to 80% of glucose disposal usually occurs.

Dr Carolyn Lam: Oh. Interesting, Greg. So what did the authors find in the study and how did these findings equate with obesity and hypertension?

Dr Greg Hundley: Well, they found that hyposialyation of the Fc glycan on IgG is identified as a key contributing factor in obesity induced hypertension. And therefore low levels of IgG Fc glycan sialylation may identify individuals at greater risk of developing hypertension. In addition, the degree of sialylation of IgG may predict the relative response of an individual to any hypertensive therapy.

Dr Carolyn Lam: Nice. So my next paper is from Dr Al-Lamee from Imperial College, London, and colleagues who studied the ability of a pre-randomization stress echocardiographic score to predict the placebo-controlled efficacy of PCI within the ORBITA trial. Now as a reminder, the primary results of the ORBITA trial showed us smaller than expected effect size of PCI in comparison with placebo in single vessel stable coronary artery disease on the primary end point of change in treadmill exercise time.

Now in the current study, 183 patients underwent dobutamine stress echo cardiography before randomization, and they found that the degree of ischemia assessed by dobutamine stress echo cardiography predicted the placebo-controlled efficacy of PCI on patient reported angina frequency.

Dr Greg Hundley: Hmm. Very interesting. So help me out again, Carolyn. What's the clinical importance of this?

Dr Carolyn Lam: Ah, so this study really provides the first placebo-controlled evidence of an association between stress echo cardiography, ischemia, and the magnitude of placebo-controlled benefit attributable to PCI. And the greater the downstream stress echo cardiography abnormality caused by the stenosis, the greater the reduction in symptoms from PCI. That's the take home.

Dr Greg Hundley: Oh wow. Very interesting. You know, especially we perform so many stress echo cardiograms. What a great relationship to unfold and present. Well, Carolyn, I'm going to walk through several other important publications in this issue of the journal. The first is from Dr Peter Eckman from the Minneapolis Heart Institute, and he provides an In-Depth review of veno-arterial extra corporal membrane oxygenation, or VA-ECMO, for cardiogenic shock and it's beautifully written for the busy clinician. Robert Platt, PhD, and colleagues discuss in an On My Mind piece the fact that those with adverse cardiovascular sequelae during pregnancy may require development of new cardiovascular risk prediction models. The hypertension or the diabetes that occurs during pregnancy, perhaps we need to incorporate that into our prediction models.

Next. Our own associate editor Torbjørn Omland provides results in a research letter from the peace trial relating the relationship between smoking and high sensitivity troponin T levels. Dr Allen Sniderman from McGill University Health Center writes a letter to Welsh and Associates regarding their study of the UK bio bank database and measures of HDLC. A paper we discussed just a few weeks ago. Dr Derek Chew from the DCRI and Durham North Carolina has another EKG challenge for us. And Dr Tracy Hampton provides an updated news report regarding cardiovascular disease from several recently published articles in the world of basic science. And then finally Dr Thomas Krieg from the University of Cambridge has a nice piece regarding clinical implications of targeting succinate metabolism in ischemia reperfusion injury.

Well, Carolyn, what a great slate, but I can't wait to get to that feature discussion related to prosthetic valve endocarditis.

Dr Carolyn Lam: Me too. Let's go.

Our feature discussion today is really the first paper that describes adjudicated evaluation of prosthetic valve endocarditis in patients with transcatheter and surgical aortic valve replacement. Very unique and valuable data from the partner's trial. I'm so pleased to have with us the corresponding author, Dr Wael Jaber from Cleveland Clinic as well as our associate editor, Dr Manos Brilakis from UT Southwestern. So Wael, very unique question. Could you please tell us how you went about doing this? And I suppose in this setting, the first question on everyone's mind is how did you make this diagnosis of prosthetic valve endocarditis?

Dr Wael Jaber: Actually we saw this as an opportunity that probably we should never miss. I think this is one of the rarer instances where we can objectively not only look at SAVR data but also TAVR data. And over the past maybe seven years, eight years, we started getting here as a referral center patients with TAVR endocarditis for surgery. And we never thought we'd start seeing these weird organisms, different bugs. Of course this is a population that's frail or elderly, but we never had any idea if they behave similarly to SAVR or differently than SAVR in our previous experience with SAVR endocarditis.

So we planned this actually about maybe five years ago, but we didn't have the data because you know the partner trials were undergoing another evolution by going to lower and lower risk population. So we pose this question about a year and a half ago to CRS by asking them, can you provide us with the data on all the endocarditis in partner.

The idea was not only to answer one question but to answer multiple questions. So the first question was in the modern era, what happens in SAVR? All the SAVR endocarditis information we have so far as you will know has been from mainly single center studies or even when we learn about it from multiple centers sites, usually IN European studies, the Swedish registry, the Danish registry, and these are usually limited by the fact that there are a multicenter. The adjudication is at the site what endocarditis happened. So that was the first question. Then the second issue for us was, does TAVR, because of the unusual access to the heart and the fact that we dilate the valve, post dilate the valve, their paravalvular AI, they could be micro-fractures of the refis. This is provide a different opportunity for these bugs to form on the valve, and do they behave differently?

And the third question was, is there any difference between SAVR and TAVR incidence of endocarditis? And bugs. And the final question was what happens to patients when they develop endocarditis in the current decade. Do they do well? Especially for septic endocarditis or do they succumb to their illness? And also this is how we came up with a strategy to answer all these questions.

Dr Carolyn Lam: Very nice. So Wael, could you just expand a little bit more about how the diagnosis or adjudication of prosthetic valve endocarditis was done? And then tell us please, what did you find?

Dr Wael Jaber: All the partner patients, the records were sent to a central place. So the ECHOS first were educated at central places. We were one of those centers. Other places were Columbia University, MedStar and Quebec, the group in Quebec. So all the ECHOS were adjudicated centrally. So that's first, as far as from the echo side of calling it endocarditis or not.

On the clinical side, again, all the records and the forms were sent to a central adjudication committee, CDC group. We served at the Cleveland Clinic as the CDC for most of these trials and actually even for the current trials. So they were sent and they were adjudicated according to the Duke criteria. Which is, you know, the most, probably, reliable way still today to adjudicate these.

And then there was the CDC and the echo core labs were separate. So the people who have information from the CDC did not have access to what's going on in the core lab and vice versa. So these were independently adjudicated as far as echocardiographic evidence and clinical evidence. And then they were fed into it. So by the end, when you hold it on a Duke criteria endocarditis, the echo was fed after the fact, not before. So this is in general how it happened. So all the events were educated centrally, not at the site. And the ECHOS, the same thing, were adjudicated centrally.

Dr Carolyn Lam: Fantastic. And I would love to hear the results.

Dr Wael Jaber: The first question was, what's the incidence of endocarditis? And we decided because of the way these trials were done, to report the incidents as you would see in the results section, to report the incidents of endocarditis per 1000 person year because of the imbalances in follow up and the competing risk for death from other reasons. So we found in general that the incidents of endocarditis was 5.2 endocarditis events per 1000 patients per year in the TAVR side and 4.1 in the SAVR side with a non statistically significant difference. More importantly, we found out that once you develop endocarditis, unfortunately most of these patients succumb to the illness and are dead after the diagnosis. So the risk of dying after developing endocarditis is 4.4 times higher than patients who did not have endocarditis in the trials. In all the trials.

Now there's some caveats here. First, these are trials with different patient populations, as you well know. Starting with partner with the inoperable patients moving on to the most modern S3 trial, which was on the lowest kind of side of population. So we have totally different population groups. Some of them had prolonged hospitalizations before and after, so this should be taken with a little bit of caution.

However, if you look at some of the individual trial data, we found that incidents of endocarditis at least have a trend towards a reduction of incidence of endocarditis over time going from partner, the initial experience with partner, all the way to the modern era.

Dr Carolyn Lam: That is so great. Manos, you know, as an interventional cardiologist yourself, could you tell us how important these results are? Does it affect your practice?

Dr Emmanouil Brilakis: Thanks again, Carolyn. I would like to congratulate Wael for a phenomenal paper. I think it's a very timely study and addresses one of the common concerns there is about whether TAVR does predispose people to more risk for endocarditis. Although again, the opposite grade was kind of low at 0.5% a year. I think this may be a little more than people are commonly seeing in the setting of TAVR, and I think the paper is a good reminder that this is something we should always be mindful and watching. Although typically we'll discuss with the patient about the risk of stroke or access complications, but the risk of infection may not be as well emphasized. And based on this one question I would have is about what can we do if there is something that could potentially lower that risk? I understand the limitations of retrospective study, but are there any recommendations that you have based on the study? Should give more aggressive antimicrobial therapy? Any other biotic prophylaxis or anything else that can be done to reduce the risk of endocarditis in those patients?

Dr Wael Jaber: Actually this is the question we raised. Unfortunately we did not. So the guidelines did not catch up with what we know. So if you look right now, like I was reviewing this paper that came up last month from the Swedish Registry for Endocarditis, it came out in Europe in the European Heart Journal, and one of the questions they raised is how to address, in the editorial, how to address the risk of endocarditis and prophylaxis in this population. There are no standards for that. This is one aspect of it. We need first an update of the guidelines of how to address this issue.

The second question is we do not have any idea, unfortunately, about duration of antibiotics. How the antibiotics prophylaxis were given before the procedure, like as we do right now commonly in surgery, and after the procedure in these patients. We do not know that. Like right now, at least at our center, if you go in for aortic or mitral valve surgery or any valve surgery, you have to have a dental clearance before you start, before you go to surgery. I don't know if this was rigorously applied in the setting of TAVR, and I think it would be a good idea to apply it to make sure that there are no dental, phosphide or potential infections and things like that. So I think it's a multi-front battle to get these patients to the lowest risk possible. I don't think there's one single silver bullet here.

Dr Emmanouil Brilakis: So thanks again, Wael for addressing this. I agree that there's a lot of information to be gained understanding the intricacies of endocarditis prophylaxis. And building on this, let's say another patient develops endocarditis as you've shown in your 170 patients in the study. It was fascinating that staph aureus was actually less common than it was for surgical valves, which has been shown in other studies as well. So you think this affects the choice of the biotic prophylaxis? And then also if the patient develops endocarditis, I understand many people who are not candidates for surgery, but from the ones who did actually undergo surgery, what are the outcomes encouraging?

Dr Wael Jaber: This is a fascinating question actually. This is one of the reasons we had... There was a delay for us in getting the paper out from when we presented it as an abstract at TCT a year and a half ago, is we didn't know. We wanted to answer that question. The second part of the question is how many patients went to surgery? And unfortunately, very few patients. So less than a handful of patients end up going to surgery. And we do not know why. So this is the dilemma here. Is why the rate of referral to surgery for redo surgery was very low.

Was it because these patients were the sickest of the sick? Maybe it is because we waited too long and we did not treat them the same way. We should have treated prosthetic valve endocarditis, which is surgery to be offered as soon as possible because there's no really antibiotic cure for that. So we do not have the answer for that because these very few patients went to surgery and actually I think of those who went to surgery, even the mortality there even was similar to people who did not go to surgery. But we cannot speculate on that because the very few patients.

As far as the bug involved, I think this could be a reflection of the antibiotics given at the time of the procedure, so probably we're covering that very well. But if you notice from the paper, most of the infections happen more than 30 days after the procedure. Whether this is something that was acquired because these patients are more likely to end up in the hospital again for other reasons, whether these patients had endocarditis because they have more instrumentation down the road... Remember this is a population in general above the age of 65 which would require colonoscopies, frequent urinary tract issues, and other procedures.

So we know that we're covering very well, at least I can speculate, we're covering very well for the first 30 days because very few patients had endocarditis right after the procedure, but we're not covering probably after the 30 days. And that remains to be studied. And the worrisome thing is to try to treat these patients with prophylactic antibiotics for a long time and then end up with bug resistance and things like that. Now the CDC issued a big warning about this yesterday. I am not comfortable to speculate from this small number of patients on how to treat for prophylaxis, but I'm comfortable to say probably patients should be sent to surgery as soon as possible after developing endocarditis, especially prosthetic valve endocarditis because the outcomes are dismal.

Dr Emmanouil Brilakis: And do you think... Let's say patient is not a candidate for surgery and gets endocarditis, and I presume they get into prolonged therapy. There were some patients like this that did okay, right? So there is some hope even for those patients.

Dr Wael Jaber: I feel like I'm the cup half full here because if you look at the mortality curves here, we're talking about north of 95% death in this population. So the people who survive this must be very few people survive. So probably about seven patients who survive. So the mortality was 96% at six months versus 46%. So there are very few people who survived that event. Maybe I should go back now and figure out what was the quality of life after survival. So I don't think the picture we have right now is very rosy as far as the way we're managing endocarditis.

Dr Carolyn Lam: Manos, I'm going to give you the final parting words from this very interesting discussion. I mean what do you think are the take home messages and future directions from here?

Dr Emmanouil Brilakis: I agree that this is a phenomenal landmark study and my key takeaways are the same ones that Dr Jaber presented before. But the main thing is, on the consent process, who can tell the patients there is about 0.5% per year. So it's not zero, but it's very high either. The second thing is that this choice between TAVR versus SAVR, that should not have to do with the risk of infection because as it was shown very convincingly, it was very similar to the two groups. And number three that everything possible should be done to prevent this because if you do get infection, the outcomes are not very good.

Dr Carolyn Lam: Thank you so much Manos, Wael. Thank you so much audience for joining us today. You've been listening to Circulation on the Run. Tune in again next week.

This program is copyright American Heart Association 2019.

Circulation December, 03, 2019 Issue

2 december 2019 | 27 min

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia, from VCU Health.

Dr Carolyn Lam: You know what, Greg, I may have a hoarse voice today and I'm a little bit scratchy, but my goodness, I couldn't be more excited about this issue. It's the TCT issue.

Dr Greg Hundley: Well Carolyn, I cannot wait to discuss with our listeners the feature article that compares Apixaban and a P2Y12 inhibitor without Aspirin, versus regimens with Aspirin in patients with AFib who have ACS, whether managed medically or with PCI, or also those undergoing elective PCI that experience regimens that include vitamin K antagonists, aspirin, or both, but more to come later. Carolyn, should I start with my first discussion article and we grab a cup of coffee?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: So my first article is from Seung-Jung Park from the Asan Medical Center at the University of Ulsan College of Medicine. So Carolyn, here's our first quiz question. In terms of Ticagrelor, have studies been performed in those from Asia evaluating bleeding risk?

Dr Carolyn Lam: You know, I have to admit, Greg, I'm not totally familiar with the literature, but I do know that it's a very important question for us practicing in Asia. We have a perception that the bleeding risk, especially intracranial bleeding, may be higher in Asians.

Dr Greg Hundley: Absolutely. Well, in this multicenter trial, 800 Korean patients hospitalized for acute coronary syndromes with or without ST elevation, and intended for invasive management, were randomly assigned to receive in a one to one ratio, Ticagrelor with a 180 milligram loading dose, and then 90 milligrams twice daily, or Clopidogrel with a 600 milligram loading dose and 75 milligrams daily thereafter, and the primary safety outcome was clinically significant bleeding, which was a composite of major bleeding or minor bleeding according to the PLATO outcomes criteria at 12 months.

Dr Carolyn Lam: Oh, so what did they find?

Dr Greg Hundley: Well Carolyn, at 12 months, the incidence of clinically significant bleeding was higher in the Ticagrelor group than in the Clopidogrel group. So it was 11.7% versus 5.3, and that included major bleeding and fatal bleeding. They were also higher in the Ticagrelor group. The incidents of death from cardiovascular causes, myocardial infarction or stroke, was not significantly different between the Ticagrelor group and the Clopidogrel group, although there was a strong trend toward a higher incidence in the Ticagrelor group with a P value of 0.07. So consequently, Carolyn, these results identified safety concerns regarding bleeding complications of standard dose Ticagrelor in East Asian, Korean patients with acute coronary syndromes, and therefore large adequately powered randomized trials are needed to determine the optimal antithrombotic regimen in this patient population.

Dr Carolyn Lam: Very important data for our patients, as is this next paper, which really examines the cost effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation. Now, these are results from the COAPT trial. As a reminder, the COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair using the MitraClip resulted in reduced mortality and heart failure hospitalizations and improved quality of life when compared with maximally tolerated guideline directed medical therapy in patients with heart failure and three to four plus secondary mitral regurgitation.

In the current paper, first author Dr Baron from Lahey Hospital and Medical Center in Burlington, Massachusetts and St. Luke’s Mid America Heart Institute in Kansas City, as well as corresponding author Dr Cohen from University of Missouri, Kansas City, and their colleagues used data from the COAPT trial to perform a formal patient level economic analysis of the COAPT from the perspective of the US healthcare system, and they found that although the follow up costs were lower with the MitraClip compared with guideline directed medical therapy, and lower by more than $11,000 per patient. However, the cumulative two year costs remain higher by about $35,000 per patient with the transcatheter mitral valve repair, and this is all due to the upfront costs of the index procedure. Now when in trial survival, health, utilities, and costs were modeled over a lifetime horizon, transcatheter mitral valve repair was projected to increase life expectancy by 1.13 years, and quality adjusted life years, or QALYs, by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost effectiveness ratio, or ICER, of $40,361 per life year gained, and $55,600 per QALY gained.

Dr Greg Hundley: Very interesting. So how do we interpret these results for clinical practice?

Dr Carolyn Lam: Ah, good question. So in order to place this in context, perhaps the most comparable case is the use of transcatheter aortic valve replacement, or TAVR. So based on the partner 1B trial, the ICER for TAVR, compared to medical therapy, was $61,889 per QALY gains. So this is very similar to what you just heard as the ICER for the transcatheter mitral valve repair. The cost effectiveness is also comparable for other commonly used treatments such as the implantable cardiac defibrillators for biventricular pacing, and was interestingly substantially more than the cost effectiveness of continuous flow LVADs, for example, and this is really discussed in a beautiful editorial by Dr Bonow, Mark, and O'Gara, and in this editorial, I think it's really important that they say the cost effectiveness projections really need to be placed in the context of continuing uncertainties regarding the interpretation of COAPT compared to that of the MITRA-FR trial, which reported no benefit of transcatheter mitral valve replacement compared to medical therapy, and so they warn that the current cost effectiveness analysis is not a carte blanche for interventional cardiologists to dramatically escalate their use of MitraClip procedure, and the data do support the thoughtful and deliberate use of this potentially life lengthening procedure in carefully selected patients and under very careful circumstances. You've got to read their editorial.

Dr Greg Hundley: That sounds excellent, Carolyn. I really like that, putting that editorial that puts that data in perspective. Well, my next study really emanates from the ABSORB III trial, and it's from Dr Dean Kereiakes at the Christ Hospital Heart and Vascular Center. The manuscript addresses the long-term cardiovascular event rates among bioresorbable vascular scaffolds and drug eluting metallic stents.

Dr Carolyn Lam: Greg, remind me, what were the results of the original ABSORB trial?

Dr Greg Hundley: Right, Carolyn. So the ABSORB III trial demonstrated non-inferior rates of target lesion failure, cardiac death, target vessel myocardial infarction, or ischemia driven target lesion revascularization at one year with the bioresorbable vascular scaffolds compared with cobalt chromium everolimus-eluting stents, but between one year and three years, and therefore the cumulative to 3 year time point, the adverse event rates, particularly for target vessel myocardial infarction and scaffold thrombosis, were increased with this bioresorbable vascular scaffold.

Dr Carolyn Lam: Ah, I see. Okay, so this current study evaluated the outcomes from three to five years beyond the implantation?

Dr Greg Hundley: Exactly. So what this study did is they looked at an interval of time between three and five years out, and they found reductions in the relative hazards for the bioresorbable vascular scaffolds compared to the common coated stents, and that particularly occurred for target lesion failure, either cardiac death or target vessel MI or ischemia driven target revascularization when compared to the earlier zero to three year time period. So therefore Carolyn, the authors conclude that improved scaffold design and development techniques to mitigate that zero to three year bio resorbable vascular scaffold risk may enhance the late benefits that one sees in this three to five year time point, because of the complete bioresorption.

Dr Carolyn Lam: So that's interesting Greg. Well, my next paper is kind of related. It is the first report of a randomized comparison between magnesium based bioresorbable scaffold and sirolimus-eluting stent in this clinical setting of STEMI with one year clinical and angiographic follow-up. So this study is from the Spanish group, Dr Sabaté and colleagues from the Interventional Cardiology Department and Cardiovascular Institute in Barcelona in Spain, and they found that at one year when compared to the sirolimus-eluting stent, the magnesium based bioresorbable scaffold demonstrated a higher capacity of vasal motor response to pharmacological agents, either endothelium, independent or dependent, at one year. However, the magnesium based bioresorbable scaffolds were also associated with a lower angiographic efficacy, a higher rate of target lesion revascularization, but without thrombotic safety concerns.

Dr Greg Hundley: Wow, Carolyn, very interesting, and Dr Lorenz Räber and Yasushi Ueki wrote a very nice editorial on this whole topic of bioresorbable scaffolds, and they wonder about some of the unfulfilled prophecies. Great for our readers to put these two articles together. Now, how about in that mailbox, Carolyn? What have you got in there?

Dr Carolyn Lam: First there's a research letter by Dr Kimura entitled Very Short Dual Antiplatelet Therapy After Drug-eluting Stent Implantation in Patients with High Bleeding Risk, and that's insights from the STOPDAPT-2 trial. There's another research letter by Dr Lopes entitled The Hospitalization Among Patients with Atrial Fibrillation and a Recent Acute Coronary Syndrome, or PCI, Treated with Apixaban or Aspirin, and that's insights from the AUGUSTUS trial. A very interesting perspective piece by Dr Rob Califf entitled The Balanced Dysfunction in the Health Care Ecosystem Harms Patients, a really, really interesting read, especially those working in the U.S. healthcare system. An ECG challenge deals with fast and slow, long and shorter. I would love to give you a clue to what it is. It's got to do with the atrial ventricular nodes, but I'll let you take a look and test yourself. There’re highlights from the TCT by Drs Giustino, Leon, and Greg Stone, and finally there's Highlights from the Circulation Family of Journals by Sara O'Brien.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a couple reviews. Richard Whitlock in a primer provides a nice historical review of anticoagulation for mechanical valves. How do we get here in anticoagulating this particular patient population? Next, Dr Mark Brzezinski from Brigham Women's Hospital in the Harvard Medical School in an on my mind piece provides very elegant figures, beautiful figures, demonstrating inadequate angiogenesis within the fibrous cap of atherosclerotic plaques, and indicates this could be a source or thought of as a contributing factor toward plaque rupture. What an issue, and I can't wait to get onto that featured discussion.

Dr Carolyn Lam: For our featured discussion today, it is a super-hot topic, and a question that comes up again and again in clinical practice. What is the right antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome, not just those treated with PCI, but also in those treated medically? Well guess what? We're going to have answers right here. I'm so pleased to have with us Dr Renato Lopes, who's a corresponding author from Duke Clinical Research Institute and our associate editor, Dr Stefan James from Uppsala University in Sweden. Wow. Very, very important question here. Renato, could you just start by outlining what is the AUGUSTUS trial?

Dr Renato Lopes: The AUGUSTUS trial was basically one of the four trials trying to give an answer, or help answering about the antithrombotic therapy in patients with anti fibrillation and/or NACS and/or PCI. So in other words, this combination of patients undergoing PCI who require antiplatelet therapy and also patients with AFib who requires anticoagulation therapy, and in summary, what the AUGUSTUS trial did was randomize patients to Apixaban versus VKA, or aspirin placebo in a double blind fashion, and this was a two by two factorial design. So these were basically the two questions that we wanted to answer. Is Apixaban better than VKA, and is it safe to drop aspirin from this treatment strategy? Remembering that everybody received a P2Y12 inhibitor for at least eight months. So this was basically the design of the AUGUSTUS trial, trying to answer two questions in the same study, a two by two factorial design.

Dr Greg Hundley: Very, very nice. And Renato, if I could, I mean I said it in the intro, but may I make sure I got it right. This is the only trial in the field that included patients with ACS that was managed medically. So that's a very important group of patients that we still don't know what the best regimen is, is that right?

Dr Renato Lopes: That is correct. The other trials, the PIONEER, the RE-DUAL PCI and the VPCI, they only included patients undergoing PCI, and when we designed the trial, we thought that it would be important to also include the whole spectrum of ACS, including not only the PCI treated patients, but also the medically managed patients.

Dr Greg Hundley: Well, super. So could you tell us now what were the results?

Dr Renato Lopes: So first, in terms of the breakdown, we found that the breakdown of the PCI, ACS versus elective PCI, was really nice. We had about 60% of the trial being ACS patients, and about 39%-40% elective PCI, and then within the PCI, I think that our results pretty much reflect practice in a lot of parts of the world, which was about 39% medically managed and about 61% PCI treated patients. So to begin with, I think a very nice breakdown that gives us power to look at these three separate groups: ACS medically managed, ACS PCI treated, and also elective PCI, which allows us to understand the whole spectrum of coronary disease in patients also with AFib, and in summary, what we showed for the primary endpoint, which was clinical major or relevant non-major bleeding. Let's start with the Apixaban versus VKA comparison, and we show that Apixaban was safer than VKA in all three groups, in the ACS medically managed, in the PCI treated patients, and also in the elective PCI patients.

There was no significant direction for those three subgroups, although it was borderline 0.052, just showing maybe a little bit less pronounced results in the elective PCI group, but nonetheless, I would say that in general, very consistent, and in terms of Aspirin for the primary endpoint, also no difference, no interaction among those three groups. In other words, as we increase substantially the risk of bleeding about two folds in all the three groups, ACS medically managed, PCI treated patients, and elective PCI patients, with about again, two fold increase in bleeding compared to placebo. If we go to ischemic events, again, that's our hospitalization and other that are ischemic events. In terms of Apixaban versus VKA, the results were very consistent with the overall trial among these three groups, and in terms of as ACS versus placebo, the results also for the ischemic events were also similar among the three groups. So again, reassuring that the main results of the trial were very consistent, regardless how patients were managed in terms of the ACS, medically or through PCI, and also included in the elect PCI group.

Dr Carolyn Lam: Thank you for explaining that so well. Stephan, I would love for you to take us under the hood. What were the editors thinking when we saw this paper, why we're highlighting it now, and what do you think are the implications?

Dr Stefan James: The AUGUSTUS trial was unique in many aspects. I think Renato highlighted a few of them. As he told, there have been several similar trials without the other DOAX, factor 10A inhibitors and the dabigatran, but the AUGUSTUS trial was larger. It includes, as you mentioned previously, patients with ACS and medical management, and it also was designed as a two by two factorial design. So it actually asks two different questions and made two different randomizations, both anticoagulation with the two different agents, Warfarin versus Apixaban, but also Aspirin versus placebo, and so it's possible from this trial to understand more of the different aspects of treating patients, these complex patients with atrial fibrillation, NACS or PCI, and gave the study group and us an opportunity to better understand all these complexities. So with that, I'd like to turn to Renato and try to, with that background that I just outlaid, and you just try to make us understand what are the clinical implications of these aspects of the trial and the treatment of Apixaban and Aspirin in these patients?

Dr Renato Lopes: I think we were in the area that we desperately needed randomized data, because basically until five years ago, the standard of care of treating these patients was the classic triple therapy with Aspirin, Clopidogrel, and Warfarin, and this was based on no randomized trials and all observational data, and we know how problematic this is, and this field has evolved tremendously almost year after year since the PIONEER trial, since the RE-DUAL trial, and this year, we had AUGUSTUS and ENTRUST and I think now, as Mike Gibson used to say, that we have about 2.8 million different combination of antithrombotic strategies to treat these patients because we have different anticoagulants, different anti-platelets, different doses, different durations, different types of stents, which makes it really impossible for physicians or for any guidelines to contemplate all these options. So we really needed a few trials to at least try to give a few options that are evidence based and not just based on low quality of data, and I think now, if you look at the Augustus results, and the totality of the data from all these trials, which now is about almost 11,000 patients all together, actually almost 12,000 patients all together.

I think that what we know today is that yes, the initial period in hospital for some time it's important to use Aspirin. I think this is an important point to highlight, Stephan, that Aspirin still needs to be used for the acute treatment, and I would say at least for the first few initial days while patients are still in the hospital, but then by the time of discharge, which sometimes might be five days, six days, seven days, I think that now the totality of data show that it's reasonable to drop Aspirin for most patients.

So based on the AUGUSTUS results, what we show is that if you're going to use anticoagulation as Apixaban at the dose that is approved for stroke preventions in atrial fibrillation, combined with a P2Y12 inhibitor without Aspirin after the initial period, you have the best outcomes in terms of lower rates of bleeding, lower rates of hospitalizations, and we don't have to pay a cost in terms of ischemic events when we actually drop Aspirin and keep only the NOAC, in this case was Apixaban, plus a P2Y12 inhibitor, which most of the time was Clopidogrel, and here with AUGUSTUS, we basically show that this is true for patients with AFib and ACS, irrespective of the management with medical managing, with medical therapy, or with PCI. So I think that's an additional piece that that is true irrespective of how we're going to treat your ACS patient, or if the patient basically underwent elective PCI, and I think we learned today that the classic treatment therapy of VKA plus Aspirin plus P2Y12 inhibitor, so in other words, the triple classic triple therapy should generally be avoided.

Dr Stefan James: Thank you Renato. I think that that was a very complete answer in this complex arena. I'd like just to mention that of course the AUGUSTUS, as well as the other trials, have their limitations, as all trials. Although it was large, it was powered for safety, for bleeding events, and it was not powered for ischemic events. Having said that, we still want to look at ischemic events and clinical outcomes, and to what degree do you think we can do that? What conclusions can we draw from an ischemic point of view because of the fact that the trial was underpowered for that interpretation?

Dr Renato Lopes: That is a great question, Stephan, and in fact, if we look at events like stent thrombosis, they are very rare, and if you really want to attack a significant difference between Aspirin versus placebo in patients having stent thrombosis, we're really going to need a trial with about 30-40,000 people, which would be not feasible and not doable. So we need to be cautious when we analyze those events in the power trial for ischemic events. Nonetheless, there was a signal, if you look at all trials, and even in the meta-analysis that we published recently, that dropping Aspirin probably increased the risk of ischemic events, not in a statistically significant fashion, but nonetheless, this trend exists. The signal exists. So probably keeping Aspirin, add some protection for ischemic events, primarily stent thrombosis and myocardial infarction. The problem is a tradeoff. The problem is that the cost of adding aspirin is too high.

So now the question to us, Stephan, is to look further into our data and in the combined data sets that we're trying to work with the other authors and try to identify, okay, Aspirin really increased the risk of bleeding, but is there a group of patients who might benefit from a little bit longer Aspirin? So that's the first question. Who are those patients? May be complex PCI, maybe bifurcation lesions, maybe multiple lesions, multiple stents, and second, if we decide to give Aspirin longer, how much longer should we give? Because again, the cost is very high in terms of bad bleeds. So we are trying now to identify what is the trade off, and who most benefit from keeping Aspirin longer, and for how long in a way the cost might be worth it to pay in exchange of potentially save some ischemic events? And with that, we can further refine the treatment that I think I highlighted before. For most patients, I think what I said before is probably reasonable. We can drop Aspirin by the time of discharge after a few days, but for a few patients, for some patients, it might be wise to keep Aspirin a little bit longer, and we are trying now to identify first, who those patients are and second, form how much longer should we keep Aspirin, since the 40,000 patient trial is very unlikely to happen.

Dr Stefan James: I like his interpretation, Renato, although I wanted to highlight that there are limitations, I think this trial is extremely informant for clinicians. We learned a lot how to treat these very complex patients with complex treatments.

Dr Carolyn Lam: No, I couldn't have agreed more. I mean quoting Mike Gibson, 2.8 million combinations. Well, at least we've talked about some of them here and had a very clear take home message, although with the caveats that we were discussing. Thank you so much, Stefan and Renato. This was really a great discussion, and thank you audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.

Circulation November 26, 2019 Issue

25 november 2019 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage passes to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article really starts to look at micro-circulatory dysfunction and abnormal coronary perfusion during exercise that can be associated with myocardial ischemia. I hear you're anxious to hear about it, but why don't we go to your article first.

Dr Carolyn Lam: Here we go. This first paper I'd like to tell you about reports a novel cardiac kinase as a potential regulator in heart failure.

Dr Greg Hundley: Now remind me, Carolyn, I got to take me back a little bit. What are cardiac kinases?

Dr Carolyn Lam: Ah, I thought you would ask. Cardiac kinases are known to play a critical role in the development of heart failure and represent potential trackable therapeutic targets. Now to identify novel cardiac kinases involved in heart failure, the corresponding authors, Dr Hind Lal from University of Alabama at Birmingham and colleagues, employed an integrated transcriptomics and bioinformatics analysis and identified homeodomain-interacting protein kinase 2 or HIP kinase 2, as a novel candidate kinase. Now this is the first study to define the role of HIP kinase 2 in cardiac biology. In essence, they performed a series of mouse experiments that showed that cardiac HIP kinase 2 expression is elevated in adults compared to embryonal and neonatal stage of mouse experiments, but down regulated in failing hearts.

Deletion of HIP kinase 2 in the cardiomyocytes led to decreased cardiac function in adulthood. The cardiac effect of HIP kinase 2 correlated to its gene expression level and impaired ERK signaling was discovered as the main driver of HIP kinase 2 deficient phenotype by enhancing apoptosis. Taken together these findings really suggest that cardiomyocyte HIP kinase 2 is required to maintain novel cardiac function via ERK signaling.

Dr Greg Hundley: All right, Carolyn, my favorite question, what does this mean for us clinically?

Dr Carolyn Lam: Two points, first since HIP kinase 2 is protective in cardiomyocytes, gene therapy using HIP kinase 2 could be a potential therapeutic method of heart failure treatment in future. Secondly, because inhibition of HIP kinase 2 has been proposed as a therapeutic approach for certain cancers and for renal fibrosis, these results suggest that caution needs to be taken for the potential cardiotoxicity of HIP kinase 2 inhibition in the adult heart. Interesting.

Dr Greg Hundley: Yeah. Very nice. Well, I'm going to switch gears a little bit Carolyn and talk about ablation for atrial fibrillation. And the corresponding author of this paper is Jason Andrade from Vancouver General Hospital. In his study, they randomly assigned 346 patients with drug-refractory paroxysmal atrial fibrillation to A, contact force guided RF ablation, B, four-minute cryoballoon ablation or C, two-minute cryoballoon ablation and they followed the patients for 12 months. Now the primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmias, whether that be AFib, aflutter, atrial tachycardia, between days 91 and 365 after the ablation or a repeat ablation procedure at any time. And the secondary endpoints included freedom from symptomatic arrhythmia and AF burden.

Dr Carolyn Lam: Interesting clinical question. What did the results show?

Dr Greg Hundley: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring, was 54, 52 and 52% with each of those therapies respectively. One-year freedom from symptomatic tachyarrhythmia defined by continuous monitoring was 79, 78 and 73% with those therapies respectively. No difference statistically in either.

Dr Carolyn Lam: Right. No significant difference in those outcomes but what about AF burden or side effects?

Dr Greg Hundley: Right, Carolyn. Well, compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99%, 99.9% and 98.4% in each of the three therapies. No significant difference. And serious adverse events occurred in two patients in the CF-RF group, in six patients in Cryo with four minutes and in seven patients with Cryo in two minutes. Again, no significant difference between those groups.

Dr Carolyn Lam: Greg, were there any significant difference in these techniques?

Dr Greg Hundley: Well, Carolyn, that contact force RF group at a significantly longer procedure duration but a significantly shorter fluoroscopy exposure. And the P was 0.001 versus the cryoballoon group. In summary, in this multicenter, randomized, single blinded trial, contact force RF ablation, and two different regimens of cryoballoon ablation, resulted in no difference in one-year efficacy, which was 53% by time to first recurrence, but 98% burden reduction as assessed by continuous cardiac rhythm monitoring. A new study in patients with ablations looking at these new techniques and for many reasons they're very similar.

Dr Carolyn Lam: Very interesting. My next paper also has to do with atrial fibrillation. Now we know that numerous skills exist for classification of major bleeding events in patients with atrial fibrillation who are anticoagulated. Now there are limited data comparing the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. And so Dr Bergmark from the TIMI study group and colleagues analyzed bleeding outcomes according to the ISTH, TIMI GUSTO and BARC bleeding scales in the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin. And they found that among patients with atrial fibrillation at risk for stroke, there was an approximately four-fold difference in the frequency of the most severe bleeding events across these commonly used bleeding scales. Further, the relative safety of edoxaban as compared with warfarin tended to increase with greater severity of bleeding.

Dr Greg Hundley: Interesting Carolyn. Tell me, what's the take home message from this study?

Dr Carolyn Lam: This analysis reminds us that the currently available and commonly used bleeding scales differ in important ways. The analysis shows us that one size does not fit all and that the most appropriate bleeding scale really depends on the clinical setting and the intervention being investigated. For patients particularly concerned about bleeding, these results should provide additional reassurance about the safety of the DOX. Finally, this analysis also illustrates how the differential effect of edoxaban compared to warfarin on bleeding, impacts the assessment of net clinical benefit. Now this is discussed in an editorial by John Alexander and Adam Nelson who highlight that one of the most interesting findings was the statistically significant and graded amplification of edoxaban safety compared to warfarin with more severe bleeding.

Greg, perhaps now's a good time, tell us what else is in this issue of the journal?

Dr Greg Hundley: Happy to do so. Ben Freedman from the University of Sydney discusses in a white paper concurrent thoughts from the AF, another atrial fibrillation paper, AF screen international collaboration, which summarizes existing evidence and knowledge gaps on searching for an AFib post-stroke using ECG monitoring. And Carolyn, our own James de Lemos suggests in an on my mind piece that subdividing type two MI into different based on etiology could lead to improved forecasting of events. In a perspective article, Tommy Wang from Vanderbilt revisits the polypill and discusses why we need population-based approaches in the precision medicine era.

Dr Carolyn Lam: Wow. Super interesting. And how about letters? What's in the mailbox?

Dr Greg Hundley: Oh gosh, Carolyn. It's really full this week. There are multiple letters ranging from science, to responses, to prior inquiries. It is really interesting to read these responses and the authors going back and forth and having that open discussion for us. And so Brody Slostad first has his own research letter that reviews unicuspid aortic valves, the demographics, comorbidities, and echocardiographic features and long-term outcomes. Darren Casteel from UC San Diego discusses blood pressure lowering by the antioxidant resveratrol is counterintuitively mediated by oxidation of the cyclic GMP dependent protein kinase. And there's a nice response by Dr Joseph Burgoyne from Kings College London. Finally, there's a letter by Daxin Wang and his associates from Yangzhou University regarding the article targeting filament A reduces macrophage activity in atherosclerosis and there's a corresponding response from Levent Akyürek event accurate from the Institute of Biomedicine. Great mailbox this week, Carolyn. How about now we go on to our feature discussion?

Dr Carolyn Lam: Oh boy, I can't wait. Thanks Greg.

How does coronary microvascular dysfunction relate to exercise physiology or inducible myocardial ischemia? Well, we are going to be talking all about that in the next few minutes and that's because our feature paper this week is the first study to really directly assess coronary blood flow during exercise in patients with microvascular dysfunction. And to compare these changes with high resolution perfusion imaging. We're really pleased to have with us the first and corresponding author, Dr Divaka Perera from Kings College London, as well as our associate editor Dharam Kumbhani from UT Southwestern. Welcome gentlemen and Divaka. Could you start by telling us what makes your study unique? What did you do? What did you find?

Dr Divaka Perera: As you said, microvascular dysfunction is being recognized as quite a common cause of angina. In fact, about 40% of patients who present to the Cath lab for a diagnosis of angina are found to have nonobstructive coronary artery disease, and a significant proportion of these are thought to have microvascular dysfunction. The definition of microvascular dysfunction has been based on demonstration of impaired coronary flow reserve, but what we haven't known is whether the Cath lab measurements that are made actually correlate with exercise maladaptation. Bearing in mind that these patients experience symptoms during exercise and whether there's actually demonstrable ischemia in these patients who don't have obstructed coronary artery disease. Our study's unique in that we were able to measure directly exercise physiology during cardiac catheterization and we were able to stratify patients upfront on the basis of their coronary flow reserve and then in a blinded fashion assess whether these patients who did or didn't have augmentation of flow reserve had ischemia.

Dr Carolyn Lam: Divaka, could you give us a detailed picture of what that meant? These patients were sitting with catheters and then riding bikes or give us a picture of what you did.

Dr Divaka Perera: Right. This is a setup we've been working on for the last 10 years or so to make sure that we have a reproducible and safe protocol that can be carried out in a Cath lab. A patient who was referred for diagnostic angiography, this may have been the first investigation they were having, or they may have had some form of noninvasive testing beforehand. These patients would undergo angiography via the right radial artery with their arm extended out to the side. And then during angiography when the time was right to assess this condition, they would carry out supine bicycle exercise. And that was a bike that was mounted onto the Cath lab table. During all of this, we would measure intracoronary pressure and flow velocity using this combo tipped wire which could give us distal coronary pressure and Doppler flow velocity and we were able to do this throughout the condition of exercise.

Dr Carolyn Lam: That's cool, but then how did the MRI come in then?

Dr Divaka Perera: Right. The MRI was actually done at a different visit and in that situation, we only carried out vasodilator testing. We also do exercise patients in the MR scanner, but we haven't included any of those data in this current paper. Patients would have two visits at least as part of this research protocol.

Dr Carolyn Lam: Maybe now with that background, tell us what you found.

Dr Divaka Perera: The first and most important finding was that patients are classified in the Cath lab on the basis of a coronary flow reserve below 2.5. The flow reserve threshold of 2.5, actually have demonstrable ischemia on a stress profusion myocardial magnetic resonance imaging scan. 82% of patients in the MVD group, the microvascular dysfunction group had inducible ischemia compared to just 22% of controls. This was mirrored by quantitative myocardial profusion reserve data as well, where the ability to augment overall myocardial blood flow was significantly diminished in patients with MVD. And perhaps most interestingly, their exercise pathophysiology was dramatically different to that of controls.

In the healthy heart, the heart actually becomes more efficient during exercise. We were able to quantify the proportion of accelerating and decelerating waves by carrying out a technique called wave intensity analysis on the data I've just described, on the physiology data that I've just described. And by doing that we were able to quantify the proportion of accelerating waves to decelerating wave energy. In the healthy heart, as we exercise the proportion of accelerating wave energy increases and we've termed that profusion efficiency. Now in stark contrast when you have MVD, the heart actually becomes less efficient and the profusion efficiency decreases. This is a normal finding and really told us that cath lab measurement based on the response to vasodilators seems to identify a population who have maladaptation during exercise and demonstrable ischemia on scanning.

Dr Carolyn Lam: Wow. Dharam, could I now ask you to help frame these results in the context of what's known or not known about microvascular disease?

Dr Dharam Kumbhani: I want to congratulate the Divaka and his group. I think this is very interesting analysis. It's really a new paradigm about what is now understood to be more and more of a common issue. It seems like a lot of work, even for the patient population that was enrolled. And I think done in an incredibly thoughtful way. Having said that, I guess what I'd like to understand as a card carrying interventionalist myself, I imagine that some of this may be perhaps in need of validation. And so do you think that this study and in some of the two distinct phenotypes that you describe that this will need to be demonstrated in other labs and other situations?

Dr Divaka Perera: Absolutely. I think we have demonstrated is a proof of concept that we can assess these patients in the Cath lab and then shown that firstly, the measurement of CFR and the classification of patients on the basis of CFR does identify a group with distinct pathophysiology, but that that doesn't tell the whole story because your CFR can be diminished for one of two broad reasons. That there's an abnormality of resting flow or an abnormality of hyperemic or flow at maximum stress. Now, the traditional paradigm of microvascular dysfunction has been that these patients will all have, or the majority will have, diminution of stress flow. Or that they might have an inability to reduce their microvascular resistance during stress.

What we have found in contrast is that actually two thirds of patients who have impaired flow reserve have impaired flow reserve because of an abnormality of rest perfusion. One third only conform to that traditional paradigm, and this, as you've rightly pointed out, is something that's going to need further investigation. It's very exciting and it might mean that we have a basis on which to try different therapies, for instance. That those therapies might be pathophysiologically stratified, but it needs a lot of work and I'm sure you won't be surprised to know that we've already embarked on that next stage of work to validate and take this forward.

Dr Dharam Kumbhani: Let's say you were able to validate this paradigm and you indeed are able to stratify patients with microvascular disease. What you have defined as a functional and a structural endotype. Do you believe that if this were validated and established further from a diagnostic standpoint in labs across other places, what kind of diagnostic testing do you imagine that this would require?

Dr Divaka Perera: At the most basic level Dharam, I think we need to get interventional cardiologists and any cardiologist doing diagnostic angiography to realize that the finding of unobstructed coronary artery disease isn't the final answer. It actually begins a whole chapter of investigation and if we can at least get people to think about doing a physiology study in a way analogous to what's happened when we find equivocal amounts of coronary artery disease that you'd reach for a pressure wire and do a functional test. If we can introduce that paradigm once we find normal or unobstructed coronary arteries in a patient with classical symptoms, that would be step number one. The next step will be that we'll have across the board a harmonized means of classifying these patients and by looking at microvascular resistance as well as coronary flow reserve, we might be able to identify endotypes that behave differently and need different forms of therapy. Once we've got that in place, then we have a basis to carry out large registries and large trials in a systematic fashion.

Dr Dharam Kumbhani: Let me just clarify that. You don't envision that let's say this all gets validated. Do you envision that labs that do CFR measurements would then in addition need to have the ability to do exercise testing as well?

Dr Divaka Perera: No, I don't think so. I think exercise testing requires a really carefully evolved set up and it's not practical to unleash this onto world at large. But it generates hypotheses and examines concepts which can then be translated. I think routine use of microvascular function testing will rely on response to vasodilators and these will be endothelium independent techniques such as an adenosine and possibly as a second stratum, endothelium dependent methods as well. Perhaps using graded acetylcholine infusions. But it would be vasodilator testing in the Cath lab rather than exercise.

Dr Dharam Kumbhani: Got it.

Dr Carolyn Lam: Fascinating. Wait, Divaka, just to be sure that the audience got this. You talked about the two endotypes, a structural and functional and the structural one is the one that has a low flow to begin with. The functional is the one that the hyperemic flow is the one that's mainly impaired. Is that correct? Just checking.

Dr Divaka Perera: Let me just clarify. Those patients that we've termed to have functional MVD have elevated resting flow, but actually essentially normal flow at stress. In contrast, those who have structural MVD have essentially normal resting flow but have an inability to augment their peak flow. The net result appears to be the same in the sense that they all have demonstrable ischemia on noninvasive testing, but the mechanisms are different and therefore the therapies that we direct towards these patients may also need to be different.

Dr Carolyn Lam: Very nicely put. Thank you. And if the audience, you still didn't get that, pick up the paper and read it. But say, one last question because you kind of teased us just now and said, actually we are going on with next steps and so on. What are the next steps? Maybe from you and then Dharam.

Dr Divaka Perera: I think the next step is to assess whether this sort of stratification allows us to treat patients more efficiently. To deliver subtype stratified therapy. And we need to assess this with reference to meaningful clinical outcomes, so quality of life, exercise-based indices, et cetera, before we get onto looking at large numbers and then looking at cardiovascular outcome data.

Dr Carolyn Lam: Great. And Dharam, maybe I'll let you have the closing words.

Dr Dharam Kumbhani: We're understanding a lot more about what is always been an enigma for clinicians as far as having patients who present with very typical symptoms, either stable or unstable symptoms and have no coronary artery disease. I want to congratulate the authors on really trying to dig deeper into this and helping us with this very difficult patient population.

Dr Carolyn Lam: Thank you, Dharam. Thank you Divaka. And thank you listeners for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

Circulation November 19, 2019 Issue

18 november 2019 | 24 min

Dr Greg Hundley: And, I'm Greg Hundley, Associate Editor, Director of the Poly Heart Center of VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature articles, very interesting, discussing hypertrophic cardiomyopathy and sudden death in young individuals. But, let's save all the details for later and start in on our coffee chat. So, Carolyn, have you got a paper that you'd like to start with?

Dr Carolyn Lam: I have, and it's a basic science paper. It's one that details the contribution of get this, M-C-U-B. Now this is a paralogue of the poor forming sub-unit MCU in mitochondrial calcium, uniporter regulation and function. Now, this paper shows, for the first time, MCUB's relevance to cardiac physiology, and it's from corresponding author Dr Elrod from Center of Translational Medicine, Louis Katz School of Medicine at Temple University in Philadelphia, and their coauthors, who showed, in a series of elegant work, that MCUB is absent from the uniporter complex in the homeostatic heart. But it's incorporated into the mitochondrial calcium uniporter following ischemic injury and thus represents an endogenous mechanism to limit mitochondrial calcium overload during stress.

Interestingly, the increased incorporation of MCUB into this mitochondrial calcium uniporter is too little and too late to limit acute cell death following ischemic reperfusion injury but may limit cell loss during chronic stress.

Dr Greg Hundley: So Carolyn, tell me what are the clinical implications of this important finding?

Dr Carolyn Lam: Well, simply put, MCUB represents a novel therapeutic target to modulate mitochondrial calcium uptake in disease states speech during mitochondrial calcium overload such as myocardial infarction and heart failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got another basic science paper and it involves Protein Kinase N and how that promotes stress induced cardiac dysfunction through phosphorylation of myocardin-related transcription factor A and disruption of its interaction with actin. This comes from the corresponding author Mikito Takefuji from Nagoya University Graduate School of Medicine. So Carolyn protein phosphorylation of course, is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes, in response, extracellular and intracellular signals. The RHOA-associated protein kinase, or ROCK Rho-kinase, in effect, are regulated by the small GTPS RHOA causes pathological phosphorylation of proteins resulting in cardiovascular diseases. RHOA also activates Protein Kinase N, however, and the role of PKN in cardiovascular disease remains unclear.

Dr Carolyn Lam: Ah, okay. So with that background, what did these authors find, Greg?

Dr Greg Hundley: Great question, Carolyn. What they found is that PKN inhibits the binding of MRTFA to G-actin by phosphorylating MRTFA and activating SRF mediated expression of cardiac hypertrophy and also fibrosis associated genes. Also, they showed that cardiomyocyte specific PKN1 and PKN2 double deficient mice are resistant to pressure overload and ANGII induced cardiac dysfunction.

Dr Carolyn Lam: Wow. There's a lot of letters in what you just said. So could you just tell us how does this impact heart failure research and management?

Dr Greg Hundley: So Carolyn, this PKN family appears to play a role in regulating hypertrophy and fibrosis in the heart and therefore could serve as a unique target for therapeutic interventions for heart failure in the future. And so maybe it's going to make its way your way.

Dr Carolyn Lam: Well, okay, well this next paper definitely is making its way my way and it focuses on the Sodium Glucose Co-transporter two inhibitors or SGLT-2 inhibitors, which we know lower cardiovascular events in patients with type two diabetes, but whether they promote direct cardiac effects as in that we can see in cardiac structure and function actually remained unknown until today's paper. And this is from Dr Subodh Verma and Dr Kim Connelly, these co-corresponding authors from St. Michael's Hospital and University of Toronto and their colleagues.

And they sought to determine if empagliflozin causes a decrease in left ventricular mass in patients with type two diabetes and coronary artery disease. So this was a six month double blind randomized placebo controlled trial. If individuals with type two diabetes, coronary artery disease and relatively normal left ventricular mass index. The primary outcome was six month change in left ventricular mass index to body surface area from the baseline and measured by cardiac magnetic resonance imaging and they found that the empagliflozin allocated group exhibited a significant reduction in left ventricular mass index compared with the placebo group.

Dr Greg Hundley: Wow, Carolyn. We have been hearing a lot about empagliflozin in the last several issues. How does this article differentiate what we do or maybe even change our practice?

Dr Carolyn Lam: Well, you know what? It enhances our understanding which is important. We knew about the events. Now we perhaps understand a little bit more of what it may be doing actually to the heart in terms of cardiac structure and function. The so the decrease in left ventricular mass associated with empagliflozin may explain and contribute to the cardiovascular benefits observed in patients with type two diabetes and coronary artery disease who are treated with SGLT-2 inhibitors. Now it's interesting the way we've gone like reverse translation in this, haven't we? Observing the events and then trying to find the mechanism. And this is in fact discussing an editorial by Mark Petrie and titled SGLT-2 Inhibitors: Searching for Mechanisms in the Wake of Large Positive Randomized Trials.

So Greg, after that, maybe you could tell us what else resides in this week's issue.

Dr Greg Hundley: Oh my goodness, Carolyn. Well, there's quite a bit. First Paola Erba from Pisa, Italy provides a nice In-Depth review of the use of echocardiography, radioisotope imaging and computed tomography for the assessment of patients with endocarditis. In another article, Wayne Batchelor and Rebecca Ortega and their colleagues discuss a Perspective piece, several strategies to improve enrollment of racial and ethnic minorities into clinical cohorts and trials addressing cardiovascular disease.

And of course we have our mailbox. And first is Dr Diamantis Tsilimigras from The Ohio State University, and he responds to a letter by Moris et al regarding the article: Effects of Arteriovenous Fistula Ligation, or cardiac structure and function in kidney transplant recipients.

Barry Borlaug from Mayo clinic discusses the importance of right ventricular volume loading and high output heart failure with arteriovenous fistulas.

And Carolyn, our own Joe Hill and a first author Dan Tong coauthor a letter pertaining to whether female sex is protective in a preclinical model of heart failure with preserved ejection fraction.

And then finally Toby Coates from Australia responds to several inquiries related to a prior publication regarding a published article involving the effects of arteriovenous fistula ligation on cardiac structure and function, again in kidney transplant recipients.

There's an On My Mind piece from Dr Heinrich Taegtmeyer from McGovern Medical School at The University of Texas Health Science Center at Houston, or UT Health, relating to characteristics of past prominent investigators. What makes them tick? What contributes to their long-term success and sharing their catch with others? And it's interesting Carolyn, because he compares the vast community of cardiovascular investigators to those that are like anglers or fisherman. Their passion is kind of like the allure of catching just one more. And in so doing, they like to share their catch with others.

Dr Carolyn Lam: That is hilarious. I don't think I've ever wanted more to be a fisherman or angler myself. Well that's great, Greg. Thanks and let's carry on with our feature discussion, shall we?

Dr Greg Hundley: Absolutely.

Welcome everyone to our feature discussion and we're going to discuss hypertrophic cardiomyopathy and sudden cardiac death and the relationship to exercise. And our study comes from Ontario and our lead investigator is Dr Paul Dorian from St. Michael's Hospital, and we also have our associate editor Mark Link from Dallas, Texas. Welcome gentlemen. And Paul, I'll start with you, tell us a little bit, what was the hypothesis and what were the aims that you were trying to accomplish with this particular study?

Dr Paul Dorian: Our hypothesis was that the likelihood of sudden death in patients with hypertrophic cardiomyopathy may be less than has previously been supposed. In brief, the community that looks after patients with HCM, we'll call it for short, is faced with a major challenge in knowing what the actual rate of sudden cardiac death is and it seems to be a little bit of a moving target. Over the last decade, I think that most clinics that look after these patients were faced with what appears to be a less and less frequent likelihood of sudden death in these mostly young patients that we follow. And because we have the opportunity to study this using a well-established prospective coroner database with autopsy results in all sudden deaths in Ontario in young individuals, that we have the opportunity to test our hypothesis that this sudden death rate is lower than had previously been suspected.

Dr Greg Hundley: It sounds like younger patients and trying to investigate the cause of sudden cardiac death. Can you tell us a little bit more about your study population and what was your study design?

Dr Paul Dorian: We had the fortune of being able to use the Coroner of Ontario database. Ontario has about 13 million population and by the longstanding design, almost all patients under the age of 45 who suffer out of hospital, sudden cardiac death receive a full coroner investigation and then 90% of them, it's an autopsy which includes a cardiac autopsy by a qualified forensic pathologist. And in the case of cardiac hypertrophy, the cases are re-reviewed by a specialized cardiac forensic pathologist. So we have very extensive, if you like, detective work, CSI-type information on virtually everybody who dies out of hospital suddenly including those individuals among them who have hypertrophic cardiomyopathy.

And what we did was we reviewed every single case of unexpected sudden death, looking for the specific diagnosis of cardiac hypertrophy or HCM. We verified the accuracy of our numbers by also using, for at least portions of our follow-up, the complete emergency medical services database for about 7 million people, mostly from Toronto. And this included all patients who had a 9-1-1 call for documented cardiac arrest. So we were able to verify that we missed essentially no patients without a hospital cardiac arrest who then died suddenly.

Dr Greg Hundley: Give us a little bit more about the numbers. So what was the age range of your study population, perhaps the gender and breakdown, things like that?

Dr Paul Dorian: We looked at individuals under the age of 45 but the median age was 36 for all of our patients. About 85% of the patients with documented HCM were male, 83% to be precise. And a pretty small minority of them. Had comorbidities that we would expect including hypertension, diabetes, et cetera. 11% were on beta blockers, and a small proportion had atrial fibrillation. So these are generally healthy individuals, or at least they had had relatively little interaction with the healthcare system and about half of these individuals had previously been diagnosed clinically with HCM and the rest had not been diagnosed as far as we could tell, or at least there was no medical record of them having been diagnosed with HCM.

Dr Greg Hundley: And what was the total number of individuals in this study? And then tell us a little bit about your study results.

Dr Paul Dorian: The total number of individuals who had definite HCM was about 45 we had 31 patients who were not known to have HCM who had definite HCM, which we defined as having myocardial disarray on cardiac microscopy and another 13 who are not known to have HCM. And then we had about another 10 patients who we thought had possible HCM because they had autopsy with hypertrophy but didn't have disarray. And a few patients that were diagnosed with HCM but didn't have autopsy. So the total population was approximately 50 patients and this is out of a total population of estimated population of about 140,000 HCM person-years using the widely estimated prevalence of HCM of one in 500.

Dr Greg Hundley: And what did you find?

Dr Paul Dorian: The bottom line, if you like, is that the annual incidence of unexpected sudden death, this would be out of hospital sudden death, was many folds lower than would've been expected based on prior publications and on prior risk calculators that are used by many physicians who for these patients. If your readers or the listeners just want single numbers, the total number of both definite probable and possible HCM related sudden death, this is the most sort of conservative estimate, would be approximately 0.4 per thousand person-years. So this would be less than one per thousand. This would be one half of one 10th of 1% so less than one per thousand per year. Patients with HCM will have sudden death. If we take the most conservative definitions.

Dr Greg Hundley: Now, could you tell whether these sudden deaths were related to exercise? That was sort of one of the feature questions.

Dr Paul Dorian: Absolutely. That's how we were of course, very interested so we defined both exercise as somebody died or doing sport or observed during exercise. I should emphasize that the coroners do extremely careful digging if you like into the circumstances. They interview paramedics, police, they have the police and paramedic report, they interview physicians, relatives, so they do a very thorough assessment of course as best as could be told after the fact. 65% of the sudden deaths occurred at rest and 18% occurred during light activity and about 10% occurred during exercise.

Dr Greg Hundley: Very good. I want to turn over to Mark now. This is Dr Mark link from University of Texas Southwestern in Dallas. Mark, how can we put the results from this study in the context of other studies relating to implementation of defibrillators in patients with hypertrophic cardiomyopathy?

Dr Mark Link: This study brings up a lot of issues and I want to applaud Paul and his gang for doing this. The data is very good. The autopsies are very good. So the quality of the data is excellent and the incidence of sudden death for a hypertrophy is lower than any other study that we've seen. And there are a number of possible reasons for that. Well, you know, one is that the Toronto group was using autopsied determined HCM or most other studies were kind of a mixed bag of clinical and autopsy and newspaper reports and all sorts of things. So the Toronto data is going to be probably the most accurate. The other issue, or the other question I think that could lead to a low incidence, is the denominator, in that there were estimated to be more hypertrophy in Toronto than there actually are. They use the commonly accepted one in 500 and I think that's a reasonable number across all sorts of populations that we see, but is it possible that maybe the one in 500 number isn't true for Toronto?

You know, I've heard one person explain this is that patients with HCM can't stand the cold weather. So they left Toronto, but it is a much lower number than we've seen in regards to sudden death. A couple of other things I think are very interesting in this study. One is that if you looked at the individuals that got ICD shocks for ventricular arrhythmias is there was about as many people as died suddenly, arguing that the Toronto physicians can actually in many ways predict who would benefit, predict which hypertrophy would benefit from an ICD. Since many of these hypertrophies didn't have appropriate ICD shocks. And I also found fascinating that more of the deaths occurred during rest or light activity than exercise. We all tend to think that HCM causes its sudden death with exercise. And what this study's telling us is that's not true that more sun deaths are during rest and light activity. So there's a lot of very interesting insights that come out of this manuscript in this data.

Dr Greg Hundley: Just following up on your last point, are there any inferences regarding activity in this patient population that we should take away from these study results?

Dr Mark Link: I think if you look at the early newspaper reports and they're in there as reports of the incidence of HCM, sudden deaths during sports. So it was because of that, that everyone associated HCM with death during sports. But you have to remember those studies didn't include athletes that died at night. Athletes that died during dinner. They only included athletes that died during sports. So we were missing a large percentage of the hypertrophs dying. And I think we sort of infer that it was exercise that was dangerous, but in fact there's really not that much data that would support that exercise is dangerous for patients with HCM.

Dr Greg Hundley: Interesting. So I'll maybe ask Mark first and then come back to you, Paul. Do you think there are tools that could be available, either blood testing or perhaps other imaging that could help identify which HCM patients may benefit from a defibrillator? Do these results help us in any way make that decision?

Dr Mark Link: Unfortunately, I don't think this study offers us any clues into which patients should get defibrillators. And clearly there are other data that look at risk factors for sudden cardiac death in hypertrophic cardiomyopathy. And one of the things that has come out over the last 10, 15 years is that magnetic resonance imaging, and in particular the scar burden magnetic resonance imaging may actually offer additional prognostic information to our traditional respect for stratification grade CM.

Dr Greg Hundley: Paul, do you have anything to add?

Dr Paul Dorian: Just a couple of things if I may. I think on that last point I completely agree with Mark. Of course we didn't have data on MRI, but the greater the scar burden, the greater our index of suspicion. It is interesting that 57% of the cases of sudden death had asymmetric septal hypertrophy, so we can at least hypothesize that it is possible that patients with septal hypertrophy as opposed to concentric hypertrophy may be at higher risk.

The one thing I might want to highlight for the listeners is that it would seem to me based on our data and based on our suspicions, is that there's probably a difference in the risk in patients who are discovered incidentally. In other words, somebody has an echocardiogram or an ECG for reasons unrelated to their heart and then HCM is discovered and these might be asymptomatic patients as opposed to patients that tend to be followed in specialized clinics who often are sent there because they have some symptoms or there's some specific signal that they have a clinically evident HCM. So I wouldn't want listeners to conclude that the risk is necessarily this low in patients that are transferred to a clinic because of disarray or atrial fibrillation or electro regurgitation or some other manifestation of a hypertrophic cardiomyopathy.

Dr Greg Hundley: Paul, I want to start with you first. What study do you think should follow yours? What's the next study?

Dr Paul Dorian: What I'd like to see, and this is technically feasible although practically challenging, is to use the big data approach and combine in one large database, all echocardiograms done in a large geographic area. All electrocardiograms done in a large geographic area with supplemented with clinical information and do, over a long period of time, a prospective study looking at all patients with cardiac hypertrophy, particularly asymmetric hypertrophy or suspected to have HCM to look at the long-term outcomes. And this should be feasible because most echocardiograms today are uploaded if you like, into a database.

Dr Greg Hundley: Very nice and Mark, how about you?

Dr Mark Link: I have similar opinion. Any one of the most important things in HCM is being able to predict who would benefit from a defibrillator, and currently our ability to risk stratify is woefully inadequate. It lacks sensitivity and specificity. And so with a larger population of HCM patients, and I think Paul's correct followed prospectively, not retrospectively, with the kind of data that we would want to be complete, including echo. Now, MRIs would be fantastic, but there's just no way that's practical, but to have echoes and EKGs and clinical factors and be followed prospectively really to hone down which patients would benefit from a defibrillator, and which patients would not benefit.

Dr Greg Hundley: Well listeners, this has been a great discussion and we want to thank Dr Paul Dorian from the St. Michael's hospital for providing this paper to Circulation and sharing these results with us and also our associate editor, Dr Mark Link from Dallas, Texas and both have emphasized in this study that those individuals with HCM, while we often see them on the sports programs and whatnot, having their, experiencing their event during activity, they also occur within activity.

For Carolyn and myself, we wish you a great week, and we look forward to talking with you next week in our next chat. Bye now.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation November 12, 2019 Issue

11 november 2019 | 25 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, we are going to have a great discussion coming right up regarding intensive versus standard ambulatory blood pressure control and its effects on cerebrovascular outcomes in older people. It's the INFINITY trial, but that's all I'm going to tell you for now because I want to hear all about your picks for this week's journal first.

Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear about that discussion regarding hypertension. My first paper though is about titin and it comes from Dr Charles Murry from the University of Washington. The giant sarcomere protein titin is important in both heart health and disease as mutations in the gene encoding for titin are the leading cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within titin motivated the authors of this article to seek a more complete understanding of this gene and the isoform it encodes in cardiomyocyte sarcomere formation and function.

Dr Carolyn Lam: Cool. What did these investigators find?

Dr Greg Hundley: Using genetically engineered human induced pluripotent stem cell derived cardiomyocytes, the authors experimentally confirmed that the gene encoding for the giant sarcomere protein titin includes an internal promoter and start site. This internal start site encodes for the isoform Cronos, which the authors demonstrate support some sarcomere formation in these human induced pluripotent stem cell derived cardiomyocytes.

Dr Carolyn Lam: Oh, nicely summarized. What are the clinical implications Greg?

Dr Greg Hundley: Well, Carolyn identification that Cronos titin, a previously unstudied form of titin is necessary for normal human cardiomyocyte function could be contributing to some of these titinopathies that are relevant for some patients with dilated cardiomyopathy.

Dr Carolyn Lam: Cool. Mine has to do with heart failure as well and presents new results regarding heart failure and heart failure related outcomes from the EXSCEL trial.

Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it find?

Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest glucagon-like peptide-1 receptor agonist or GLP-1 receptor agonist trial reported to date where once weekly, exenatide had a neutral effect on hospitalization for heart failure with no differential treatment effect on major adverse cardiovascular events or MACE, by baseline heart failure status. However, the question remains, what about exenatide's effects on secondary endpoints based on the heart failure status? This is from Dr Rob Mentz and colleagues from Duke Clinical Research Institute who aim to explore the effects of exenatide on secondary outcomes in patients with and without baseline heart failure and test the effects of exenatide on recurrent heart failure hospitalization events.

Now they found that out of more than 14,750 EXSCEL participants, 16% had heart failure at baseline and when stratified by the presence or absence of baseline heart failure, there was no observed reduction in all cause death with exenatide in patients with baseline heart failure. While the risk of mortality was reduced with exenatide in the no heart failure group. And that was a significant interaction P value of 0.031. Similar results were observed for the combined outcome of all cause death or heart failure hospitalizations.

Now regarding recurrent heart failure hospitalizations, 450 patients experienced at least one hospitalization for heart failure, but there were 713 hospitalization heart failure events in total. The effect estimate that included the recurrent events was separately, statistically significant while the primary analysis based on just first events was not.

In conclusion in EXSCEL, the use of exenatide in patients with or without heart failure was well tolerated, but the benefits of exenatide on reduction in all cause death and first heart failure hospitalization were attenuated in patients with baseline heart failure. Now this is accompanied by a great editorial by Bruce Neil and Claire Arnett who caution against using post talk subgroup analysis, but the interaction of exenatide tout with baseline heart failure, it's interesting, although should be treated with caution until confirmed by findings from another trial.

Dr Greg Hundley: Very nice Carolyn, especially a nice issue regarding heart failure and I'm going to steer a little bit away from that and talk about atrial fibrillation duration and CHA2DS2-VASc scores. Putting those two together and this article comes from Rod Passman from Northwestern University. Studies of patients with cardiovascular implantable electronic devices show a relationship between atrial fibrillation duration and stroke risk though the interaction with a CHA2DS2-VASc score is poorly defined. The objective of their study was to evaluate rates of stroke and systemic embolism in those patients with cardiovascular implantable electronic devices as a function of both the CHA2DS2-VASc2 score and A-fib duration.

Dr Carolyn Lam: Interesting. What did the authors do?

Dr Greg Hundley: They had 21,768 non-anticoagulated cardiovascular implanted electronic device patients from the Optum electronic health record, de-identified database from 2007 to 2017 and they link those to the Medtronic CareLink TM database of CIEDs capable of continuous AF monitoring. Now the age averaged about 69 years and 63% were men and they found that increasing a fib duration, and of course increasing CHA2DS2-VASc2 score were both significantly associated with annualized risk of stroke and systemic embolism. These rates were low however, in those individuals with CHA2DS2-VASc2 scores of zero to one, regardless of the device detected a fib duration.

Dr Carolyn Lam: Ah. Were there any particular threshold values that seemed important?

Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk crossed an actionable threshold defined as greater than 1% per year in those with CHA2DS2-VASc2 score patients of two or more with greater than 23 and a half hours of a fib or those patients with CHA2DS2-VASc2 scores of three or four with greater than six minutes of a fib duration or finally in those individuals with CHA2DS2-VASc2 scores greater than five even if they had no atrial fibrillation.

Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions here. Thanks Greg. I'm going to tell you what else is in this issue. There's also a research letter by Dr Rosenmeier entitled, “Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin 6 Receptor Dependent Mechanism.” And this is a cardiac analysis of a double blind randomized controlled trial in abdominal obese humans. We have an on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to Explore the Role of Genetic Heterogeneity in Conferring Phenotypic Variability.” And this discusses among other things, the role of induced pluripotent stem cells and functional studies of bioengineered HFpEF patient derived cardiac micro tissues that could potentially enable several important questions to be answered for the first time. There's an ECG challenge as well by Dr Naru Kanya, and it's really interesting. It's a hiccup artifact. If you haven't heard about that, you should take a look. And finally cardiology news by Dr Kuhn and it's entitled, “Nourishing Native American Communities by Increasing Access to Traditional Food.” A very interesting paper right there.

Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten provides a perspective piece regarding emerging affinity reagents for high throughput proteomics, sort of an emerging field, everyone doing proteomic studies, we have to pay a special attention to the reagents that are being used. And then Andrew DeFilippis from University of Louisville as well as Johns Hopkins reviews important concepts related to the definition of MI.

Dr Carolyn Lam: Is this pertaining to that fourth universal definition of MI?

Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this white paper, the authors review the epidemiology, risk factor associations and diagnostic tools that may assist in differentiating between non-ischemic myocardial injury, type 1 MI and type 2 MI. And then finally from Suowen Xu from the University of Rochester, there's a letter discussing the CCN family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are mechano-sensitive proteins that are differentially regulated by sheer stress, the frictional force exerted by blood flow in our vessels. Well Carolyn, that's a great issue. How about we move on to our feature article?

Dr Carolyn Lam: Let's go Greg.

For our feature discussion today we are talking about intensive versus standard ambulatory blood pressure control and that effect on cerebral vascular outcomes in older people or the INFINITY trial. Very, very important stuff and I'm so pleased to be with the corresponding author, Dr William White from Calhoun Cardiology Center in University of Connecticut School of Medicine. Dr White, thank you so much for being here. Could you maybe set up already the background of what you were thinking when you started this trial? Especially given the results that we know from SPRINT and SPRINT mind. Could you perhaps comment on how this INFINITY trial is different?

Dr William White: We started work in this area about 15 years ago and we initially were interested in interactions among vascular risk factors including ambulatory blood pressure, lipids and other sort of thrombotic factors and so forth with the development of small vessel disease in the brain that led to these fairly classic images on MRI called white matter hyperintensity lesions. And we learned from a prospective cohort study that we started about 15 years ago, that there was a very strong relationship between ambulatory blood pressure and the development and progression of these white matter hyperintensity lesions on MRI, but not very nice relationship with the clinical blood pressures measured in the standard office practice.

We decided to pursue a clinical trial, a randomized clinical trial in which we would evaluate different levels of ambulatory blood pressure versus the development of the small vessel disease as imaged by MRI, but very importantly we also wanted to link it to functional outcomes because this was in older people, typically in their late seventies, eighties and even nineties in which cognitive impairment begins to develop. There's problem with mobility, bladder function and things of that nature. And since our funder was always the National Institute of Aging of the NIH, there's a great deal of interest in more than just the vascular risk factors and even the cerebral vascular disease that we would detect on the MRI. That was the background of why the study got developed the way it did.

Dr Carolyn Lam: That's so interesting. You've already pointed out ways that this was very different from SPRINT OR SPRINT MIND in looking at ambulatory instead of clinic blood pressure and I suppose in the population you selected, out of curiosity, you mentioned that your prior work showed a relationship between white matter hyperintensity on MRI and perhaps future dementia. In which direction? And is there any basis to suspect low, too low blood pressure may also be bad in these older people who already have microvascular brain disease?

Dr William White: Absolutely. Very important point. When we look at our prospective cohort which was about a 100 older people, we followed for four years without any intervention. This was just a mixture of normal tensive and hypertensive individuals. Some on meds, some not on meds. But we did show that when you got too low or if you stay too low during those four years with a systolic blood pressure of under 115 on a 24-hour blood pressure monitor, it seemed like there was an almost like U shaped relationship with progression of white matter disease. Below 115 there was more accrual of white matter disease. Above 150 there was a systolic blood pressure, there was also a greater accrual, but in between about 125 and 145 we weren't really sure if there was going to be a difference. And that there was the target is that everybody's talking about for clinical measurement, so we decided to pursue that in this study to determine if we could figure out whether or not there was a sweet spot for the desk blood pressure without getting into trouble with hypotensive symptoms.

Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely. Now I get it that you chose the targets that you did, which just for everyone, just a reminder, it was a 24 hour mean systolic blood pressure by ambulatory blood pressure control and the two targets were 130 millimeters mercury and less versus 145 millimeters mercury and less. With that, could you please tell us the results?

Dr William White: Right. We called the 130 or less systolic group, the intensive treatment group and the 145, the standard group. We focused on the primary endpoint was changes in mobility parameters in conjunction with changes in white matter hyperintensity lesion growth. And after a period of about three to four months of randomization, post randomization, we achieved a 24-hour systolic blood pressure about 128 millimeters of mercury in the intensive treatment group and 144 in the standard group. And we maintained a pretty good separation in blood pressure, ambulatory blood pressure throughout the three years of treatment. Now the changes in gait speed, which was one of our primary parameters for mobility actually turned out not to be different between the treatment groups. That is intensive versus standard. However, the changes in the accrual of light matter hyperintensity volume was smaller in the intensive treatment group of a 0.29% versus a 0.48% in the standard treatment group. That was significant at a P value of 0.03.

We actually also had a pre-specified sensitivity analysis, sort of a per protocol analysis that allowed us to look at people who stayed in their sort of assigned treatment groups based on blood pressure throughout the three years of the trial. And in that circumstance, there was actually a stronger separation because these are people who stayed clearly at 130 or less than about 145 throughout the three years and now the differences were approximately 0.23% in the intensive group and 0.58% in the standard group. And now the P value is smaller, .0028.

I think we proved in the study that maintaining a systolic blood pressure on the ambulatory recorder over 24 hours of 130 or less benefited patients by reducing the accrual of white matter hyperintensity lesions by about 40% relatively speaking compared to a standard ambulatory blood pressure value of a 145. One of course caveat is that after that happened within three years, but we did not see the expected benefit on mobility or on most of the cognitive parameters either. And while we were a little bit surprised about that, when we went back and analyzed our situation with where people started from as far as this particular cohort of patients, they might've been a little on the healthy side compared to some other studies. A very educated group, very compliant with everything that they did. And probably three years was just not long enough to show the result of this white matter hyperintensity benefit on some of the functional outcomes.

Dr Carolyn Lam: That's really interesting and I'm glad you sort of tackled head on that sort of apparent dissociation between the clinical end points and the MRI end point. Could I also ask, wouldn't those findings also be consistent with SPRINT and SPRINT MIND?

Dr William White: In many ways our results were consistent with SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course, just let me mention the differences between the two studies. Of course, SPRINT was very large but there are sub-studies were not as large as the parent study. The MRI study had about 300 plus patients randomized into it, but the measurement of blood pressure was done in the standard clinical fashion and used that digital device that was able to take measurements without somebody present in the exam room. Though they were a bit lower than what I would have seen on an ambulatory monitor during the day time. And their goals were 120 systolic versus 140, whereas ours were an ambulatory systolic of 135 and 145.

But the results were actually comparable because they showed a benefit with regards to lesser accrual of white matter hyperintensity volume in the intensive group versus this banner treatment group. But they also showed no differences after 3.4 years in the incidence of dementia. And they also showed in a separate study, no differences in gait speed in the population who are in intensive versus standard treatment. One would say that results were really actually comparable despite the age differences and the blood pressure measurement differences. And I think both studies really point to the fact that lower systolic blood pressures in older people should be our target because it's safer actually then than maintaining people in the 140s.

Dr Carolyn Lam: Maybe the follow-up period was not long enough. Could it be possible too that maybe blood pressure control should start earlier in life. Could that be it? And then also, could you give us an idea of the kinds of changes, the magnitude of the change on MRI that you see for those of us that don't think about this all the time, is this a big change considered for your cohort or is it a little change?

Dr William White: I think it's true that these people started out around 81 years old in this trial and so by the time they got to that age and had systolic hypertension for probably as many as 20 years, that some of the damage that was done was obviously permanent and we don't really know how long it took for that to accrue. What we did know is that with three years of intensive treatment, we benefited patients by reducing the continued growth or confluency of these small vessel lesions in the brain. Now the range in the amount of damage varies from about half a percent of the overall brain volume to about 5%, so a 10-fold magnitude difference in our cohort.

And as a result of that, certainly somebody who's got about two to 3% of their brain occupied by better hyperintensity lesions or damage is going to have a great deal more functional disability than somebody who's .5%. I think we have to look at the outliers as well as the mean and median changes that we saw. The mean changes are not huge. The difference between 0.2 and 0.6% for example, in our protocol analysis, 0.4% to me it's clinically relevant because I know that that means that there are some people who went up by a percent or two over the years versus the standard versus the intensive treatment group. That's a big difference in an individual over that period of time.

Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my brain.

Dr William White: Yeah. Plus it's also where it's located because the lesions are typically around the ventricles of the brain and it's exactly where neurons are going sort of posteriorly to anteriorly to transmit information. For example, from the visual center to the sort of spatial motor cortex. And when those are interrupted, even if it's in one or 2% of the tissue, it can cause substantial difficulties for people. And it's for both the flow of cognitive information as well as this flow of a mobility and balance. I think that it is very relevant, but the gray matter is affected much less by this compared to the white matter. But there are still studies that show that gray matter sort of follows in line with that so that of course also enhances thought processes and cognitive function as well.

Dr Carolyn Lam: Wow. I love the way you explained that. Very important question would of course be the safety and tolerability of this more intensive approach. Any comments there?

Dr William White: Our sponsor, the National Institute of Aging did recruit a data safety monitoring board that was independent from the study for all the years. Impressively over the course of this trial, even though there wasn't a large sample, it was a 199 people, we saw a significant benefit in the intensive group for cardiovascular events, so there were less admissions for heart failure. There were less myocardial infarctions, there was less strokes. All these kinds of things that we worry about in our patients as they get older with vascular disease was reduced by about 75% in the intensive treatment arm versus the standard arm. As far as the events that we were concerned about, such as falls and syncope and presyncope and things of that nature, they were virtually identical in the intensive treatment group and `the standard treatment group. When you take that into consideration, along with the fact that you're reducing the accrual of small vessel disease in the brain, it's clear that this population, even though they're older, would benefit from a lower systolic blood pressure.

Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That was a beautiful summary. That is the take home message right there.

Listeners, I'm sure you agree with me. Thank you so much for joining us this week, and don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

Circulation November 5, 2019 Issue

4 november 2019 | 23 min

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC simultaneous publication issue, isn't it? So the original papers were simultaneous publications at the European Society of Cardiology meeting this year.

Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So Carolyn, later we're going to listen to the authors of this feature discuss the association between ICD use and all-cause mortality in a contemporary heart failure reduced ejection fraction cohort and examine relevant subgroups. So Carolyn, I'm going to get started with my first paper and it's a randomized trial of one hour, one-hour deponent T protocol and suspected acute coronary syndromes and it's a rapid assessment in emergency rooms and it's from professor Derek Chew from Flinders Medical Center. High sensitivity troponin assays promise earlier discrimination of MI, yet the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols with respect to subsequent testing and clinical events has not been evaluated in an in-practice, patient level, randomized study. So this multicenter study evaluated the non-inferiority of a zero to one hour, zero to one-hour, high sensitivity troponin T protocol compared with a more traditional zero to three-hour mask, high sensitivity troponin T protocol in those suspected with ACS.

Dr Carolyn Lam: Interesting. So what did the study show?

Dr Greg Hundley: So participants in the zero to one-hour arm were more likely to be discharged from the ED quicker and that would be expected. So 45% versus the standard arm, which was 32%. Also their median ED length of stay was shorter, and we would expect that. Four and a half versus five and a half hours. Those randomized to the zero to one-hour protocol were less likely to undergo functional cardiac testing. The zero to one-hour high sensitivity troponin T protocol was not inferior to standard of care and among patients discharged from the ED, the zero to one-hour protocol had a negative predictive value of 99.6% for 30-day death or MI. So Carolyn, how about your first study?

Dr Carolyn Lam: Well, from MI risk stratification to heart failure risk stratification. I'm going to tell you about a paper describing the TIMI Risk Score for heart failure in diabetes, which is a novel integer base clinical risk score for predicting hospitalization for heart failure in patients with type two diabetes. This is from Dr Mark Sabatine and the TIMI study group who developed a clinical risk score for heart failure hospitalization in more than 8,200 patients with type two diabetes in the placebo arm of saver TIMI 53, as well as externally validated this score in more than 8,500 patients with type two diabetes in the placebo arm of declare TIMI 58.

They found that five clinical variables were independent risk predictors of heart failure hospitalization. These were prior heart failure, history of atrial fibrillation, coronary artery disease, estimated GFR, and urine albumin-to- creatinine ratio, a simple integer base score from zero to seven points. Using these predictors identified a more than 20 full gradient of heart failure hospitalization risk in both the derivation and validation cohorts with high SES statistics. Although the relative risk reductions with dapagliflozin were similar for patients across the risk scores, the absolute risk reductions were greater in those with higher baseline risks.

Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical implications of this really thorough study?

Dr Carolyn Lam: In summary, the risk score had excellent discrimination in two large clinical trial cohorts. It was well calibrated, and it identified a strong gradient of increasing absolute reduction in risk of heart failure hospitalization with the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk Score for heart failure in diabetes, which is a simple validated clinical risk score, clinicians could better educate patients about their risk for heart failure hospitalizations and could perhaps better identify those patients who have a greater absolute risk reduction in heart failure risk with SGLT two inhibitors.

Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back to the world of troponins and talk about a paper from Nicholas Mills from University of Edinburgh. And in this study, they evaluated the safety and effectiveness of risk stratification thresholds of high sensitivity troponin in patients with suspected acute coronary syndrome. 48,282 consecutive patients with suspected ACS were enrolled in a multicenter trial from 10 hospitals within Scotland and they're pre-specified secondary and observational analyses. They compared the performance of the limit of a detection of less than two nanograms per liter versus the optimized stratification threshold of less than five nanograms per liter using the Abbott high sensitivity troponin I assay. Patients with myocardial injury at presentation with less than two hours of symptoms or with ST segment elevation myocardial infarction were excluded and the negative predictive value was determined in all patients in subgroups for a primary outcome of MI or cardiac death within 30 days. And they had a secondary outcome that was MI or cardiac death at 12 months.

Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was the optimal one?

Dr Greg Hundley: So the negative predictive value for the primary outcome was 99.8% and 99.9% in those with cardiac troponin I concentrations of less than five or less than two nanograms per leader respectively. At both thresholds, the negative predictive value was consistent in men and women across all age groups. Although the proportion of patients identified at low risk fell with increasing age. Compared to patients with cardiac troponin I concentrations of greater than five nanograms per liter but less than the 99th percentile, the risk of MI or cardiac death at 12 months was 77% lower in those with less than five nanograms per liter and 80% lower in those with less than two nanograms per liter. So in conclusion, use of risk stratification thresholds for high sensitivity cardiac troponin I identified patients with suspected acute coronary syndrome in at least two hours of symptoms at low risk presentation irrespective of both age and sex.

Dr Carolyn Lam: Very nice. Well, more risk stratification in this next paper, which really evaluated the application of the 2018 ACC AHA Cholesterol Management Guideline recommendations for additional lipid lowering therapies in patients with established atherosclerotic cardiovascular disease and residual dyslipidemia despite maximum tolerated Statin who were enrolled in the ODYSSEY OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol Management Guidelines recommend additional lipid lowering therapies for secondary prevention in patients with LDL above 70 or non-HDL above a hundred despite maximum tolerated Statin therapy.

Such patients are considered at very high risk based on a history of more than one major atherosclerotic cardiovascular disease event or a single event and multiple high-risk conditions. So in this paper from Dr Matt Roe from Duke Clinical Research Institute and colleagues, they found that in the ODYSSEY OUTCOMES trial, patients classified as very high risk by these 2018 ACC AHA guidelines and either because of a history of multiple atherosclerotic cardiovascular events or a single event, which is a trial qualifying acute coronary syndrome and multiple high risk conditions, these very high risk patients had more than double the risk of recurrent cardiovascular events as compared to patients classified as not very high risk.

They further looked at the association of Alirocumab with outcomes and found that Alirocumab was associated with a consistent relative risk reduction in both risk categories. But the absolute risk reduction for major adverse cardiovascular events was numerically greater, although not statistically different, in the very high-risk group versus those not at very high risk and among patients at very high risks with multiple prior events versus a single prior event.

Dr Greg Hundley: Wow, Carolyn. Can you put all this together? This is a lot of information in this study.

Dr Carolyn Lam: Yes, so it would appear that the application of the new ACC AHA 2018 guideline recommendations for risk stratification and the use of additional lipid lowering therapies in patients with established cardiovascular disease clearly identifies patients at very high risk of recurrent cardiovascular events after an acute coronary syndrome and these patients may derive substantial benefit from additional lipid lowering therapy, for example, with a PCSK nine inhibitor.

Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off with what other articles we have in this ESC featured issue of our journal. So Jonathan Stamler and John Lundberg in separate letters discuss findings related to whether hemoglobin beta 93 cystine is not required for export of nitric oxide bio activity from the red blood cell. And in additional separate letters, Doug Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and attenuation of pathological and metabolic cardiac remodeling through selective lipid trafficking. In a perspective piece, Blake Thomson from the University of Oxford discusses what Medicare for all in the United States can mean for US medical research and provides lessons from the United Kingdom. In a letter from the United States, Gregory Marcus from University of California San Francisco discusses incident atrial fibrillation among American Indians in California and then both Marco Bergonti from University of Milan and Derek Chew from University of Calgary present two separate cases in our ECG challenge feature. Well, Carolyn, what a great issue and how about we turn to our feature discussion?

Dr Carolyn Lam: Yes, let's go. Thanks, Greg.

Dr Greg Hundley: Welcome, everyone, to our feature discussion today we have Gianluigi Savarese from Karolinska Institute in Stockholm, Sweden and our own associate editor, Sana Al-Khatib from Duke University. We're going to be discussing implantable cardioverter defibrillators in their mortality and looking at a more recent take on this relative to some of the previous published studies. So Gianluigi, I'd like to start with you. Could you tell us a little bit about the hypothesis and why you wanted to perform your study?

Dr Gianluigi Savarese: Yes. Basically we design our study based on three main considerations. First one is recent studies show that the advance in heart-failure therapies have impact patients' risk profile leading to roughly 40% reduction risk of sudden cardiac death in HFrEF and RCTs on ICD use for primary prevention of sudden cardiac death and rural patients more than 20 years ago and thus, nowadays the beneficial prognostic effects of ICD may be different due to the improved risk profile in this population.

The second consideration was that efficacy of ICD patients with heart failure with non-ischemic cardiomyopathy patients receiving a contemporary heart failure therapy as being a question in Danish trial and the third consideration is that efficacy of ICD in elderly is still debated due to findings again from the Danish trial showing a significant reduction in all-cause death associated with ICD use in patients age younger versus older than 70 years old. Based on these considerations, we decided to assess the use of ICD for primary prevention propose in a contemporary and selected FRF population and to assess the association between ICD use and outcomes in such a population.

Dr Greg Hundley: So it sounds like we're doing an update on the utility of ICDs. Can you tell us a little more about your study population and your study design and then let's hear a little bit about your results.

Dr Gianluigi Savarese: Sure. First of all, I would like to first highlight of course the observational natural of this study. Our analysis is performed using data from the Swedish Heart Failure Registry, which is a large enough select court of heart failure patients, enrolling patients regardless of ejection fraction. So today we have roughly around 70,000 patients. And of course for the current analysis we select the patients with HFrEF. There were around 15,000 patients with the HFrEF who were eligible for ICD use for primary prevention according to the ESC guidelines. A study design, we used propensity score matching design in order to try to address the issue of potential compounders. Of course this is a very important point in observational studies. So basically, we amassed patients receiving the ICD versus those not receiving ICDs. And we assessed the association between ICD use and all-cause death and cardiovascular death and we accessed one year and five-year outcome.

Dr Greg Hundley: And so what were some of those results?

Dr Gianluigi Savarese: What we observed is that there was a statistically significant 25 relative risk reduction in all-cause mortality in ICD recipients versus those who didn't receive an ICD within one year and there was also a 12% reduction erased within five years. And we also serve a statistically significant 29% reduction in risk of cardiovascular mortality within one year. But we were not able to observe any association for cardiovascular mortality within five years. We thought it was particularly relevant to have subgroup analysis in our studies since there are so many questions regarding ICD use in specific subgroups, which are, for example, older versus younger patients, those with versus without ischemic heart disease, males versus the females and so on. So what we observed was that results in terms of all-cause mortality were consistent in all of the subgroups considered such as patients older versus younger than 70 years old, versus those without history of ischemic heart disease and those with versus without concurrent CRT use.

Dr Greg Hundley: What about the frequency of implanting ICDs? Was the frequency expected in your results?

Dr Gianluigi Savarese: We add that only 10% of our patients received an ICD at the baseline. This person's age is quite low in particular. If we compare these with other studies in US for example, or also in other European countries and basically, we can only speculate about the underuse of ICD in primary prevention propose. First of all, a certain proportion of ICD underuse may be explained by the fact that we could not assess whether life expectancy was longer than one year, and this is one of the eligibility criteria for ICD according to the guidelines.

Then another point is that in Sweden, the majority of heart failure patients are seen by primary care physician and general practitioners who may have less knowledge and acceptance of device therapy and then higher perception of contraindication. In our previous analysis, we showed that patients not seen by cardiologists have lower likelihood of receiving an ICD and use of devices is higher in centers who do implants, CRT, ICD. So this may be some of the explanation that I can anticipate that some more analysis will follow where we will try to assess the predictors for an under use of ICD for primary prevention.

Dr Greg Hundley: Well, thank you very much. Sana, now we're going to turn to you and help us put this study in perspective to what we have already found or observed in other prior studies related to implantation of cardio defibrillators.

Dr Sana Al-Khatib: As was mentioned earlier, I was the handling associate editor for this paper, so I really enjoyed the handling it and writing an editorial on it. The main points that I wanted to touch on are number one, the significantly low or reduced utilization rate of ICDs. So as was mentioned, the 10% of this patient population received a primary prevention ICDs. Even if you account for some of the new ones is that you can't estimate life expectancy. You can't capture granular clinical data on these patients. So of course some of the non-use of ICDs may have been appropriate. I think 10% by anyone's definition is still pretty low and I'm very encouraged to hear that there are plans to look at predictors of non-use, the characteristics of those patients and hopefully the office can build on their findings and try to implement some strategies to improve the utilization of this life saving therapy.

The other thing that I wanted to touch on is clearly the results are positive in favor of the implantable cardioverter defibrillator. Showing that it significantly reduces all-cause mortality within one year, within five years, certainly reduces cardiovascular mortality within one year. As was mentioned, the reduction in cardiovascular mortality within five years was not significant and to me that is probably mostly explained by competing causes of death in this patient population, but I also cannot rule out the possibility of some mis-classification of causes of death, which is not uncommon. I do want to commend the authors for the great and robust methods that they applied in their analysis. As was mentioned, this was a comparative effectiveness research using observational data. These kinds of analyses can be pretty challenging, but the authors defined their patient population very clearly. They used propensity score matching. In fact, they took it a step further by doing a negative control analysis, meaning looking at hospitalizations for renal failure, for pneumonia, respiratory infections, things like that that you don't expect to be affected by the ICD and they found no difference in that.

And that is amazing to kind of see this level of analysis that I believe really lends their results more credibility. It is important though to keep in mind that when you have 10% of patients getting an ICD, I suspect that this was a highly selected patient population and most likely people who were thought to benefit the most from ICDs were implanted with an ICD. And yet, as I said, that given the robustness of the methods that they use, I actually believe the results. I think the results are credible.

The one last point that I want to comment on is the subgroup analyses that were mentioned. Absolutely important subgroups to look at from a clinical perspective. But I point out the fact that when you start looking at subgroup analyses, and especially when you have a smaller sample sizes and lower event rates that it makes you start thinking about, "Well, are these results valid? Are they believable?" I mean, even honestly, in the setting of a randomized clinical trial, I look at subgroup analyses as hypothesis generating. So I liked that they included those just to kind of really emphasize the importance of looking at these subgroups. But I certainly would not put too much weight on the subgroup analysis results, but overall great results and congratulations to the authors.

Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on behalf of Carolyn Lam and myself, we wish you a great week and we look forward to speaking with you next week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation October 29, 2019 Issue

28 oktober 2019 | 23 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results.

Dr Greg Hundley: How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers.

Dr Carolyn Lam: So... What did they find?

Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients.

Dr Carolyn Lam: Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized.

Dr Carolyn Lam: So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP.

Dr Carolyn Lam: So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes.

Dr Greg Hundley: Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study?

Dr Carolyn Lam: Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more.

Dr Greg Hundley: Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells.

Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find?

Dr Greg Hundley: First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart.

Dr Greg Hundley: So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy.

Dr Greg Hundley: So Carolyn, how about the other articles in this issue? Can you tell us a little more about them?

Dr Greg Hundley: Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer.

Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap.

Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece.

Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter.

Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock.

Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy.

Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study?

Dr John Eikelboom: Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer.

Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population?

Dr John Eikelboom: The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk.

Dr Greg Hundley: And who did you include in this study?

Dr John Eikelboom: We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention.

Dr Greg Hundley: And how many subjects were in your study? Was this a large study?

Dr John Eikelboom: The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations.

Dr Greg Hundley: So what did you find? What were your results?

Dr John Eikelboom: We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis.

To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis.

Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis.

Dr Greg Hundley: Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women?

Dr John Eikelboom: The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding.

Dr Greg Hundley: Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies?

Dr Shinya Goto: This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer.

And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear.

Dr Greg Hundley: Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation?

Dr Shinya Goto: If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial.

Dr Greg Hundley: John, do you have any perspectives? Where do you see your research going in this area over the next five years?

Dr John Eikelboom: In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier?

Dr Greg Hundley: Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy.

And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation October 22, 2019 Issue

21 oktober 2019 | 22 min

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article?

Dr Carolyn Lam: I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm.

Dr Greg Hundley: Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first?

Dr Carolyn Lam: Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm.

Dr Greg Hundley: Interesting. What did they find, Carolyn?

Dr Carolyn Lam: They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery.

Dr Greg Hundley: Fantastic, Carolyn.

Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension.

Dr Carolyn Lam: Huh. What did they find Greg?

Dr Greg Hundley: In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients.

Dr Carolyn Lam: Wow, that is super interesting. Thanks Greg for that great summary.

Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry.

Dr Greg Hundley: Carolyn, what did they find?

Dr Carolyn Lam: They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag?

Dr Greg Hundley: Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.

First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal.

Dr Carolyn Lam: Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion.

Dr Greg Hundley: You bet.

Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods.

Dr Senthil Selvaraj: I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.

I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation.

Dr Greg Hundley: What was your overall study design and your study population?

Dr Senthil Selvaraj: The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important.

Dr Greg Hundley: And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms?

Dr Senthil Selvaraj: PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan.

Dr Greg Hundley: Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF?

Dr Senthil Selvaraj: We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.

The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.

We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes.

Dr Greg Hundley: Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct?

Dr Senthil Selvaraj: That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well.

Dr Greg Hundley: Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works?

Dr Mark Drazner: Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?

And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion.

Dr Greg Hundley: What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy.

Dr Mark Drazner: I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients.

Dr Greg Hundley: Very good. Senthil, do you have anything to add to that?

Dr Senthil Selvaraj: I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses.

Dr Greg Hundley: Listeners, we look forward to speaking with you next week and have a great week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation October 15, 2019 Issue

14 oktober 2019 | 20 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health.

Well, Carolyn, we've got a great feature article to discuss later in our interview today. We're going to compare surgical versus percutaneous aortic valve replacement, but now with coronary artery revascularization. So, very exciting results from the SURTAVI trial.

So, Carolyn, do you have a couple papers to discuss?

Dr Carolyn Lam: For sure. Actually, it's exactly a couple, and it's a couple of GWAS papers. The first is a GWAS of the cardiac magnetic resonance imaging derived left ventricular phenotypes of the UK bio bank. It comprises almost 17,000 European-UK bio bank participants without prevalent myocardial infarction or heart failure. So this was led by professors Petersen and Monroe from Queen Mary University of London, and colleagues who found that prognostically important left ventricular imaging phenotypes were highly heritable, with a heritability of 22 to 39%. A total of 14 genetic susceptibility low PSI, eight of which were unique, enriched in the cardiac developmental pathways and regulation of contractile mechanisms were discovered, and the polygenic risk scores of left ventricular phenotypes were predictive of heart failure events independently of clinical risk.

Dr Greg Hundley: Well, Carolyn, knowing me and MRI, something I really am interested in. So tell us a little about what are the clinical implications?

Dr Carolyn Lam: Well, the findings not only enhance our understanding of the genetic basis of prognostically important left ventricular phenotypes in the general population, but they also underscore the intricate genetic relationship between these endo phenotypes and the pathogenesis of heart failure. The prioritized genes in the genome whites significant load size should be followed up in the functional studies to aid the development of potential novel therapies in future. The polygenic risk scores of left ventricular phenotypes may have a role in personalized risk stratification. But this, of course, is dependent on further validation of the clinical robustness in future studies.

I want to skip onto my second GWAS paper, and this time dealing with bicuspid aortic valve. So, first a little reminder that bicuspid aortic valve disease is a congenital defect that affects 0.5 to 1.2% of the population, and is associated with comorbidities including ascending aortic dilatation and calcific aortic stenosis. To date, while a few causal genes have been identified, the genetic basis for the vast majority of bicuspid aortic valve cases remains unknown. Today's paper from Dr Lipschultz from Medical University of South Carolina reports novel human genetic based models, which developed bicuspid aortic valve and aortic stenosis with high penetrance.

Dr Greg Hundley: Very interesting. So, how did the authors do this, Carolyn?

Dr Carolyn Lam: Yeah, it is interesting. What they did is they performed a GWAS and replication study using cohorts of more than 2,000 patients with bicuspid aortic valve and more than 2,700 controls, which identified the primary Celia genes as associated with the bicuspid aortic valve phenotype. Specifically the most associated snips were identified in or near genes that are important in regulating Ciliogenesis through the exocyst, which is a shuttling complex that chaperone Celia cargo to the membrane. Genetic dismantling of this exocyst resulted in impaired Ciliogenesis through the XO CIS, disrupted Ciliogenic signaling, and resulted in a spectrum of cardiac defects in zebra fish and aortic valve defects including bicuspid aortic valve, valve stenosis, and Velveeta calcification in murine models as well. So this data really supports that the exocyst is required for normal Ciliogenesis during aortic valve morphogenesis and really implicates the disruption of Ciliogenesis, and its downstream pathways may contribute to bicuspid aortic valve and its associated comorbidities.

Dr Greg Hundley: Wow. Very interesting. Learning more and more about bicuspid valves through our journal. I'm going to shift Carolyn and talk about an article from Dr Marc Sabatine from the TIMI study group at Brigham and Women's hospital. This study performed a systematic review and a trial level meta regression analysis of three classes of lipid lowering therapies that reduce triglycerides to a greater extent than they do LDLC. Fibrates, Niacin, and Marine derived Omega-three fatty acids and key inclusion criteria were a randomized, controlled trial that reported on major vascular events. The study also incorporated data from a previous Meta-regression of 25 Statin trials, and the main outcome measure was the risk ratio for major, vascular events associated with absolute reductions in lipid parameters.

Dr Carolyn Lam: Oh, very interesting. So did the study show that it was beneficial to lower triglycerides or not?

Dr Greg Hundley: Let me tell you a little more about it. The study encompass 374,358 patients that sustained 46,180 major cardiovascular events, and in their multi-variable Meta-regression model, that included terms for both LDLC and triglyceride surrogates for LDL and VLDL. The risk ratio was 0.8 per one millimole per liter reduction in LDLC, and 0.84 per one millimole liter reduction in triglycerides. Therefore, a reduction in non-HDLC, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid lowering drug class, and triglyceride lowering is associated with a lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction then with LDLC. Interesting, Carolyn one study reduce it and impacted the study results, and nearly all non-statin trials did not achieve significant non-HDLC lowering to detect a clinical difference in major vascular events. Now how about in regards to Omega- three dose?

Well, each one gram per day of EPA administered was associated with a 7% relative risk reduction in major vascular events, whereas there was no significant reduction in major vascular events with DHA. So the benefits of Marine-derived Omega-three fatty acids, particularly high dose EPA, appear to exceed their lipid lowering effects.

Dr Carolyn Lam: Wow. Interesting. So Greg, take it home for us. What should we do clinically about this information?

Dr Greg Hundley: Carolyn, developing drugs that achieve large reductions in VLDL and triglycerides and are targeting patients with high baseline levels of triglycerides would likely increase the probability of showing a meaningful clinical benefit, and fibrates could be considered in patients needing further non-HDLC lowering, being mindful of side effects, as they should offer clinical benefit proportional to the degree of non-HDLC lowering, and if a disproportionate relationship between lipid lowering and cardiovascular risk reduction is validated in ongoing high dose Omega-three fatty acid trials, it will support the hypothesis that confers a unique benefit of this class of agents beyond simply their lipid lowering.

How about that?

Dr Carolyn Lam: Very nice Greg and I think very balanced and good clinical take home messages. Tell us what else is in the mailbag.

Dr Greg Hundley: We have so many interesting articles in Circulation and let me just run through a quick list of those that are also in this issue. First, Dr Jere Mitchell, from UT Southwestern, reviews the 50th anniversary of the Dallas Bedrest Study that involve five 20-year-olds that underwent several weeks of bedrest, and he discusses how this informs many of our thoughts regarding the benefits of activity today, and one of his major coauthors is Dr Ben Levine. Our own Josh Beckman reviews the ongoing efforts of physicians to understand the role of paclitaxel coated stents for those undergoing peripheral arterial interventions. Dr Berlinde von Kemp, in our case series, identifies that not all cardiomyopathy, after delivery, is simply postpartum cardiomyopathy. In another article, Dr Anurag Agrawal discusses what's on their mind regarding the use of spirometry as a cardiovascular disease risk assessment tool, should it be incorporated into existing cardiovascular disease risk models.

Then, we have a great letter back and forth discussion from Dr Junfeng Wang, Dr Daxin Wang, and our own Naveed Sattar in three separate letters that discussed the relevance of age of onset for type two diabetes relative to cardiovascular risk. Then, finally our own Carolyn Lam reviews the role of biomarkers in heart failure and preserved ejection fraction.

Dr Carolyn Lam: Let's hop on to our feature discussion, shall we?

Dr Greg Hundley: Absolutely.

Dr Greg Hundley: Welcome everyone to the discussion of our featured article today where we're going to review an excellent study comparing TAVR versus SAVR in patients with aortic stenosis, but also now considering simultaneous coronary artery revascularization. Discussing our article today we have Dr Thomas Engstrøm and then our own associate editor, Dharam Kumbhani. Well Thomas, welcome to our podcast featured article discussion. I wonder if you could start us off with a little background regarding your study. What were your hypotheses, and then tell us a little about your study population and your methods.

Dr Thomas Engstrøm: Now, as you know, up to 50% of patients that are treated for aortic stenosis have coronary artery disease, and this may be considered as a bystander disease to develop disease, but definitely also adds to the prognosis for the patients. A priority guideline recommends that if you do SAVR, you'll also have significant coronary artery disease. What we don't know is if the complete percutaneous approach is as good as a surgical approach. Maybe do TAVR plus PCI comply with fiber plus CABG. That's the background for the study.

Now, the population involved in this study is the population from the search TAVR trial, which as you know compared TAVR to SAVR in patients that were clinically at intermediate risk and in patients that had severe aortic stenosis. If patient had additional coronary artery disease with a syntax called Bob 22, they were excluded from the trial. We are talking about intermediate risk patients with low syntax score. Of the patients in the TAVR trial, 20% had additional coronary artery disease and were resterilized. In the paper, we compare TAVR plus PCI versus SAVR plus CABG in those patients with significant coronary artery disease.

Dr Greg Hundley: How did you define the presence or absence of coronary disease? Just real quickly before we get to your results.

Dr Thomas Engstrøm: This was at the discretion of your operator to define where the patients had coronary artery disease or not. In the paper, patients were defined as having significant diseases. More than 70% of stenotic lesions were present in one or more coronary arteries.

Dr Greg Hundley: And so can you tell us, Thomas a little about the results of your study?

Dr Thomas Engstrøm: First of all, the patients that had additional coronary artery disease had a poor prognosis than those that only had valve substitution, which is probably not a surprise. Within those that also had coronary artery disease, TAVR plus PCI appeared to be as good as CABG plus SAVR in terms of the primary endpoint, which was all because mortality or disabling stroke after two years. Then, if you dive more deeply into the endpoint and the number of secondary endpoints were pre-specified, there were no differences regarding any stroke myocardial infraction and in total no differences between what you could call major heart end points. If you look more into detail of the secondary endpoint, there are subtle differences. Patients that were in the SAVR plus CABG had more atrial fibrillation as they also had more acute kidney injury following that treatment. Whereas, in the TAVR plus PCR, more patients had vascular complications and of course had the need for pacemaker implantation. There are differences between the outcome in the two groups, but not in regard of pre-specified primary and more important secondary endpoints.

Dr Greg Hundley: Dharam, I was wondering if you could help us think about what this means for the field in terms of both from aortic valve replacement, and then also the concomitant management of coronary disease in patients that require aortic valve replacement.

Dr Dharam Kumbhani: As Thomas just pointed out, I think this is a very important question. This comes up all the time in patients with severe aortic stenosis, being evaluated for best options, and the guidelines have stayed true to this that if somebody has concomitant coronary artery disease, then the guidelines typically would recommend SAVR as the first option because then they can have CABG at the same time. This study really seeks to address a very important knowledge gap in the field, and as he very well pointed out, this does restrict itself a little in terms of the population, because they couldn't have a high syntax score, actually an intermediate or high syntax score, and they need in the trial...I think the main syntax score was eight or nine. I think that is important, but having said that, more than 50% of the patients had multi-vessel disease, and it was really impressive that nearly 15 or 17% still had three vessel PCI even in this arm.

I think it's important for people to recognize that although this was the lowest syntax score, multivessel PCI was still pursued. I think that's definitely an important takeaway from the strike. It's a really important trial. It's one of the very few pieces of information that we have that is prospectively done under the auspices of a big trial like SURTAVI, and with low risk approval in and what this means for patients going forward I think will be very exciting to see how this few devolves.

Thomas, as this field matures, could you walk us through, in terms of did you do the valve first and then the coronaries, or where the coronaries worked on first and then the valve? That's sort of the first question. Can you walk us through how you make those decisions?

Dr Thomas Engstrøm: It was up to the discretion of the operator whether to do a concomitant procedure, both PCI and TAVR, or to state the procedures in that way that PCI was done first, and this could be done up to seven days before the TAVR. If you compare those two groups, and now numbers become a little bit few, so we can't be conclusive here. It appears that patients that had stage procedures did poorer than those that had concomitant procedures done. Of course, it raises some questions. The prioritization as to do it in one way or the other was that through concomitant procedure, you may introduce too much of stress to the patient. Otherwise, if you do a stage procedure, it's best to do the PCI first, because the actual appearance of the valve may make it more difficult and cumbersome to address the coronary arteries. To sum this up, in the patients that we have, it appeared that a concomitant procedure is safe.

Dr Greg Hundley: Dharam, tell us, what do you think is the next step forward for this field? What do see as the next study moving forward here?

Dr Dharam Kumbhani: I think this study really sets the stage for, I think future trials where perhaps we would have... So I'm doing this in this trial. The stratification was done based on whether or not they need to revascularization. I think going forward, again with LOTUS approval here and proliferation of the number of TAVR procedures that are being offered everywhere, I think it will be helpful. This study would set the stage for future studies, where I think you would prospectively have patients with needing an aortic valve replacement and perhaps even complex revascularization, and how that was kind of actually the randomization, which is the stratification strategy, which again was very helpful. These are really among the first few data that we have of this, but I think this kind of sets the stage for future investigations in this space. And then as I briefly alluded to, I think this may help evolve or this may help in the evolution on the guidelines as well.

Thomas, would you like to add anything to that?

Dr Thomas Engstrøm: Yeah, I completely echo that. Going back to the old syntax trial, it would be very interesting to see if PCI holds through, even in high tunes, syntax scores with newer drug eluting stents, and also of course the question of the diabetics is totally unsolved in this cohort. CABG plus SAVR may turn out to be the best solution, but we still are waiting to see data that can support any of the two strategies in those patient cohorts.

Dr Greg Hundley: We want to thank Thomas Engstrøm and also our own Dharam Kumbhani. We look forward to seeing you next week.

Dr Carolyn Lam: This program is copyright American Heart Association, 2019.

Circulation October 2019 Issue

7 oktober 2019 | 25 min

Dr James de Lemos: My name is James de Lemos. I'm the executive editor for Circulation and I'll be filling in today for Carolyn Lam and Greg Hundley, and delighted to host the podcast for the annual cardiac surgery themed issue. I'm joined today by Tim Gardner from the University of Pennsylvania who leads the surgical content in Circulation year-round, as well as by Dr Marc Ruel, who's the guest editor for this issue and the Chief of Cardiac Surgery at the University of Ottawa and has really led the development of this issue. Marc, Tim, welcome.

Dr Timothy Gardner: Thank you.

Dr Marc Ruel: Thank you. Good afternoon.

Dr James de Lemos: And Marc, thanks for all you've done to bring this issue home again this year. It's really wonderful to see this thing develop. Why don't you start us off and tell us how this issue came together and what the purpose of this is? Why do we publish a specific issue focused on cardiac surgery?

Dr Marc Ruel: We're really delighted that Circulation has taken the stance as the cardiovascular community's premier cardiovascular journal. I think as an important piece of this is the fact that cardiovascular surgery already has a resurgence intermediate with importance despite new percutaneous options and medical therapies available. There's more and more patients who find himself in need advance path if you will, of an advanced cardiovascular disease and surgery can be performed with safer and better outcomes constantly.

So, I think this issue obviously aims to gather the very best of cardiovascular surgery, not only including cardiac surgery, but also there's actually one of the papers on peripheral vascular surgery.

Dr James de Lemos: We'll start Tim with you if you don't mind. I'd like to talk about two papers. One from Stanford that focuses on inter-facility transfer of Medicare patients with Type A dissection and then a research letter that studies hospital volume effects with abdominal aortic aneurysm surgery from Salvatore Scali and colleagues at the University of Florida. Can you walk our readers through these papers and lead the discussion on these?

Dr Timothy Gardner: The first paper focused on inter-facility transfer of Medicare recipients with Type A dissections. First off, underlines the fact that this is a very difficult, serious condition with mortality rates in this series there ranging between about 22 and 30%. And the purpose of the study was to analyze how these Medicare patients with acute aortic Type A aortic dissections are managed and whether the effect of high or low volume hospital experiences influences the mortality. As I think we might expect, patients who receive care at high volume aortic surgery centers have a lower mortality. Then the question is, what is the effect of transfer from a low volume or from a hospital without aortic surgery capabilities? What is the net effect there? The benefit of care and a high volume hospital is pretty clear. The mortality rate is significantly lower and the need to transfer or the actual fact of transfer does not increase the risk to the patient.

It's an interesting challenge because we do know that patients with acute aortic dissection, if their repair or surgery is delayed, we'll have a predictable accumulating mortality. However, what this study shows is that the benefit of transfer and the importance of experience with this complicated aortic surgery. And it really brings up this very challenging issue of regionalization, of acute care or specialized care.

We really struggle with this in so many aspects of surgical care, medical care in general, but especially procedural care. We realize that we need to be able to provide emergency care in many areas and we don't want to suggest that that smaller hospitals may not be able to care for patients with acute complex illnesses. But on the other hand, if transfer can be accomplished and if the availability of high volume experience can be achieved, that this is something that we really need to look at carefully. I think that this study brings that into pretty good view.

Dr Marc Ruel: James, I think that Tim has already captured the essence of this paper. The results are impressive in this excellent series and the really carefully led analysis. This is an important paper and it's very thought provoking.

There’re two clans among surgeons. Those that believe that every cardiac surgeon who was named as such should be able to perform safely aortic dissection repair and another client and somewhat sustained or supported by the data from this paper that says that this is a special expertise that should be or regionalized and put through centers of excellence. So this paper would support the latter theory.

Dr James de Lemos: The next paper, which was a research letter, sort of adds fuel to this fire of regionalization, doesn't it? At least insofar as we're talking about the more complex procedures.

Dr Timothy Gardner: Yes, this paper studies the hospital volume effects on surgery for abdominal aortic aneurysms, an even more common and somewhat less lethal, but very morbid condition. And this analysis of center volume for care of these patients is complicated even a little bit more because as we know, endovascular repair of abdominal aortic aneurysms is now the most common form of treatment.

Interestingly, in looking at the outcomes in a variety of centers with varying volume procedural volumes, there was no difference in outcomes when endovascular repair was done, but there was inverse relationship between volume and outcomes after classical surgical repair. This really highlight a change that's occurring in vascular surgery where, with endovascular repair being done more commonly, surgeons are having less exposure unless experience with open repairs. This is particularly a challenge for training programs where you have a surgical resident or fellow for two years and he or she may experience relatively few open repairs.

So, this again, the data seems to suggest that higher volume vascular surgery centers, where the numbers of open repairs are done, have better results and that this is not nearly as much, in fact, it wasn't an issue for endovascular treatments, but it again highlights the procedure of volume outcomes relationship. I think this is something we're going to have to deal with both in terms of optimizing patient care, even considering when we're training new or young avascular surgeons, they may have to move to different centers to ensure that they have the kind of exposure to classical surgical treatment for those complex patients who are not candidates for endovascular repair.

Dr James de Lemos: Let's change gears. We've been talking about two systems of care issues, but let's get back to the complicated patient themselves and talk about a paper Mark from Kato and Pellikka from Mayo Clinic, focusing on hemodynamic and prognostic impact of concomitant mitral stenosis in patients undergoing surgery or TAVR for Aortic Stenosis.

Dr Marc Ruel: As you say, this is an intricate clinical problem that we not uncommonly meet when we provide care for patients who have severe aortic stenosis. These are not young patients. These patients in this particular series of 190 patients with severe aortic stenosis, they also had some significant degree of mitral stenosis. These are patients that had a mean age of 76 years. I think we've all encountered these patients estimations, so someone has severe aortic stenosis and has some form of calcific mitral stenosis. And indeed in this series, more often than not, the vast majority of those patients had calcific MS as opposed to a Rheumatic MS. So, a different type of pathology probably to what we see in the elderly patients coming in with some degree of inflow obstruction.

So, the authors took their 190 patients, mostly from the Mayo clinic, but also from Tokyo, about five patients contributed from Japan, and matched in one to two with some controls who also had the same degree of severe aortic stenosis, the same age, same gender, same left ventricular ejection fraction, but didn't have mitral stenosis. And then compare their fate over a couple of years. Essentially, what the authors found is that in patients with severe MS, which was defined as a trans-mitral gradient of equal or higher than four millimeters of mercury, the midterm survival was decreased. The hazard of death was increased by about 90% or so. And there was also a classification, the sub classification based on the fate of the patient with regards to the echocardiographic findings, as to whether the patient truly had mitral stenosis at the time of presentation. So prior to the aortic valve replacement or whether the patient had pseudo-mitral stenosis. How the authors classify this, is those patients in whom the mitral valve area remained less than two centimeters square before and after aortic valve replacement were classified as having true mitral stenosis.

The authors provide a number of maybe predictors, if you will, or correlates perhaps a more appropriately termed as such, of patients who would be generally believed as having true mitral stenosis. And these included, for instance, in the mitral valve area was less than 1.5 centimeters square at the time of presentation, if calcium involved at both the anterior and the posterior leaflet on echo. And there was also the concept of Andler excursion. So, basically the distance between the apex and the analyst of the mitral Valve, half of the patients had true mitral stenosis and the other half saw an increase in the mitral valve area above two centimeters squares after aortic valve replacement.

I think still that we don't have an answer to the question as to whether the mitral valve should already be intervened upon in this series. It was an observational series, so there's no arm where the mitral valve was actually intervened on, and we know that often this intervention is not easy to do if it's by TAVR, there's not a lot we can do on the aortic valve and if it's at surgery, often these patients may have extensive mitral annular calcification, which is not an easy undertaking to fix at the time of surgery.

So, whether these patients, even the ones with true MS are better served by just addressing the aortic valve or adding a mitral valve intervention in addition to the AS treatment still remains an unresolved or unanswered question. But I think this paper helps tremendously with regards to identifying patients who may have the true mitral stenosis concomitant problem at the time of presentation with a severe AS.

Dr James de Lemos: This was news for me actually. The high prevalence of pseudo MS in this context, I think many of us are very familiar with this with aortic stenosis and low output, but to see this in the context of serial valve lesions was really instructive for me. Tim, what are your thoughts?

Dr Timothy Gardner: I think this is a really important observation to remind ourselves of in this TAVR era. If you have the heart open and you're doing the aortic valve replacement and you notice this, you can get a picture of this severity of the mitral stenosis or the mitral valve involvement, but I think that in the TAVR era, this finding, this possibility of significant mitral stenosis related to a more severe aortic stenosis has to be accounted for and taken into account.

Dr James de Lemos: Excellent. The next paper I'd like to talk about is another original article from Shudo and Joe Wu at Stanford. Remarkable series really of almost a thousand heart-lung transplants that were done and reported in UNOS. Tim, can you walk us through this paper and its implications?

Dr Timothy Gardner: heart-lung transplantation was done first at Stanford and actually by one of my close colleagues. Bruce Reitz in 1981. It was a really an operation and in the tradition of the innovation there in transplant surgery at Stanford. The operation, primarily for patients with end stage lung and heart disease, was done reasonably often at adventuresome and well-experienced transplant centers in the eighties and nineties and it's used less often today because we found that even in patients with end stage lung disease and concomitant ventricular failure that many of those patients can be treated successfully with double lung transplantation.

So, that has resulted in a decline in use of heart-lung block transplantation. The other problem is that as they mentioned in the article that a donor becomes available and you can get two or three patients treated by taking the individual lungs and the heart for three recipients rather than using the whole block for one. That's been another reason why it's been harder to get these heart-lung blocks. But for some patients with end stage heart disease and irretrievable lung disease, this is a great option. There's a few patients with end stage congenital heart disease who have developed irretrievable Eisenmenger's complex with severe pulmonary irreversible form of hypertension who are still candidates for this, but this analysis of the 30 year experience at Stanford and using the UNOS database as well is very interesting and shows the importance of donor selection as a really significant effector of outcomes.

Dr James de Lemos: Yeah, well I was also struck by the recipient factors too. It looks like selection in both directions is so important. The group that was remarkable to me was the markedly poor outcomes in the group that had heart-lung transplant after ECMO, that five times increase in mortality. That really struck a chord, particularly given what we're seeing now with ECMO accelerating somebody's status on wait lists. I don't know Mark or Tim, do you want to comment?

Dr Timothy Gardner: That's a very useful observation and where an individual patient ends up on the acuity list as a potential recipient with UNOS rules, it is ECMO support does get them to a higher level of urgency and yet, as is shown in this series, the morbidities or co-morbidities associated with a patient who requires ECMO support prior to transplantation is pretty consequential. And as you said, those were the features of the recipient, the degree of co-morbidities or co-morbidity complications also impact the outcome.

We're still struggling to find the best way to deal with rescue patients both with mechanical support and with transplantation, organ transplantation, and even in the case of heart failure, with destination therapy with mechanical devices, we're still struggling in an area where the challenges are high, and the best practices are not always as well clarified as we would like.

Dr Marc Ruel: And I would echo those concerns. I think the prohibitive results that we see after ECMO reflect the reality that there's not a lot of intermediate therapies available for patients who require heart-lung transplants. We have them for the heart now. We can move from ECMO and not go directly to an LVAD or to a transplant because we have implantable axial devices that can be put in percutaneously and basically can arrest the inflammatory response and the major cascade derangements that we see with ECMO.

Unfortunately that is not available to replace both the heart and lungs, so I think there's still some medical advances, surgical advances that are necessary to bridge the gap because that gap right now is real and it's not a gap, it's a cliff.

Dr James de Lemos: Great discussion gentlemen. Let's talk next Marc, about a research letter that was a case series from Cleveland Clinic from Donnellan and Desai, focusing on a fairly large group of individuals that had received mediastinal radiation therapy previously and then underwent valve surgery for radiation-induced valve disease.

Dr Marc Ruel: We were happy to receive this research letter from the Cleveland Clinic because clearly that institution, and maybe a few others around the world, have a special expertise in dealing with the uncommon, but very, very challenging issue of patients with the surgical radiation-induced mitral valve disease. And in fact, radiation-induced carditis. On average, these were patients who were seen about 17 years after their chest irradiation and I guess the main message that can be seen from this paper is that there's often multiple cardiac issues in those patients. They don't just have, for instance, a single valve, in this case the mitral valve, being affected. But the vast majority all tolled of around 80, 85% of patients required not only either another valve, but valve plus bypass or bypass surgery to be performed as well.

So, there are clearly patients where there's been a lot of physical/irradiation damage, not only to the mitral valve, but to the entire heart. It's also, when you look at this series of these 146 patients, you can see that many had an increase in the right ventricular systolic pressure on echo and probably some degree of RV dysfunction as certainly we've seen episodically in our practices.

So, hospital mortality outcomes are pretty good, but the results are humbling. 51% mortality at 2.8 years. And these patients were on average 60 years of age. So looking at U.S. life tables, when someone's 60 years, I've made it to 60, they usually have at least another 20 years on average to live. But these unfortunate patients, despite their cardiac operation performed, having been performed safely, have about an 18% death rate per year.

I think the jury's still out as to which are clear indications to offer these patients surgeries with the humbling results that we see even at a center of excellence by the Cleveland Clinic. But I think this is a foray into a very difficult cardiac problem for which there was limited literature before and certainly that's something that's very relevant as we refer to very advanced cardiac surgical therapies for patients with advanced disease.

Dr James de Lemos: Mark, you're actually a coauthor on our State-of-the-Art piece, evaluating arterial grafts and CABG, reviewing after the publication of art and radial. What were the main conclusions from your review and interpretation?

Dr Marc Ruel: Essentially, there's a discrepancy right now with regards to the use of multiple arterial grafting. The observational series have almost uniformly showed that patients who receive multiple arterial grafts live longer and do better, et cetera, but I think this has to be taken for what it is. There's an inherent indication bias or confounding by indication that goes into allocating that therapy to patients who are perceived to have the potential to do well in the long-term. There may also be an expertise bias at the institutions that provide this and those patients may be receiving better secondary medical therapy or guidelines directed medical therapy, etc. So, maybe a halo effect that comes into play.

In counterpart, the randomized control trials of which the latest was the arterial revascularization trial. Now available with data at 10 years, have shown essentially very little difference which regards to the use of multiple arterial grafts on long-term outcomes. Even looking at cardiac-specific outcomes like myocardial infarction. Actually the more compelling data came from their Radial Alliance, also led by Mario Gaudino who is the author of this, State of the Art paper.

The conclusion of the article is that we need a trial and we need to include the radial artery. The answer may not necessarily lie with the use of mammary arteries, but it may be that the radial artery is more user friendly and more robust. So the new ROMA trial has been designed with that in mind. Comparing one arterial graft versus as many arterial grafts, as long as it's more than one in the test group that the surgeon wants to use. And the surgeon, she or he can use the right internal thoracic artery or radial artery in order to complete the revascularization.

That trial is ongoing. Enrollment is on track and hopefully should provide answers to this very relevant question.

Dr James de Lemos: You know that discussion about the limitations of clinical trials, Tim, I think leads really nicely into the frame of reference you received from Eugene Blackstone and Cleveland Clinic, doesn't it?

Dr Timothy Gardner: Yeah, and it was really an article worth everybody reading. It's a short opinion piece and he points out the fact that we really have competing standards for choosing therapy. Sort of the standard traditional evidence based medicine, evidence-based medical care versus precision medicine which focuses on individual patients risk factors and so on. It's sort of the average treatment effect that we may be able to demonstrate well in randomized clinical trials versus real world experience with various therapies based on the risk profile of the patient. It's a really excellent article and as many of us know Gene Blackstone is a very thoughtful student of statistics in surgery and this is, I think, an excellent article. I'm really grateful for his doing this opinion piece for us.

Dr James de Lemos: The last opinion piece we have is from Mike Farkouh in the group in Toronto. Can you just give the readers and listeners a bullet about what they might expect in that piece?

Dr Marc Ruel: I think it's one of the remaining big questions, if you will, in myocardial revascularization as to what should be done with diabetic patients in multi-vessel coronary artery disease who have an acute coronary syndrome and require revascularization. A very well written piece and certainly that instructs what probably the next five years we'll see in terms of big study questions in coronary REVASC.

Dr James de Lemos: First I'd like to recognize Sarah O'Brien from the Circulation Editorial Office for her tremendous work for pulling this issue together. She's really the glue that brings this issue together every year and thank as well Marc, for your leadership again of this effort and Tim for your ongoing leadership at circulation with our cardiac content and vascular content as well as liaisoning with our surgical colleagues.

Dr Marc, you get the last word. Can you please summarize the thoughts you'd like to leave our listeners with?

Dr Marc Ruel: Thank you, James, for your generous comments and also for your support of cardiovascular surgery in and of the team issue. I think again, we have a fantastic issue this year and we really want to gather the very best of cardiovascular surgery and we want to get the highest impact papers. Circulation is home for the best data, the best outcome, say the most interesting answers to important clinical questions that are around cardiovascular surgery.

There's definitely an editorial desire to help with the best of cardiovascular surgery science. And I think I want to again launch a call to cardiac surgical investigators and cardiovascular and surgical investigators in general to consider circulation as your home.

Dr Timothy Gardner: Yes. And if I could just add to that, not only are we interested in a surgery-themed issue annually that really highlights some of the best articles that we have to publish, but we also want some of the best surgery science during the course of the year. And just remind our surgeon colleagues that the particular advantage to having a paper published in circulation is the exposure of that study to a broad cardiovascular community. Not just surgeons, the predominant readership obviously of circulation, or cardiologists and other cardiovascular specialists. So that's the big advantage you get by having your best work published in circulation. We'd love to see more of it.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation October 1, 2019 Issue

30 september 2019 | 27 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor at Circulation and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, have you ever wondered about instead of coding a stent, coding balloons with paclitaxel? Well, the feature article day is going to look at mortality assessments of paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE clinical program, the three-year outcomes. Do you have a paper you want to start us off?

Dr Carolyn Lam: I sure do. First of all, we know that diabetes impairs atherosclerosis regression following cholesterol lowering in both humans and mice. Now in this process of plaque regression, what's the role of functional high density lipoprotein or HDL, which is typically low in patients with diabetes?

Well, this first paper that I chose looks just at that and it's from Dr Fischer from New York University School of Medicine and colleagues, who aimed to test if raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages and enhances atherosclerosis regression following cholesterol lowering. So to do this, the authors used aortic arches containing plaques, which were developed in LDL receptor null mice, and these were transplanted into either wild type or diabetic wild type or diabetic mice transgenic for human APL lipid protein A1, which have elevated functional HDL.

Dr Greg Hundley: So Carolyn, what did they find in this interesting study?

Dr Carolyn Lam: Well, diabetic wild type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. The benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte neutrophil production capacity. ACL also suppressed the general recruitability monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2 phenotype, which is an atherosclerosis resolving state. There was also a decrease in plaque neutrophil extracellular traps or nets, which are atherogenic and increased by diabetes. So raising apolipoprotein AI and functional levels of HDL promoted multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques in diabetic mice after cholesterol lowering. And this may represent a novel approach to reduce cardiovascular risk in patients with diabetes.

Dr Greg Hundley: Really interesting, Carolyn. Well, I'm going to talk to you a little bit about a large study in patients with valvular heart disease and it's a contemporary presentation and management study and it's from the Euro Observational Research Program Valvular Heart Disease II, Roman numeral two, survey. And the corresponding author is Professor Bernard Iung from Bichat Hospital. So the VHDII survey was designed by the Euro Observational Research Program of the European Society of Cardiology to analyze actual management of valvular heart disease and compare practice with guidelines.

Now in short, patients with severe and native valvular heart disease or previous valvular intervention were enrolled prospectively across 28 countries over a three-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients corresponding to class one recommendation specified in the 2012 ESC and in the 2014 American Heart Association American College of Cardiology valvular heart disease guidelines.

Dr Carolyn Lam: Wow. So what did they find, Greg?

Dr Greg Hundley: Okay, so there's 7,247 patients. 4,483 were hospitalized, and 2,764 were outpatients, and they were included across 222 centers. The median age was 71 years and 1,917 patients were over the age of 80, and 3,400 were women. Now, aortic stenosis was present in 2,000 plus patients, aortic regurgitation in 279, mitral stenosis and 234, mitral regurgitation in 1,114. And multiple left-sided valvular heart disease was present in 1,297, right-sided valvular heart disease in 143, and 2,028 patients had prior vascular intervention.

So the decision for intervention was concordant with class one recommendations in symptomatic patients with severe single left-sided valvular heart disease in 79.4% of those with AS, 77% with aortic regurgitation, 68.5% for mitral stenosis, and 71% for primary MR. Valvular interventions were performed in 2,150 patients during the survey. Of them, 47.8% of the patients with single left-sided native valvular heart disease were in New York Heart Association class three or four, and transcatheter procedures were performed in 38.7% of the patients with AS and 16.7% of those with MR.

Dr Carolyn Lam: Wow, Greg. So what are the take home messages? That was a lot of numbers.

Dr Greg Hundley: Yep. Lots of data there. And so couple things. First, recommendations for interventions in symptomatic patients with severe valve disease are better applied today in this paper than in the previous European survey conducted in 2001, particularly for those individuals with aortic valve disease. Second, multi-modality imaging is now more frequently used, but stress testing remains underused in asymptomatic patients. And finally, transcatheter therapies are now widely used in patients with stenotic valve disease, and we would expect that, particularly for the use in the elderly.

Dr Carolyn Lam: Great, Greg. So what are the clinical implications?

Dr Greg Hundley: Okay, so Carolyn, first, late referral for intervention shows the need for increasing awareness of valvular heart disease by general practitioners and cardiologists. Second, the high burden of elderly patients highlights the need for multidisciplinary heart team approaches to assess the risk benefit ratios of the different modalities of valvular interventions. And finally, number three, echocardiographic quantification of regurgitation should be more accurate and pay more attention to quantitative measurements. Those are the main take homes from this large registry analysis.

Dr Carolyn Lam: Nice. Thanks, Greg. My next paper is the characterization of the first transgenic mouse model of ARVC 5. Now, that is the most aggressive form of arrhythmogenic right ventricular cardiomyopathy caused by a specific mutation in transmembrane protein 43. So this paper's from co-corresponding authors, Dr Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital Universitario Porto de Hero in Madrid, and with their colleagues, they generated transgenic mice over expressing transmembrane protein 43 in either it's wild type or that specific mutant form in postnatal cardiomyocytes under the control of alpha-myosin heavy chain promoter.

And they found that these transgenic mice expressing the specific mutant in transmembrane protein 43 showed fibro fatty replacement of the myocardium and died at a young age. The model confirmed that transmembrane protein 43 is mostly localized at the nuclear membrane and provides new information regarding the pathophysiological mechanisms underlying ARVC five. One of them is that the GSK3 beta signaling pathway plays an important role in this disease.

Dr Greg Hundley: So that's great, Carolyn. Sounds like we have a new model that's been created by this group and certainly this disease has spread. It's something we definitely worry about. Do you see any therapeutic implications for their work?

Dr Carolyn Lam: Great question, and indeed the authors tested two new therapeutic approaches for ARVC five. In the first they found that targeting fibrosis really had no beneficial effect. But in the second, they found that inhibition of GSK3 beta improved cardiac function and survival, thus opening the way to a new therapeutic approach focused on GSK3 beta inhibition in patients with ARVC five.

Dr Greg Hundley: Very good. So we look forward to seeing what the results of that study will be. How about now we talk about some of the other articles in this issue?

Dr Carolyn Lam: I love that. I think it's a great idea to tell everybody about this amazing issue. So we start with an article from our Global Rounds, and this time from Argentina, so a great status update and future strategies for cardiovascular disease in Argentina. We also have a perspective paper and that's on the new World Symposium on Pulmonary Hypertension guidelines, really questioning some of the cutoffs that we've taken for granted and asking, "Should 21 be the new 25?" Intrigued? Well, you really need to pick this one up and read it.

And then there's a white paper, and this is a report from the 2018 NHLBI workshop that really talks about unlocking the secrets of mitochondria in the cardiovascular system and asking if this may be a path to cure in heart failure. We also have a research letter, and I love these. They're so succinct and really contain an important message. And this one talks about the evolution of Medicare formulary coverage changes for antithrombotic therapy after the guideline update. So very topical subject.

Dr Greg Hundley: Very good, Carolyn. So I've got a couple. There's a Paths to Discovery article that John Rutherford did discussing with Paul Zimmet regarding reflections of the evolving global diabetes epidemic. Second, there is a very nice On My Mind piece from Samuel Tretheway from Birmingham, England who discusses medical misinformation, kind of like medical fake news. And he discusses how this occurs and it depends on the motivation of both authors and publishers, and he reviews responsibilities of all of us, how to avoid generating this type of material. And then finally, a really interesting Cardiology News piece by Bridget Kuehn, who discusses diet and microbes in heart failure, and with that there's a very nice piece of artistry work that would be great for your office. So that's all included in the journal.

Dr Carolyn Lam: Oh, you got us all curious. Finally, I just want to highlight, we have a section called Highlights from Major Meetings, and this time from my part of the world with Dr Aijun Sun and Dr Junbo Ge summarizing the 13th Oriental Congress of Cardiology takeaways. Cool issue, isn't it?

Dr Greg Hundley: Absolutely. So how about onto our feature discussion?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion. And this afternoon or this morning, wherever you may be, we are going to have an opportunity to discuss the utility of paclitaxel-coated balloons in terms of management of patients with peripheral arterial disease. And our article today comes to us from Bill Gray and colleagues from Mainline Health in Philadelphia, Pennsylvania. And we have our own Josh Beckman, associate editor from Vanderbilt, who will be joining us in the discussion. Bill, welcome to Circulation. We really appreciate you sending us this article. Can you tell us a little bit about the background of why you wanted to perform your study and also, what was your study design, study population?

Dr William Gray: The study was really prompted by a prior report by Katsanos et al in JAHA about nine months ago. When we started this study, it was much more fresh. And what we did was we realized we had data from multiple studies using the Stellarex drug-coated balloon that we could use to address some of the issues raised with the Katsanos paper. Just to review that briefly, the Katsanos paper suggested that there was a significant mortality signal in patients who were randomized to drug-coated balloons using paclitaxel versus PTA or patients randomized to drug eluting stent versus PTA or other stents. That signal was seen late at two years and at five years, and so we sought a given the data, the tightly controlled and well-reported data and this experience to see if we could see a signal as well.

The study design really involved taking all the data from the randomized trials, and there were two, which comprised an aggregate of about 600 patients, unequally randomized, about 400 in the drug-coated balloon arm and about 170 or 200 patients in the PTA arm. And then we also looked at all the poolable data, which was controlled data, so we had two randomized control studies I mentioned just a minute ago, as well as three single arm studies in one registry. Now, these had quality oversight and data reporting. And then those data were adjudicated for adverse events, including death, by a blinded third party CEC, and then those data reported out by Kaplan–Meier estimates as well, and then we do a multi-variable analysis looking at predictors of death, and then I can talk about that in a moment. Importantly, the data here has followed out to three years. As I mentioned before, the original paper which incited the concern had reported unequal deaths at two and five years, so we're somewhere splitting that difference. That's the genesis of the study and the study design.

Dr Greg Hundley: So Bill, tell us now about the results.

Dr William Gray: It turns out the baseline characteristics were largely similar between these trials and the patient arms, even though they weren't strictly speaking the same trials, except that the drug-coated balloon arm was a bit younger and smoked more frequently, so they were at a little bit more risk. In the randomized control analysis, which was done first, there was no difference in all-cause mortality between the PTA patients and the patients who received paclitaxel drug-coated balloons. That was true at one year, two years and three years. When we looked at the pooled analysis, which included not only the drug-coated balloon randomized trial patients, but also all the single arm studies and registries, we also found that there was no differences between those treated with drug-coated balloons in those additional studies and the control group of 170 patients in the randomized trial arm of PTA alone.

Interestingly, when we started to look at the multi-variable analyses, we did something that we ordinarily would not do, but because of the pressing issue around paclitaxel mortality, we actually did a standard covariate analysis looking at predictors and then we forced drug and drug dose into the model to see if they would come up positive as a predictor of outcome. As you might expect, not surprisingly, we found that age, congestive heart failure, diabetes and renal insufficiency were the four major predictors of mortality in a group of patients who were largely claudicates with significant peripheral vascular disease. No surprise there. We all know the patients don't die of claudication, they die of cardiovascular disease, and this I think bears that out.

When we force drug into the model, in point of fact, not a dose nor the presence of drug had any impact on death rates in the model, so there was no predictive value there whatsoever. Those are the results. Again, they're out to three years, and I think one of the important things that we have to recognize is that the numbers are relatively small and the follow-up is relatively limited and by itself, although it doesn't show any signal, it probably doesn't stand on its own to refute a larger meta-analysis, but does I think contribute to the dataset that is becoming more evident that the individual analysis do not appear to show mortality effects.

Dr Greg Hundley: Very good. So this is Dr Josh Beckman at Vanderbilt University. Josh, could you talk to us a little bit and put this paper in perspective relative to the prior published literature in terms of how you manage patients with peripheral arterial disease?

Dr Joshua Beckman: I have to say first, I'm really glad that we're able to publish this paper from Bill Gray and his group. We are, and I'm going to put this in really muted terms, in extraordinary times. I have never seen what is going on now happen with any other technology or really even medical therapy in the 20 plus years I've been a practicing physician. I think for the audience, it's really important to understand what is going on right now because if you don't pay attention to this space, you may not realize what's really been happening. Bill did a nice job at telling you why he did the study, which was this Katsanos aggregate level meta-analysis that was published in JAHA back in December.

On the basis of this paper, there has been a rapid development of worry and concern that these devices may be associated with late mortality. This concern has spread to the Food and Drug Administration, which has now put out three letters to healthcare professionals, each of them basically suggesting that you should choose non drug-coated either balloons or stents first, and if you want to use these, you have to have an extended conversation with the patients discussing the risks. And so in response to this aggregate level meta-analysis, which had an extensive number of lost to follow-up patients and didn't account for crossovers and the usual problems with this kind of information, I have been really impressed by the community of people who are interested in this topic and work with these kinds of devices.

And by that, I mean, the response has not just been a series of editorials. The response has really been, "Let's find every single piece of data that we can find to see whether or not this signal holds up," because as evidence-based physicians, we take one piece of data and say that it is one piece of data, and then we have to put it into the context of all of the other pieces of data that were published. And so I know that Dr Gray is old enough to remember 10 years ago when these devices were being used in the coronary arteries with drug eluting stents. And as far as anybody can tell with studies that were two to three times larger or meta analyses two to three times larger than the study published in December, there was no mortality signal.

It should be made clear that in doses that dwarf the doses from these devices, when these medications are given to pregnant women who have breast cancer, not only is the mother fine but the fetus is fine. And so I think paper that we are discussing this morning in particular, but the group of investigators in the space has really stepped forward to publish as much data as possible to fill out our understanding and place the original study in the correct context. And so when you understand what's happening in the community, and there's been a significant reduction in the use of these devices on the basis of that one publication at the expense of patients for whom these devices are really much better at limb outcomes, then you can understand why we were so interested in the paper by Dr Gray.

This is another brick in creating the foundation to really have a fuller and better understanding of any possible relationship between the use of these devices and a nonspecific increase in mortality two to five years later, which as far as I can tell, I've never seen something that may end up being a poison that doesn't have a specific mechanism of causing morbidity or mortality. And so when we got this paper, I was really happy to be able to work with Bill and bring it to the level that it is now so that when it's published in October, it's going to be another really important contribution and I just want to congratulate the authors for doing that work. I will say, and I'd like to get Bill's perspective on how he thinks the information that's now being published is going to help us understand what to do with these devices.

Dr William Gray: Yeah, that's a great question, and I want to emphasize something you brought up, which I did not, which is at the aggregate level data that Katsanos used to publish his analysis was really all he had access to, which means that he had some numerical data from prior published publications but did not have patient level data. And so what Josh is referring to appropriately is the concept that each individual holder of those data, those patient level data, are now coming forward with their own analysis of those data at a patient level, which allows us to look more granularly and more clearly at the causes of death. For example, in this study, the causes of death did not cluster around cancer. They were largely cardiovascular, and they were not dis-equally distributed or unequally distributed between the two groups.

So I think that patient level data, to get back to your original question, Josh, the patient level data will be incredibly important from each of the experiences with the various drug-coated balloons and drug eluting stents on the market because it does allow us to look more closely at the mechanism of death and whether there's any putative cause that might be assigned to paclitaxel. As you mentioned, the pharmacology of this is not understandable. The only type of pharmacology that would work like this was if paclitaxel was radioactive and accumulated a hazard along the way, but we know that's not true.

I think extend your question, it's important to say that both the FDA and other independent groups like VIVA have looked closely at the meta analytic data both from a patient level and aggregate level data set, and they have seen a signal at five years. The problem with that is that data starts to winnow down very quickly at five years. There's not a lot of numbers, so that's the first problem, and the meta-analysis that have followed the publication by Katsanos. The second problem is, as Josh alluded to, there's a lot of missing data. Either patients withdrew or got lost to follow-up, and that didn't happen at an equal distribution between the control and the active arms, so there's some ascertainment bias there.

And lastly, there's a crossover, that is patients who are in the control arm crossed over near as we can tell at a rate of about one in five or one in four to an active arm in the first year alone, which means they need to be reassigned to a risk pool that includes the original assignment of paclitaxel randomization. My sense is that those data will not get any better in the near-term future because the problems I just listed are not going to go away anytime soon. And so we are left with these individual patient level data and other big data, like Medicare analyses of tens of thousands of patients or Optum insurance analyses of again, tens of thousands of patients, which actually show no difference between the treatment with paclitaxel in the real world and patients treated with non-paclitaxel devices. So while we are comfortable and happy to publish these data and we think that are meaningful in terms of contributing to the larger dataset, we recognize the flaws and the limitations in the meta-analysis, which will not be solved soon or quickly.

Dr Joshua Beckman: So, I totally agree with what you just said. I will also say that every time data like this is published, it adds to the picture to make our understanding clearer. And you are responding directly to the Food and Drug Administration, who basically said they are not settled on this question either. It is noted, they are worried about it, and what they've really asked for is for more data to be published. And so when people analyze data like these, I think it is really helpful to the rest of us to create a fuller and more granular picture of the overall state of the field.

Dr Greg Hundley: We want to thank again both Josh for his time and Bill for his time. Hope you have a great week, and both Carolyn and I look forward to sharing with you again next week. Take care everyone.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation September 24, 2019 Issue

23 september 2019 | 25 min

Dr Gregory Hundley: I'm Greg Hundley, also associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, what do you think is the association between preeclampsia and hypertensive diseases of pregnancy and cardiovascular disease and future? Well, we're going to find out in a large U.K. pregnancy cohort of linked electronic health records, the CALIBER Study, but that's a feature discussion that's coming right up.

I think we need to start by discussing this week's hot issue. For the first paper, we know that the incidents of acute cardiovascular complications are highly dependent on the time of day. Greg, have you ever wondered what mechanisms drive the rhythmicity of ischemic vascular events?

Dr Gregory Hundley: You know what, Carolyn, I had a dream about that and I think that somehow maybe it might be something to do with leukocytes.

Dr Carolyn Lam: Good guess, Greg. Well, Dr Christoph Scheiermann and his colleagues from University of Geneva looked at this and they examined the role of rhythmic leukocyte adhesions and what those play in different vascular beds. They did this by evaluating leukocyte recruitment in vivo with real time, multichannel fluorescence intravital microscopy of a TNF alpha induced acute inflammation Murine model.

Now, they also used ablation of sympathetic nerves or adrenergic receptors to assess their relevance for these rhythmic leukocyte adhesions. Basically what they found was that leukocytes adhere to arteries and veins following a circadian rhythm in mice, with adhesion peaking in the arteries in the morning and in the veins at night.

These peaks in leukocyte adhesion at different times in the two vascular beds were associated with increased vascular inflammation and shortened times to local basal occlusive events occurring out of phase between the arteries and the veins. The differences in cell adhesion molecules and leukocyte adhesions were ablated when disrupting the sympathetic nerves, thus demonstrating their critical role in this process and the importance of beta2-adrenergic receptor signaling. Neat, huh?

Dr Gregory Hundley: Really neat. It's interesting how that ties together sympathetic nerve activity and leukocyte adhesion.

Dr Carolyn Lam: You got a paper?

Dr Gregory Hundley: I've got a paper to discuss and it's from Dr John Cooke at the Houston Methodist Research Institute. It's involving nuclear S-nitrosylation and how that defines an optimal zone for inducing pluripotency, the ability to generate induced pluripotent stem cells or I.P.S.C's from somatic cells as it enhanced the field of regenerative medicine.

It has facilitated studies of development in differentiation, promoted insights into pathobiology, and generated a novel platform for drug discovery and testing. In fact, work in this area has been sufficient to induce nuclear reprogramming to pluripotency and galvanized our whole scientific community. Recently in 2012, this work was recognized by the Nobel Prize for physiology or medicine.

Dr Carolyn Lam: Wow. What did this week's paper show in this area?

Dr Gregory Hundley: Well, Carolyn, in this study, the team identified an optimal zone. They call it the Goldilocks zone of innate immune activation for nuclear reprogramming to pluripotency. The authors believe that this Goldilocks zone for nuclear reprogramming may have broad relevance for epigenetic control, for regenerative processes, and for the pathobiology of cancer and even other diseases.

Consequently, the results from this study may help to develop methods that identify whether a patient or tissue is in an optimal zone of inflammatory signaling to improve surgical and medical therapies. In addition, they may provide a method to detect early inflammatory signaling and DNA accessibility and thereby reverse these processes to guide cancer prevention.

Dr Carolyn Lam: Oh wow, Greg. It sounds like a real landmark paper. Everyone, you've got to pick that one up. As with this next paper, it is the first randomized trial comparing internal cardioversion by commanded shock and external cardioversion in patients with ICD's who present in atrial arrhythmias.

Dr Lüker and colleagues from University Hospital Cologne randomized 230 consecutive patients with ICD's undergoing elective cardioversion for atrial arrhythmias at 13 centers and they randomized them to either internal or external cardioversion. The primary safety endpoint was a composite of lead or device malfunction and conversion of the atrial arrhythmia to sinus rhythm was the primary efficacy endpoint. Myocardial damage was studied by measuring troponin release in both groups.

Dr Gregory Hundley: I really like where this study's going. What did they find?

Dr Carolyn Lam: They found that external cardioversion was superior for the restoration of sinus rhythm, with shock efficacy of 93% in the external cardioversion group compared to 65% in the internal cardioversion group. There were three cases of preexisting silent lead malfunction that were unmasked by the internal shock resulting in lead failure. Troponin release did not differ between the groups.

In summary, these findings suggest that external cardioversion may be considered as the first line approach to electrical cardioversion in patients with ICD's and atrial fibrillation. Because silent lead malfunction may be present in some ICD patients, internal cardioversion may be considered in select patients to detect it and with no difference in adverse events associated with internal or external shocks. That's a good sign but needs to be evaluated in larger randomized trials.

Dr Gregory Hundley: Oh, very nice, Carolyn. Well, my next paper is entitled the Androgenic Effects on Ventricular Repolarization and it's a translational study from the International Pharmacovigilance Database to iPSC-cardiomyocytes. The corresponding author is Dr Joe-Elie Salem from Vanderbilt University Medical Center.

Male hypogonadism arising from a range of ideologies, including androgen deprivation therapies and other things, has been reported as a risk factor for acquired long QT syndrome, as well as torsade de pointes. The authors searched the International Pharmacovigilance Database, VigiBase, for men and they had 6,560,000 plus individual case safety reports presenting with long QT syndrome, torsade de pointes, or sudden death associated with androgen deprivation therapies.

In cardiomyocytes derived from induced pluripotent STEM cells from men, they also studied the electrophysiological effects of androgen deprivation and dihydro testosterone.

Dr Carolyn Lam: That's super interesting. What did they find, Greg?

Dr Gregory Hundley: It's one of these combinations of a clinical study as well as basic science. Of the 10 androgen deprivation therapies examined, seven had disproportional association reporting odds ratios of one four to four seven with long QT syndrome, torsade de pointes, and sudden death. The minimum medium times to sudden death were from 0.25, a quarter of a day, to 92 days respectively. The androgen receptor antagonist, enzalutamide was associated with more deaths than any other androgen deprivation therapy used for prostate cancer.

In the basic science experiment, in induced pluripotent STEM cells acute and chronic enzalutamide at 25 micromolar, a. Significantly prolonged action potential durations, b. Generated after depolarizations and activity, c. Inhibited delayed rectifier potassium currents, and d. Chronically enhanced late sodium currents.

Interestingly, dihydrotestosterone at 30 nanomolar reversed the enzalutamide electrophysiologic effects on these induced pluripotent STEM cells.

Dr Carolyn Lam: Again, really interesting approach from this Pharmacovigilance Database as well as bench work and clinical work, but what do we do with this information?

Dr Gregory Hundley: Couple of key points, Carolyn. One, men receiving androgen deprivation therapy are at increased risk for drug induced QT prolongation and torsade de pointes. Two, in men developing acquired long QT syndrome or torsade de pointes, a diagnostic workup might include evaluation of testosterone blood levels, androgen deprivation therapy intake, and evaluation for endocrine conditions associated with hypogonadism. Three, in men treated with androgen deprivation therapy for example, for prostate cancer, other risk factors for torsade de pointes should be sought and corrected to avoid any accumulation of risk. And finally number four, in men treated with androgen deprivation therapy, the role of electrocardiographic monitoring to detect QT prolongation really requires an additional study.

Dr Carolyn Lam: Cool, Greg. What else in the journal did you find cool?

Dr Gregory Hundley: Yeah, this is great, Carolyn. We're going to start now with sort of a new format where we go through all the other wonderful information. We're just going to trade back and forth.

The first one I'm going to tell you about is a letter from James Tisdale who is from the College of Pharmacy at Purdue University, and he demonstrates in a small randomized controlled trial that transdermal testosterone attenuates drug induced QT lengthening in older men. Really kind of links back to that study I just told you about.

Dr Carolyn Lam: Nice. Well, I want to highlight an on my mind paper and it's entitled, Chronic Severe Aortic Regurgitation, Should we Lower Operating Thresholds? This is from Dr Desai at Cleveland Clinic and he considers newer EchoMRI methods to assess the severity of aortic regurgitation and determine suitability for valve intervention. It's a large study and just a really nice read of a short on my mind paper.

Dr Gregory Hundley: Excellent. Well, you know we also highlight excellent reviews in circulation and the one I'm going to discuss briefly is from Schuyler Jones from Duke and he revisits the role of primary aspirin for primary prevention of cardiovascular disease.

He talks about the indications, that there are really few indications for aspirin in those with diabetes mellitus, community dwelling elderly individuals, and patients without diabetes who are at intermediate risk for atherosclerotic events. Also, he discusses the role of aspirin and reviews very nicely the role of aspirin in primary prevention including the optimal drug formulations, different dosing schedules, weight-based dose selection, and the interplay between sex and treatment response. It's a great review.

Dr Carolyn Lam: Ah, and then from a nice in-depth review we also have a perspective, a nice short read. This one is from Dr Simari from Kansas who discusses diversity in clinical trials and you know, his title is actually a question, when will clinical trials finally reflect diversity? Really lovely paper. He points out that to increase the diversity of enrollment, we need to consider expanding the diversity of investigators. So, a nice piece there, too. Thanks, Greg. That was a super chat. Shall we go on to our feature discussion now?

Dr Gregory Hundley: Absolutely. Welcome everyone to discussion of our featured article focusing on hypertensive disorders in pregnancy, and then the subsequent long-term outcomes related to that. For our author discussion, we have Fergus McCarthy from Ireland and the Irish Center for Fetal and Neonatal Translational Research at Cork. Then, we also have our associate editor, Sharon Reimold.

Fergus, could you tell us a little bit about what was your thinking behind starting this study? What type of questions were you trying to answer? And then after that, tell us a little bit about the study design.

Dr Fergus McCarthy: I'm an obstetrician by trade and we have this funny paradox where a lot of us know that pregnancy is not just about the nine-month periods that a woman is pregnant and then ultimately delivers, that what happens in pregnancy can influence long-term maternal health. But despite this, we have this paradox whereby a woman becomes pregnant, the pregnancy may be complicated by hyper pressure in pregnancy, the woman delivers her baby, goes home and often doesn't see a healthcare practitioner for possibly another 10, 20 years.

Even though we know if a pregnancy is affected by high blood pressure, we don't really do a huge amount about it and we deal with this funny situation. We know that high blood pressure in pregnancy affects two to 8% of pregnancies, depending on the population studied. What we wanted to do was examine specifically the impact of hypertension or high blood pressure in pregnancy on long-term maternal health.

But importantly, what we also wanted to try and determine was is there any factor that may be modifiable that may be ultimately able to improve or reduce the long-term morbidity associated with having hyper pressure in pregnancy? So, if you have high blood pressure in pregnancy, is that it or is there anything that we maybe could make women aware of that may ultimately improve their long-term health?

Also as I said, despite research documented in the association between preeclampsia, which is high blood pressure in pregnancy and major cardiovascular disorders later in life, but we felt also that there was a lot of limitations with the evidence that's there.

Firstly, a lot of the evidence is focused on more composite endpoints and secondly, over the past several decades, the pattern of initial presentation of cardiovascular disease has changed significantly. And thirdly, a lot of the studies that are out there have been unable to adjust for post-pregnancy factors such as hypertension. We wanted to see whether that was a significant factor. But that's the thought process behind why we undertook this study.

Then we had a great opportunity with the collaboration with the Fire Institute in London and University College London, whereby we were able to use a database which is called CALIBER. What CALIBER stands for is cardiovascular research using linked bespoke studies and electronic health records, bit of a mouthful. But what CALIBER is, is basically it's a combination of the GP database in the U.K., which is called the Clinical Practice Research Database, hospital episodes, statistics, and the Office for National Statistics cause specific mortality records. What that does is basically it combines a lot of pregnancy data with long-term really well phenotyped cardiovascular disease.

In particular, what CALIBER is very strong for is they have phenotypes, 12 cardiovascular phenotypes, in an extremely strong robust way. So, we were able therefore to examine the impact of pregnancy using the GP database, using the CPRD with these 12 cardiovascular phenotypes as our outcomes.

Dr Gregory Hundley: Tell us a little bit about your study population and what were some of the results of your study?

Dr Fergus McCarthy: What we did was we used electronic health records from a period of 1997 to 2016 and we looked at a U.K. population core of about 1.3 million women. The mean age of delivery of these women was about 28 years of age and they had about just under 2 million, 1.9 million completed pregnancies.

Over the 20-year study period, we were able to observe just over 18,000 cardiovascular disorders, 65% of which had occurred in women under the age of 40. Again, this was quite surprising because using cardiovascular disease, you think a much older group, and when we looked at the pregnancies that were affected by hypertension in pregnancy, we were able to see that compared to women without hypertension in pregnancy, women who had one or more pregnancies affected by preeclampsia had increased hazard ratio for stroke, atherosclerotic events, heart failure, atrial fibrillation, cardiovascular death, and for chronic hypertension.

What was particularly interesting was that the differences in the cumulative incidence curves that we were able to see. According to preeclampsia, we were able to see these differences within one year of the first index pregnancy. So again, this was quite fascinating from our point of view because I think prior to this study, maybe we thought that it was happening a bit earlier than we thought in women's lives, but actually, to see something so soon occur after pregnancy was quite interesting.

The other thing that, and one of our motivations to do this was to say, okay, well is there anything we can do about it? Is there anything that might be modifiable here? What we were able to do within our study was we were able to examine, is this just because women are leaving hospitals with high blood pressure and this high blood pressure is not being treated? What we were able to do was we were able to adjust into our models this concept of having postpartum hypertension. If we were able to adjust for the mediating effect of post-pregnancy hypertension, we observed a 35% reduction in the point estimates of the hazards ratio for any cardiovascular disease event.

One of the things I think that this study shows is that it is critically important that women have appropriate medical follow-up after their pregnancy. It's a very difficult period. People have young babies, they may be going home to more children at home, and often the neglected person in this situation is the mother. What we're saying is that actually even if we could focus on that one factor which is post-pregnancy adequate control of hypertension, we may be able to reduce the hazards ratio of developing a cardiovascular disease by approximately 35% is what the study is suggesting.

Dr Gregory Hundley: Really interesting results, Fergus. Sharon, I wanted to turn to you a little bit. How do the results of this study change for us the way we might practice in terms of managing this patient population?

Dr Sharon Reimold: This study, I think, is very interesting because of the large population and the significant number of unfortunately adverse outcomes and the ability to compare those with and without preeclampsia and hypertension. I think that we end up with two or three different issues or ways that we think about dealing with them.

First of all, just as Fergus alluded to is we need to make sure that we take hypertension seriously in pregnancy and since it's a small, but significant number of women leave the hospital and will remain hypertensive, we need to assure that they are getting care. The other thing that I think is important in this group, but you would never be able to capture in the current study is my approach is also to think about, well, what other risk factors does this woman have other than just high blood pressure? Is she at risk to be a diabetic? Does she smoke? Is she getting enough exercise? What other things can we do to modify their long-term risks?

This points out a method to identify those patients pretty easily. Are they hypertensive early post-pregnancy, and then it's up to the medical community to really develop strong guidelines and training that emphasizes using prevention in the outpatient setting.

The two things I found very interesting about this work, first of all, the rapid separation of these curves. I know that they had some very young women that gave birth and then some obviously women of what I guess would be termed advanced maternal age. But we do think of a woman who has a child at 30 maybe being at higher risk when she's 50 or 60, but the risk is much earlier, and patients are really not aware of this.

Then, the ultimate thing is how do we identify these women early in their pregnancy or before they're pregnant, so we can help avoid these complications altogether? I guess the take home message is if somebody has hypertension or they're going home hypertensive, they need early follow-up and we need to be aggressive about their treatment.

Dr Gregory Hundley: Both of you have emphasized the point that this paper makes of early identification of hypertension. In the paper, it talks about hypertensive disorders of pregnancy. I think many of us understand about preeclampsia or eclampsia and relatively high blood pressures, HELLP syndrome, et cetera. Are there other issues that we need, like what blood pressure ranges are we thinking about?

If I'm picking up a chart of a woman in their early forties, late thirties what should I be looking back for retrospectively in terms of blood pressure levels? Do I follow the new guidelines and I'm looking for blood pressures above 120 systolic? Can either of you give us some guidance on what to look for, how I would set up a program, what the timing would be, when I need women to come back? Just practical things like that.

Dr Sharon Reimold: I believe that is still in the obstetric world that the older guidelines are really what are used and whether those shift over time to lower thresholds for the diagnosis of hypertension is not clear, but usually it's 140 over 90. You want to try to get the patient history and differentiate between those people that perhaps were hypertensive prior to their pregnancy, people who had isolated short-term hypertension during their pregnancy, and those people who then left pregnancy remaining hypertensive. But I'll ask Fergus since he deals with this a lot more than I do with the pregnancies, what they use as the cutoff in the U.K.

Dr Fergus McCarthy: In general, we had the CHIPS Study, which was published several years ago. That advocated, certainly during pregnancy, that a tighter control of blood pressure was associated with an improved pregnancy and improved maternal outcome. That type of control generally aimed for a systolic blood pressure of under 135. In general, when we are managing our patients, that's usually what we're aiming for, to keep the systolic blood pressure under 135.

I think the other thing that is becoming apparent from a lot of the work that's been done is that it's maybe not just about the pre-eclamptic woman, which is generally the woman with hypertension and proteinuria that gestation and hypertension, which often is nonproteinuric by definition, is also playing a significant part.

Certainly, when you look at populations where I previously worked in the U.K. and London, women with chronic hypertension, pregnancy is becoming a huge issue, both with increasing obesity and certain ethnic groups, and with advanced maternal age women coming into pregnancy with chronic hypertension is really becoming a major issue for us, as well, and is associated with a much worse pregnancy outcome. But to answer the question, that's usually where we're aiming for and we're trying to, where possible, run as tight a control of blood pressure as possible.

Dr Gregory Hundley: Thank you very much, and we look forward to talking and discussing with you with Carolyn next week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation September 17, 2019 Issue

16 september 2019 | 25 min

Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley: I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam: Greg, you know I'm vegetarian and any paper on plant-based diet will always interest me, and of course, we have one as a featured paper this week, very interestingly talking about changes in plant-based diet quality, meaning that there could be good plant-based diets and not so good plant-based diets. I mean we all know that potato chips, for example, are still plant-based. But, anyways, so this feature paper discusses the changes in these plant-based diet quality and association with total and cost-specific mortality. Neat, huh?

Dr. Greg Hundley: Yeah. I can't wait to hear about that one. I know that's a favorite topic of yours. How about if we have a sip of coffee and jump into our other articles?

Dr. Carolyn Lam: Sure. I'm sipping away, and have already picked my first paper. This talks about mutations in plakophilin 2, which are the most common cause of gene-positive familial arrhythmogenic right ventricular cardiomyopathy.

Dr. Greg Hundley: No quizzes for me on plakophilin 2, please.

Dr. Carolyn Lam: All right, well, let me tell you all about it. Plakophilin 2 is classically defined as a protein of the desmosome, which is an intracellular adhesion structure. Studies though have suggested that plakophilin 2 also translates information at the initiation. Recent studies have also shown that plakophilin 2 translates information initiated at the site of cell to cell contact into intracellular signals that maintain structural and electrical homeostasis. Now, the important thing is that mutations in plakophilin 2 associated with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy or ARVC. However, the molecular and cellular mechanisms responsible for arrhythmias in ARVC remain unclear.

Dr. Carolyn Lam: In today's paper, Doctors Delmar and Cerrone from New York University School of Medicine and their colleagues studied the role of cardiomyocyte plakophilin-2 expression in cardiac function. To do that, they utilized a cardiomyocyte-specific, tamoxifen-activated, plakophilin-2 knockout murine line. They found that loss of plakophilin-2 expression caused, as an early event and predominantly in the right ventricle, a non-transcriptional and likely arrhythmogenic, connexin-43-dependent disruption of calcium homeostasis.

Dr. Carolyn Lam: The phenotype included accumulation of calcium in three intracellular compartments, the junctional sarcoplasmic reticulum, the cytoplasm, and the mitochondria. Right ventricular myocytes also showed increased eagerness of ryanodine-receptor-2 channels to release calcium from the sarcoplasmic reticulum. Intrinsic ryanodine-receptor-2 properties were also modified further contributing to the pro-arrhythmogenic state. In summary, the authors postulated that disruption of calcium homeostasis in the right ventricle is a major arrhythmia trigger in patients with ARVC. The data identified both the ryanodine-receptor-2 channel and the connexin-43 hemichannel as targets for antiarrhythmic therapy in this population.

Dr. Greg Hundley: Very interesting that ARVC is such a worrisome concern, and gathering this mechanistic information is just so helpful.

Dr. Carolyn Lam: Exactly.

Dr. Greg Hundley: I have a basic science paper, but it was actually interesting because of the conduct was in many, many human subjects. It emanates from the large Million Veteran Program. There are a whole list of coauthors that are recognized as equal contributors, but Scott Damrauer actually serves as the corresponding author from the VA Medical Center. What it's addressing, about 13% of African American individuals carry two copies of the APOL1 risk alleles, G1 or G2, that are associated with a one and a half to two and a half fold increase in the risk of chronic kidney disease.

Dr. Greg Hundley: There've been conflicting reports as to whether an association exists between these APOL1 risk alleles and cardiovascular disease independent of the effects of the APOL1 on kidney disease. Here, the investigators thought to test the association of these G1 and G2 alleles with coronary artery disease, peripheral arterial disease, and stroke among African American individuals in the Million Veterans Program.

Dr. Carolyn Lam: Seems like a great study population and designed to look at this. What did they find?

Dr. Greg Hundley: Among 30,903 African American Million Veterans Program participants, 3,941 or about 13% carried the two APOL1 risk allele, high-risk genotype. Individuals with normal kidney function at baseline with the two risk alleles had a slightly higher risk of developing coronary artery disease compared to those with no risk alleles. Similarly, modest associations were identified with incident stroke and peripheral arterial disease. However, when modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease while no significant association with the cardiovascular disease endpoints could be detected. In conclusion, what the authors are indicating is that the APOL1 risk variants display a modest association with cardiovascular disease, and this association is likely mediated by the already previously known association of APOL1 with chronic kidney disease.

Dr. Carolyn Lam: Interesting.

Dr. Carolyn Lam: My next paper also has to do with chronic kidney disease and this time looking at metformin use and clinical outcomes in patients with diabetes with or without heart failure or kidney dysfunction. We know that metformin is the first-line therapy for type 2 diabetes, although its effects on the cardiovascular system are actually, not fully proven. In this next paper, the authors examine metformin use in the SAVOR-TIMI 53 Trial.

Dr. Greg Hundley: Tell us a little bit about that SAVOR-TIMI 53 Trial. How is that organized?

Dr. Carolyn Lam: Just as a reminder, the SAVOR-TIMI 53 trial was a multinational, randomized, controlled cardiovascular outcomes trial that compared the dipeptidyl peptidase-4 or DPP4 inhibitor, Saxagliptin, with placebo, enrolling almost 16,500 patients with type 2 diabetes and cardiovascular disease or elevated cardiovascular risk.

Dr. Carolyn Lam: Now, in the current paper led by Dr. Bergmark from TIMI study group in Brigham and Women's Hospital and Harvard Medical School, the authors performed the post hoc analysis and looked at patients in SAVOR-TIMI 53 with baseline biomarker samples of whom there were more than 12,000 patients and classified these patients as ever versus never taking metformin during the trial period. The associations between metformin exposure and outcomes were estimated using inverse probability of treatment weighting, Cox modeling.

Dr. Carolyn Lam: They found that among patients with type 2 diabetes and high cardiovascular risk in the SAVOR-TIMI 53 trial, metformin use was associated with lower rates of all-cause mortality including after adjustment for clinical variables and biomarkers, however not lower rates of the composite endpoint of cardiovascular death, MI or stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.

Dr. Greg Hundley: Excellent.

Dr. Greg Hundley: I'm going to transition to another clinical trial and this one is looking at ezetimibe in elderly patients and looking at efficacy for preventing cardiovascular-related events. The paper comes from Yasuyoshi Ouchi from Toranomon Hospital in Japan. Evidence regarding the primary prevention of coronary artery disease events by LDL-C/lipid-lowering therapy in order individuals that are above the age of 75 years, is somewhat incomplete. This trial tested whether LDL-C lowering with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. They implemented a multicenter, prospective, randomized but open-label, blinded, endpoint, however, evaluation design conducted among 363 medical institutions in Japan.

Dr. Greg Hundley: In the study, there're 3,796 patients that are aged greater than 75 years with elevated LDLC without a history of coronary artery disease that already were receiving dietary counseling. They're randomly assigned one-to-one to receive as ezetimibe 10 milligrams once daily versus usual care with their randomization stratified in a block design on age, sex, and baseline LDL-C. The primary outcome is the composite of sudden cardiac death, myocardial infarction, coronary revascularization, and stroke.

Dr. Carolyn Lam: Ooh, so tell us the results.

Dr. Greg Hundley: There were several patients that had to be excluded, so what ended up happening, there's 1,716 and then 1,695 that are included in each of the two respective arms for the primary analysis. What they found is that as ezetimibe reduced the incidents of the primary outcome. Then, regarding some secondary outcomes, the incidents of composite cardiovascular events and coronary revascularization were lower in the ezetimibe group than in the control group. But, there was no difference in the incidents of stroke, all-cause mortality, or adverse events in the two different groups.

Dr. Carolyn Lam: Can you sum it up for us, Greg? What should we take home regarding ezetimibe and what further do we need to do?

Dr. Greg Hundley: Good point, Carolyn. I think what we can take away from this study is that LDL-C lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals greater than 75 years of age with an elevated LDL-C. However, remember, it was open label, so I think a placebo, controlled, randomized clinical trial will be required to validate the data that were obtained in this study. I think another study is probably going to be needed.

Dr. Carolyn Lam: Thanks, Greg. Well, let's move on to our feature discussion, shall we?

Dr. Carolyn Lam: Today's feature paper is of personal interest to me and I'm sure of widespread interest to everybody. Why? It's on plant-based diet. We've heard a lot about it. I'm vegetarian and very, very loudly self-confessed, but does the quality of a plant-based diet actually matter? Such an important question.

Dr. Carolyn Lam: I'm so pleased to have the authors of this very remarkable paper, Dr. Megu Baden as well as Dr. Shilpa Bhupathiraju, both from the Harvard T.H. Chan School of Public Health; and our associate editor, Dr. Mercedes Carnethon from Northwestern University Feinberg School of Medicine. Welcome, ladies. What a nice chat we're going to have on this very personal topic to me as well.

Dr. Carolyn Lam: First of all, maybe, could I ask, Shilpa, do we need another study on plant-based diet? Could you tell us the rationale for what you did this time?

Dr. Shilpa Bhupathiraju: Like you said, when we talk about plant-based diets and what people usually think is, well, it's vegetarian or not. But, I think there's much more to a vegetarian diet. It's the quality that matters. Previous studies really then differentiate the quality of a vegetarian diet.

To this extent, we developed plant-based diet indices, which actually capture the quality of a plant-based diet, so we have an overall plant-based diet index which captures the amount of plant-based foods; a healthy plant-based diet index, which captures the quantity of healthy plant-based foods; and again, the unhealthy plant-based diet index, which captures the quantity of unhealthy, plant-based foods.

Dr. Carolyn Lam: Thanks. Meg, if you don't mind, I know everybody is asking this as they're listening. Could you give us some examples of what an unhealthy plant-based diet index would consist of compared to healthy? Then, perhaps, tell us a little bit about your study and what you found.

Dr. Megu Baden: First of all, let me explain again. In this study, we use three versions of plant-based diet indices that can assess the quality of plant foods in general population. The first index is an overall plant-based diet index, PDI for short. A second one is a healthful plant-based diet index, HPDI. The third one is an unhealthful plant-based diet index, UPDI. In order to create these indices, we divide all food groups into three larger categories. One is the healthy plant foods, which contains whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea, and coffee; less healthy plant foods such as fruits juice, refined grains, potatoes, sugar-sweetened beverages, and sweets or desserts; and animal foods, which is animal food, dairy, eggs, fish, meat, miscellaneous animals-based food.

Dr. Megu Baden: We investigated the association between preceding trailblazing changes in these indices and subsequent total and cause basic mortality in two large US cohorts. We found that compared with participants whose diet remained stable, the hazard ratio for total mortality, among those risks, the greatest increase in PDI was 0.95; for the greatest increase in HPDI, the healthful versions of the PDI was 0.90; and the greatest increasing in unhealthful PDI was 1.12. In contrast, the hazard ratio among participants with the greatest difficulty is in PDI, was 1.09; the greatest decrease in healthful PDI was 1.10; and the greatest decreasing in unhealthful PDI was 0.93. For CVD mortality, the risk was 7% lower for our 10 point increase in PDI, and 9% lower for HPDI and 8% higher for UPDI.

Dr. Megu Baden: In summary, we found that improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Dr. Carolyn Lam: Could I ask, Shilpa, to maybe add a line of ... have you applied this information in any way yourself or with patients, or is there an overwhelming take-home message you'd like people to remember?

Dr. Shilpa Bhupathiraju: Yeah, I'm not a clinician myself, but I'm a public health researcher. I'm in India currently and I'm giving a talk to South Asians and the emphasis on vegetarianism. But, again, the quality of the vegetarianism is important. Being a vegetarian is not enough, but what goes into it is really important. If it's a white rice and sugar-sweetened beverages, it's not good, so really the emphasis should be on whole grains, consuming more nuts and legumes. I think that's important.

Dr. Carolyn Lam: Oh, that's great. Mercedes, we've discussed this paper as associate editors, so proud to be publishing this in circulation. Could you share some of your thoughts on the implications of these findings?

Dr. Mercedes Carnethon: The authorship team has done an outstanding job of clarifying a very complicated issue. I think what we really like about this and the ways in which it really adds to the literature, what you point out, that every vegetarian diet isn't the same. I was very impressed with the thought that went into classifying vegetarian foods as healthy or unhealthy. I would be interested in hearing more from the authors, particularly, since I feel they did a good job of how they dealt with complicated foods or mixed foods. I think one example given was a pizza, which has tomato sauce, but it also has other things, so I would love to hear from the authors how they classified complicated foods.

Dr. Shilpa Bhupathiraju: The decision to classify pizza as an animal food was somewhat, I would say, arbitrary. I do agree that there's lots of tomato sauce, but again, I think the decision that went to it, it does have a ton of cheese, processed cheese, I think that's why we classified that as an animal food. The other complicated foods are mixed dishes that we struggled with were cream soups. We thought about what the base was or what the general preparation of that would be. Given that heavy cream is a major ingredient, so those were again, classified as animal foods.

Dr. Mercedes Carnethon: I think there's a lot of logic in that and I really like the thought and care that you put into that. The other questions I have, I feel that you did a really nice job of, are even portion sizes. Tell me how you handled portions.

Dr. Megu Baden: We basically take the information from our food frequency questionnaire. All of them are per the serving sizes, so we considered how participants reported how often on average they had consumed each food of our standard portion size in the past year. I know it's difficult to indicate the portion size. Shilpa, would you add something for the portion size for that?

Dr. Shilpa Bhupathiraju: Yes. Like Megu said, we use standardized portioning sizes, so a cup of fruit, a cup of vegetables, an eight-ounce, or a cup of tea or coffee, so that's how we use what people use in general. The portion sizes are all specified on the food frequency questionnaire, so the nurses or the health professionals, they understand exactly what they're reporting. Is it a glass of fruit juice or half a glass? Then, we can word those frequencies into standardized serving sizes onto servings per day.

Dr. Carolyn Lam: Great. Shilpa, could I follow up from Mercedes very important question? How does the index account for portion size too, as an is too much of even a good thing become a bad thing? You know what I mean?

Dr. Shilpa Bhupathiraju: The index itself is a score. The way we capture it, as you know, everything is converted from frequencies into servings per day for each participant. Then, what we did was we divided the participants based on the distribution of the data into quintiles. Those in the highest category of the healthy plant foods received the highest points. The scoring varied a little bit based on which index we were calculating. But, in general, what we did was we divided everybody into five groups or quintiles. Then, the scoring varied depending on what we were calculating. For the HPDI, which is the healthy plant-based diet index, those in the fifth group or the highest intake received the maximum number of points, which was five. For the unhealthy plant-based diet index, those people received the reverse scoring, so they received zero points. Essentially, the participants were divided into quintiles and the scoring was done accordingly.

Dr. Carolyn Lam: Maybe I could ask you a question on a different track, and I'm not sure if you have some answers here, but I noticed that your study population was impressive, almost 49,500 women from the Nurses' Health Study, almost 26,000 men from the Health Professionals Follow-up Study. Did you find any sex differences?

Dr. Shilpa Bhupathiraju: We didn't find any sex differences. We did some sensitivity analysis by cohort and we didn't find a statistically significant interaction, which is I think good to note because we would expect the effects to be similar in men and women.

Dr. Carolyn Lam: I think both men and women need to hear that. None of us are excused from, I suppose, trying to gear towards a healthy plant-based diet. I think that's what I'm hearing. Mercedes, do you have more thoughts to add?

Dr. Mercedes Carnethon: I do. One thing I really like about this particular paper is the way the you acknowledge some of the limitations that we face when interpreting findings from observational studies, particularly observational studies of a health behavior when we know that health behaviors often cluster or correlate with other health behaviors. Can you tell us a little bit about some of the cautions and interpretation that you certainly acknowledged and presented very well?

Dr. Shilpa Bhupathiraju: Sure. Our primary analysis was looking at changes, so long-term changes. When people change a diet or their lifestyle, they change something else. As you can see from our paper, those who improve the plant-based diet quality, we're also, in general, tended to be healthier. This being an observational study, we tried to control for those as to the greatest extent possible, but again, they could be residual confounding. We maybe failed to measure for certain things that we were unaware of or that we did not measure. I think we really can't get at causality, but I think the consistency of the evidence from our previous papers and from this paper point to a suggestion that improving plant-based diet quality is definitely associated with better health outcomes and a lower risk of death. But, again, it is important to know that this is observational and there could be changes in other health behaviors that we did not measure that could explain this association. But, we did as well of a job as we could in trying to control for these changes and other behaviors, lifestyles or even health conditions.

Dr. Mercedes Carnethon: Thank you.

Dr. Carolyn Lam: Thank you so much, Meg and Shilpa. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Carolyn Lam: This program is copyright American Heart Association 2019

Circulation September 10, 2019 Issue

9 september 2019 | 26 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley: And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia.

Dr. Carolyn Lam: Greg, I'm so excited about the feature paper this week. You know it deals with machine learning. It's such a hot topic now, and this one particularly deals with machine learning and the prediction of the likelihood of an acute myocardial infarction. So everyone's going to want to listen to it. Let's discuss a couple of papers and get to it, shall we?

Dr. Greg Hundley: Absolutely Carolyn, would you like to go first?

Dr. Carolyn Lam: I sure would. So my first pick is the first study to investigate the overall importance of translational regulatory networks in myocardial fibrosis. This is the study from doctors Rackham and Cook from Duke NUS Medical School here in Singapore.

Dr. Carolyn Lam: What they did is they generated nucleotide resolution translatome data during transforming growth factor beta one, or TGF beta one-driven cellular transition of human cardiac fibroblasts to myofibroblasts. So this technique identified the dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early responder genes.

Dr. Carolyn Lam: Now, very remarkably about one third of all the changes in gene expression in activated fibroblasts was subject to translational regulation and dynamic variation in the ribosome occupancy, affected protein abundance independent of RNA levels. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggest that the same post-transcriptional regulatory network, which was underlying cardiac fibrosis. Now key network hubs included RNA binding proteins such as PUM2 and QKI that worked in concert to regulate the translation of target transcripts in the human disease hearts.

Dr. Carolyn Lam: Furthermore, the authors showed that silencing of both PUM2 and QKI inhibited the transition of fibroblasts towards profibrotic myofibroblast in response to TGF beta one.

Dr. Greg Hundley: You know, Carolyn, this whole aspect of fibroblasts and how they turn on and turn off, become myofibroblasts, such a hot topic in heart failure. What are the clinical implications of this work?

Dr. Carolyn Lam: Yes, I agree. Well, threefold. First, these authors identified previously unappreciated genes under translational control, which could be novel candidates for disease biology and therapeutic targets.

Dr. Carolyn Lam: Number two, they found that critical fibrosis factors impacted cellular phenotypes at a protein level only, and hence these cannot be appreciated using single cell, or bulk RNA sequencing approaches. So that was significant. Finally, RNA binding proteins was shown to be central to the fibrotic response and represent unexplored gene expression regulators, and of course potential diagnostic or therapeutic targets.

Dr. Greg Hundley: Very nice Carolyn. Well, my next paper is also from the world of basic science, and it comes from Dr. Joseph Hill. Have we ever heard of him? Well of course, he's our Editor in Chief. He's going to discuss, he and his team investigated Polycycstin-1. Well, what is Polycycstin-1? It's a trans membrane protein, originally identified in autosomal dominant polycystic kidney disease, where it regulates the calcium permeate cation channel polycystin-2. So autosomal dominant, polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, atrial fibrillation and other cardiovascular disorders. These individuals harbor PC1 loss of function mutations in their cardiomyocytes, but the functional consequences of this are relatively unknown.

Dr. Greg Hundley: Now PC1 is ubiquitously expressed in its experimental ablation in cardiomyocyte specific knockout mice reduces contractile function, and in this paper the authors set out to determine the pathophysiologic role of PC1 in these cardiomyocytes.

Dr. Carolyn Lam: Huh--very interesting. I liked the way you laid that out. So what did they find?

Dr. Greg Hundley: What the investigators identified is that PC1 ablation reduced action potential duration in cardiomyocytes. They decreased calcium transients and therefore myocyte contractility. PC1 deficient cardiomyocytes manifested a reduction in sarcoplasmic reticulum calcium stores due to reduced action potential duration and circa activity, an increase in outward potassium currents decreased action potential durations in cardiomyocytes lacking PC1. PC1 coimmunoprecipitated with a potassium 4.3 channel and modeled PC1 C terminal structure suggested the existence of two docking sites for PC1 within the end terminus of K4.3. Supporting a physical interaction between the cells. Finally, a naturally occurring human mutant PC1 manifested no suppressive effects on this potassium channel activity. Thus, Carolyn, Dr Hill and colleagues' results help uncover a role for PC1 in regulating multiple potassium channels, governing membrane repolarization and alterations in circa that reduce cardiomyocyte contractility.

Dr. Carolyn Lam: Oh wow. What a bonanza of really interesting papers in this week. Now my next pick is a secondary analysis of the reveal trial. It hinges on the hypothesis that was generated from prior trials that the clinical response to cholesterol ester transfer protein or CETP inhibitor therapy may differ by ADCY9 genotype. So in the current study, authors Dr. Hopewell and colleagues from Nuffield Department of Population Health, University of Oxford examine the impact of ADCY9 genotype on the response to the CETP inhibitor Anacetrapib within the reveal trial.

Dr. Greg Hundley: Tell me, I've forgotten a little bit, but can you remind me a little about what was the reveal trial?

Dr. Carolyn Lam: Yes, of course. So the randomized placebo controlled reveal trial actually demonstrated the clinical efficacy of the CETP inhibitor Anacetrapib among more than 30,000 patients with preexisting atherosclerotic vascular disease. Now, in the current study, among more than 19,000 genotyped individuals with European ancestry, 13% had a first major vascular event during four years median follow up. The proportional reductions in the risk of major vascular events did not differ significantly by ADCY9 genotype. Furthermore, the authors showed that there were no associations between the ADCY9 genotype and the proportional reductions in the separate components of major vascular events, or any meaningful differences in lipid response to Anacetrapib.

Dr. Carolyn Lam: So in conclusion, the reveal trial being the single largest study to date to evaluate the ADCY9 pharmacogenetic interaction provided no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor Anacetrapib. The ongoing dal-GenE study, however, will provide direct evidence as to whether there's any specific pharmacogenetic interaction with dalcetrapib.

Dr. Greg Hundley: Oh, very good. So we've got some results coming from dal-GenE.

Dr. Carolyn Lam: Mm.

Dr. Greg Hundley: Well, Carolyn, my last selection relates to a paper regarding the incidence of atrial fibrillation among those that exercise, and I mean really exercise.

Dr. Carolyn Lam: Ooh.

Dr. Greg Hundley: So the paper comes from Dr Nicholas Svedberg from Uppsala University, and studies have revealed a higher incidence of atrial fibrillation among well trained athletes. The authors in this study aim to investigate associations of endurance training with the incidents of atrial fibrillation and stroke, and to establish potential sex differences of such associations in this cohort of endurance trained athletes. They studied all Swedish skiers, so 208,654 that completed one or more races of the 30 to 90 kilometer cross country skiing event called the Vasaloppet from 1989 through 2011, and they had a matched sample of 527,448 non-skiers, and all of the individuals were followed until their first event of either atrial fibrillation or stroke.

Dr. Carolyn Lam: Wow. What an interesting and what a big study. So tell us, what are the results and especially were there any sex differences?

Dr. Greg Hundley: Well, interesting that you ask about those sex and gender differences. So female skiers had a lower incidence of atrial fibrillation than female non-skiers, independent of their finishing time and the number of races, whereas male skiers had a similar incidence to that of non-skiers. Second, skiers with the highest number of races or fastest finishing times had the highest incidents of the AFib, but skiers of either sex had a lower incidence of stroke than non-skiers independent of the number of races and finishing time. Third, skiers with atrial fibrillation had a higher incidence of stroke than skiers and non-skiers without atrial fibrillation. That's true for both men and women. We would think that. Finally after one had been diagnosed with atrial fibrillation, skiers with atrial fibrillation had a lower incidence of stroke and a lower mortality compared to non-skiers with atrial fibrillation.

Dr. Carolyn Lam: Very interesting. Could you sum it up for us? What's the take home?

Dr. Greg Hundley: Couple things. One, female endurance athletes appear to be less susceptible to atrial fibrillation than male endurance athletes. Second, both male and female endurance athletes have a lower risk of stroke independent of their fitness level. Third, after the diagnosis of atrial fibrillation, participants in a long distance skiing event with atrial fibrillation had a 27% lower risk of stroke and a 43% lower risk of dying compared to individuals from the general population with the diagnosis of atrial fibrillation.

Dr. Greg Hundley: So there's some clinical implications. Although very well trained men have a higher incidence of atrial fibrillation than less trained men, the incidence is on par with that of the general population and not related to a higher incidence of stroke at that group level. This indicates that exercise has very beneficial effects on other risk factors for stroke. Then lastly, atrial fibrillation in well trained individuals should be treated according to our other usual guidelines for the population at whole.

Dr. Carolyn Lam: Wow. What a fantastic study to end our little coffee chat on, but it's time to move on to our feature discussion.

Dr. Carolyn Lam: Today's feature discussion touches on super-hot topics. First of all, the perennially interesting and hot topic of the prediction of acute myocardial infarction, or should I say the more precise predictions that we can do these days. The second part of the hot topic is machine learning. Oh my goodness. This is creeping into cardiovascular medicine like never before. So I'm so glad to welcome to this discussion corresponding author of the featured paper Professor Nicholas Mills from the University of Edinburgh, as well as our Associate Editor Doctor Deborah Diercks from UT Southwestern. So welcome both, and Nick, if I could start with you, tell us about MI Cubed.

Prof Nicholas Mills: First thing to say, it was a major international collaboration, involved researchers from over nine different countries and we got together to develop and test an innovative algorithm that estimates for individual patients the probability when they attend the emergency department with acute chest pain that they may or may not have had a myocardial infarction.

Prof Nicholas Mills: Machine learning is a really new area in cardiovascular medicine as you say. Our algorithm called MI Cubed uses a fairly simple algorithm which is a decision tree. It takes into consideration really important patient factors such as age, sex, troponin concentration at presentation, and troponin concentration on subsequent testing, and the change in troponin in between those two tests in order to estimate or calculate the probability of the diagnosis. One of the really interesting aspects of this is it's not just an algorithm for research, it's a clinical decision support tool as well. So what we've done is taken the output from that algorithm and translated it into something that is meaningful for clinicians. We've kept it quite simple. It gives an output between zero and a hundred, which is directly proportional to the likelihood of the patient having a myocardial infarct. We also provide estimated diagnostic metrics. So sensitivities and specificities that relate to that individual patient. It's really going to change the way we think about the interpretation of cardiac troponin in clinical practice.

Dr. Carolyn Lam: Indeed, and first audience please, please look up the beautiful figures of this paper. I think it summarizes it all. The algorithm shows you what MI Cubed is and then compares it to the ESC three hour algorithm, one hour algorithm. Then I love the last figure, where you actually show us that very important component that you just said. As a clinical support tool, how it's going to work. So we actually have pictures of your cell phone and showing you the pictures that you're going to get from it. So super cool. Beautiful paper.

Dr. Carolyn Lam: Now I just have so much to talk about, first the machine learning bit, always sexy sounding, but a bit scary for clinicians. So I really like the fact that you broke it down to actually say what components go in so that people aren't afraid of this black box. We don't know what's going on. Is there like a set time between samples, or how does this work? Do you need to have it within a certain timing? How does that fall in? Is it a particular type of troponin, what are some of the specs of the model that a practicing clinician needs to know?

Prof Nicholas Mills: Well, in order to answer that question, I might explain to you the rationale for developing it. So when you're assessing a patient in the emergency department, we all recognize in our daily practice that patients differ. So interpreting troponin has been challenging. One threshold for all may not be the right way to approach this really important clinical diagnosis. Troponin concentrations differ in men and women. They differ by age, and as a surrogate of the presence of comorbidities. They differ depending on the timing of when you take that sample and when you repeat that measurement, and that has introduced some complexity. So many interesting pathways have been developed for guidelines which try and apply fixed thresholds and fixed time points, and it's pretty tough to deliver in the real world setting of a super busy emergency department. So the premise for developing this algorithm was we wanted something that was really flexible, that recognized that patients are different, they're not all the same.

Prof Nicholas Mills: That's why we went for a machine learned approach rather than a more conventional statistical model. So you asked about the specification. You can do your two troponin tests whenever you like. So I had across the 11,000 patients huge variation in the timing of samples, but that is okay for MI Cubed. If you repeat the test within an hour, two hours, three hours, six hours, it still provides the same diagnostic performance. I think that's really important.

Prof Nicholas Mills: You also mentioned specification about the assay. This algorithm has been developed using a particular high sensitivity cardiac troponin assay developed by Abbott Diagnostics. It will be effective for other high sensitive troponin assays, but it's unlikely to be as effective using a contemporary assay. So if your hospital uses a contemporary or conventional cardiac troponin assay, this might not be the right algorithm for you.

Dr. Carolyn Lam: Great. Thank you for breaking down the issue so beautifully and practically. It really makes me think, oh my goodness, this paper's just far more than about MI. Because you know, natriuretic peptides, you could say the same thing. A prediction of heart failure is the same thing, you know? So the whole approach is novel. Deb, could you please share your thoughts and perspectives on where this is going perhaps?

Dr. Deborah Diercks: I think this study is terrific because I think it does, as Dr. Mills stated, reflect reality. We don't draw measures at zero, exactly at zero, and exactly at one and exactly at three, especially in a busy emergency department. So I think it provides flexibility to the physician and provider in using it to be able to interpret values in a world that doesn't fit complete structure like the guidelines are written out. What I find really interesting about this study, and I'd love to hear more about, is how you decided the thresholds of where low risk and high risk were cut at. It mentions by consensus, and I guess I would have loved to have been a fly on the wall to hear how those discussions went, and would love to hear more from you Dr. Mills about that.

Prof Nicholas Mills: Fascinating discussions amongst all the investigators on this project as to how we would define that. The first point I would make though is we designed the algorithm to provide a continuous output, a continuous measure of risk. So your MI Cubed score is between zero and a hundred. You don't have to apply a threshold, but we are used to in clinical practice having processes that support our triage of patients, and identifying people as low risk and high risk. Therefore we felt upfront that we should evaluate specific low risk and high risk thresholds.

Prof Nicholas Mills: So low-risk, we were completely unanimous on how to define that, and it was based on some really nice work done by emergency physicians in New Zealand. Martin Fan, who's the first author on this paper, surveyed many emergency physicians and asked about their acceptance of risk. They came up with the concept that an algorithm to be considered safe in emergency medicine would be acceptable if the sensitivity was greater than 99% or the negative predictive value was greater than 99.5%.

Prof Nicholas Mills: So we agreed up front that we would hold our low risk thresholds to those bars. Those metrics. Where there was less agreement was how you defined high risk. That didn't surprise me hugely. The positive predictive value of troponin is one of the most controversial topics around. Most cardiologists [crosstalk 00:20:52] of troponin has been difficult for them in clinical practice because with the improvements in sensitivity we are seeing lower specificity and lower causative link to value. If I put it into context, just measuring troponin and using the 99 percentile in consecutive patients gives you a positive predictive value of around about 45 to 50% in most healthcare systems for the diagnosis of type one myocardial infarction. Therein lies the problem. So one in every two patients has an abnormal troponin result but doesn't have the condition that we have evidence based treatments for, and whom cardiologists who are often quite simplistic in their approach to the assessment of these patients know how to manage.

Prof Nicholas Mills: Every second patient we don't know how to manage, and therefore we wanted an algorithm that would help us identify those patients who can go through our often guideline-based pathways and treatment pathways for acute coronary syndromes more effectively. We eventually agreed that a positive predictive value of 75% would be ideal. So three out of every four patients would have the diagnosis that we knew how to manage and treat. That was our target. We got pretty close to it in our test set. I think the actual positive predictive value at the threshold of around an MI Cubed value of 50 was 72%, so pretty effective. Certainly a lot better than relying on a kind of binary threshold such as the 99 percentile to identify high risk patients.

Dr. Deborah Diercks.: Thanks for that great answer. My next question is how do you think MI Cubed is going to integrate, or will it even replace the need for other risk stratification tools that we often use the emergency departments such as TIMI or the heart score?

Prof Nicholas Mills: Fabulous question. In this analysis, we haven't specifically compared the performance of MI Cubed with TIMI or heart, so my answer is going to be a little speculative. You can forgive me hopefully. Both those scores were developed prior to the widespread use of high sensitive cardiac troponin tests. I think what we've learned since the introduction of high sensitive cardiac troponin is that we're using this test as a risk stratification tool, and a lot of the power of the MI Cubed algorithm comes from the way that it identifies extremely low risk patients with very low and unchanging cardiac troponin concentrations way below the diagnostic threshold.

Prof Nicholas Mills: TIMI and heart simply consider troponin as a binary test, a positive or negative test, and do not take advantage of the real power of the test to restratify patients. All the evidence to date that has compared TIMI and heart with pathways that use high sensitive troponin in this way, both to restratify and diagnose patients show that these risk tools add very little in terms of safety, but do make pathways more conservative. So they identify fewer patients that are lower risk and permit discharge of those patients.

Prof Nicholas Mills: So my concern about using an algorithm like MI Cubed with an existing tool like heart is that it will undermine much of the effectiveness of this tool which identifies around about two thirds of patients as low risk. If you were to combine that with a heart score, you would reduce the effectiveness. I don't think you get a gain in performance, but further research is required to do a head to head comparison with these sorts of traditional restratification tools.

Dr. Carolyn Lam: I'm so grateful for this discussion, both Nick and Deb. In fact, I was about to ask what are the next steps and I think Nick you just articulated it. Deb, I want to leave the final words to you. Do you have anything else to add?

Dr. Deborah Diercks: I think this study represents a real change in how we can practice medicine, where we can actually take our biomarkers that actually have really strong value and utilize them in a manner that is pragmatic. It can actually introduce and take full advantage of them, and so I think this is a great opportunity for us to rethink our usual approach, which frankly, especially for troponin has really been very binary and very static. Thank you so much Dr Mills for the innovation and the willingness to look into this area.

Dr. Carolyn Lam: Thank you so much. This paper is like a sneak peak into the future of what we'll be practicing medicine like. Well, audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

Circulation September 3, 2019 Issue

3 september 2019 | 24 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events?

Dr Greg Hundley: Well, being a runner, and you are too, I actually have wondered about that.

Dr Carolyn Lam: Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis.

Dr Greg Hundley: So Carolyn, what is Mendelian randomization analysis?

Dr Carolyn Lam: Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.

Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.

Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.

They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh?

Dr Greg Hundley: You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.

So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation.

Dr Carolyn Lam: Nice. A lot of work. So what did they show?

Dr Greg Hundley: So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.

Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction.

Dr Carolyn Lam: Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one.

Dr Greg Hundley: Tell us a little bit about notch signaling.

Dr Carolyn Lam: Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.

So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.

So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation.

Dr Greg Hundley: Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications.

Dr Carolyn Lam: Indeed, very important topic. So please tell us what they found.

Dr Greg Hundley: Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.

So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work.

Dr Carolyn Lam: Yeah. Very interesting. Now let's get to our feature discussion.

Dr Greg Hundley: You bet.

Dr Carolyn Lam: Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that.

Dr Thijs Eijsvogels: The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time.

Dr Carolyn Lam: Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right?

Dr Thijs Eijsvogels: Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance.

Dr Carolyn Lam: Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me?

Dr Thijs Eijsvogels: So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example.

Dr Carolyn Lam: Great. That's important. So now with that backdrop, please tell us your main findings.

Dr Thijs Eijsvogels: We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference.

Dr Carolyn Lam: That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts?

Dr Torbjørn Omland: So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.

But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk.

Dr Carolyn Lam: That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically?

Dr Thijs Eijsvogels: I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.

And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well.

Dr Carolyn Lam: And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that?

Dr Torbjørn Omland: No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice.

Dr Carolyn Lam: There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct?

Dr Torbjørn Omland: Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test.

Dr Carolyn Lam: Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually.

Dr Thijs Eijsvogels: First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course.

Dr Torbjørn Omland: I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.

And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march.

Dr Carolyn Lam: That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs?

Dr Thijs Eijsvogels: I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies.

Dr Carolyn Lam: Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation August 27, 2019 Issue

26 augusti 2019 | 23 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: In just a moment, we will be discussing further results from the CREDENCE trial. That's canagliflozin in patients with type 2 diabetes and chronic kidney disease, this time focusing on the cardiovascular outcomes as well as both primary and secondary prevention groups. Really exciting stuff, huh, Greg?

Dr Greg Hundley: Absolutely, Carolyn. Got any papers you want to have a coffee chat about?

Dr Carolyn Lam: Absolutely. So my first pick really tells us that allele-specific RNA silencing of human alleles may be effective in treating inherited cardiomyopathies. Want to hear more?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: So, this is a study from Dr Ashley and colleagues from Stanford University School of Medicine who performed a selective allele-specific silencing of the human restrictive cardiomyopathy, a specific mutation of asparagine to lysine in the regulatory light chain, which is encoded by MYL2. So they did this in a humanized transgenic mouse model using an adeno-associated virus RNA interference approach. Using this approach, they showed that an interfering RNA treatment ameliorated disease phenotypes by specifically reducing the cardiac expression of the mutated allele, hypertrophic carb biomarkers and intramyocardial fibrosis. In fact, isolated cardiomyocytes from the treated animals showed normalization of contraction and relaxation dynamics with partial restoration of calcium re-uptake dynamics.

Dr Greg Hundley: Boy, Carolyn, sounds like improvement in cardiovascular function, but were there any adverse effects?

Dr Carolyn Lam: Great question. Well, they also performed cardiac genome-wide transcriptome profiling, which showed a reduction in the hypertrophic program without significant off-target effects, so that's important. So in summary, these results show the feasibility, efficacy, and safety of RNA interference therapeutics directed at human restrictive cardiomyopathy. A really promising step towards targeted therapy for a prevalent disease.

Dr Greg Hundley: Very nice. Carolyn. So I'm going to start my discussion also with a basic science paper that's going to focus on ischemia reperfusion injury and looking at the mechanism by which mitochondrial dysfunction can be avoided. So, the paper emanates from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital Medical University in Beijing. The study from Dr Li identifies an important mechanism of this myocardial ischemia-reperfusion injury in a mouse model and found, in human subjects, a biomarker that was predictive of adverse cardiovascular events after those individuals had sustained an MI.

Dr Carolyn Lam: Oh, interesting. So tell us more, Greg.

Dr Greg Hundley: Yeah, so the authors utilized a dynamic transcriptome analysis of mouse hearts exposed to various myocardial ischemia-reperfusion periods to identify a new inflammatory molecule that they termed S100A8/A9, and it was an early mediator. And then they measured this new inflammatory molecule level in patients, human subjects, after myocardial infarction, before and after they had undergone percutaneous intervention. So this S100A8/A9 was identified as the most significantly up-regulated gene during the early reperfusion stage and knockout of that molecule markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of the molecule exacerbated myocardial ischemia-reperfusion injury.

The authors then demonstrated that the levels in patients significantly increased day one post-PCI in anterior MI patients and elevated molecule levels were associated with the incidents of future MACE. So perhaps, in the future, targeting this molecule-initiated signaling may represent a novel therapeutic intervention for myocardial ischemia-reperfusion injury.

Dr Carolyn Lam: Interesting and very nicely explained. Now my next paper, the title says it all. Three Public Health Interventions Could Save 94 Million Lives in 25 Years. So we know that preventable noncommunicable diseases, which are mostly cardiovascular diseases, are responsible for 38 million deaths annually. So, these authors who are Dr Danaei and colleagues from Harvard T.H. Chan School of Public Health in Boston, Massachusetts, quantified the global mortality impact of three high-impact and feasible interventions. One, scaling up treatment of high blood pressure to 70%, two, reducing sodium intake by 30% and, three, eliminating the intake of artificial trans fatty acids.

So, they used global data on mean blood pressure levels and sodium and trans-fat intake by country, age and sex from a pooled analysis of population health surveys and regional estimates of current coverage of antihypertensive medications as well as cause-specific mortality rates in each country, along with projections from 2015 to 2040. They used the most recent meta-analysis of epidemiologic studies to derive the relative risk reductions for each intervention.

And, in summary, they found that the combined effect of the three interventions delayed 94.3 million deaths during 25 years. Increasing the coverage of antihypertensive medications to 70% alone would delay 39.4 million deaths, whereas reducing sodium intake by 30% would delay another 40 million deaths and eliminating trans-fat would delay an additional 14.8 million deaths.

Dr Greg Hundley: Aha. So controlling blood pressure, cutting salt, eliminating trans fats, but are there any regional differences around the world, Carolyn, your part of the world versus United States?

Dr Carolyn Lam: Good question as always. So the authors also estimated the impact in different parts of the world and found that the estimated impact of trans fat elimination was largest in South Asia. Sub-Saharan Africa had the largest proportion of premature delayed deaths out of all delayed deaths. National and international efforts therefore need to scale up these interventions and this should be a focus of cardiovascular disease prevention programs.

Dr Greg Hundley: Oh, my. Really interesting. Well, I'll tell you what, Carolyn, my next article is going to take us to space, the unified efforts of all these countries in the world trying to examine the effects of prolonged space flight. So this article, it's headed up by Dr Ben Levine at University of Texas Southwestern Medical Center, but it has a very large group of coauthors and examines the impact of prolonged space flight on orthostatic tolerance as those astronauts return to earth.

So, as we know, astronauts returning to earth usually demonstrate reduced orthostatic tolerance, especially when you assess them on a tilt table. But no studies to date have evaluated sort of the post-flight return to earth effects of orthostatic on activities of daily living, and those are most clinically relevant. So in this study, ambulatory blood pressure variability, that's already been known to be associated with orthostatic intolerance in other patient populations and can capture clinically significant orthostatic hypertension during activities of daily living. So, in the study, ambulatory beat-to-beat blood pressure was recorded using a portable device for multiple 24-hour time periods before, during, and after six months of space flight in 12 astronauts, four women, age averaged 48 plus or minus five years.

Dr Carolyn Lam: Fascinating. What a clever study. So what did happen to the astronauts when they returned to earth?

Dr Greg Hundley: So, in contrast to previous studies which employed the tilt tables or the stand test, no astronaut experienced orthostatic intolerance or hypertension during activities of daily living before or after space flight. 24-hour systolic blood pressure decreased in space as we might expect, but it returned to normal upon landing and diastolic blood pressure was unchanged during and following space flight. Systolic and diastolic blood pressure variability remained the same before, during, and after space flight. Given the current countermeasures that include exercise, training in flight, volume resuscitation on return, no astronauts experienced orthostatic hypertension or intolerance during routine, for landing day, activities in the initial 24 hours after landing, following six months in space. And prolonged exposure to space fight, therefore, had little impact on systolic blood pressure variability and its distribution. Though the latter showed just a transient change in space and that might be expected. It returned, however, to preflight values when we got back to earth. Very nice work.

Dr Carolyn Lam: Yes, indeed. Very clever. But let's carry on with our feature discussion, shall we?

Dr Greg Hundley: You bet. Welcome everyone to our featured article discussion, and we're going to learn more about primary and secondary cardiovascular-related events from the CREDENCE trial and we have with us, Dr Ken Mahaffey from Stanford Medical Center in California and our associate editor, Professor Naveed Sattar from Glasgow in the United Kingdom. Welcome to you both and we feel very honored to be able to discuss this paper today with you, Ken.

Can you just refresh our memories a little bit about the CREDENCE trial? What were its primary results? I understand they had patients with diabetes and chronic kidney disease. Maybe tell us a little bit about how that was defined and then transition to what were the hypotheses in your study that you were going to test?

Dr Kenneth Mahaffey: So, the CREDENCE trial was a trial of an SGLT2 inhibitor, canagliflozin, in patients with diabetes who had chronic kidney disease with albuminuria. And it was the first of any of the SGLT2 inhibitor trials that was done in a dedicated renal population with a primary outcome that was a composite of renal outcomes along with cardiovascular death, and the trial was stopped early by the data safety monitoring board on an interim analysis when they found overwhelming efficacy. And, at the end of the day, the final results showed that canagliflozin compared with placebo showed a 30% reduction in the composite renal outcome as well as important reductions in cardiovascular outcomes without any evidence of increase in amputations.

Now, the study that we're talking about today is a pre-specified, pre-planned subgroup analysis from CREDENCE where we wanted to look at how canagliflozin worked in people or participants who had known cardiovascular or cerebrovascular or peripheral vascular disease and those who did not. And one of the reasons this was an important analysis was that in previous studies of SGLT2 inhibitors, there has not been a consistency in the message about whether the drug worked in both primary and secondary-prevention populations.

And what we found here in this analysis was that in the primary-prevention participants, which actually was 50% of the overall trial recruitment, had very similar reductions in renal outcomes and cardiovascular outcomes compared with those who were a secondary-prevention cohort. So a very different results and a very important result in this patient population.

Dr Greg Hundley: Really interesting. So in terms of the patients that you evaluated in this sub study, were they any different than the whole cohort and, in terms of participants and compliance with the therapy, was there any difference with the placebo versus the study drug that you noticed and can you infer from that any particular groups of patients that may benefit more or be able to take the therapy more? Just more about compliance.

Dr Kenneth Mahaffey: First of all, you asked how the primary and secondary-prevention groups in the study were different and they were, as one would expect. Those participants who did not have prior atherosclerotic cardiovascular disease tended to be younger. They were more often women. They had shorter durations of diabetes and they were less often treated with cardiovascular preventive medications, in terms of staph and antiplatelet therapies. All the patients were on an ACE or an ARB.

In terms of overall compliance with canagliflozin, it was very good. Now, the SGLT2 inhibitors, as a class, have a number of important side effects including genital mycotic infections in both men and women. They do cause some hypovolemia and volume depletion, but we found overall in the CREDENCE trial that fewer participants stopped the study drug prematurely in the canagliflozin arm than in placebo arm. So we feel that we had a very, very good comparison of the two therapies in the overall trial and in the primary and secondary-prevention analyses.

Dr Greg Hundley: And so just general thoughts of how do you think this might impact the results of your study, or treatment, when we see patients with diabetes and chronic kidney disease?

Dr Kenneth Mahaffey: I think there's potentially a big impact moving forward. Now, the SGLT2 inhibitor classes were approved based on the early cardiovascular outcome trials, did not enroll participants with lower EGFRs. So once these data are reviewed by the FDA and if they accept these findings and change the label, then the proportion of patients with diabetes who also have EGFRs down to 30 would be potential candidates for this therapeutic intervention. And it's important to point out that the CREDENCE trial that showed this reduction in renal events in patients with type 2 diabetes and chronic kidney disease, this is the first positive trial in 20 years of an intervention and 20 years ago we had both ACEs and ARBs based on large outcome trials, but we've had nothing since then that could be a therapeutic intervention to improve outcomes in this very important patient population.

Dr Greg Hundley: Thank you so much, Ken. And, Naveed, I would like to just turn to you and ask you a couple things. One, can you put this study on the SGLT2 inhibitors with all the other information that's coming out related to potential benefits, not only in controlling blood sugar, but impacting cardiovascular disease-related events? How does this fit in to all of the other studies that we're learning about in such rapid fashion?

Dr Naveed Sattar: This comes on the back of the three major trials and extends the evidence based so that, yes, I think we now show clear evidence that these drugs work in people with impaired renal function down to a level of 30 which I think is very important, so that will extend the guidelines. Yes, they seem to work in primary prevention. Of course. I think Dr Mahaffey would accept that these are probably high-risk primary prevention individuals because you also have evidence for chronic kidney disease and I suspect a lot would probably have subclinical cardiovascular disease if we went to look for it.

Nevertheless, I think it will extend the guidelines in the sense that physicians are not only going to be potentially using these drugs in people with existing cardiovascular disease but also patients like those in CREDENCE with chronic kidney disease or a very high risk of cardiovascular disease without having had an event. So I think that's also very reassuring as well and exciting. And I think also the benefits of kidney outcomes is, as we said beautifully, that this is a game changer. Over the last few decades we've not really had any major trials to excite the renal community. But now we have. This trial extends the promise that we saw in the three previous trials and takes it a bit further, that these drugs have substantial and meaningful benefits in prevention of important kidney outcomes in our patients with diabetes. It looks like those benefits appear across the spectrum of diabetes. Whether they've existing disease, chronic kidney disease, or even a primary prevention when previous colleagues looked at it in a meta-analysis.

So, I think that's exceptionally exciting and I think, therefore, given the profile of these drugs and as we're improving our safety in the sense we're able to use these drugs better in groups and also advise how to reduce side effects. I think really they're changing the paradigm of how we care for many of our patients with diabetes and I'd be interested to see what Dr Mahaffey thinks about those comments. My sense is this is really exciting.

Dr Greg Hundley: Ken, any thoughts?

Dr Kenneth Mahaffey: I think it was nicely articulated, some of the important observations here. I do agree that the patient population here that has chronic kidney disease but no known atherosclerotic disease and therefore primary prevention, it had higher risk. The event rates in CREDENCE were much higher than event rates in the CANVAS trial where the mean eGFR was much higher and so I agree that these patients may have some subclinical atherosclerotic disease, but they are clearly at higher risk of developing it.

Dr Naveed Sattar: Again, this would be interesting to take Ken's take. But if people have chronic kidney disease, they are, in a sense, revealing themselves to have evidence of end organ damage or be at the level of the kidney but not necessarily the heart. So my sense is there's still people with evidence of disease and it's just that we're seeing it in a different way. I don't know what Ken thinks about that as a kind of interpretation.

Dr Kenneth Mahaffey: Again, I think they're at high risk and we know that people who have kidney disease often are at higher risk of having cardiovascular disease during their lifetime and where we are in the spectrum of those new disease processes. We don't necessarily have the data in CREDENCE to understand that at a very granular level, but I think it's an important area that we need to evaluate sooner and it raises that issue of treatment for primary prevention should occur earlier and what we're seeing now is that when people develop type 2 diabetes and we notice that they have chronic kidney disease with microalbuminuria, that is the time to intervene, intervene soon. We now have a single therapy that's safe and effective and reduces the metabolic derangements with improved glucose control, improved blood pressure control, improved weight. It also has an important impact on the renal outcomes and important impact on cardiovascular outcome. So it's really a trifecta from a single therapy that can be prescribed easily.

Dr Naveed Sattar: I agree. And all those means of treatments were very, very favorable as well across the board, which I think is also important.

Dr Greg Hundley: So, Ken, what are some key clinical aspects related to your study that you feel we need to address?

Dr Kenneth Mahaffey: What we need to think about carefully is we now have a new therapy. These types of patients are actually seen by a whole host of clinicians in our healthcare systems, at least in the United States. They're seen by diabetologists, cardiologists, nephrologists, and primary care. And we need to think of ways that we can educate all four of those groups of clinicians about these important data and provide learning and other mechanisms to integrate these therapies into clinical care. It's a message I've been trying to get out.

Dr Greg Hundley: Well, listeners, what a great discussion between Ken and Naveed on this very important topic, the emergence of SGLT2 inhibitors and the results of these primary and secondary cardiovascular prevention group analyses from CREDENCE.

We want to thank each of you for listening with us this week. Carolyn and I look forward to talking with you next week. Take care now.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation August 20, 2019 Issue

19 augusti 2019 | 23 min

Dr Gregory Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature is from Professor Carl Lindstrom from Helsinki University Hospital and the University of Helsinki and evaluates whether administration of simvastatin via nasogastric tube in brain-dead individuals prior to cardiac transplant donation improves transplant recipient cardiac-related outcomes. It is a randomized trial using an inexpensive therapy, and I look forward to that discussion with Professor Lindstrom. How about we grab a cup of coffee and start off our discussion today.

Dr Carolyn Lam: All right, so here goes. The first paper that I want to discuss really looks at the question, is DNA methylation related to incident coronary heart disease? Well, Dr Agha from Columbia University in New York and colleagues looked at this and profiled epigenome-wide blood leukocyte DNA methylation in 11,461 individuals from nine population-based cohorts in the United States and Europe using the Illumina Infinium 450K microarray and prospectively ascertained coronary heart disease events.

Dr Gregory Hundley: So Carolyn, what did they find?

Dr Carolyn Lam: Well, they found that differences in blood leukocyte DNA methylation at 52 cytosine phosphate guanine sites were associated with incident coronary heart disease or myocardial infarction with a false discovery rate of less than 0.05. Several of the differentially methylated loci mapped to genes related to calcium regulation and kidney function. Exploratory analyses with Mendelian randomization supported a causal effect of DNA methylation on incident coronary heart disease at loci in active regulatory regions with links to noncoding, RNAs and genes involved in cellular and tissue structural components.

Very nice Caroline. So what's the summary for us clinically?

Dr Gregory Hundley: So, these findings really provide the first evidence that genomic regulation via epigenetic modifications in kidney function and calcium homeostasis related pathways may be involved in the development of coronary heart disease. The findings of epigenetic, loci related non-coding RNAs highlight pathways that have not immersed in genome-wide studies of coronary heart disease and therefore represent novel therapeutic targets, which thus far have not been explored.

Dr Carolyn Lam: Very good, Caroline. Well, I've got a basic paper that I want to present and it's from professor Xander Wehrens from the Baylor College of Medicine. And this study addresses factors that promote atrial fibrillation. The investigators found that reduced levels of protein phosphatase-1 regulatory subunit R3A in human atria are causally linked to abnormal calcium handling and atrial fibrillation pathogenesis.

In the absence of protein phosphatase-1 regulatory subunit R3A reducing binding of PP1 catalytic subunit increases phosphorylation levels of the ryanodine receptor, R2 calcium release channel, and phospholamban. Complex zone, profiling, a technique that combines native gel electrophoresis with mass spectrometry to obtain the composition of multi protein assemblies revealed that PP1 R3A is part of a macro molecular protein complex containing the ryanodine calcium release channel and the circuit 2APLN calcium uptake transporter.

Dr Gregory Hundley: Wow. Complex zone profiling. That's so cool, but what does it all mean for us clinically, Greg?

Dr Carolyn Lam: Well reduced levels of PP1 regulatory subunit contribute to abnormal calcium release and re-uptake and atrial monocytes, thereby promoting atrial fibrillation pathogenesis. And thus normalizing levels of PP1R3A phosphatase sub unit may represent a novel therapeutic approach to manage atrial fibrillation.

Dr Gregory Hundley: That's so cool. I next have a preclinical paper which contributes really to the understanding of molecular basis of pathological myocardial remodeling in heart failure. And this is from co-corresponding authors, doctors, Jung, Liu, and Lin-Jung from Shanghai East Hospital Tongji University School of Medicine in China. And the paper really focused on Forkhead box transcription factor P1 or Foxp1 in endothelial cells.

Dr Carolyn Lam: So Foxp1 Carolyn, tell me a little bit more about that.

Dr Gregory Hundley: Is it good that you asked before I asked you. Forkhead box proteins P or Foxp are large modular transcription repressors that bind to DNA via their highly conserved Forkhead DNA binding domains. Fox p1 is highly expressed in vascular endothelial cells and it's essential for normal cardiac development.

So, these authors found significantly down regulated Fox P1 expression in cardiac endothelial cells during cardiac remodeling induced by to angiotensin 2. Endothelial cell Fox P1 loss of function resulted in cardiac dysfunction following angiotensin 2 infusion and in the transverse aortic constriction model with severe cardiac fibrosis and mild adaptive cardiac hypertrophy.

Whereas endothelial cell Foxp1 gain of function protected against pathological cardiac remodeling and improved cardiac dysfunction transforming growth factor beta 1 signals were identified as Foxp1 direct target genes in endothelial cells which mediated the pathological cardiac fibrosis through cardiac fibroblasts proliferation and myofibroblast formation and maladaptive cardiac hypertrophy through TGF beta 1 promoted endothelial one expression during pathological cardiac remodeling.

Dr Carolyn Lam: Wow. Carolyn, this was very sophisticated work. What do we take away from it clinically?

Dr Gregory Hundley: These data really identified endothelial Foxp1 mediated TGF beta 1 signal pathway involvement in the promotion of cardiac fibrosis and cardiac hypertrophy via TGF beta 1 induction of the endothelin one pathway. So targeted delivery of TGF beta 1 silencing RNA or small interfering RNA to inhibit endothelial cell specific TGF beta 1 for the improvement of pathological cardiac remodeling may actually represent a future novel therapeutic strategy in managing this maladaptive cardiac fibrosis and hypertrophy during progression of heart failure.

Dr Carolyn Lam: That was an excellent summary of a very technical but informative basic science paper. I'm going to shift gears a little bit and talk a little bit about a study relating to clopidogrel and aspirin from the point study.

This study comes from Claiborne Johnston at the Dell Medical School and University of Texas. And in patients with acute minor ischemic stroke or high risk transient ischemic attack enrolled in the point trial. The combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. This current paper is a secondary analysis of Point and involves 4,881 subjects in which the investigators assess the time course for benefit and risk from the combination of clopidogrel and aspirin.

The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction or ischemic vascular death, and the primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left truncated models.

Dr Gregory Hundley: So, what did the study show Greg?

Dr Carolyn Lam: Well through 90 days, the rate of major ischemic events was initially high, then decreased markedly while the rate of major hemorrhage remained low but stayed constant throughout the study. Using a model based approach the optimal change point for major ischemic events was 21 days with a hazard ratio of 0.65 for clopidogrel aspirin versus aspirin at a P value of 0.0015 compared to later at 22 to 90 days. Where that hazard ratio was 1.38 and the P value only 0.24.

And the models showed benefits of clopidogrel aspirin for treatment delayed as long as three days after symptom onset. So Carolyn, the authors conclude that the benefit of clopidogrel aspirin occurs predominantly within the first 21 days and outweighs the low but ongoing risk of major hemorrhage. When considered with the results of the CHANCE study, a similar trial treating with clopidogrel aspirin for 21 days and showing no increase in major hemorrhage. The combined results suggest limiting clopidogrel aspirin use to 21 days may maximize benefit and reduce risk after TIA or minor ischemic stroke. Very practical paper.

Dr Gregory Hundley: Indeed. Thanks Greg. That was nice.

Dr Carolyn Lam: You bet.

Dr Gregory Hundley: Welcome everyone to our podcast and we're very pleased today to have Dr Antti Nykänen from Helsinki University in Finland as well as an associate editor, Justin Ezekowitz from Edmonton, Canada to discuss a very interesting randomized clinical trial related to the administration of simvastatin in those that are donors for heart transplantation and looking at subsequent outcomes in the patients that received the transplants. Antti, we're very excited for you to bring this to circulation. This particular paper and I wonder if you might outline for us what were your hypotheses that you are trying to test and what was your overall study design.

Dr Antti Nykänen: These things are routinely admitted to heart transplant recipients starting one to two days after transplantation. As previous clinical studies show that recipient that treatment has beneficial long-term effects on mortality and cardiac allograft vasculopathy. So in this clinical study, we basically tried to answer the question whether having the statin effect on the board even earlier before the transplant procurement by giving statins to the organ donor, if that would protect the transplanted hearts.

And this question was based potential rapid vascular and cardioprotective effects of statin and when our previous experimental study showing that treating the organ donor with statins will decreases vascular profusion injury in a heart transplant model. So basically we went on the test donor simvastatin clinically and randomize brain dead heart transplant donors either to a control group or to receive a signal 80 milligram dose of simvastatin before organ procurement.

Dr Gregory Hundley: I'm imagining that you would administer the simvastatin through either an intravenous mechanism or perhaps an NG tube, something like that. Maybe tell us a little bit about how you accomplish this and then what were your study results?

Dr Antti Nykänen: So, the simvastatin was administered to the donor via a nasogastric tube so there is no intravenous simvastatin formulation available. It needs to be absorbed and then activated through the liver so that can form. So, what we did in our previous experimental study was that we included a few clinical human brain-dead donors and basically investigated whether by giving simvastatin through the nasogastric tube would be metabolized and if you could detect that in in the donor plasma.

And that was actually the case. So in a few hours we saw up-regulated levels of simvastatin and also the active form in the donor or so basically showing off that treatment in a clinical brain dead donor of situation would be feasible. So we went on to use that method, clinical study and basically our primary outcome was plasma levels of cardiac injury biomarkers after transplantation.

And interestingly by treating the donor with simvastatin decreased and recipients for troponin INT levels six hours after transplant's profusion. Therefore, it seems that organ donor’s statin treatment reduces biomarkers of myocardial injury after transplantation in a clinical setting.

Dr Gregory Hundley: And did you examine any other functional measures of these patients? For example, ejection fraction by echo or anything, or was it primarily a biomarker study? That's the first question. Second question. Do you have any other information on other organs that also may have been donated? Would the statin have impacted, for example, liver transplantation?

Dr Antti Nykänen: That's a good question. So we did follow up cardiac function and the routine and serial measurements with the echocardiographic and we did not find any changes in the left ventricle. It took some traction after transplantation.

We did however find the decrease in proBNP levels into recipients. And that was maybe then at one week after transplantation and then it's leveled out after that.

And then regarding the next question about other transplanted organs. So once he was in a multi organ donor situation, so the same donor could have donated kidneys or livers, lungs, pancreas. So we did a follow up of the close recipients also. And I can say that there was no adverse effects, no decline in the survival or primary function of the transplanted organs. And interestingly we did find in the liver recipient that if the recipient received the liver from a donor simvastatin treated the liver function tests were better at day seven post-transplant.

Dr Gregory Hundley: Very interesting. And then lastly, just another outcome related question. Sometimes I know these patients undergo assessments for rejection by biopsy. Any information that you can share with us on outcomes related to biopsies.

Dr Antti Nykänen: We took routine biopsies, myocardial biopsies from the recipients and we did not find any significant differences in the biopsy program rejections either at 30 days or one year after transplantation. We did also monitor, we checked some treatments, so during the first 30 days there was significant decrease in the amount of rejection treatments for hemodynamically rejects it about not for the first year.

Dr Carolyn Lam: Wow. Just fabulous results. Thank you so much Antti. So Justin, I wanted to turn the conversation over toward you. Tell us about post-transplant management of these patients and then how do you see these study results integrating into our current standards of care.

Dr Justin Ezekowitz: Thanks Greg and Dr Nykänen and thanks for also letting us look at your work, which is terrific and extremely hard to do from the translation of your original 2011 circulation publication in animals and moving forward into the current publication years later. And thinking forward into the next few years of how we translate this into practice so that the current management after transplantation obviously involve multiple anti-rejection medications and many activities around detecting rejection is one of the key ways in which patients are managed other than their hemodynamics and other things that happen early.

What I was interested in is the generation of the idea where the simvastatin will really affect the clinical outcomes on the recipient and thinking that into the practice environment is, it's a very simple intervention to think about that would be easily applicable in, I think, most hospitals that do transplantation as either the recipient or the donor.

And Dr Nykänen, when you think about translating this into practice over either Europe or in Finland, I don't sense that this is going to be very difficult. Statins are well tolerated. The cardiology and other communities are very familiar with using a statin. But do you anticipate any barriers to translating this into practice as I think the guidelines may pick this up as something of interest.

Dr Antti Nykänen: Yes, I think we can show that it's feasible and we did a result on the biomarkers, so indicating that the damage the heart undergoes during the transplantation was smaller after donor statin treatment, so it is feasible, it's very cheap and it generally has a good safety profile. The timeframe for the treatment also feeds into the window of creating a brain dead organ donor. So in that sense it would be applicable in a donor treatment situation.

Dr Justin Ezekowitz: Right. And so I think this is the key point is even though it's a smaller trial in terms of the cardiology thinks about its trials. This is an area that doesn't have a lot of clinical trials were randomized clinical trials and so any evidence of benefit with a known, generally considered safe medication such as a statin, you would think that we should be able to broadly apply pretty quickly even on what are often not hard outcomes that are softer outcomes.

Because the benefit to risk ratio is generally favorable here. Dr Nykänen, my only other question to you is to think about the team getting this done must have been incredibly hard, but do you think there is a need for a larger trial to test this hypothesis on clinical outcomes or do you think this is really as far as you can go in the transplant world for an RCT.

Dr Antti Nykänen: So, it's been a long road from artery to single center clinical trial, which took time, so the patient numbers are fairly small in our study. We had 42 in the control group on 42 in the treatment group. I agree the risk benefit ratio is probably beneficial. But for sure it would be very nice to see larger studies that would look at the biomarker effects, but also would look at the other clinical end points.

Dr Justin Ezekowitz: Right, and that's a great point. It's only 84 patients, but a continued study of the area's important while perhaps implementation studies could go on to take what you found in both an animal translation into humans in a single center RCT and now translation into a larger population of recipients and their donors. I think that's probably the key next step in the transplantation world which has a tougher time getting larger number of patients into clinical trials for a variety of reasons.

So, congratulations to you and your team in getting this one to the point where we could probably apply this in a reasonable way with reasonable safety and an expected benefit to a broader group of patients.

Dr Gregory Hundley: Well this has been a fascinating discussion, Antti as well as Justin and what a relatively simple, clever idea that could have profound outcomes for this transplant population. We certainly want to thank you Antti for bringing this to circulation and sharing it with our readership. Are there any few last words you'd like to share with us before we close today?

Dr Antti Nykänen: Very nice to see how things evolve after this. We will for sure try to look more closely at the mechanisms and follow up the patient population for a long term follow up. And I hope this will stimulate some other experiments in the field.

Dr Gregory Hundley: Justin, any parting comments from the editorial team?

Dr Justin Ezekowitz: This is a great example of a full clinical trial that is mechanistic, but also has MR outcomes, and I just want to congratulate the authors on providing a very full picture of all the pieces that it takes to do in a clinical trial environment. Plus also collecting genetic and other biomarker material and imaging material. So, my compliments to the authors both to yourself, Dr Nykänen, but also the team that you assembled over the last six or eight years of doing this project, which we know was a huge task and my congratulations to you and your team.

Dr Gregory Hundley: We want to thank Dr Nykänen and his team from Finland and Justin Ezekowitz. We look forward to chatting with you next week.

Dr Carolyn Lam: This program is copyright American Heart Association, 2019

Circulation August 13, 2019 Issue

12 augusti 2019 | 23 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia. Carolyn, oh, this is going to be an exciting featured article today, and we're going to discuss the combination of agents or their administration et al that are best suited for managing both anticoagulation and antiplatelet therapy and those with coronary disease, peripheral arterial disease and heart failure. And, we'll speak with Dr Kelley Branch from the University of Washington.

Dr Carolyn Lam: And me!

Dr Greg Hundley: Yes. How am I going to interview you? And, we'll discuss the utility of Rivaroxaban with or without aspirin in patients with heart failure or peripheral arterial disease from the compass trial.

Dr Carolyn Lam: Well, I'm not going to let you get there until I tell you about this first basic paper I've chosen because it focuses on the unfolded protein response.

Dr Greg Hundley: What's that?

Dr Carolyn Lam: Well, Greg, I was really hoping you'd ask. The unfolded protein response is a cellular adaptive process to cope with protein folding stress. Now, approximately 40% of human proteins are predicted to be either transmembrane or secretory. The synthesis, the folding, the cellular transportation and location of these proteins rely on proper functioning of this secretory pathway. Numerous studies have established that the unfolded protein response plays versatile roles during development and under physiologic and pathophysiologic conditions. However, the role of this unfolded protein response in the regulation of cardiomyocyte growth is unclear.

Dr Greg Hundley: That's fantastic, Carolyn. I've already learned something here. So, what did this paper show?

Dr Carolyn Lam: This is from Dr Wang and colleagues from UT Southwestern, and basically, they use both gain and loss of function approaches to genetically manipulate spliced X-box binding protein one or XBP1, which is the most conserved signaling branch of the unfolded protein response in the heart. In addition, primary cardiomyocyte cultures were employed to address the role of XBP1S in cell growth in a cell autonomous manner. They found that XBP1S expression was reduced in both human and Rhode and cardiac tissues with heart failure deficiency of XBP1S lead to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac restricted over expression of XBP1S prevented the development of cardiac dysfunction. Mechanistically, they found that XBP1S stimulated adaptive cardiac growth, your activation of mechanistic target of rapamycin or MTOR signaling which is mediated via the FK-506 binding protein 11, which is a novel transcriptional target of XBP1S. So in conclusion, this study really showed a critical role of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in coupling the unfolded protein response and cardiac cell growth regulation.

Dr Greg Hundley: Boy Carolyn, you explained that so well, and I learned a lot from that. I hope I can do as well with this next article from Professor Johann Backs from the University of Heidelberg. Now paradoxically, some glucose lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling, and this study from his group focused on one of the class two histone deacetylases or HDAC's namely HDAC-4, which functions as an important epigenetic regulator by responding to upstream stress signals, and linking them to downstream gene regulatory programs involved in among other things, metabolic regulation.

Dr Carolyn Lam: Very interesting. So what did they find?

Dr Greg Hundley: What they found is that HDAC4 acts as an important maintenance factor of cardiac function in diabetes and O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the production of cardio-protective HDAC F-end terminal fragment and attenuates cardio detrimental Cam kinase two mediated phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase two mediated phosphorylation of HDAC4 at searing 632 attenuates HDAC-4 n terminal production. Thus, these findings lay the ground for the development of novel therapeutic strategies for diabetic patients with heart failure by inhibiting Cam kinase phosphorylation at CIHR 632 or enhancing o-glycine and escalation at searing 642.

Dr Carolyn Lam: Fascinating, Greg. Well, my next paper is a subgroup analysis of EUCLID and is the first to assess acute limb ischemia in the context of a large-scale clinical trial studying a primary peripheral artery disease population.

Dr Greg Hundley: So Carolyn, reminded us what was the EUCLID trial.

Dr Carolyn Lam: Okay, so EUCLID stands for Examining Use of Ticagrelor in Peripheral Artery Disease, and this was a randomized clinical trial that included acute limb ischemia as an adjudicated outcome in a primary peripheral artery disease population randomized to ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not superior to Clopidogrel for the prevention of cardiovascular events in patients with stable peripheral artery disease. However, a EUCLID subgroup analysis of patients with and without prior limb revascularization demonstrated significantly higher risk for acute limb ischemia hospitalization in patients with prior low extremity revascularization.

Dr Greg Hundley: So Carolyn, that's interesting. So, what did they find related in this study that focused on the acute limb ischemia?

Dr Carolyn Lam: Right. So, today's paper is from Dr Hess and colleagues at University of Colorado School of Medicine and CPC, clinical research in Aurora, Colorado. And, they found that acute limb ischemia occurred in 1.7% of almost 13,900 randomized patients with a median time to hospitalization for acute limb Ischemia of 320 days after randomization. In this population, prior lower extremity revascularization, atrial fibrillation and lower ankle brachial index identified patients at higher risk for acute limb ischemia. Hospitalization for acute limb ischemia was associated with subsequent cardiovascular and limb ischemic events. So, the take home message is providers should monitor for signs and symptoms of acute limb ischemia in patients with stable symptomatic peripheral artery disease, particularly those with prior lower extremity revascularization, atrial fibrillation, and lower ankle brachial index.

Dr Greg Hundley: That's very instructive, Carolyn. Fantastic message. So, I'm going to ask you if you could select one lipid biomarker to forecast future adverse cardiovascular events, which would you select? Total cholesterol, HTLC, non-HTLC, direct and calculated LDLC, APO-A1, or APO-B?

Dr Carolyn Lam: Well, I'm traditional. I would have chosen LDL.

Dr Greg Hundley: Okay. Well, the authors of this study led by Dr Paul Welsh at the University of Glasgow attempted to answer this question by studying participants from the UK Biobank without baseline cardiovascular disease and not taking statins with relevant lipid measurements. They had 346,686 participants. An incident fatal or nonfatal cardiovascular event occurred in 6,200 participants of which 1,656 were fatal, and they occurred over a median time of 8.9 years. So, the associations of non-fasting lipid measurements, total cholesterol, HDLC, non HDLC, direct and calculated LDLC, APO-a1, and APO-B with cardiovascular disease were compared using Cox models, adjusting for classical risk factors and predictive utility was determined by the C-index and net reclassification index. Also, prediction was tested in 68,649 participants taking a statin with or without baseline cardiovascular disease, and that group experienced 3,515 cardiovascular events.

Dr Carolyn Lam: Okay, so drum roll. What did they find?

Dr Greg Hundley: So, measurement of total cholesterol and HDLC in the non-fasted state is sufficient or was sufficient to capture the lipid associated risk in the cardiovascular disease prediction with no meaningful improvement from addition of APO lipoproteins, direct or calculated LDLC. And, similar findings were reproduced in those taking a statin at baseline.

As such, the authors feel like calls for widespread use of APO lipoproteins are not warranted given the negligible difference in risk prediction beyond total cholesterol in HDLC. And, direct LDLC is also not required for risk prediction. Non HDLC is a cheaper or equivalent predictor of risk on and off statins without the requirement of one of us being fasting. This is an excellent article for our listeners to review or download.

Dr Carolyn Lam: Wow, that is so cool. So, from one excellent paper to another excellent paper in our feature discussion. Let's go, shall we?

Dr Greg Hundley: Welcome everyone to discussion of our featured article. We have Dr Kelley Branch from the University of Washington and our own Carolyn Lam, and they're going to be discussing the compass trial. So Kelley, could you tell us a little bit about the rationale for compass as opposed to the previously published commander study?

Dr Kelley Branch: So, in order to understand compass and compare it to commanders, we're going to have to go back a little bit in time here. And recall, you know well over 20 years ago that when we used anticoagulants in coronary artery disease, that was actually shown to be more beneficial than aspirin alone, but because of the excess bleeding risk, warfarin or vitamin K antagonists not used, and aspirin won. Fast forward a number of years, and now we have the non-vitamin K anticoagulants, and the was potentially that we could find the goldilocks, if you will, the good balance of benefit as well as less bleeding maybe used to these new agents. So, the compass trial was really born from an atlas ACS one and Atlas ACS two, which found that a low dose of, in this case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams VAB were shown to be beneficial in patients after acute coronary syndrome.

And then, it was thought what happens if we treat these patients with now chronic coronary disease as well as arterial disease? And from this 27,000 patients, 47,395 patients were tested, and our study very specifically looked at patients with a baseline or a history of heart failure when they answered compass. Compass were shown to be beneficial with specifically the use of aspirin plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test this in patients with this baseline or history of heart failure. Now, this is in real contradistinction to what the commander tried to do. And the reason why encompass, we actually excluded patients with severe heart failure. This was defined as a New York Heart Association class three or four or an ejection fraction less than 30%. Now if you looked at patients with commander, these patients had ejection fraction less than 40%. That was a criteria to get in. And of course, these patients had to have a recent hospitalization for heart failure. So, these are very different patient populations. Well, both of them, yes, they did have coronary artery disease, but really very different patient populations.

Dr Greg Hundley: Very good. So Kelley, tell us specifically, what were your treatment group assignments and the doses and the outcomes that you were going to follow, and then lead us into what did you find? What were the outcomes of your study?

Dr Kelley Branch: Sure, so compass was actually developed as a partial three by two factorial. The arm that we're going to be talking about is the rivaroxaban arm. There was also another arm that tested the use of Proton pump inhibitors, and that actually was shown to not be as beneficial as we thought to decreased bleeding. But specifically for rivaroxaban, the baseline was aspirin, and this was on top of guideline based medical therapy. And then patients were randomized to either aspirin alone plus placebo or Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5 milligrams BAD. Those were really the three treatments. Patients were going to be followed for about three to four years. That's what we expected to get our 2200 events , an event-driven trial. But, because of the overwhelming benefits at 23 months median follow up, this trial was actually stopped early, so we only had a little over 1300 events at that time.

And with that we saw substantial reduction in major adverse cardiovascular events, about 24% mortality was reduced 18%, and there was a bleeding risk along with this, major bleeding, little different way of actually measuring major bleeding, but that was increased by about 70%, and that was the overall trial results. So, looking at the patients with heart failure, though, there was actually a relatively large proportion of patients, so 5,902 patients, about 22% of patients, actually had either baseline heart failure or had a history of heart failure coming in. Now, this was defined specifically by the PI's. These were not rigorously defined as compared to say commander, but these were patients where the PI said this patient has history or has chronic heart failure. So, with these 5,902 patients, we looked specifically at the outcomes of major adverse cardiovascular events similar to what we saw with compass and that is cardiovascular death, myocardial infarction, or any stroke, that combination. And then, looked at some others exploratory analysis like mortality.

And, what we found is that in patients with heart failure, the baseline rate was substantially higher for a mate's. Not too surprising because this tends to be a higher risk patient population. But, what we found is that the hazard ratio was about 0.68, so pretty similar to what we've seen the 24% relative risk. In this case, this was a 32% relative risk reduction in those patients with heart failure. Now, if we looked at a patients without heart failure, the hazard ratio is 0.79, so fairly similar and the [conference intervals 00:16:33] overlap. No statistical heterogeneity or no difference between those, but what we did see if we looked at the absolute risk reduction, was an absolute risk reduction in heart failure of 2.4% reduction. That means a number needed to treat of about 42. If you look at the absolute risk reduction for those patients without heart failure, that was 0.9 to 1.0 depending on what the rounding was. We took 1.0 so that means the number needed to treat of 103. So, these were slightly different relative risks, but overall, what we saw is that the hazard ratio is very consistent with the overall effect of compass in the same direction.

Interestingly, and actually I think even for me it was surprisingly, we actually looked at the hazard ratios for bleeding, and when we looked at the hazard ratios for bleeding, we fully expected that because it's the higher risk patient population, we actually expected that to go up. What we saw is that the bleeding actually was no difference at all, and if anything in the heart failure population was slightly lower. And, this was fairly surprising to us because we thought that the patients with heart failure, the bleeding would actually trend up because this was a higher risk patient population. So it looks like it's something can be used and really no substantial increase in bleeding.

Dr Greg Hundley: Very good. Well Carolyn, as someone that's managing patients with heart failure, what do you see are the clinical implications of this study?

Dr Carolyn Lam: That is a beautifully simple, direct question but is not as easy to answer as I may have thought. And, that's because the commander trial that Kelley did describe a bit earlier was neutral on its primary outcome. And, the commander trial is what we would traditionally think of as a heart failure trial. And why? Because those were patients that we rigorously define heart failure, including a naturally acid peptide inclusion criteria. And, because we really wanted these to be severe heart failure patients, we recruited them very close to their hospitalization or decompensation event. So, I just want to reiterate what Kelley has already so beautifully described that commander was neutral, whereas this heart failure subset of compass showed very impressive results that were consistent with the very impressive positive results of the overall compass trial.

So, how do we reconcile all of it? Well, first of all, I have to humbly remind myself that this heart failure subset of compass, the entire subset was actually bigger in numbers than the entire of the commander trials. So, this is not a small little subgroup analysis. This is a huge subgroup analysis. And that's why a paper like this, we're so proud to be publishing in circulation.

So, how do I apply it? Well, when I have a compass like patient, which means it's a stable coronary artery disease or peripheral artery disease patient who happens to have some mild heart failure. I think of this patient as a compass patient and I think that the combination of aspirin and low dose Rivaroxaban has been shown to be effective in these patients. So, in such a patient, I continue the aspirin rivaroxaban combination. However, if I have a new patient coming in with decompensated heart failure, a very low ejection fraction and has some coronary artery disease, by the way, I see that as a commander patient, and I just want to make sure that in such a patient I'm not trying to reduce their overall mortality by treating them with a combination of aspirin Rivaroxaban because commander has shown that I don't impact their overall survival with this combination, even though we may still have beneficial effects on their thromboembolic thrombotic events.

Kelley, would you agree?

Dr Kelley Branch: I would completely agree. That was actually born out very, very well by Barry Greenberg who had a really a wonderful sub analysis which he looked at the thrombotic events published in Jama cardiology and really showing that yes, you can affect the thrombotic events, but I mean really what it comes down to is we want to save lives. We want people to be better. There's just an overwhelming risk for these patients with heart failure that is really non thrombotic, primarily. And so, you're really not going to move the needle very much. You may prevent a stroke here, you may prevent some cardiovascular death from a thrombotic problem, but overwhelmingly pump failure, arrhythmia, et cetera. Those are really going to be the drivers for the commander like population.

Dr Carolyn Lam: But Kelley, this comes up a lot when we've chatted, but if you have a compass patient who has heart failure and then gets admitted with heart failure, what would you do then?

Dr Kelley Branch: That's a really interesting question, right? It depends on what the overall goal is. So, if the patient gets admitted for heart failure, now has it decreased ejection fraction sick. So has an MI, now decreased the ejection fraction. What's the end game? Right? Well you know, you may not be affecting mortality in this case because there's now competing events. However, if the goal was to decrease stroke, we've seen that. Still this goal is to decrease MI to some extent than we see that also. So, it would be reasonable to continue in order to prevent those events. But, just knowing full well that there's many other medications which actually do much better for the patients with decreased ejection fraction. And, those would probably be considered first line, but it's reasonable to continue. But, I would never start it.

Dr Carolyn Lam: Kelley, I couldn't agree more. And here I think the, your data showing that the bleeding risk is not significantly increased in this patient matters a lot. So, if I had a patient, a compass patient who was already on the combination and then gets admitted with heart failure, I too, if there's no additional bleeding risk, I would continue the combination as well.

Dr Kelley Branch: Couldn't agree more.

Dr Greg Hundley: Well listeners, this was a fantastic discussion, and we look forward to seeing you next week. Have a great week.

Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Circulation August 06, 2019 Issue

5 augusti 2019 | 26 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts, I'm Dr Carolyn Lam, associate editor from National Heart Center and Duke National University of Singapore

Dr Gregory Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Our feature article today really invokes thought regarding LVAD bridging to heart transplantation. I really look forward to the conversation with Dr Veli Topkara from Columbia University, the corresponding author and our associate editor, Dr Mark Drazner from UT Southwestern. And it's regarding the outcomes from their study, evaluating patients waiting for transplant that are bridged with an LVAD versus not. But before we get to that, let's dive into some of our other original articles with our little coffee chat. Do you have an article that you'd like to discuss?

Dr Carolyn Lam: You bet I do Greg and I have my coffee here. Have you ever wondered, does microvascular disease, in any location in the body, increase the risk of lower limb amputation? Well, this was looked at in the paper that I chose first today. It's from Dr Beckman from Vanderbilt University Medical Center in Tennessee and his colleagues, and they basically examined 125,674 participants in the Veterans Aging Cohort Study from 2003 to 2014 and analyzed the effect of prevalent microvascular disease defined as retinopathy, neuropathy and nephropathy and peripheral artery disease status on the risk of incident amputation events, of which there were 1,185 amputations over a median of 9.3 years.

Dr Gregory Hundley: Wow, Carolyn. What did this study find? What did Josh and his colleagues find?

Dr Carolyn Lam: They found that the presence of microvascular disease increases the risk of amputation significantly in the absence of peripheral artery disease. As many as one in six below knee amputations may result from microvascular disease, even without peripheral artery disease. Microvascular disease also potentiates the amputation risk in persons with peripheral artery disease to more than 20-fold, compared to persons with neither peripheral artery disease nor microvascular disease. Further research is really needed to understand the mechanisms by which this occurs. And in the meantime, clinicians should bear this increased risk in mind when screening for and managing lower extremity disease.

Dr Gregory Hundley: Ah. Well Carolyn, my first paper is somewhat related because we're going to talk about triglycerides. And this paper is from Zahid Ahmad from UT Southwestern Medical Center. He's the corresponding author. And can you imagine Carolyn an antibody that could correct elevations in serum triglycerides?

Dr Carolyn Lam: Tell us about it, Greg.

Dr Gregory Hundley: Well, I'm going to give you a little background first. Low levels of triglycerides and other lipids are observed in individuals with loss of function mutations in angiopoietin-like protein 3 which inhibits lipoprotein lipase activity, increasing triglycerides and other lipids, and providing a rationale for development of a monoclonal antibody therapy.

Dr Carolyn Lam: Interesting. What did this study do Greg?

Dr Gregory Hundley: It evaluated evinacumab. They looked at the safety of this. This is a fully human angiopoietin-like protein 3 antibody, and it was compared with placebo, with no serious treatment emergent adverse events, no events related to death or treatment discontinuation was reported. They did two phase one studies evaluating single and multiple ascending doses. In addition, substantial and sustained percent reductions from baseline versus placebo were observed and triglycerides with absolute levels reaching about 50 milligrams per deciliter for several of the evinacumab doses at specific time points in both studies. And therefore, the data from these two phase one studies in this one paper support further clinical evaluation of this new antibody in larger studies of hypertriglyceridemic individuals.

Dr Carolyn Lam: Definitely a space to look out for. Well Greg, my next paper is a basic paper. Genome wide association studies have identified chromosome 14 Q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterized gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the function of this gene and its role in atherosclerosis has previously been unknown, well, until today's paper. But Greg, here's your quiz. What do you know about the hedgehog proteins?

Dr Gregory Hundley: Well, I know hedgehogs are friendly little animals and I know they must have great proteins because they're so friendly.

Dr Carolyn Lam: Why did I expect that? Oh, let me tell you a little bit about them. The mammalian hedgehog proteins like sonic hedgehog, desert hedgehog, and Indian hedgehog are secreted molecules that exert a concentration and time dependent effect on target cells following binding and complex signal transduction pathways. They induce the transcription of target genes, primarily involved in cell proliferation, survival, and fate specification.

Now in adults, the hedgehog signaling is involved in the maintenance of adult vasculature and ischemia induced neovascularization, including after myocardial infarction. Today's authors, however, including Tom Webb from University of Leicester and colleagues, report the first experimental investigation of HHIPL1 and the present evidence that it is a secreted proatherogenic protein that regulates smooth muscle cell proliferation and migration. So, that's novel.

Through a series of experiments involving coronary artery disease, relevant human cells and mouse models, they showed that HHIPL1 is a secreted protein that interacts with sonic hedgehog and is a positive regulator of hedgehog signaling. In murine models, HHIPL1 deficiency attenuates the development of atherosclerosis by reducing smooth muscle cell proliferation and migration. The clinical implications are two-fold. First, this study supports HHIPL1 as the causal gene at that 14 Q32 coronary artery disease locus that we did not really understand previously. And secondly, HHIPL1 is a promising therapeutic target that affects a pathogenic mechanism not addressed by current mechanisms for coronary artery disease. Room for novel development.

Dr Gregory Hundley: Very interesting Carolyn. Well, I've got another basic science paper, and this is from Dr Kenneth Walsh at University of Virginia and it's going to look at the role of neutrophils, not necessarily macrophages but neutrophils and their role in pressure overload induced cardiac dysfunction. While the complex roles of macrophages in myocardial injury is widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. This study examined the regulation and function of neutrophils in pressure overload induced cardiac hypertrophy as mice underwent treatment with Ly6G antibody to deplete neutrophils and then subjected them to transverse aortic constriction or TAC.

Dr Carolyn Lam: Huh? What did they find?

Dr Gregory Hundley Caroline, the study revealed that neutrophils played a critical role in the hypertrophy of the left ventricle that results from pressure overload in this murine model of heart failure and identified that a non-canonical Wnt protein is essential for the recruitment of neutrophils to the injured myocardium.

Dr Carolyn Lam: Hmm. What do you think are the clinical implications of this?

Dr Gregory Hundley This study demonstrates how neutrophils contribute to the hypertrophy of the left ventricle under conditions that do not involve ischemia or myocardial necrosis. Also, since cardiac hypertrophy is a risk factor for the development of heart failure, this study implicates WnT5a mediated neutrophil infiltration as an early step in the progression of this disease.

Dr Carolyn Lam: Wow, thanks Greg. That was so cool. But let's hurry on to our feature discussion, shall we?

Dr Gregory Hundley You Bet.

Dr Carolyn Lam: Bridge to transplant with left ventricular assist devices is a mainstay of therapy for heart failure in patients awaiting heart transplantation. The criteria for heart transplantation listing does not differ between patients medically managed versus mechanically bridged to heart transplant. However, are there differences in post-transplant outcomes between medically managed and mechanically bridged patients? Well, today's paper provides important data to address this question. So pleased to have with us the corresponding author, Dr Veli Topkara from Columbia University Medical Center, New York Presbyterian as well as Dr Mark Drazner, associate editor from UT Southwestern. Welcome gentleman. Veli, this is an important question. Could you please tell us how you addressed it and what you found?

Dr Veli Topkara: We decided to visit an old question of whether bridging with LVAD confers at risk for post-transplant mortality. Because the field and pump technology has been rapidly changing. There has been a significant increase in utilization of devices nationwide to the extent that more than 50% of patients already have an LVAD in place by the time they receive a heart transplant. And patients also wait much longer on these pumps before they could get a heart.

Currently, available devices provide continuous flow and patients essentially live without a pulse for many months to years waiting for a heart. And with this unique physiology, they also have unique complications such as RV failure and there has also been pre-survey reports including one from our center suggesting an increase in the primary graft failure rates after heart transplant. And mostly seen in patients who were bridge to transplant with an LVAD.

To address some of these questions, we took advantage of the UNOS database, which is the largest prospective transplant data registry in the United States. We were able to identify more than 14,000 patients who are either medically or mechanically bridged to transplant. We then derived a cohort from patients who were LVAD baseline by propensity score and we looked at their outcomes.

And what we found was that patients who were mechanically bridged to transplant with an LVAD, had 9.5% mortality at one year, compared to 7.2% in patients who were medically bridged. And this is more than 30% increase in relative risk of death for LVAD patients. When we looked at the specific cause of death at one year, LVAD patients had a higher number of cardiovascular death secondary to primary graft failure, confirming findings of the recent studies at a larger scale.

Next, we looked at whether mortality risk factors were similar in the mechanical versus medical bridged patients. And this is a very important question clinically because the criteria for transplant listing do not distinguish between the two patient cohorts. For example, at my center age cutoff transplant listing is less than 72 years of age and that is whether or not patients are on VAD support. And same applies for example, GFR cutoff for renal function or PVR cutoff for pulmonary hypertension. And all the cutoffs that are utilized are essentially identical for transplant candidates irrespective of the bridging strategy.

But what we found in this paper, however, what's quite different that if we apply the same thresholds for mechanical versus medical bridged patients, for some of these risk factors, you end up having outcomes that are remarkably different. For example, for patients with a normal renal function, the mortality risk is similar going into transplant with or without an LVAD, but for patients with borderline renal function observed mortality has more than doubled for those going into transplant with an LVAD, as opposed to medical therapy.

And we also observed similar trends for recipient age, BMI and PVR, in which numerical increase in these factors would translate to high risk of mortality in LVAD patients going into heart transplant. Despite the limitations of this large registry analysis, I think these findings suggest that we may need to think of it differently when it comes to listing or transplanting patients who are on LVAD. And there seems to be a group of patients who are perhaps maybe better served by staying on an LVAD as opposed to moving on to heart transplant and we need to better identify who these patients are.

Dr Carolyn Lam: Oh Wow. Veli, thank you. First, congratulations on a very important paper and also how you beautifully summarized. Mechanically bridging patients associated with a higher risk of early post-transplant mortality and even providing data on the cause and risk factors associated with that mortality. Mark, could I bring you in here? Not just as AE (associate editor), but as a doc[tor] who manages many of these patients. What were your perspectives?

Dr Mark Drazner: As I step back and as Veli said, there's an increasing number of patients who are being bridged with a VAD, so the question clearly is important, and we don't really have any randomized data available to us in terms of how the bridging strategy may impact outcomes. When you look at the groups of patients who are supported with VADs or not, they're very different and so you need to do some statistical manipulation which here they did propensity matching, to try to come up with equal groups as you look at their outcomes. That was nicely done.

And then theoretically I think you could argue there may be reasons why patients bridged with VADs may do better or they may do worse. They may do better because you may restore their functionality, you may improve renal function and, but they may do worse because they have coagulopathies, the VAD itself may lead to complications and so it's a question you can't really answer just logically. You really need some data which is I think the best study that's been brought forward so far as the one we're discussing today. Veli, let me ask you because the obvious question then is why do you think the outcomes are worse among the patients who are bridged?

Dr Veli Topkara: I think they are doing worse for multiple different reasons. Having an LVAD is clearly an additional surgery which technically makes the second transplant surgery more complicated. But when we looked at the risk factors for primary graft failure at our institutions, the predictors of primary graft failure in LVAD patients were also very similar to factors we identified in this nationwide analysis which included renal failure, RV dysfunction, as well as trans-transplant and increased time on device support. I think it's clear that some subset of LVAD patients who have these risk factors are at higher risk for increased post-transplant mortality for some of the mechanistic reasons are unclear at this point.

Dr Mark Drazner: Do you think their continuous flow exposure is part of it?

Dr Veli Topkara: That's clearly one of the hypotheses that we have been talking about because as we discussed, these patients are exposed to continuous flow for a long time and one of the concerns is whether they lose their peripheral arterial venous-reactivity over time. And this could potentially also be the reason why patients who are on pump support for longer times are at higher risk for PGF. That's a possible underlying mechanism. But in this data set, we didn't have fair data with regards to pulse pressure and pulsatility, which could have helped answering this question.

Dr Mark Drazner: And just for clarification for the listeners, this was pre-HeartMate 3 data, is that correct?

Dr Veli Topkara: Yes. This analysis doesn't include any HeartMate 3 patients.

Dr Carolyn Lam: And Mark, if you don't mind, could you also clarify for the listeners why you specifically pointed out HeartMate 3 in the setting of the pulsatility?

Dr Mark Drazner: There is some degree of pulsatility reintroduced with the HeartMate 3, whether that has any physiological consequences is not yet known. Certainly, in terms of the impact of transplants. But as Veli said, the dataset available didn't yet include the HeartMate 3 so that's, remains an unanswered question for us currently, but certainly an important one.

Dr Veli Topkara: We would probably be able to do this analysis now that we have accumulated more patients with HeartMate 3. At the time of the study we didn't have any HeartMate 3 patients in the registry. In terms of primary graft failure, we have implanted over 160 patients with HeartMate 3 at my center, but we still see primary graft failure in HeartMate 3 patients going into heart transplant, but that would clearly be an interesting follow up project.

Dr Mark Drazner: Yeah, for sure. Another point that people, as they looked at your paper and asked me, is in terms of the impact of the VAD complications, whether the patients who are doing worse or those who, because they are patients who had VAD who have had complications and then went on a transplant and the impact of that, in terms of your findings. I know you did some analyses on that. Could you just clarify that for our listeners as well?

Dr Veli Topkara: Sure, so we wanted to look at for the LVAD patients, if there were any VAD related factors that would impact the posttransplant mortality and one of the things that we looked at was, their specific complications on LVAD support and were able to pull that data by looking at their reason for 1A upgrade status which clarifies the complication pipe. And when we looked at, based on complication type, we didn't see any impact of complication on the post LVAD mortality. In other words, the other patients who are transplanted with an infection or they were transplanted because of device thrombosis, they did not have any difference in terms of their posttransplant mortality.

We also compared patients who were supported by axial flow devices versus centrifugal flow devices and again, there was no significant difference in terms of posttransplant mortality. One factor that we found that was significant was the duration of the LVAD support and patients who stayed on the LVAD for longer times clearly had increased higher risk of posttransplant mortality. And this is also something that we had found in our institutional data.

Dr Mark Drazner: And Veli that would potentially speak to the impact of the continuous flow if duration of VAD is a risk factor.

Dr Veli Topkara: That's our hypothesis Mark. And I think we all tend to think that continuous flow is not natural, and we have pulse style flow for a reason. Now it's possible that if our bodies and end organs and vessels are exposed to continuous flow for a long time, that may be potentially a reason for, increased risk of PGF or raise of PGF after heart transplant. But I don't think we have enough data yet.

Dr Mark Drazner: Veli, one of the other interesting findings was the lack of impact on long-term outcomes. I'd be interested in your thoughts about that, why there was an impact on the first year but not long term.

Dr Veli Topkara: Absolutely. And that was a critical part of the findings and when we looked at our survival, when we visually looked at the curve, it seemed like the curves really separated early on and they sort of remain parallel to each other after one year. And for that reason, we did a conditional survival analysis starting from one year and then we compared starting for one year. There was actually no difference between the LVAD versus medical group. Again, confirming that the adverse impact of survival was really early, within the first year after transplant and I think that really has to do with primary graft failure as well as vasoplegia which are, typically seen early posttransplant. And I think the reason the VAD support is increasing mortality is most likely through increasing risk of PGF as well as vasoplegia. Now that's my read on the early risk rather than the late impact.

Dr Mark Drazner: Do you think that speaks to maybe not as big an impact on the immunological milieu of VADs as one might anticipate?

Dr Veli Topkara: Certainly, I mean the immunology, one thing we know is that LVAD patients have higher HLA sensitization going into transplant. However, primary graft failure is typically very early after transplant. And in general, we don't find, obviously we don't see any rejection in these patients. The mechanism is not related to HLA mediated rejection.

Dr Mark Drazner: That's interesting.

Dr Carolyn Lam: Well Mark and Veli, thanks so much. This is such an important and interesting discussion. Could I wrap it up now by asking each of you, you've already covered possibly the important areas for future research including the pulsatile devices, but what should clinicians take home right now? Veli, if I could start with you, because you had already said earlier that perhaps these patients need to be more carefully considered. What do you mean by that? What's the take home for now?

Dr Veli Topkara: I think the question is whether we should be listing or transplanting LVAD patients who are high-risk, and I think the research should focus on developing tools to better identify LVAD patients who are too high-risk for transplant. In this project, we only worked with a limited number of variables that were available in the UNOS registry, but there may be more specific clinical risk factors or even biomarkers predicting outcome in this unique cohort of LVAD patients potentially transitioning into transplant. I think that's an important question to figure out.

And another important question is whether we should be using identical cutoffs for listing patients with or without LVAD and if not, what would be the ideal cutoff for each one of these risk factors? Because what I read from this paper is that, a creatinine level of 1.8 may signal a different risk in an LVAD patient versus another patient on a minor trump. That's another important question.

And also, since October of last year, the new heart allocation policy has been in place, which now defines LVAD patients to appear status three or four based on their complication profile. And it will be interesting to see how the new allocation system would impact patients are on LVAD support waiting for an organ. And it's possible that these patients may end up waiting longer compared to patients who are with cardiogenic shock and are assigned to higher tier status. And if LVAD patients wait longer as we see from this data, they will have worse posttransplant outcomes. It's going to be very interesting to see how the new allocation policy impacts.

Another point I want to make is that with the recent MOMENTUM-3 trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality risk at one year and this is actually lower than 17.6% mortality at one year in high risk LVAD patients in our study. Again, questioning transitioning from LVAD to transplant in high risk patients.

Dr Mark Drazner: I might take a step back even further. It's an important, it touches on a critical question in my mind, which is if you have a patient who needs to go into transplant and they're not crashing and burning. I'm assuming if they're crashing and burning, you need to go onto an LVAD, the following comments won't apply to that group. If you're a patient who's relatively stable, is it a better strategy to try and get them to transplant directly? Or is it better to go through and VAD and then transplant them? And ultimately that strategy question I think would require randomization to really answer that. But the data that we have discussed today, I think are opening that question and touch upon that in terms of the strategy of the impact of bridging people with VADs itself, which is why I think this is such an important question.

Dr Carolyn Lam: Thanks again, Mark and Veli. That was an amazing discussion.

Thank you, audience, for joining us. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

Circulation July 30, 2019 Issue

29 juli 2019 | 23 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, Associate Editor of Circulation, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, guess what? We are going to be talking later about non-inferiority trials. Now, you're going to go like, "Huh? What?," but then we see more and more non-inferiority cardiovascular trials. And do we really know the advantages and limitations of this type of trial design? Which is so important to understand, because we need to understand the factors that may impact our confidence and interpretation of these results. So, that's going to be a really important feature discussion, coming up right after our coffee chat. Greg, what are your papers?

Dr Greg Hundley: Thanks Carolyn. Boy, I can't really wait to get to that feature discussion. That's something that we deal with all the time, and I look forward to that explanation and that discussion. I'm going to talk a little bit of basic science, with two papers right in a row.

And the first one involves catecholaminergic polymorphic ventricular tachycardia through inhibition of calcium/calmodulin-dependent kinase II. The lead author is Dr Vassilios Bezzerides from Boston Children's Hospital.

Carolyn, this paper focuses on treatment of catecholaminergic polymorphic ventricular tachycardia, an underlying diagnosis in at least 12% of pediatric patients who present with unheralded cardiac arrest. ICDs, as you know, are frequently implanted, but are problematic because of increased complication rates in pediatric patients, failure to convert ventricular arrhythmias, and the risk of fatal ICD-induced electrical storm. Modulating CaM Kinase II within the heart shows promise to treat this, but CaM Kinase II is essential in other tissues, most notably the brain.

Dr Carolyn Lam: How interesting. So, what did the study show?

Dr Greg Hundley: Well, the investigator used adeno-associated viral gene therapy, which is proven to be a safe and efficient vector for sustained gene transfer into many cell types to selectively inhibit CaM Kinase II in cardiomyocytes. They were able to express the specific CaM kinase II inhibitory peptide AIP in cardiomyocytes without significant extra cardiac expression, and an inhibition of CaM Kinase II effectively suppressed ventricular arrhythmias in a murine model of catecholaminergic polymorphic ventricular tachycardia after a single therapeutic dose. So thus, in animal models, delivery of a CaM Kinase inhibitory peptide by AAV represents a novel single dose gene therapy for catecholaminergic polymorphic ventricular tachycardia. How about that?

Dr Carolyn Lam: Wow. You've got a second paper?

Dr Greg Hundley: I sure do. So now we're going to jump into, again, looking at polymorphic VT from engineered human heart tissue. And this article is from Kevin Parker at Harvard University, "Modeling of Human Arrhythmias Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes has Focused on Single-Cell Phenotypes."

With this said, it is important to realize that arrhythmias are emergent properties of cells assembled into tissues and the impact of inherited Arrhythmia mutations on tissue level properties of human heart tissue. And therefore, newer technologies are needed to develop more satisfactory therapeutic interventions. Ones that encompass all of the tissue, not just single cells.

Dr Carolyn Lam: Interesting. So, what did this particular study do?

Dr Greg Hundley: So, Carolyn, in this study, the investigators report on an optogenetically-based human-engineered tissue model of catecholaminergic polymorphic VT, which as we have discussed in the previous article is promoted by mutation of the cardiac ryanodine channel 2, which is promoted by mutation of cardiac ryanodine channel and triggered by exercise. They developed a human IPSC cardiomyocyte-based platform to study the tissue level properties and investigated pathogenic mechanisms in polymorphic VT by combining this novel platform with genome editing. The authors found that engineered heart tissue, fabricated from human pluripotent stem cell derived cardiomyocytes, effectively modeled catecholaminergic polymorphic VT caused by dominant mutations in the cardiac ryanodine receptor, including induction of arrhythmias by conditions that stimulate exercise. Using selective pharmacology and genome editing, the authors identified activation of calcium/calmodulin-dependent kinase II, or CaM Kinase II, and CaM Kinase II mediated phosphorylation of ryanodine at Serine 2814 as critical events that are required to unmask the latent arrhythmic potential of catecholaminergic polymorphic VT, causing ryanodine mutations, highlighting a molecular pathway that links beta adrenergic stimulation to arrhythmogenesis in this disease.

Dr Carolyn Lam: Wow Greg! So, two very interesting and important linked genetic papers. Well, we're going to switch tracks a little bit and talk about, well, my favorite topic: heart failure with preserved ejection fraction and the whole complex issue of the diagnosis of this syndrome. Now we know that the diagnosis is kind of complex and there is currently no consensus but several proposed definitions. So how do the clinical and hemodynamic profile of patients vary across the different definitions of HFpEF?

So, this question was answered by Dr Jennifer Ho from Massachusetts General Hospital and her colleagues, who examined consecutive patients with chronic exertional dyspnea and an ejection fraction above 50% who are referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. They applied societal and clinical trial HFpEF definitions and compared the clinical profiles, exercise responses, and cardiovascular outcomes by these different definitions. So, of 461 patients, 416 met the ACC/AHA definition, 205 met the ESC definition, and 55 met the HFSA criteria for HFpEF.

The clinical profiles and exercise capacity varied vastly across the definitions, with peak oxygen uptake averaging 16.2 for those with the ACC/AHA definition and down to 12.7 in those satisfying the HFSA definition.

Dr Greg Hundley: Wow. What a difference from these societies.

Dr Carolyn Lam: Mm-hmm (affirmative).

Dr Greg Hundley: So Caroline, it sounds like they looked at all comers with exertional dyspnea. Now how about those that had hemodynamic evidence of heart failure with preserved ejection fraction?

Dr Carolyn Lam: Yeah, good question Greg. So, you caught me telling you that all these patients had hemodynamic cats as well, and a total of 243 had hemodynamic evidence of HFpEF, which was defined as an abnormal rest or exercise feeling pressure. Of these, 222 met the ACC/AHA criteria, 161 met the ESC criteria, and only 41 met the HFSA criteria. Over a mean follow-up of 3.8 years, the incidents of cardiovascular outcomes range from 75 for the ACC/AHA criteria to 298 events per thousand-person years for the HFSA criteria.

The application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. So in summary, the authors demonstrated significant diversity in the number of patients meeting HFpEF criteria. And using different HFpEF classifications variably enriched for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure really highlighted the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF sub-grouping to test therapeutic interventions. Now, these are all discussed in an important accompanying editorial by Michele Senni, Sergio Caravita, and Walter Paulus.

Dr Greg Hundley: Wow Carolyn. It appears, depending upon the definition, we could really classify patients drastically differently.

Dr Carolyn Lam: Yeah, an important paper indeed. And again, I would strongly encourage everyone to read that editorial as well. For my second pick, we're going to switch to CPR in children.

So these authors, now led by Dr Rohan Khera from UT Southwestern, examined the prevalence and predictors of survival of children who progress from bradycardia to pulselessness in in-hospital cardiac arrest despite cardiopulmonary resuscitation. So they looked at almost 5,600 pediatric patients age more than 30 days to under 18 years of age, who received CPR at hospitals participating in the Get With The Guidelines - Resuscitation during 2000 to 2016 each CPR event was classified as bradycardia with pulse, bradycardia with subsequent pulselessness, and initial pulseless cardiac arrest. And the authors assessed for risk adjusted rates of survival to hospital discharge.

Dr Greg Hundley: So Carolyn, what did they find? This is really interesting.

Dr Carolyn Lam: Well, among hospitalized children in whom CPR was initiated, half had bradycardia with poor perfusion at the initiation of chest compressions and nearly one third of these progressed to pulseless in-hospital cardiac arrest despite CPR. Survival was significantly lower for children who progressed to pulselessness despite CPR compared to those who were initially pulseless. So, these findings suggest that pediatric patients who lose their pulse despite CPR are at particularly high risk and require a renewed focus on post resuscitation care.

Dr Greg Hundley: Very interesting, Carolyn.

Dr Carolyn Lam: Well, that wraps it up for our discussion. Let's go onto the featured discussion. Shall we, Greg?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: Non-inferiority cardiovascular trials are increasingly being published and in the highest impact journals. Yet how much do we really know about these designs of the trial, of the non-inferiority trials? Well, I have to admit not much in my point of view, and I was so pleased to see our feature discussion paper really published in this week's journal, which really digs deep into non-inferiority trials and talks about time trends and perhaps some lessons that we should all bear in mind when we look at these. I'm so pleased to have the first author, Dr Behnood Bikdeli, to tell us about the study. And he is from Columbia University Medical Center, New York Presbyterian Hospital, Yale Center of Outcomes, Research and Evaluation Core, as well as the Cardiovascular Research Foundation in New York. We also have Dr Naveed Sattar, associate editor from the University of Glasgow. Behnood, could you tell us, so what made you look at this question and what did you find?

Dr Behnood Bikdeli: For a while we've been very interested in profiling the cardiovascular trials, trying to understand a little better, what are the specific characteristics of the major child that we rely upon for research but also for clinical practice? Years ago, we did some studies for surrogate outcome trials and this, let's just say subsequent piece, where we tried to look into a randomized cardiovascular trial that use a non-inferiority design. We had a series of features in terms of quality metrics and methodological metrics that we wanted to look into. The over eight almost 27-year period, we identified 111 of these trials. Reassuringly, most of these trials inherited several important quality and methodological metrics that we were looking into. However, we also saw a significant room for improvement. There were quite a few quality or methodological metrics that some of these trials were not adhering to and we think it's important because ultimately for the design reporting and last reading of these trials, knowing these pluses and minuses would help inform people.

Dr Carolyn Lam: That's great, Behnood. Now for those of us listening who don't think about this every day, could you give us some examples of the top errors perhaps to look out for?

Dr Behnood Bikdeli: For example, in the typical superiority trials, when we want to test an intervention a versus intervention B, all that matters is we do a very good and adequately sized trial and rest of it is up to the study and how it goes to see whether or not something panned out. There was a significant difference between the new intervention versus the older ones, but in non-inferiority trials we have something called the non-inferiority margin and that's very highly relevant when it comes to the outcome that you're assessing when it comes to the ultimate results of the trial.

If the investigators choose a very lenient y non-inferiority margin, they may end up calling an intervention non-inferior. They may give it a pass. While in reality the intervention has quite a lot of a risk or harmful profile compared with standard of care. But in the other side, as a clinical example, we have several interventional tools at hand, like transcatheter aortic valve replacement. Most of the indications where it's currently used came from large bell designed non-inferiority trials. Where they showed that it was almost as good as surgery, in some cases better, but also it had a lot of ancillary advantages.

Dr Carolyn Lam: Thanks, Behnood. And you know here, I just want to call out to the readers. You have to look at this paper. Look at the tables and figures which are really so helpful. And Naveed, can I bring you in on this now? I mean, I just love this paper. It's such an important topic and I've never seen it addressed like this before. Could you tell us a little bit about what the editors discussed when we looked at this?

Dr Naveed Sattar: I've been involved in a few non-inferiority trials and some of the factors that many of us discuss and some of course associated, sort of our clinical trials, and I've been involved normally in superiority trials, but increasingly we have cut our teeth in non-inferiority trials. So, some of the points that the paper picks up resonated well with us in terms of, one of the examples was Behnood and his team found that around about 40% of trials didn't even justify what their non-inferiority margin was. And that's something I've actually had detailed discussions involved in various trials with. And that's a really important point, but it isn't a, you have to be able to justify why you choose particular margin and what that margin would mean to the community. Otherwise you potentially could just pick something out there which really doesn't allow you to make a really strong non-inferiority claim. And I think that's one of the factors that you found, Behnood. Is that correct?

Behnood Bikdeli: Absolutely. And that's a great point. Thank you. To us, there were two things about it. One was whether or not they provided any detailed justification for it exactly as you said, not that they're just picking up something because that's the sample size that they could achieve or that's the number that they felt comfortable with. But also the second piece of it, a respective of how they calculated or came up to the number, their readers have a right to know how this was calculated or were this came from, so it's the reporting part of it. Sometimes they reported both in the published paper and a study protocol or a design paper. Sometimes it was only in one of them. Sometimes as you mentioned, it was not mentioned in either, which puts the reader in a very difficult situation.

So we think, and these were the best of the best trials in the highest impact journals. Probably if we look high and low elsewhere it's going to be even more challenging. So, we think there's a lot of room for improvement for the readers to expect cleaner, more comprehensive papers to come, but also for the trialist to report them with more clarity.

Dr Naveed Sattar: And going forward, issue a nice figure that shows that the trend is that we are going to see more of these trials probably because you've got lots of better treatments now. So, you know it's getting harder, in the sense, in many areas of cardiovascular medicine to show superiority. So, there is a need for more trials which actually show benefits beyond just perhaps the main outcome in ways that you've explained in the particular paper.

Do you think the FDA does enough in this particular area in terms of this helping investigators decide what the non-inferiority margins are? Or is that something in terms of the quality of the trials that needs a bit more investigation? I think your papers partly are pushed to say, "Actually we need to do these better. We need to justify them better. We need to look at them better." Because actually they do have a greater influence going forward.

Dr Behnood Bikdeli: First, I cannot agree more. We are going to see a lot more of non-inferiority trials sort of, maybe because we have reached a ceiling effect when traditional intervention for superiority, but there's a lot of room to find interventions that are at least as safe or as good but have a lot of side advantages and ancillary benefits that's happened with some of the anticoagulants among other therapies available.

In terms of the regulatory aspects, one of the things we were fortunate about was within our team, we had people with expertise on the trialist side while communicating with the regulatory bodies and also from people who were consulting to the FDA for assessment of non-inferiority trials. So, we were fortunate to look into several of the methodological or quality metrics that were being thought of and we consulted with the in-source guidelines and FDA guidelines. That said, I completely agree that, for example, the suggestions that you provided in one of the tables could hopefully help shape some of these trials in a more rigorous way. Or at least a reporting, which is also an important piece, would be more transparent ultimately for the readership.

Dr Naveed Sattar: Absolutely. And transparency is really pivotal so that the readers completely understand what was done, what was predefined, and what was found so that they can make a proper judgment. And probably the final question I have in terms of, you make a good point that actually if the trials are not done well and there's a bit of slippage either in terms of loss of data or methodological issues, that then really pushes a trial towards a "no", in a sense you get a false reassurance of non-inferiority, but partly because the methodology wasn't robust enough. And it's really very critical for these trials, perhaps at least as critical as they are in superiority trials, but perhaps even more so. Is that a fair judgment?

Dr Behnood Bikdeli: No, no, no. You're absolutely right. That's another very important point in the typical superiority trial, if any bias drives the results toward no difference. Investigators are naturally guarding against that because it's going to be very problematic in non-inferiority trials. Depending on the effect measure that they choose, it could actually falsely favor the intervention of interest because it might show a false assessment of non-inferiority, and there are ways to work around it. There are ways to correct for it, such as choosing both absolute and relative effect measures, which practically addresses this concern. Again, gets back to the importance of appropriate design and appropriate transparency to report the results in a robust way, both intentions to treat and has treated or per protocol, both relative effect measures and absolute effect measures.

Dr Naveed Sattar: My sense of and getting back to you, but I think this will be a really seminal paper for the community to look at and really help us as a community to improve our conduct of such trials in the future because there will be more of these coming forward.

Dr Carolyn Lam: And I couldn't have said that better, Naveed. I think the take home message is right there. Pick it up, have a look and especially have a look at those tables and figures. It's really going to help you read many, many journals.

Thank you so much, Naveed and Behnood. Thank you audience for joining us on Circulation on the Run. Talk to you next week.

This program is copyright American Heart Association 2019.

Circulation July 23, 2019 Issue

22 juli 2019 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, Associate Editor at the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well Carolyn, did you ever wonder whether cardiovascular drug effects could be investigated through natural variation in the genes for the protein targets? In our feature discussion today, investigators from the British Isles, Germany, and the United States use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs. Sound interesting? Well listeners, we look forward to the results later in our program, but Carolyn, how about we chat about some of the other papers in this issue?

Dr Carolyn Lam: You bet Greg. So, have you ever asked yourself "What is the role of protein glycosylation in regulating LDL metabolism?"

Dr Greg Hundley: That was going through my mind when we were playing basketball just the other night.

Dr Carolyn Lam: Well this is truly a great study from Dr Holleboom at Academic Medical Center Amsterdam and Dr Lefeber from Radboud University Medical Center, both in the Netherlands. And their colleagues will study 29 patients of the two most prevalent types of Type 1 Congenital Disorder of Glycosylation, and these are the ALG6 and PMM2 types. They also study 23 first and second-degree relatives with a heterozygote mutation and measured their plasma cholesterol levels. LDL metabolism was studied in three cell models. They found that patients with type 1 congenital disorder of glycosylation have hypobetalipoproteinemia through increased LDL receptor expression. Carriers of the mutation in glycosylation enzymes affected in this syndrome had decreased LDL cholesterol levels compared to controls, and defects in glycosylation enzymes could play, therefore, an important role in LDL cholesterol metabolism.

Dr Greg Hundley: Boy, this is pretty insightful I think, Carolyn. So, what are the clinical implications?

Dr Carolyn Lam: Well, given that LDL cholesterol was also reduced in a group of clinically unaffected heterozygotes, the authors propose that increasing LDL receptor mediated cholesterol clearance, by targeting N-glycosylation in the LDL pathway, may therefore represent a novel therapeutic strategy to reduce LDL cholesterol, and of course prevent cardiovascular disease.

Dr Greg Hundley: Very interesting work. You know, we just keep learning more and more about LDL. I'm going to switch and jump back with Empagliflozin. And this is a study in diabetic mice that really has an interesting in-vivo imaging component. As an imager, I was really excited about this. The article is from Dr Kengo Kidokoro from Kawasaki Medical School. And we don't often talk about it, but listeners, if you have a chance, there's a very interesting video-enhanced file associated with this article, and if you can download it, it's really just so cool with multiple image clips demonstrating an operative mechanism of SGLT2 inhibition on renal function. And it really gives us an opportunity to revisit renal function.

Quick quiz Carolyn. In diabetic kidney disease, is glomerular hyperfiltration good or bad?

Dr Carolyn Lam: Bad.

Dr Greg Hundley: Yeah, absolutely. So, hyperfiltration is characteristically observed at earlier stages of diabetic kidney disease and involves activation of the renin-angiotensin-aldosterone system at the efferent arteriole and tubuloglomerular feedback mechanisms, especially at the afferent arteriole. So, as they go through this, just picture in your mind that glomerulus and afferent is arriving, and efferent is leaving.

So, SGLT2 upregulation in diabetes is thought to play an important role in TGF signaling by increasing sodium reabsorption at the proximal tubule, thereby decreasing distal delivery to the sodium sensing macula densa at the juxtaglomerular apparatus. This decline in distal sodium delivery is interpreted as a decline in effective circulating volume, leading to inappropriate afferent vasodilation in an effort to preserve intra-glomerular pressure and GFR.

In diabetes, these TGF effects lead to intra-glomerular hypertension and hyperfiltration. You got that quiz right, Carolyn. Which promotes diabetic kidney disease progression and impaired kidney function, ultimately increasing overall cardiovascular risk and mortality. Conversely, blocking SGTL2 pharmacologically reduces renal hyperperfusion and hyperfiltration in animals and humans, which may preserve renal function, thereby reducing risk associated with diabetic kidney disease progression.

Dr Carolyn Lam: You know what, Greg? I kind of had an unfair advantage in this quiz. I work with a lot with the SGLT2 inhibitors, but I just love that you asked us to picture it and look at that video. Anyways, so this article really allows us to review SGLT2 inhibition at the glomerular level, which is truly hot. So, tell us what did they find?

Dr Greg Hundley: So, this is the first report of changes in renal hemodynamic function by SGLT2 inhibition using direct in-vivo visualization techniques in a diabetic animal model. The videos, they're spectacular, and they're excellent so that you can download them for educational purposes. Afferent arteriolar vasoconstriction, and reduced hyperfiltration occurred within a few hours after a single dose of a SGLT2 inhibitor. And Adenosine signaling, through tubuloglomerular feedback, is a key pathway to prevent diabetic hyperfiltration via SGLT2 inhibition.

Clinically, Carolyn, now I know you would ask me about that, so I got ready, this study highlights another potential mechanism for the benefits of SGTL2 inhibition. The SGLT2 inhibitor-related mechanism's responsible for reducing cardiovascular risk in clinical trials may be due to protection against diabetic kidney disease progression, thereby attenuating risk factors for heart failure, such as volume overload and hypertension.

Dr Carolyn Lam: Ah. That is just so cool, and really just so consistent with the clinical data that's emerging too. Thank you, Greg. So, have you ever asked yourself this other question, what role do platelets play in ischemia reperfusion injury? So, I'm not going to quiz you. I'm actually kind and loving and a good person. And so, I will tell you about ischemia reperfusion injury, which is a common complication of cardiovascular disease.

Now, resolution of the detrimental effects of ischemia reperfusion injury generated prothrombotic and proinflammatory responses, is essential to restore homeostasis. Now, although platelets are known to play a crucial role in the integration of thrombosis and inflammation, their role as participants in the resolution of thrombo-inflammation is really under-appreciated. And hence, this other paper that I chose today, and it's from Dr Gavins from Louisiana State University Health Sciences Center Shreveport, and her colleagues, who used pharmacological and genetic approaches, coupled with murine and clinical samples to uncover key concepts underlying this role for platelets.

Dr Greg Hundley: So Carolyn, what did they find?

Dr Carolyn Lam: Well, they found that exacerbation of thrombo-inflammatory responses occurred in ischemia reperfusion injury mouse models of middle cerebral arterial occlusion, as well as lower plasma levels of the anti-inflammatory pro-resolving protein Annexin A1. And this was a lower plasma level of this Annexin A1 among patients with acute ischemic stroke.

Administration of Annexin A1 promoted cerebral protection against thrombo-inflammation and the development of subsequent thrombotic events post-stroke. Annexin A1 was also able to reduce platelet activation and thrombosis, via the suppression of integrins. So, overall, these data reveal a novel multi-faceted role for Annexin A1 to act both as therapeutic and prophylactic drug via its ability to promote endogenous pro-resolving anti-thrombo, anti-inflammatory circuits in the cerebral ischemia reperfusion injury. And collectively, these results further enhance our understanding in the field of platelet and ischemia reperfusion injury biology.

Dr Greg Hundley: Oh wow. So, another important insight from this author group on platelet activation and thrombosis in key clinically relevant syndromes. Well, my last paper is going to be talking about a risk prediction score for life-threatening ventricular tachyarrhythmias. And they're going to study this in laminopathies, and the lead investigator is Dr Karim Wahabi from Cochin Hospital in France.

To estimate the risk of life-threatening ventricular tachyarrhythmia in patients with LMNA mutations, and thus select candidates for implantable cardiac defibrillators, the investigators evaluated 444 patients of about 40 years in age in a derivation sample. And then, 145 patients that are about the same age, 38 years, in a validation sample, for the occurrence of a) sudden cardiac death or b) ICD-treated or hemodynamically unstable ventricular tachyarrhythmias.

Dr Carolyn Lam: Oh. Very important. These laminopathies are really not that uncommon. So what did they find, Greg?

Dr Greg Hundley: Carolyn, predictors of events included male sex, non-missense LMNA mutations, first-degree and higher AV block, non-sustained ventricular tachycardia, and LVEF. The authors developed a new score to estimate the 5-year risk of life-threatening ventricular tachyarrhythmias in patients with LMNA mutations. And compared to the current standard of care, the proposed risk prediction model offered more accurate prediction of life-threatening ventricular tachyarrhythmias, and correctly re-classified almost 30% of the patients in the study.

Nicely, the authors have made this available, and the score can be derived from readily collected clinical and genetic parameters and estimated using an online calculator that's provided in the journal. But, it's https://lmna-risk-vta.fr.

Future prospective studies should focus on the estimation of the clinical benefit conferred by the use of this score in terms of sudden cardiac death prevention.

Dr Carolyn Lam: That is super cool, Greg. But, I am so excited now to move to our feature discussion. Shall we?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: Can we use natural variations in our genes for the protein targets as a way to look at cardiovascular drug effects? Man, this is going to be such an important and exciting discussion, because this is what our feature paper talks about. I am so pleased to have with us our corresponding author, Dr Dipender Gill from Imperial College London, as well as our Associate Editor, Dr Wendy Post from Johns Hopkins.

So, first of all, Dipender, please, could you give us a background on what you did? This is really very novel in approach.

Dr Dipender Gill: It was also a lot of fun to conduct. I think, currently, we're living in an era where there's been a recent explosion in the availability of genetic data, and this really inspired us to think about how we could use that to learn more about commonly prescribed drugs. The implementation of genetics, or genetic variance, to study drug effects isn't entirely novel. It's actually been undertaken for some years now.

Most of the work has been related to lipid lowering drugs, for example, statins, where people can take genetic variance, or versions of genes, corresponding to the drug effect, and study these to investigate what effects these drugs might have, both on the intended target, but also potential side effects. To my knowledge, this hadn't previously been done for anti-hypertensive drugs. But yet, the data for this was available. And therefore, we thought that actually we could very well go ahead and do this, and perhaps find some interesting things.

Dr Carolyn Lam: Oh, that's so interesting thing, Dipender. You know, there was this term in your abstract, and mentioned multiple times, Mendelian randomization. Now, for those of us that don't think about this every day, could you tell us a little bit what that means?

Dr Dipender Gill: Yeah. So, I'll actually give a little bit of background. One of the main limitations of traditional epidemiological research is that any association, it's sometimes difficult to infer causation. They can be confounded by environmental factors, lifestyle factors. In the Mendelian randomization technique, what we do is we use randomly allocated genetic variants to study the effect to an exposure.

So, we select these genetic variants because they are related to the exposure of interest. And because these genes are randomly allocated at conception, they're not subject to confounding from environmental or lifestyle factors. Whether you have a gene or not, is not necessarily related to your lifestyle or your environment. And therefore, the association of these genetic variants with certain outcomes isn't subject to confounding.

Dr Carolyn Lam: That makes so much sense, and I suppose that, not to allow cause and effect to be determined. So please, tell us, in this particular case of the anti-hypertensive drugs, what did you do and what did you find?

Dr Dipender Gill: First, we decided specifically which drugs we wanted to look at, and we thought, actually, let's start off with the most commonly prescribed anti-hypertensive drugs. So, we short-listed these based on recent consensus guidelines, and we looked at ACE inhibitors, beta-blockers, calcium channel blockers, thiazide type diuretics. And then, we went back to various online databases to identify which genes correspond to the target protein of these drugs.

We took these genes, and we then identified genetic variants at their specific genetic loci, their specific region of the genome, and we identified the variants in these regions that were also related to systolic blood pressure. And in this way, we inferred that genetic variants, at the protein coding targets of these genes, that were also related to systolic blood pressure, likely represented the effect of variations in these proteins that also implicated blood pressure, and therefore, could serve as proxies, or instruments, to study the effect of these drug targets.

We then went ahead to validate the selection of these genetic variants by forming Mendelian randomization, and specifically, we checked whether people that have genetic variants that correspond to, say, ACE inhibitor activity, or beta-blocker activity, or calcium channel blocker activity, if they also have correspondingly lower risk of coronary heart disease and stroke, to the same degree that we would observe in randomized control trials against placebo.

And indeed, we found that actually, the results were fairly similar, and this gave us confidence. And studying these genetic variants that mimic the effect of these drugs could be used as a proxy or as a surrogate to study their clinical effect of taking these drugs. So, that was the first phase.

Dr Wendy Post: Dipender, congratulations to you and our team. This is a really exciting paper, and the editors were especially interested in the novelty, and the potentially impactful findings, especially of the second part of the study, which I think you'll describe briefly next. And that was using an approach that many who are listening may not have heard about too much before called PheWAS, or a phenome wide association study. And maybe you could tell us briefly what you found in that part of the analysis.

Dr Dipender Gill: The first part, it was very cool, because it allowed us to identify versions of genes that corresponded to the effect of these drugs. But in itself, it didn't tell us anything novel. It didn't tell us anything new. So, the real question was, how could we use this new information to make progress towards helping patients? So, we went back and we thought, "So okay." So, we knew that these drugs are used for certain conditions already to prevent heart disease, to prevent stroke.

But, what about their side effects? What about their repurposing potential? How could we use our new approach to study that a little bit more carefully? As you alluded to, when we used this new technique, relatively new technique called phenome wide association study, and we essentially investigated the association of our genetic variants for each respective anti-hypertensive target with all clinically relevant outcomes throughout the phenome, using the UK bio-back cohort, which was the main population used for this PheWAS, this phenome wide association study.

We were actually able to rapidly investigate over 900 disease outcomes, and their association with our genetic risk score for these drugs. And this was very exciting for us, because it allowed us to very rapidly, efficiently, and cost-effectively explore the potential repurposing opportunity and side effects of these very commonly prescribed drugs, which to our mind, offered significant advantage over previous approaches.

We all know that sometimes randomized control trials can be very expensive and time-consuming, and of course, traditional observational research can be limited by reverse causation, assessment-vise confounding. And so, what we were able to do here had several important advantages, and not to mention the efficiency by which it allowed study of these outcomes.

Dr Wendy Post: Dipender, tell us what you found in your PheWAS study.

Dr Dipender Gill: We identified genetic variants for 3 commonly prescribed anti-hypertensive targets. The first were ACE inhibitors, second, beta blockers, and the third were calcium channel blockers. When performing PheWAS for all of these drug targets, we identified associations with common cardiovascular disease that are related, or implicated in hypertension, specifically hypertension itself, but also circulatory diseases, things like atrial fibrillation, coronary heart disease. They all came up.

And this actually gave us a lot of confidence because that's exactly what we'd expect. We know that these medications prevent or reduce risk of these diseases, and therefore, this served as kind of a positive control that our approach was doing it what it was supposed to do. The novel finding came when we investigated the genetic risk score, or the genetic variants for calcium channel blockers, in this PheWAS approach.

And we actually identified an association which we weren't expecting. We showed that blood pressure reduction through the genetic risk score for calcium channel blockers was an association with an increased risk of diverticulosis, a condition not conventionally thought to be associated with blood pressure. We were very excited and interested by this, and we went on to investigate it further using some other techniques as well.

Dr Wendy Post: The really impactful part of this, many things, but especially this association with diverticulosis. So, maybe you can briefly summarize what you think the potential clinical implications are, and what the next step should be.

Dr Dipender Gill: The first question we had was whether this was related to blood pressure alone, the effect of calcium channel blockers, or perhaps some other effect of these drugs. We investigated the genetic risk score for systolic blood pressure generally and found that this itself wasn't associated with risk of diverticulosis, which suggested that the effect isn't really mediated by blood pressure alone, but it's some other property of calcium channel blockers.

We know that sometimes calcium channel blockers can be associated with constipation, and it may be through this mechanism that they're having consequent effects on risk of diverticulosis. Other possible mechanisms might be through effects on blood flow, through the vasa recta in the bowel. But, what was very interesting was that we went forward with this finding, and investigated, observed, drug use in the UK bio-bank.

Specifically, we looked at people taking non-dihydropyridine, and dihydropyridine calcium channel blockers at baseline, and found that those taking non-dihydropyridine calcium blockers only were known to have a higher risk of diverticulosis as compared to those taking other anti-hypertensive classes, which further added support for our findings. The interesting point here is that looking at the genetics doesn't allow us to discriminate between these drug classes.

That was only possible with the observed data, and that was because the genes for these drug classes were the same.

Dr Carolyn Lam: Well, congratulations. Wow. I'm just so intrigued listening to all of this. Wendy, I would love if you could help put all of this in context for us. The US, the novel information, and the approach that could potentially go way beyond just anti-hypertensive.

Dr Wendy Post: So, this is a very exciting new approach to doing genetic studies that can help us to understand potential targets for therapy in the future, and understanding more about causality, which as Dipender explained, can sometimes be confusing, as it may be confounded by environmental factors. So, using these genetic approaches through Mendelian randomization, and what we heard about today, which is PheWAS, or phenome wide association study, we can learn much more about how the potential observational analyses can be related to new discoveries through mechanisms, or potential side effects, as we heard about here of calcium channel blockers.

So, wanted to congratulate Dipender again with his impactful paper here.

Dr Carolyn Lam: Thanks, Wendy. And then if I could, I'm just going to steal minutes here, because this is so interesting. Where do you think the field's going to go next? And Dipender, with these findings of diverticulitis and diverticulosis, what next? How do we apply this?

Dr Dipender Gill: There's 2 main points to cover here. The first is what we do specifically with the findings we got for calcium channel blockers and diverticulosis. I should emphasize that on their own, I don't think that this should currently change practice. But, I think it should inspire and capitalize further research into this association. If we're able to replicate and validate it further, then perhaps there might be some implications for the drugs that we prescribe with patients at risk of diverticulosis.

The second point I wanted to make is more generally, what does this mean for research, and particularly, genetic research. I think we're living in very exciting times, and there's a lot of really great work that's going to come out using these types of approaches. I think 2 areas that we could expand further is what else we can do with our genetic instruments, or our genetic variants that proxied these drugs. How do we look at other targeted refocusing potential? Can we try and explore other side effects? Can we investigate efficacy for other disease outcomes? Specifically, for these anti-hypertensives.

And the other thing is, which other drugs can we identify genetic variants to proxy? We've been thinking about looking at diabetes medicines. There's a variety of other drugs that correspond to specific gene targets, and proteins. And in theory, these could also be studied using genetics. So, there's a lot more work to come out from this.

Dr Carolyn Lam: Thanks so much, both of you, for joining us today. This was just such an exciting discussion.

Thank you for listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association, 2019.

Circulation July 16, 2019 Issue

15 juli 2019 | 23 min

Dr Greg Hundley: And I'm Dr Greg Hundley: Hundley, Associate Editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Well Carolyn, our featured article this week addresses the age at which to initiate clinical screening of relatives for hypertrophic cardiomyopathy. Our guidelines suggest screening of relatives from age ten and onwards but data are lacking to substantiate this suggestion. I look forward to the authors' discussion of their findings regarding initiation of screening in children. For now though, do you have an article that you'd like to share?

Dr Carolyn Lam: You bet, Greg. So, the first paper I chose really demonstrates that patients inducible pluripotent stem cells or IPSC cardio derived myocytes can be used as a disease modeling platform to delineate the functional mechanisms that underlie cardiac hypertrophy and in this particular case they looked at Noonan Syndrome and showed that how these techniques can be subsequently used to identify novel molecular and genetic therapeutic targets. So, Greg, here's your quiz. The genetics of Noonan Syndrome.

Dr Greg Hundley: I remember it was on our board exam.

Dr Carolyn Lam: Let me tell you about it. So more than 90% of patients with Noonan Syndrome have a mutation in the hinge region CR2 domain of Raf-1 and they exhibit severe hypertrophic cardiomyopathy for which there is no treatment. Authors, Dr Jaffrey from Cornell University and Dr Kontaridis from Masonic Medical Research Institute in Utica in New York and their colleagues used Noonan Syndrome Raf-1 patient and CRISPR corrected IPSC cardiomyocytes to recapitulate the Noonan Syndrome cardiac phenotype.

These Noonan Syndrome IPSC derived cardiomyocytes exhibited the same hypertrophy and myofibrillar disarray that's really observed in Noonan Syndrome patient hearts, so mechanistically the authors showed that activation of mitogen-activated protein kinase or mech-1 or -2, but not the extracellular regulated kinase, which is ERK1 or 2 triggered abnormal cardiomyocytes structure and conversely ERK5 mediated increased cell size in these Noonan Syndrome mutant IPSC derived cardiomyocytes.

RNA sequencing further identified genes dysregulated in the Noonan Syndrome cardiomyocytes that may underlie hypertrophic cardiomyopathy downstream if the mech-1 or -2 and ERK5 genes.

Dr Greg Hundley: So, Carolyn, that's a lot of genetic information, so what can I take home as I think about this further and what may come down the line as we manage patients with Noonan Syndrome?

Dr Carolyn Lam: Thanks, Greg. The real take home message is that these pathways could serve as novel therapeutic targets to treat hypertrophic cardiomyopathy in patients with Noonan Syndrome and Raf-1 mutations. Overall, the elucidation of rare disease mechanism of hypertrophic cardiomyopathy may further unravel and reveal causes of other more common idiopathic congenital disorders and hypertrophic diseases.

Dr Greg Hundley: Oh, very good. Well, I'm going to switch gears and talk a little bit about infective endocarditis prophylaxis and this article comes from Pallavi Garg at the London Health Scientist Center. Carolyn, as you may recall, given the lack of proven efficacy and concerns about the perceived risks of antibiotic prophylaxis like development of antibiotic resistance, the American Heart Association in 2007 and the European Society of Cardiology in 2009 published revised guidelines recommending cessation of antibiotic prophylaxis prior to dental procedures for patients at moderate risk of infective endocarditis while continuing the practice in high risk patients. This Canadian study was conducted from 2002 to 2014 among all adults and those at high and moderate risk for infective endocarditis and they were stratified by age. Prescriptions for antibiotic prophylaxis were obtained from the Ontario Drug Benefit Database for adults 65 and older and outcomes regarding antibiotic prophylaxis prescription rates and the incidents of infective endocarditis related hospitalization were assessed.

Dr Carolyn Lam: Ooh, interesting. What did they find?

Dr Greg Hundley: The authors found a sustained reduction in antibiotic prophylaxis prescriptions among individuals at moderate risk for infective endocarditis that coincided with the change in guidelines. In contrast, while there was a decreasing trend in antibiotic prophylaxis among individuals at high risk of infective endocarditis and a minimal drop following the guidelines released, the overall rates of prophylaxis prescribing in this group continued to climb since early 2007, and collectively, these findings suggest that appropriate uptake of the revised AHA guidelines occurred.

Furthermore, over the thirteen-year study period, the authors identified an increase in hospitalizations for new episodes of endocarditis approximately three years after the AHA guidelines were revised. This timeline along with the rise of endocarditis incidents in both the high and moderate risk groups suggests that this observed increase in endocarditis is likely unrelated to the change in the prescribing practice of antibiotic prophylaxis. This conclusion is further supported by the overall decrease in endocarditis cases attributable to streptococcal infections over time, a finding contrary to what might be expected as a result of the reduction in antibiotic prophylaxis.

Dr Carolyn Lam: Oh, very interesting, Greg. At first a little bit scary and then after when you described it more, it does seem a little bit more reassuring. Very interesting. Well, thank you. My next paper deals with functional tricuspid regurgitation, which as you know is really common in heart failure with reduced ejection fraction or HFrEF and mostly consequent to pulmonary hypertension. However, what is the access mortality associate with functional tricuspid regurgitation in HFrEF? Well, this paper from Dr Maurice Serrano from Mayo Clinic and colleagues looked at all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B and C and an ejection fraction less than 50% who had functional tricuspid regurgitation grading and systolic pulmonary artery pressure measured by Doppler echocardiography.

Now among more than 13,000 patients meeting these inclusion criteria, functional tricuspid regurgitation was detected in 88%. Functional tricuspid regurgitation was independently associated with more dyspnea, more impaired kidney function, and lower cardiac output. For the long term outcomes, the higher the degree of functional tricuspid regurgitation compared with a group with trivial tricuspid regurgitation was independently associated with a higher mortality hazard. The five year survival was substantially lower with increasing severity of tricuspid regurgitation so it was 68% on average for trivial functional tricuspid regurgitation versus 34% for severe functional tricuspid regurgitation.

Importantly, this access mortality observed with moderate or severe functional tricuspid regurgitation was independent of pulmonary hypertension and any other clinical characteristics.

Dr Greg Hundley: Hmm, interesting but Carolyn, wouldn't we expect this?

Dr Carolyn Lam: You know what, you may expect it, but this is really the largest series, I think, that has shown this and shown this in the systematic way that functional tricuspid regurgitation in and of itself may play an important pathophysiologic role and thus, may represent a potential therapeutic target in HFrEF. In other words, the present study really advocates for a trial to test treating functional tricuspid regurgitation in patients with HFrEF.

Dr Greg Hundley: Oh wow, you really put that in great perspective, Carolyn. Well, your reward is going to be a quiz.

Dr Carolyn Lam: Oh my gosh, Greg.

Dr Greg Hundley: We're going to talk about ...

Dr Carolyn Lam: What now?

Dr Greg Hundley: Caveolin-1, an atherogenesis and nitric oxide and this is from Professor Carlos Fernandez Hernando at the Yale University School of Medicine. Okay, multiple choice. What are caveolae? Now I'm going to give you some choices, you get to pick A. Are they crypts within the walls of vessels. B. Crypts within the membranes of endothelial cells. Or C. Crypts within the border zones of infarcts.

Dr Carolyn Lam: Wait a minute, Greg. I'm not even sure we're pronouncing it the same. You're asking about caveolae like ... Potato potata. They're invaginations of cell membranes, that's all I know.

Dr Greg Hundley: Oh wow, fantastic. This study focused on the effect of Caveolin-1, a protein integral to the formation of caveolae. The investigators found in a series of mouse experiments that A. The athero-protection observed in mice lacking Caveolin-1 is independent of endothelial nitric oxide synthase activation and nitric oxide production. B. Endothelial Caveolin-1 controls lipoprotein infiltration in vascular inflammation in early stage atherosclerotic lesion. C. Endothelial Caveolin-1 promotes pro-atherogenic matrix deposition leading to endothelial cell activation in atheroprone regions of the aorta and finally, D. Atheroprone regions of the aorta are characterized by increased intracellular and basolateral caveolae distribution in endothelial cells compared to athero-resistant areas.

Dr Carolyn Lam: Wow, I like the way you broke that down into four points, but could you summarize what it means clinically?

Dr Greg Hundley: Yeah, so I think if you had to summarize all of this in a sentence, perhaps the suppression of Caveolin-1 expression in endothelial cells might prevent the progression and promote the regression of atherosclerosis so in the future perhaps an interesting target to treat atherosclerosis. Well, now Carolyn, I guess we should proceed to that talk with our featured discussion.

Dr Carolyn Lam: Absolutely. Thanks, Greg.

Hypertrophic cardiomyopathy is an inheritable myocardial disease with age-related penetrance. Current guidelines recommend that clinical screening of relatives start from the age of ten years onwards by the European Society of Cardiology and twelve years onwards by the American College of Cardiology or American Heart Association. There are of course caveats for earlier screening but the clinical value of this approach has really not been systematically evaluated. That is until today's feature paper and we are so pleased to be here discussing it. This is Greg Hundley and Carolyn Lam and we're your co-hosts for Circulation on the Run. So happy to welcome Dr Juan Pablo Kaski who's the corresponding author of today's feature paper from Great Ormand Street Hospital in London and we also have Dr Gerald Greil, Associate Editor from UT Southwestern.

Welcome, everyone. Juan, if you don't mind, could you start by summarizing this very important study of yours?

Dr Juan Pablo Kaski: Thank you very much. Hypertrophic cardiomyopathy is a genetic muscle condition that is characterized by hypertrophy and is most commonly inherited as a dominant trait. Previous studies have suggested that in familial disease at least ventricular hypertrophy doesn't usually present until adolescence and this has led to the current guidelines which do not recommend routine screening of children below the age of twelve according to the American guidelines below the age of ten and the European guidelines for hypertrophy cardiomyopathy but own clinical experience was different and suggested that perhaps sarcomeric disease and familial disease could present in younger children, so what we aimed to do with this study was to assess the validity of this approach and tried to assess the yield of clinical screening in children from families of hypertrophic cardiomyopathy.

Dr Juan Pablo Kaski: We took our collective experience in our institution over a period of many years and recruited just on the 1,200 consecutive children all aged less than eighteen years at the time of initial assessment coming from just under 600 families and these were children who were referred for clinical screenings because a first degree relative had been diagnosed with hypertrophic cardiomyopathy. What we found was that in 5% of these children and in fact, in 8% of the families that we screened, we were able to pick up early phenotypic features of hypertrophic cardiomyopathy. In 72% of patients, we made a diagnosis before the age of twelve, so before current clinical screening guidelines we'd recommend and importantly, a third of these patients during follow up had a change in their management as a result of the diagnosis. Their medication was commenced, they underwent procedures or implantations of defibrillators.

Dr Greg Hundley: Juan, this is Greg Hundley and I was wondering when did the participants that were enrolled experience events? Did those that were say under fourteen or even under twelve, did they experience events relative to those that were a little older?

Dr Juan Pablo Kaski: The events that our participants experienced were relatively few. Many of these occurred during the childhood age but some occurred once the children had transitioned into the adult age. We did look to see whether there was any difference in terms of early diagnosis and subsequent events, but we didn't find anything, we didn't identify two separate populations in that respect.

Dr Greg Hundley: And then did you perform genetic analyses? I know you described phenotypic characterization of the patient population but how about genetically? What results did you find there?

Dr Juan Pablo Kaski: The main aim of the study really was to determine a yield of clinical screenings, so this is a reflection of a real-world practice where genetic testing may not necessarily be routinely available. Having said that, we did have genetic data in a third of our families and in fact, in maybe 70% of those children who made clinical diagnosis of hypertrophic cardiomyopathy was made and what we find in those individuals who have undergone genetic testing is that the vast majority of those had mutations in sarcomeric protein genes and pathogenic or likely pathogenic variants in sarcomeric genes in just under 70% and these were well characterized mutations that are very similar to those that are seen in adolescence or adult onset hypertrophic cardiomyopathy.

I think what was interesting about these genetic results is that we seem to have identified a population of early onset sarcomeric disease that genetically appears to be indistinguishable from a sort of later onset adult disease but with the clinical presentation and natural history curve shifted somewhat to the left.

Dr Greg Hundley: Gerald, just switching over, can you tell us some of your thoughts about how the results of this study will impact clinical practice, both in the European countries as well as U.S.?

Dr Gerald Greil: I mean, I was obviously delighted to see the study being submitted to circulation because there's a very important message particularly for pediatric cardiologists which is potentially influencing the guidelines and Dr Kaski may comment on this as well as the next step meaning that it seems like screening patients older than ten or twelve years and once again, there's a slight discrepancy between the European and U.S. guidelines, seems to be ... Can be questioned and potentially we should screen these patients earlier.

Another amplification of this study is that we should think about how much genetic screening can be an essential tool in our methods in looking at these patients and I want to point out that because of these discrepancies we also initiated an editorial letter for this publication done by Dr Ommen and by Dr Mital kind of pointing out there needs a lot of work to be done maybe even including rewriting the current guidelines.

There's another paper that came out recently in European Society Cardiology, the European Heart Journal about a similar topic so it's something which is very, very heavily discussed in our community. We think how we are looking at these patients and how we're following them up.

Dr Greg Hundley: What would you suggest are next steps for the world community in this space in regards to modifying those guidelines?

Dr Gerald Greil: I think there's now enough literature around which suggests that we should look at these patients earlier and screen them earlier on both sides in European, in the U.S., in the Asian world, and ideally these two groups should sit together and write combined guidelines. It's still interesting that the European and U.S. guidelines are slightly different in that we're talking about a similar group of patients, so I'm very, very delighted to see that this is coming up in the national literature as a new topic and I think everything is open now to rethink this topic and rewrite these guidelines.

Dr Greg Hundley: Do you think prospective studies would be necessary because I believe, and Dr Kaski please weigh in here, this was a retrospective review, and do you think there could have been triggering circumstances that prompted early screening? I mean, would a next step be some sort of prospective registry?

Dr Gerald Greil: I mean definitely that's the next step. I think we have enough data material around once again to rethink the strategy which age these patients should be looked at. A prospective registry and Dr Kaski can probably comment on it better than I can, I think that something which is a logical next step and there may be even something being on the way to make this happen.

Dr Juan Pablo Kaski: I agree. I think further validation and confirmation of these data from prospective studies would be extremely helpful. I think one of the things that we need to bear in mind is the potential cost implications of expending screening to ever increasing populations and so perhaps an additional further step would be to try to refine the screening tools so that we are able to identify clinical by a chemical of those individuals who are more likely to present in childhood and perhaps set a target screening towards that population.

I can just go back to one of your sort of previous points also about a potential bias and it is true that these patients were referred for clinical screening at a time when clinical recommendations do not suggest that this is necessary and although we didn't specifically in this cohort look at those that would have fulfilled current early screening criteria, the vast majority of the patients were asymptomatic at the time that they were referred. We also looked to see whether there was any link between those individuals who had a family history of early onset disease and an early diagnosis, and that was the only factor that came up as potentially significant so perhaps the current guidelines that do recommend considering earlier screenings if there's a family history of childhood disease are still applicable.

Dr Carolyn Lam: That was just an amazing interview, by the way. I've learned so much and thank you so much for publishing this very important paper with us.

You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation July 09, 2019 Issue

8 juli 2019 | 24 min

Dr Greg Hundley: And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: I'm so excited about our feature discussion today, Greg, because it is about a familiar but very important problem of hypertension, and we will be looking at trial results of a new drug, a first in its class type of drug. And tackling a problem that is particularly important perhaps in black patients with hypertension. Well, more very soon. First, let's discuss some papers, shall we? Do you have one?

Dr Greg Hundley: My paper is from Joseph Burgoyne from King's College in London and pertains to resveratrol. Now, resveratrol is a non-flavonoid polyphenolic compound that has been found in the skin of several fruits, with the most notable being grapes. The compound exhibits beneficial effects, including the prevention of cardiovascular neurologic diseases, cancer, metabolic syndrome, as well as it promotes bone and eye health. And in this study, the investigative team explains how resveratrol may mediate its numerous beneficial effects including lowering of blood pressure by direct thiol oxidation. Also, they demonstrate that resveratrol can counter-intuitively induce direct protein oxidation, a process that is enhanced under pro-oxidative conditions associated with disease. The oxidation of cyclic GMP dependent protein kinase 1 alpha, or PKG1 alpha, by resveratrol lowers blood pressure in hypertensive mice.

Dr Carolyn Lam: Okay. But what does that mean for us clinically, Greg?

Dr Greg Hundley: Well, the results demonstrate how blood pressure can be lowered by using resveratrol, and targeting cysteine 42, or PKG1 alpha, may provide a new class of anti-hypertensive agents. In addition, identifying additional proteins modified by resveratrol may provide new targets for therapy to treat cardiovascular disease. Carolyn, how about your first paper?

Dr Carolyn Lam: We are going to look at the further results of the ODYSSEY OUTCOMES trial. And as a reminder, ODYSSEY OUTCOMES was a double-blind randomized comparison of the PCSK9 antibody Alirocumab with placebo in almost 19,000 patients who had an acute coronary syndrome 1-12 months previously and elevated at the atherogenic lipoproteins despite intensive statin therapy.

And that trial found that Alirocumab reduced the risk of the primary composite outcome of coronary heart disease, death, ischemic stroke, myocardial infarction, or unstable angina requiring hospital admissions. The current paper looked further at the effects of Alirocumab on death.

Dr Greg Hundley: So Carolyn, what did they find?

Dr Carolyn Lam: Well, there are quite a number of findings here. The first, there were fewer deaths in total that occurred with the PCSK9 inhibitor Alirocumab versus placebo, and this resulted from a non-significantly cardiovascular and non-cardiovascular deaths with Alirocumab. The second finding was that in a pre-specified analysis of more than 8,200 patients eligible for 3 or more years of follow-up, Alirocumab reduced death.

And then, the third finding was that patients with non-fatal cardiovascular events were at increased risk for both cardiovascular and non-cardiovascular deaths, and a post-Hoc analysis found that compared to patients with a lower LDL, those with a baseline LDL above 100 had a greater absolute risk of death, and a larger mortality benefit with Alirocumab. In the Alirocumab group, all cause death declined with a lower achieved LDL achieved at 4 months of treatment to a level of approximately 30.

So in summary, Alirocumab added to intensive statin therapy, has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for 3 or more years, and if baseline LDL is 100 or more, or if achieved LDL is low.

Dr Greg Hundley: That's great, Carolyn. My next paper is going to talk a little bit about endothelial cells. And what I think we're going to learn is that not all endothelial cells are alike. This comes from Dr Rajat Gupta from Brigham and Women's Hospital, and I really thought this was an interesting article that used single-cell RNA sequencing to make it possible to identify and characterize cellular sub-populations.

Dr Greg Hundley: The investigative team performed enzymatic dissociation of 4 whole mouse aortas, followed by single-cell sequencing of over 10,000 cells.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Well using cluster analysis of gene expression from the aortic cells, they identified 10 populations of cells representing each of the main arterial cell types. There were fibroblasts, vascular smooth muscle cells, endothelial cells, immune cells, including monocytes, macrophages, and lymphocytes. And importantly, there were 3 distinct endothelial cell sub-populations with differences in them driven by major functional gene programs including adhesion and lipid handling.

Comparison of aortic single-cell RNA sequence data sets from normal and Western diet-fed mice suggested that these sub-populations exist under both dietary conditions and have some unified responses to diet alteration. Also, immunofluorescence using single marker genes to identify endothelial cell sub-populations showed that the VCAM1 positive population was spatially located in regions of disturbed flow like the lesser curve of the aorta.

Dr Carolyn Lam: Okay. So bring it home for us, Greg. What does this mean clinically?

Dr Greg Hundley: Yeah exactly, Carolyn. So, characterizing functional sub-populations may serve as a novel method for understanding endothelial health in patients with vascular disease. And although aortic endothelial cell sub-populations demonstrate some unified responses to vascular disease relevant stimuli, like a Western diet, functionally different sub-populations may contribute differentially to vascular diseases, enabling sub-population targeted therapies to perhaps be implemented in the future.

Dr Carolyn Lam: Cool. So Greg, cardiomyopathies have often been seen as genetic in origin, but what about potentially modifiable causes? So, this next paper that I picked looked at that, and it's from corresponding author Dr Rosengren from Sahlgrenska University in Gothenburg, Sweden, who with her colleagues, sought to investigate a potential link between obesity in adolescence and being diagnosed with cardiomyopathy in adulthood.

So, this was a nation-wide register-based prospective cohort study of almost 1 million 690,000 adolescent men who were enlisted for compulsory military service from 1969 to 2005. Now at baseline, body mass index, blood pressure, and medical disorders were registered, along with test results for fitness and muscle strength. Cardiomyopathy diagnosis was then identified from the National Hospital Register and Cause of Death Register.

So, they found that during a median follow-up of 27 years, 4,477 cases of cardiomyopathy were identified, of which 59% were dilated, 15% were hypertrophic, and 11% were alcohol or drug-induced. Increasing body mass index, or BMI, was strongly associated with elevated risk of cardiomyopathy, especially dilated cardiomyopathy, starting at levels considered normal, meaning a BMI of 22.5 to less than 25 kilograms per squared meters.

And this was even after adjusting for age, years, center, and baseline comorbidities. There was a more than 8 fold increased risk of cardiomyopathy at a body mass index of 35 and above, compared with a BMI of between 18.5 and less than 20.

Dr Greg Hundley: So, it sounds like BMI elevations and cardiomyopathies don't go together. So, what are the clinical implications?

Dr Carolyn Lam: This really shows that even mildly elevated body weight in late adolescence may contribute to being diagnosed with cardiomyopathy in adulthood. So, the already marked importance of weight control in youth is really further strengthened by these findings, as well as the greater evidence for obesity as a potential important cause of adverse cardiac remodeling that is independent of clinically evident ischemic heart disease.

Dr Greg Hundley: Outstanding. So, BMI, not good.

Dr Carolyn Lam: Nope, Greg. High BMI, not good. That was fun, Greg. So, shall we move on to our feature discussion?

Dr Greg Hundley: Absolutely.

Dr Carolyn Lam: For our feature discussion today, we are talking about a familiar problem, but just so very important, and that is hypertension. And guess what? Our feature paper discusses a new first in class centrally-acting renin-angiotensin system blocker that has such remarkable initial results. I am so pleased to have with us the corresponding author for the paper, Dr Keith Ferdinand from Tulane University School of Medicine, as well as our Guest Editor, Dr David Calhoun from University of Alabama and Birmingham.

Keith, could you start by telling us a little bit about the kinds of patients you see there in New Orleans that struggles with hypertension control perhaps? And then, please tell us about Firibastat.

Dr Keith Ferdinand: I'm in New Orleans. In fact, I'm a native New Orleans. And as you know, most of the south and southeast and part of the United States has a high proportion of African American or US blacks. This population has higher rates of hypertension, increased prevalence, more severe hypertension, and more uncontrolled hypertension.

We also note in the south that there tends to be an increase in obesity, which is a powerful risk factor for all patients with hypertension, regardless of race or ethnicity. And unfortunately, the rates of obesity appear to be increasing. So based on the fact that we have an increase in obesity, we have many patients whose blood pressures are not controlled, and some of the previous data have suggested less response to first step or monotherapy with ACE inhibitors and angiotensin receptor blockers, I initiated a trial with a first in its kind oral active brain aminopeptidase A inhibitor.

Dr Carolyn Lam: Wow. Could you tell us a little bit more about brain aminopeptidase, and this new drug Firibastat?

Dr Keith Ferdinand: Most people don't know anything about this molecule, because this is something that was discovered by some French physiologists. They approached me to design the clinical trial here in the United States. And what it does is, it blocks the conversion of angiotensin II to angiotensin III in the brain. Angiotensin III is actually the active component of the renin-angiotensin system centrally, and if you block angiotensin III production, it has a triple therapy effect.

One is that it causes the diuresis. It decreases sympathetic tone, and it stimulates the carotid artery, such that you have, again, a decrease in sympathetic tone. Now, why choose it for patients who are obese, and why want to include a large proportion of non-Hispanic blacks here in the United States? Well, the reasons are that when you look at some of the bench research using rats, it appears to have a more beneficial effect in DOCA-salt rats, which is a model for salt-resistant hypertension.

Salt-resistant hypertension is more common in blacks, more common in patients with obesity, and may indeed be one of the reasons why monotherapy or first-step with conventional renin-angiotensin system agents, specifically ACE inhibitors and ARBs, have not been as effective in the past.

Dr Carolyn Lam: Gosh. That is so interesting, and it's really making me think about my patients too here in Asia, where we have a lot of salt-sensitive hypertension. Now, could you please tell us about the trial you did, and what you found?

Dr Keith Ferdinand: We looked at a cohort of patients. All of the patients were overweight and obese. They were washed out for 2 weeks, and had a systolic blood pressure of 145-170, and a diastolic of less than 105. We wanted to get at least 50% self-identified blacks or Hispanics, and I suspect that any patient who meets this phenotype, and that would include Asians, or even Whites, may respond similarly.

We then placed them in an open label format, and I can discuss why we used an open label, with monotherapy with Firibastat. After 2 weeks, we then titrated the dose level from 250 twice daily to 500 twice daily if needed, and we had a low dose thiazide and hydrochlorothiazide 25 mg addition, if needed, for escape, if patients had a blood pressure greater than 160/100.

The other thing that was interesting and unique about this particular trial is that we used the automatic office blood pressure, where the blood pressure was taken 6 times. The first time was discarded, and then averaged, without a particular doctor or a nurse being there to do the blood pressure. We felt that this was a valid means of getting blood pressure loaded. It tends to mimic, to a large extent, what you see in 24 hour inventory daytime systolic blood pressure.

So, this was a valid means of measuring blood pressure loads. This was a relatively high risk patients. And these were patients whom, previously, probably would not have responded as well to monotherapy with ACE inhibitors or ARBs.

Dr Carolyn Lam: That's really clear, and clever design. I would love to hear a little bit more about why the open label, and of course, the results.

Dr Keith Ferdinand: Well, that's one of the criticisms of this study, but actually, we presented to the FDA when we were discussing designing this trial, perhaps doing a placebo control trial. And we were told by the FDA that if you use a valid means of measuring blood pressure load, so that would be ambulatory blood pressure, or automated office blood pressure, that a placebo would not be necessary, because those means of checking blood pressure load would be considered a true valid means of finding a blood pressure effect.

The other thing is, dealing with minority patients, and really dealing with patients in general, for blood pressure, if they have substantial hypertension, the message has been out there that this is a killer and cause of cardiovascular disease. It would probably have been very difficult to enroll the patients, you've got 254 patients in a national study. It would have been very difficult to enroll these patients, who would have known easily that they had substantial elevation of blood pressure, and we said, "You know, 50% chance you're going to get a sugar pill that has no effect."

Dr Carolyn Lam: Right. Right. Very nice. The results?

Dr Keith Ferdinand: Well, the results were a robust 9.7 mm reduction in systolic blood pressure. At day 56, the p-value was less than 0.0001. And when you do a sub-group analysis of patients who were in the study, it was effective for persons who are under 65, or over 65, male or female. All patients were overweight, and the patients who were obese, with a BMI of 30 or above, had a trend towards even a better blood pressure effect, which again, is not seen with first step with conventional ACE and ARBs.

We also did an analysis based on black and non-black, and there was no difference, again with the trend towards the black patients actually doing fairly well. So, the take home from the particular study was this is the first in its kind, new approach to central Ras blockage with aminopeptidase A inhibitor, that was effective in a population which was overweight and obese, with over 50% minority, and showed substantial blood pressure reduction using a valid means of checking blood pressure, the automated blood pressure in the clinic.

Dr Carolyn Lam Keith, congratulations. A very important study. David, could I bring you in here? What were your thoughts as you were managing this paper, and what do you think are the future steps here?

Dr David Calhoun: Looking at the submission, I was obviously excited about the results and the potential implications. I think, like Keith, in treating a lot of resistant or obesity-related hypertension, we're frustrated that control rates are not better, that the initial response to monotherapy is not better, and that's particularly true of Ras blockers. I think many of us are investigating the initial use of Ras blockers for a variety of reasons related to outcome benefit and reduction in incident and diabetes.

So, I know I like to start with such an agent. I'm particularly excited that there may be, firstly, a new opportunity to block the Ras system, and potentially comparable or even better in the most difficult patients to treat. That is, the African American and the Hispanic patients, who often have very severe hypertension. So, my initial reading was I was very excited to see the potential, and that was brought out by the reviews as well. They shared my excitement. So, I'm looking forward to Keith advancing this compound.

Dr Carolyn Lam: Indeed. Keith, I'm sure everyone's thinking now, wow, remarkable results. What's the drawbacks? How well-tolerated was this drug?

Dr Keith Ferdinand: One of the drawbacks is that the structure of Firibastat included a sulfhydryl group. And we saw with early studies with captopril, which also has a sulfhydryl group, some skin rash, and we saw those similar changes with some of the patients in this particular study. At least 2 of them were suggested to potentially have erythema multiforme, although this was not proven. This was an investigator initiated adverse event.

So, I don't know if we're going to be able to structure a similar type of aminopeptidase inhibitor without a sulfhydryl group. The other thing is that in its presence formulation, it's given twice daily. We know optimally you'd like to have a long-acting agent that can be given once daily. And I don't think we need a placebo control trial, but we may need to do a trial where patients are on 2 or more medications, and then, you add the Firibastat versus adding placebo. But, I don't think at this particular point, we need to get some of these more difficult to treat patients, and just place them on placebo, and watch and see what happens.

We know what happens. The blood pressure goes up. Many of them may have acute heart failure, or progression of renal failure. And I just don't think it's necessary. And the FDA doesn't think it's necessary to prove that hypothesis.

Dr Carolyn Lam: David, what do you think about that? Do we need a placebo control trial? And that use of ambulatory blood pressure, that's novel aspects of this trial too.

Dr David Calhoun: I think use of placebo comparison has been for the traditional or conventional approach. I think most investigators, most clinicians, sort of anticipate seeing the placebo corrected effect. So, I think the results would have been, or will be potentially, more compelling if that's done. But, I can also appreciate Keith's contention, and it sounds like the FDA, that in this day and age, with use of automated office blood pressure measurements tend to minimize that white coat effect, and particularly true of ambulatory monitoring, that it may be that not using a placebo comparison maybe is compelling as well.

Dr Carolyn Lam: Indeed. I really enjoy actually just digging deep into the study like this. Keith, if I could just ask for some final words from you, learning lessons, or even what have you got planned next.

Dr Keith Ferdinand: The first lesson is, we need to continue to pay attention to hypertension. It's kind of been placed on the back burner with more interest now in diabetes and sugar, a lot of interest in lipids because of some of the new agents. But if you look across the globe, Asians, blacks, whites, regardless of race or ethnicity or geography, hypertension is the most potent cardiovascular risk factor, and I think we need to continue to address that.

In terms of this particular agent, I believe that we will have to have some sort of placebo arm, but again, I think it's going to be built on a conventional medication, and then randomized with Firibastat versus placebo on top of conventional medications. In a more severe or a more difficult to treat hypertension, I'm just not really convinced that we need to do a purely placebo arm.

Dr Carolyn Lam: Great, Keith. And David, how about yourself? Any take home messages?

Dr David Calhoun: I think when there's a new in-class compound, I think that's always exciting, particularly when it has the initial results, preliminary results, that Keith is reporting. As many agents as there are out there to treat hypertension, we still are not doing as well as we should be. I think it can only help to have additional classes of agents as therapeutic options, and I think that's particularly true with minority patients, who are, as Keith has indicated, are at the biggest need in terms of controlling blood pressure. Keith, these initial results are very exciting, and I look forward to future studies.

Dr Carolyn Lam: Completely sharing your enthusiasm here. Thank you so much, Keith, for publishing this remarkable paper with us at Circulation. Thank you, David, for helping us manage it.

And thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation July 2, 2019 Issue

1 juli 2019 | 29 min

Dr Greg Hundley Welcome back everyone from our week hiatus for this July 2nd issue of Circulation On the Run. I'm Dr Greg Hundley, from the Pauley Heart Center at VCU health in Richmond, Virginia.

Dr Carolyn Lam: And I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. So good to be back, Greg.

Dr Greg Hundley Absolutely. So Carolyn, our featured articles going to focus on amyloid and transthyretin amyloid is recognized in middle age and older individuals with increases in LV mass and heart failure. And in our featured article from the United Kingdom, Dr Gilmore and colleagues are going to discuss the natural history of this disease and compare outcomes of those with acquired versus hereditary forms of the disease. But before we get to that interview, how about we discuss several other original articles?

Dr Carolyn Lam: For sure, Greg. Thanks. I want to pick two genetic papers in this issue. They're really exciting. The first one is actually the first study to consider the association between rare genetic variance in a large set of cardiomyopathy genes and the occurrence of cancer therapy induced cardiomyopathy. So this paper is from co-corresponding authors, Dr Garcia-Pavia from hospital Universitario Puerta de Hierro from Madrid, and Dr Christine Seidman from Harvard Medical School in Boston, Massachusetts. The authors studied 213 patients with cancer therapy induced cardiomyopathy from three cohorts. The first retrospectively recruited adults with diverse cancers, the second prospectively phenotyped breast cancer patients. And then the third prospectively phenotyped children with acute myeloid leukemia. They showed an increased prevalence of rare variants in cardiomyopathy genes, particularly the truncating variants of the TTN gene in both adults and pediatric cancer patients with cancer therapy induced cardiomyopathy. They confirmed the human genetic data with experimental analyses showing that anthracyclines induced protracted left ventricular dysfunction in mice with truncating variants of TTN genes but not in the wild type mice.

Dr Greg Hundley Aha. So what are the clinical implications of this study, Carolyn?

Dr Carolyn Lam: Well, the findings show that variance in cardiomyopathy genes contribute to cancer therapy induced cardiomyopathy susceptibility among adult and pediatric cancer patients. And thus the identification of genetic risk factors really opens the door to new opportunities to define patients at high risk of cancer therapy induced cardiomyopathy and associated adverse outcomes.

I want to go onto the next paper because it's so related. It's another genetic paper. This time looking further at the truncating variants of the TTN genes and a very novel approach, they aim to assess a genomics first approach to assess the consequences of these TTN variants. So, this was from corresponding author Dr Zoltan Arany from Perelman School of Medicine in University of Pennsylvania where he and his colleagues reviewed whole exome sequence data for more than 71,000 individuals to identify anyone with truncating variants of TTN genes. They further selected individuals with these variants in exons highly expressed in the heart and using a linked electronic health record, they evaluated the associations of these truncating variants of TTN genes with the diagnosis and quantitative echocardiographic measures. They also reviewed data from the Jackson Heart study to validate specific analyses for individuals of African ancestry.

Dr Greg Hundley Interesting. So we're hearing a little bit about different ancestry and TTN genes. What did they find?

Dr Carolyn Lam: So, I should have first clarified that that first look was in individuals of European ancestry. And they found there that the individuals of European ancestry identified through this genomics VERSE approach had a much greater odds of developing dilated cardiomyopathy and had lower left ventricular function than their peers, whether or not a clinical diagnosis of dilated cardiomyopathy was present. They also found that the association of the TTN variants and dilated cardiomyopathy was much weaker in individuals of African ancestry. So in summary, truncating genetic variants of TTN had a measurable effect in large clinical populations with respect to both strong associations with cardiomyopathy and with associations with quantitative differences in cardiac structure and function. Given the caveat though, that these association appeared strongest in individuals of European ancestry. So Greg, what did you have?

Dr Greg Hundley Well, Carolyn, the overlap of inflammatory processes operating in atherosclerosis and the rich presence of macrophages within plaques make macrophages a strong candidate for therapeutic targeting in atherosclerosis. And so this study comes from Levent Akyürek at the Institute of Biomedicine and involves targeting filament A to reduce macrophage activity in atherosclerosis. So filament A is a large actin binding protein that has been implicated in atherosclerosis and this study tested the hypothesis that targeting filament A in macrophages would impair atherosclerosis in vivo in mice and the investigators evaluated the expression of filament A in human atherosclerotic plaques.

Dr Carolyn Lam: Huh, interesting. So what did it show?

Dr Greg Hundley: Well, in humans, expression of filament A is increased in macrophages and advanced atherosclerotic plaques of human carotid arteries. In mice, in the absence of filament A, macrophages displayed impaired migration, proliferation and lipid uptake and secreted lower levels of inflammatory IL 6, also lack of filament A and macrophages in vivo reduced aortic plaque size and atherogenic mice.

There were additional mechanistic findings and that the C terminal fragment of Filament A produced by calpain cleavage regulated IL 6 secretion in macrophages and treatment with calpeptin, which inhibits calpain cleavage, reduced aortic plaque size and atherogenic mice. And so therefore, filament A might serve as a prognostic biomarker and atherogenesis and perhaps targeting the C terminal proteolytic fragment of filament A could be a strategy to reduce inflammation and atherosclerotic plaque development. Carolyn, I've got another paper, but guess what? This one has our first quiz of the academic new year. This is a paper about Nexclin, and it discusses a new component of junctional membrane complexes required for cardiac T-tubule formation. The corresponding authors are led by professor Zhou Shen from the University of California, San Diego. So, Carolyn in this quiz, what is a T-tubule?

Dr Carolyn Lam: Greg, that is mean! T-Tubules, something inside the cell. Something to do with membranes folding over.

Dr Greg Hundley Yeah, you know this is one of those, it's not multiple choice. It's an open ended question. You need your little blue book. You've got to write the answer. So T, or transverse, tubules are extensions of the cell membrane that penetrate into the center of cardiac muscle cells and interact with the sarcoplasmic reticulum to facilitate calcium release and thus help modulate myocardial contraction. T-tubule uncoupling and remodeling are known features of heart failure.

Dr Carolyn Lam: Alright, so that's T-tubules. Guess what Greg, I'm going to ask you before you ask me. So, what's Nexilin?

Dr Greg Hundley I read the paper like a good student of the American Heart Association. This was answered by the investigative team of Chen and his associates. Nexilin has been identified as an actin binding protein and multiple mutations in the nexin gene are associated with cardiac diseases. In this study, Nexilin was required for initiation of T-tubule invagination and overall T-tubule formation, with a loss of next sullen leading to impaired calcium handling. Clinically, these results identified Nexilin as a new possible target for T-tubule remodeling and provide mechanistic insight into molecular pathways leading to cardiomyopathy in patients with mutations in Nexilin. So Carolyn, great job on our first quiz of the academic new year. And how about we move on to that featured discussion?

Dr Carolyn Lam: Absolutely.

Dr Greg Hundley Welcome everyone to our featured article discussion on this July 2nd and we are going to discuss with Dr Julian Gilmore from London, and our editor Dr Justin Grodin from Dallas, regarding amyloid. And Julian, I understand this particular study you have investigated a natural history of transthyretin amyloidosis cardiomyopathy. Can you tell us a little bit about transthyretin amyloid as opposed to light chain amyloid? And then also I think there's two types of transthyretin amyloid, both a hereditary and then a wild type.

Dr Julian Gilmore: Amyloidosis is a disorder of protein misfolding, and there are in fact many different proteins that can misfold and form amyloid fibrils. When they form fibrils they become insoluble and tend to build up and cause damage to whichever organ they're depositing in. Two of the proteins that form amyloid fibrils in humans in vivo are transthyretin, known as TTR for short, or immunoglobulin light chains, known as immunoglobulin light chains, and those two proteins cause transthyretin amyloidosis and AL amyloidosis or immunoglobulin light chain amyloidosis respectively. Those are the main two types of amyloid that affect the heart or cause a cardiomyopathy and they behave very differently in terms of their natural history in that AL amyloidosis is a very aggressive, rapidly fatal cardiomyopathy if untreated. Whereas cardiac transthyretin amyloidosis tends to be a more gradual albeit progressive cardiomyopathy.

Transthyretin amyloidosis, as you alluded to, can either be acquired, known as wild type or hereditary and in the hereditary version it's associated with mutations in the transthyretin gene of which there are more than 130 now that are recognized to cause disease. The wild type version of the disease, the non-hereditary version of the disease, is now an increasingly recognized cause of heart failure, mainly in older individuals and particularly older males. And the hereditary version essentially remains a rather rarer disease, although the mutation that is associated or it is associated with a risk of developing this disease occurs in certain populations and in particular occurs in 4% of people of African descent, as a particular genetic mutation that occurs in 4% of individuals of African descent. So and that is associated with risk of developing this hereditary transthyretin cardiomyopathy.

Dr Greg Hundley: And so, there's the UK National Amyloidosis Center. Tell us a little bit from that center, what did you do with this particular study in terms of its design and what were your results?

Dr Julian Gilmore: Essentially the UK National Amyloidosis Center is the single center in the UK, which is commissioned centrally to diagnose and type, stage, and provide treatment FYS for patients with amyloidosis. And that includes all parts of amyloidosis. We studied a large number of patients with cardiac transthyretin amyloidosis, so cardiac ATTR amyloidosis, who referred to our center and studied them longitudinally, if you like, over the course of many years. So this was a natural history study for a condition for which at the time of the onset of the study and until the end of the study there was no disease modifying treatment and essentially what we found is that there was a great delay in diagnosis amongst most patients diagnosed with the disease and in fact the median number of attendances in hospital for patients diagnosed with the disease before they were actually diagnosed with 17 which is quite amazing and unsurprisingly in a gradually progressive disease, by the time they were diagnosed, their quality of life was very poor.

We found that their quality of life symptoms gradually progressed and that they became more and more functionally impaired and had relatively poor survival with a median survival of somewhere in the region of five years. What we did find is that patients with a particular type of hereditary, ATTR amyloidosis, the type that I alluded to earlier, the mutation for which is present in 4% of people of African ancestry, he planted the V122I mutation. Patients carrying that particular mutation actually have more aggressive disease and survive for shorter than patients with the wild type disease.

So, 17 hospitalizations before diagnosis and the proceeding three years. Were there factors in your study that you could identify that we should now be looking for to try and make this diagnosis earlier?

Absolutely. So one of the reasons for not diagnosing the condition is basically the poor sensitivity and specificity of echocardiography, which is generally the first investigation that a cardiologist will request when a patient presents with symptoms of heart failure. There are some particular features on echocardiography that can provide clues such as strain measurement on tissue doppler imaging, where one can get a bullseye pattern, that's been reported in the literature. So there are particular features on echocardiography that one can look at to increase the chance of picking up this disease. And in particular the big increase in the number of diagnoses over recent years has been because of cardiac MRI scanning, which has become an increasingly used tool for the investigation of heart failure in which one gets a very characteristic picture of late gadolinium enhancement when it's performed in a patient with cardiac amyloidosis, which immediately triggers people to think, ah, here it is, we've got amyloid.

And the other sort of novel diagnostic technique as being bone scintigraphy. In the UK we use a bone tracer called DPD and in the US a bone tracer called PYP, and those bone tracers have exquisite sensitivity for cardiac amyloidosis. So if one injects these tracers in a patient with cardiac amyloidosis one gets cardiac uptake into the heart, which can't really be missed on a planar scan. So those two techniques basically, the increasing needs of cardiac MRI and the increasing use of bone scintigraphy to investigate patients with heart failure have resulted in a great increase in the number of diagnoses.

The last thing to say is that a huge proportion of patients with amyloid or transthyretin amyloid cardiomyopathy have actually had carpal tunnel syndrome previously. The median time from carpal tunnel syndrome to presentation with heart failure is about seven years, but that is another red flag, if you like, that ought to at least trigger a doctor to think could be amyloid. A thick walled heart in the context of someone whose had previous carpal tunnel syndrome. So there are a few clues there as to how one might make an earlier diagnosis, which is absolutely necessary given the nature of our data, sharing the delays that I outlined down here.

Dr Greg Hundley And Julian, last quick question before we get with Justin here. In your data, can you describe for us the importance of that earlier diagnosis related to long-term outcomes as opposed to the group that was diagnosed much later, you know, beyond your median. What was the difference in prognosis in those two groups?

Dr Julian Gilmore: There is no doubt that if patients are diagnosed earlier, they survived for longer, reflecting the natural history of the disease. So these patients, as I mentioned earlier, did not receive any disease modifying therapy and we did divide the patients into pre 2012, when patients were essentially diagnosed by endomyocardial biopsy, or the vast majority of them were diagnosed by endomyocardial biopsy, and post 2012 by which time most patients were diagnosed via an imaging, if you like, algorithm that we published in 2016 in the same journal in circulation. And the patients who were diagnosed earlier had significantly improved survival. Just corroborating really the fact that they were actually diagnosed earlier. What's particularly relevant there, is that the treatments that have been developed for this condition, and there are some recent new potential disease modifying treatments that have been developed, they find that things seem to slow progression of the disease rather than stop it or reverse it, so that if one can diagnose a patient early when their quality of life is still good and then slow progression, there's a high chance of improving quality of life quite substantially and obviously prolonging life.

Dr Greg Hundley Thank you so much, Julian. And Justin as the managing editor of this article, what struck you most in terms of its results and conclusions, and how we should manage patients today suspected of transthyretin amyloid?

Dr Justin Grodin: Well, I would say that really there are four things that in my opinion that were quite striking. The first at least as highlighted by Professor Gilmore is that the UK National Amyloid Center, they get the national case load. So this is unlike other cohorts and other centers across the world in that this is subject to less referral bias than others. So I think that's the first thing that's quite impressive. And I think Professor Gilmore really hit the nail on the head when he highlighted that this paper, that this analysis really underscores the importance of an early efficient diagnosis. And a lot of this is really through his seminal work in achieving a non-biopsy diagnosis of ATTR amyloidosis and his findings have been replicated in other cohorts as well. So I think those, I would like to say are really one and two.

And then number three, which is one that I don't think Dr Gillmor mentioned, I think he mentioned indirectly, but we were also struck by the prognostic importance or I should say the prognostic meaning of having the V122I mutation. So these are individuals like hereditary amyloidosis and they have a single mutation. This is the one that is prevalent, at least we think from population studies, in approximately 4% of the African or Afro-Caribbean population. And we really see unequivocally that the time from symptom onset to diagnosis was shorter and the prognosis was actually worse in comparison to other mutations or in individuals with wild-type amyloid. And this is an important finding really for two reasons. Number one, it is largely confirmatory from other studies, but it's important to note that those studies were subject to referral bias. And we could never ever successfully incorporate whether or not socioeconomic status had actually influenced the bad outcomes of these individuals.

And I would say that Professor Gilmore's findings are quite compelling in that regard. And then the second thing for this point is really this underscores I think the importance of genetic testing. I mean I think all the readers can take that message away. And then the fourth thing, which as Professor Gilmore alluded was the striking amounts of healthcare utilization, although it was in a minority, certainly quite compelling and really what it speaks to is multiple missed opportunities. Even in the UK where they have a centralized center of excellence, just like Professor Gilmore's, that there were delays in diagnosis and then when delayed these patients are quite ill. And I think I'm making all these points because at least in 2019, the regulatory environment about amyloidosis, specifically ATTR therapies. In The United States, it's actually changed. So a disease where we had therapies that might be off label or our therapies were largely symptomatic, where we managed the patient's signs and symptoms, we now actually have disease modifying therapies.

So, in the United States in 2018, there were two biological agents that actually silence the livers production of transthyretin or TTR and they were approved for hereditary ATTR polyneuropathy. But there is some suggestion from sub-studies that those will have the efficacy in cardiac amyloid. And then number two in the United States, we recently gained approval in May of a drug that actually stabilizes the transthyretin protein or tetramer. So in other words, just as Professor Gilmore had highlighted at the beginning of this call, it stabilizes the breaking up, if you will, of this protein, which is the rate limiting step of amyloid formation. So you take this pill and then the transthyretin molecule does not then deposit amyloid. So this is really exciting because professor Gilmore's cohort study really captures now at least the impact that these therapies might have, and in the United States and across the world and in the UK, these therapies are being studied for all types of ATTR amyloid and really they're on the horizon. So it's given us very deep insights into how these might impact our patient's lives with ATTR.

Dr Greg Hundley Julian, Justin, that was just such an impressive discussion of a very important topic and something that again, with echocardiography, we really need to start thinking about when perhaps we appreciate some LVH, diastolic dysfunction. We have apical sparing of systolic function, but abnormal basal systolic function. Could you just summarize one point, each of you, that we should be thinking about as we move forward and we're seeing patients in our clinic that might have this disorder.

Dr Justin Grodin: The first thing to say is that awareness is all important. You know, 25% of male individuals in autopsy studies over the age of 80 have ATTR amyloid deposits in their heart, and when one sees a thick walled heart in any situation, and particularly in an elderly individual, one needs to think, could this be, amyloid, that's the first thing. And the second thing I'd like to say is that if that thought occurs, which it should occur at a much earlier stage than it does probably in most cardiologists minds, then one should think about either a bone scan, which is a cheap, simple tests. The PYP scan in the US or DPD scan in the UK and or an MRI scan, which has a very characteristic picture in a patient with cardiac amyloidosis. So those would be my take home messages to try and improve early diagnosis.

You know, I'd like to dovetail what Professor Gilmore had said cause he just about took the words out of my mouth and I would like to emphasize the first point in that the diagnosis of AL, we mentioned earlier, or an ATTR amyloidosis, really necessitates a very, very high index of suspicion. What do I mean by that? When somebody has a thick heart muscle and it's not explained by something else, in other words, they don't have a lifetime history of high blood pressure and they don't have high blood pressure seeing you, or maybe they don't respond adequately to standard heart failure therapies when something is not fitting, it's always incumbent to the treating clinician to think amyloid.

I would also like to highlight some of the clues that Professor Gilmore had mentioned, that any individual with carpal tunnel syndrome or who might be hospitalized with heart failure, in other words, they have shortness of breath and swelling, and the squeeze of their heart is normal, or the ejection fraction is normal, that should increase your index of suspicion for amyloidosis. And then individuals that might've had lumbar canal surgery or really any issue impacting their tendons. And then they're now presenting with a thick heart muscle. That should be a clue. It doesn't necessarily mean it's diagnostic. In fact, the majority of those individuals might not have, or a large proportion, might not have ATTR amyloid, but it should certainly raise an eyebrow and then kind of allow the clinician to move forward with the evaluations that Professor Gilmore had mentioned.

Dr Greg Hundley Well, listeners, what a phenomenal discussion that we've had from Professor Julian Gilmore from London, and Dr Justin Grodin from Dallas, Texas, educating us on transthyretin amyloid and thinking about that early and being suspicious as we evaluate patients, particularly older individuals that are symptomatic with heart failure. Well, on behalf of Carolyn Lam, this is Greg Hundley. We look forward to seeing you next week. Have a great week.

Circulation Subspecialty Journal's Editors-in-Chief June 2019

24 juni 2019 | 31 min

Dr Amit Khera: Welcome to Circulation On The Run. Our weekly podcast summary and backstage pass to the Journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas, and I had the distinct privilege of standing in for Dr Carolyn Lam and Greg Hundley this week. Twice a year, we are very fortunate to have some unique podcasts when we don't have circulation issues, and in the past we've met with many fellows in training and heard about some interesting studies that they're doing. Today we have a very special podcast we have not done before, and that is one where we had the opportunity to learn about our Circulation Family of Journals, and more importantly to hear from the dynamic editors in chief of these various journals. I think you're really going to enjoy it, we'll walk through and hear from each one of them, hear about some of the innovative things that are happening, some of the future that they see for their journal in their field, and I really enjoyed it, and I'm sure you will as well. So, without further ado, we'll start with our first editor.

Dr Sunil Rao: I'm Sunil Rao. I'm an intervention cardiologist at Duke, and I'm the Editor-in-Chief for Circulation Cardiovascular Interventions, which is one of the daughter journals of the Circulation Family. We publish articles really related to the broad spectrum of interventional cardiology, from coronary interventions to peripheral arterial disease, and Endovascular interventions to structural heart disease interventions. We also published review articles in all of those areas, as well as any health policy or outcomes studies that are in that space.

Dr Amit Khera: Tell us what are some of the innovative things that your journal is doing this year.

Dr Sunil Rao: We're really excited about two things, one is our extremely successful Assistant Editor program that we launched last year at A.H.A. 2018. This is a program where we have five early career individuals that are within five years of completing their fellowship program who joined the editorial team at Circulation Cardiovascular interventions, and in that role they really learn a lot about the mechanics of how scientific publishing works, they commit to doing manuscript reviews, and receive feedback on improving their peer review process, and even independently handles some manuscripts as well, that are in their areas of interest. This is our way, I think, of encouraging the next generation to stay engaged with science, and with the scientific publishing process. It's been extremely successful. Assistant editors are part of our team for a two year term. So, in 2020, we will be selecting the next class of assistant editors, and after their term is ended, they join our editorial board as editorial board members. So, we're really excited about that, it's been an overall positive experience, for I think everybody involved. The second thing that we're really excited about is that we launched a social media presence for the journal, which it previously did not have. So, we have a very active Circulation Cardiovascular Interventions Twitter handle, I encourage all the listeners to join Twitter if you're not on Twitter, and if you are on Twitter please follow at Cirque intervened. It's " at C.I.R.C.I.N.T.V.". That is the official Twitter handle for our journal. Dave Fishman is our social media editor, and Chadi Alraies is our assistant social media editor, and we're not just tweeting out the articles, and providing summaries when the papers get published, we're holding Twitter journal clubs once a month ,and these have been extremely successful, it's an hour long Twitter journal club where the discussion gets very intense, and there's a lot of back and forth. We try to have the authors on as well, so that they can explain the rationale for their study, some of the challenges that they face when they are doing the study, and hopefully provide some implications for clinical practice, and what the next steps are. That's a way for us to engage our readership, it's almost a form of post publication peer review, which I think is becoming very popular. In addition, remember we don't have a print format of our journals, so this is a way to get the readership more engaged with the Web site, and to come to our website and learn what elsewhere publishing, and how they can get involve with the Journal as well, both as authors who submit their work, or if they want a peer review for us, please contact us and let us know.

Dr Amit Khera: I really love hearing about the Twitter journal club, I know that they are well received, and certainly getting a lot of traction. Tell us about what initiatives or topics you're most excited about this year, and maybe some things that are coming later in the year.

Dr Sunil Rao: We're really excited about the big areas in interventional cardiology, which are coronary physiology, we've published quite a few papers on looking at different physiological parameters, and how they can drive the appropriate use of PCI and how that affects outcomes. I think that's going to continue to be a huge topic over the next year, Certainly such a heart disease has exploded, and with the data on low risk patients undergoing TAVR, and having really good outcomes, we're seeing a lot more submissions in the low risk TAVR space, the other area that's really exploding right now is Mitral and Tricuspid Valve Interventions, one of the areas that I think has seen a tremendous amount of device innovation. So, we're seeing a lot of submissions from really high quality papers in that space, but I think it's also important to note, that unlike previous iterations of the Journal, we're actually having a review article, we're trying to have a review article every month on a major area that is burgeoning, so that the readership can understand the overall lay of the land, with respect to evidence, how that guy's clinical practice, and what's coming next. So, we've published quite a few review articles already, and there are more to come, and I think that's a really important way for the readership to keep current with what's going on in Interventional Cardiology.

Dr Amit Khera: What about the advancing aspects of your subspecialty? There's so much going on in interventional cardiology, it's a bit dizzying, just tell us a little bit about some of the ways that your journal's helping advance that mission, not just now but perhaps in the future.

Dr Sunil Rao: I think one of the challenges that we have at Interventional Cardiology, and maybe this is true across Cardiology, is that the evidence is developed very rapidly, and oftentimes it almost seems like the field is lurching back and forth in certain areas, a prime example of that is the drug coated balloon controversy for Peripheral Interventions. The Journal Of The American Heart Association published a meta-analysis, showing that there may be an association between the use of these devices and increased mortality, that has led to a lot of discussion in the interventional community, and quite frankly I think there's a fair amount of confusion out there about whether we should be using these devices, should we put a moratorium on these devices, is the signal real, if it is, what's the mechanism of death. So, a lot of conversation around that, in fact, it's led to what's going to be a focused FDA meeting in June, specifically on the drug coated balloon controversy. Where I see our journal playing a role is really in trying to, not only publish the latest science, which is rigorous in the field for controversial topics such as this, but also to help provide some context for that science, and I think our integrated strategy of original science review articles, and social media really helps us to communicate with the readership, and with the Interventional Cardiology community writ large, meaning not just physicians, but also Cath lab staff, nurses, noninvasive cardiologists who obviously have patients who are undergoing interventions, and even policymakers, to keep them abreast of what's going on, so that they can have the same level or base of knowledge, so that the conversation is on a level playing field.

Dr Amit Khera: Okay, well you heard it from Dr Sunil Rao. Thank you for your time.

Dr Kiran Musunuru: I'm Kiran Musunuru, I'm the outgoing Editor-in-Chief of Circulation Genomic and Precision Medicine. Let me start by saying a little bit about the content of the journal, it considers all types of articles related to, as the name implies, Genomic and Precision Medicine, and more specifically, Clinical Genetics, the molecular basis of complex cardiovascular disorders, considered at a variety of levels, that can include a lot of different, what we would call Omics Techniques, from Genomics to Transcriptomics, Proteomics, Metabolomics, Metagenomics, and, so forth. It also deals with big data applications, that includes Electronic Health Record Data, Patient generated data combined with any of the things I've already mentioned, Genome Wide Association Studies, Pharmacogenomics, Gene Therapy, Therapeutic Gene Editing, Systems Biology. So, it's a pretty comprehensive look at all the various topics that would fall under the rubric of Genomic and Precision Medicine.

Dr Amit Khera: Now, Dr Musunuru, you mentioned the outgoing Editor-in-Chief, let's introduce the incoming Editor-in-Chief, Thatcher Christopherson Semsarian.

Dr Chris Semsarian: I'm the incoming Editor-in-Chief. My name is Chris Semsarian, I'm a cardiologist at the Royal Prince Alfred Hospital in Sydney, Australia.

Dr Amit Khera: What are some of the innovations you and the Journal are doing this year, or, what are some of the things you see coming in the future?

Dr Kiran Musunuru: Something I'm very excited about, is that we are just starting a pilot project with the American Heart Association's Institute for Precision Cardiovascular Medicine. The institute has a very nice platform called the Precision Medicine platform, and, in brainstorming last year, we realized there was a very nice opportunity to try to create a new type of journal article. There's also a big move in science nowadays to improve transparency, and rigor, and reproducibility, especially in science. The idea being that ideally other investigators should be able to take one team's work, and be able to run through the entire analytical process, and reproduce the original findings, and perhaps even find ways to improve upon those original findings, and, so we realized working with the institute's Precision Medicine Platform, we had the opportunity to actually make a new type of article, we think of, as the paper of tomorrow, a virtual article. The idea would be, that we would have primary data on the Precision Medicine Platform, the analytical tools used to process the data would also be on the Precision Medicine Platform, the analytical plan, in the form of a so-called Jupiter notebook, that basically takes people step by step through exactly which tools were used in which order, in which way, with which parameters, would be on the Precision Medicine Platform, and then there would be some verbal explanation, some background, to explain the context of these analysis, and to really put it into perspective, as how it fits into the body of literature, and so the idea would be, this would live on the Precision Map Platform in a virtual format, and then anyone else who is interested in this work could come, and actually directly interact with the data, and the tools, and the analytical plan, and could actually rerun the entire papers work from scratch, thus reproducing it, and then could actually tweak the analytical plan, or install tools of their own, and be able to build upon the work that had already been done. It's a very different way of thinking about journal articles, more as living entities rather than static work that just lives on a page, and is there as reported, and then never has an opportunity to be fully produced or improved upon.

Dr Amit Khera: There's so much happening in the space of genomics, and obviously, we hear the word "Precision Medicine" so commonly. Tell us a bit about how your journal in specific is advancing the mission of your area.

Dr Kiran Musunuru: I'll say a little bit, and then maybe turn it over to Chris, give his perspective as the incoming Editor-in-Chief. I think it's a vibrant field, but it's also a very new field, it's evolving rapidly, and I think the Journal has a very important role to play, and not only reporting the results that are coming out of studies in this field, but actually having a role to play in helping to shape the field, helping to define the field, it's very exciting, it's very much in rapid evolution. Just ten years ago or so, when the Journal first started, we were just starting to see the first Genome Wide Association studies, and now we've gone so far beyond that.

Now, again, we're talking about these large bio banks, we're talking about Precision Medicine, we're talking about applying this information in health care, we're talking about combining all of these various streams of data and many levels to be able to do studies, that are, I would even say, exponentially advanced beyond what we able to do just ten years ago, and so, it's very exciting times for the journal, then maybe I can ask Chris to share his thoughts on that.

Dr Chris Semsarian: Yeah Kiran, I mean, it's a great honor system to follow in your amazing footsteps, and what you've done for the Journal, and as the incoming Editor-in-Chief, I really want to sort of try, and build on the platform that you've established over the last few years, and really, one of the areas that I'm particularly interested in is the area of Translation of Genomic Findings. I mean, ultimately what we do in our lives, as clinicians, is to help patients improve diagnosis, to improve the treatment of these patients, and to be able to do studies with very basic understanding of how our genomes work, and how Narcotic Genes interact, and translating those findings into these improved diagnostic approaches, and even in guiding management is really exciting, I think, in terms of clinical medicine, and improving patient care as we look ahead. I really want to be able to continue to publish really, state of the art, novel, innovative, research areas, that you've already covered, Kiran, which would lead to better care of our patients, who are ultimately the beneficiaries of this type of amazing work.

So, I'm really excited looking at the Journal, it's a tremendous area of interest and research, where there's twenty-two thousand genes approximately now genomes, and we really don't understand most of them in terms of their intricate function, and I figured it's a great time ahead, in terms of Precision Medicine.

Dr Amit Khera: Okay, well, that was Dr Kiran Musunuru, and Christopher Semsarian, we appreciate both of your time today for Circulation on the Run.

Dr Paul Wang: I'm Dr Paul Wang, I'm the Editor-in-Chief of Circulation Arrhythmia and Electrophysiology. Our Journal covers really the expanse of our field, going from basic mechanisms of arrhythmias, so very basic science work, to really clinical practice, clinical outcomes, to population based studies, and genetic based considerations in our field. So, we really feel we encompass the entire range, and there really isn't any topic within our area, that we don't feel is outside our realm.

Dr Amit Khera: I know there's so many innovative things you're doing, Dr Wang, with your journal. Why don't you tell us a little bit about your plans for this year.

Dr Paul Wang: We've been excited; our team has been at the Journal for two years now, and we focused on a number of different areas. So, I think one of our biggest advances, and we've tried to be more responsive to the authors, so we've really reduced the time to first decision very substantially, from over twenty days, to ten days or less, I think we hit a record of 7.8 days in the journal. So, really, we hope we're more responsive, we've involved the editorial board, we've substantially expanded it, so that more of our reviews of greater proportion going to our editorial board, which is a really fabulous, internationally recognized group, with really high quality reviews, so we've been very pleased, with both a level of science that we've received, as well as the level of the reviews that we have. One other area is, we really want to make sure that the reviewers, who do much of the heavy lifting, in addition to our editors for The Journal, and so we've established a new Reviewer Recognition Award System, they can be designated as silver, gold or platinum, and we've reached out to department chairs, or their deans, and recognizing that they won this prestigious award for their performance, and great work with the Journal, so there are a number of different things that, in fact, we think we've made some advances in, the other areas are really that of extending our reach, and so, one of the things we concentrated on, initially with the adding of podcasts, so we do that monthly.

All the articles are now available in review, and then what we're starting at our new initiatives is, we'll be starting a Twitter Journal Club. I've been recording at least two of our articles, as the interview with the authors, and then we're going to be having a journal club, in which we will have the opportunity for people around the world to comment, and have a discussion that will really be exciting, we think. So, there are a number of other areas that we're thinking about, in terms of that kind of work.

Dr Amit Khera: The field of Electrophysiology seems to be changing by the day, maybe you can tell us a little bit, about how the journal is advancing the mission of the field of electrophysiology.

Dr Paul Wang: So, one of the things that we focused on is the role the Journal can play, in terms of connecting with other elements of our field, and one of the ways that we've really concentrated on is, in particular, working closely with the American Heart Association, and its committees. We're related to a number of committees, but particularly, there is a committee on Electrocardiography, Electrophysiology, part of the Clinical Cardiology Council, and so, we work very closely with that group, and, in fact, we've invited that group to create proposals for a number of review articles, state-of-the-art reviews, that we hope will come out in the next year or so. The ways in which we can tie together our committees to AHA overall, I think, is really the direction we're looking for our journal, and we feel we can play a very novel, and innovative role in that regard. We, for example, also reached out to the American Heart Association funded researchers in our area, and invited them to participate in the journal, participate in our committees, become fellows or FAHA's of the American Heart Association, so we really want to create this family, a real community, and sense of community, that we hope will stem from the Journal. So, we're very excited about the future, and what we might be able to achieve together.

Dr Amit Khera: Thank you so much, Dr Paul Wang for your time today, and we appreciate your insights on Circulation, Arrhythmia and Electrophysiology.

Dr Nancy Sweitzer: Hi, I'm Nancy Sweitzer. I'm the Editor-in-Chief of the Journal Circulation Heart Failure. At Circ Heart Failure, we deal with all things related to heart failure. Heart failure is an expanding specialty, relatively new subspecialty in cardiology, and we're very interested in the physiology, and mechanisms of heart failure, as well as treatments of heart failure, and the innovative evolution of the specialty which includes Advanced Hemodynamics, Mechanical Circulatory Support, and transplant as therapies, as well as all Implanted Device Therapies, and new, and Innovative Pharmacologic, and Gene Therapies as well.

Dr Amit Khera: Tell us a bit about initiatives, or features in Circulation Heart Failure, that you're planning on tackling not only this year, but into the future.

Dr Nancy Sweitzer: The effort we're most excited about at Circulation Heart Failure has been ongoing now for a little over a year, but continues, and is really focused on the emerging scientists in the Heart Failure Space; we call it our "Featured Emerging Investigator Spotlight", and this spotlight focuses on authors of manuscripts, who are within ten years of their terminal training, and can take full responsibility for the content of a manuscript. When we publish a featured emerging investigator article, which we've done more than half of the months since launching the feature in late 2017, we schedule a Twitter Journal Club with that author, where we participate, over the course of several hours, in pretty intensive conversation, about not only the science, but career development in Heart Failure Space, the importance of mentoring, and sponsorship obstacles that people are facing in development as physician scientists or scientists, and insights they may have into fostering success in the Heart Failure Space. This has been a great feature, we launched it because we feel that the emerging scientists, in the Heart Failure Space, need a virtual community in those critical years, before you have a lot of resources to start traveling, and setting up a network that's based on personal interaction, and we felt that, the modern era of social media was perfect for this. We found our emerging investigators are getting to know one another, they participate in one another's Journal Clubs, the Journal Clubs are incredibly fun, and interactive and we're getting a lot of Twitter engagement from the Heart Failure Community, there's a lot of "Twitteratti" in Heart Failure that really are engaged, and engaged with the Journal, which has really been fun for all of us, I think, so that's the thing we're most excited about.

Dr Amit Khera: It's really wonderful to hear how you're spotlighting authors in creative ways. Tell us a bit about how your journal is advancing the mission of Heart Failure and Transplantation.

Dr Nancy Sweitzer: I see the journal as central to advancement of the subspecialty, as I mentioned earlier, Heart Failure is a relatively young subspecialty in the United States, we received a CGMC designation as a subspecialty just in 2008, just eleven years ago, and it's been a board certifiable subspecialty only since 2014. So, we're very young, and I think really developing into our own. We've seen tremendous growth in the number of people seeking subspecialty training in Advanced Heart Failure and Transplant Cardiology, and we are really enjoying helping the Journal evolve with the specialty, as it evolves, and that's happening very actively right now. So, I think what Heart Failure is in 2019 is different than what it was just five years ago in 2014. We're doing a lot more ,as I mentioned, Complex Chemo Dynamic Thinking, thinking about the path of physiology in our patients, and how we can target that effectively, not only with existing therapies, but with strategies, and, as I mentioned, the burgeoning growth of Mechanical Circulatory Support, and support devices, which the field has embraced quite actively, and The Journal is increasingly publishing content in these spaces, as well as the spaces of Advanced Heart Failure, but, I guess also, we're interested in every aspect of Heart Failure, from Complex Multidisciplinary Care Management, to Palliative Care, to the interaction of the heart with other organ systems, and Heart Failure such as the brain, we have a paper on Cognitive Function Abnormalities, and Heart Failure in this month's issue. So, the interaction with the brain, the kidney, the liver, many other organs, that are affected when the heart becomes quite ill with Advanced Heart Disease. So, basically we're interested in everything that touches Heart Failure Development Care, and treatment of patients with Heart Failure, and particularly we're interested in the newest and latest. We love publishing, and some of our highest impact papers in the last couple years have been new therapies, just being tested for the first time in patients with heart failure. Small studies that may not have large impact in terms of heart outcomes, but where we're learning about the pathophysiology of the disease, and new treatments, that's really exciting to us. We've published a couple of methods papers in the last year, really innovative models. One describing a model of pacing in mice, which has been a really challenging thing to do in Heart Failure, but several groups have now developed Tachycardia induced Cardiomyopathy models in mice, which is important for rapid discovery work, because mice have such a short reproductive span, and can be genetically altered, and then a recent publication on the methods paper, looking at a new initiative by the FDA, to potentially approve therapies based on patient reported outcomes, rather than just heart mortality and morbidity outcomes, so we're really excited about the innovations, and the Heart Failure Space, the work that describes where we're going as a field and as a profession. You'll see some features coming up in the journal, from opinion leaders across the globe on where this specialty sits in 2019, and where we, as the leaders in the field, can guide it as we move into our next decade, and I think that some of the most exciting work the journals doing.

Dr Amit Khera: Thank you, Dr Sweitzer. We really appreciate your time today for the podcast, and your insights on the Journal.

Dr Robert Gropler: Good afternoon, I'm Rob Gropler. I'm the Editor-in-Chief of Circulation Cardiovascular Imaging. It's one of the journals within the family of Circulation Journals, and our focus is really on being the most influential source of leading edge imaging sciences, as it relates to transforming cardiovascular care, so what that means is, that we're interested in all imaging studies that are applied to the care of the cardiovascular patient, and although our primary focus is really on clinicians, and researchers, but we also want to expand our viewership, if you will, to anyone who is interested in how imaging is used to understand Cardiovascular Medicine, and to treat patients with Cardiovascular Disease. So, we are edged in all forms of imaging, this can be from MR, to echo, to nuclear, to CPT, to optical imaging, it involves all types of disease, ranging from Congenital Heart Disease, up to diseases in the elderly, it also involves not just it is in humans, but also understanding disease in the preclinical space, particularly as it helps us understand new technologies that may ultimately reach human use, either for investigational purposes, or ultimately, to be used in the treatment of a patient with Cardiovascular Disease.

Dr Amit Khera: What are some innovative things you and the Journal are planning for this year?

Dr Robert Gropler: We're doing quite a few things. One of the first things we did, as you know, were relatively new, where we've only been an editorial team, if you will, for one year. One of the major efforts has been to increase our presence, in terms of digital media strategies, across the board. And so, this meant expand our Twitter presence, if you will. It also meant increasing our offerings in that digital space by, for example, having a journal club, what we would do is on a every other month basis, discuss a paper we published that's of significant interest via Twitter. And it would involve the authors, the associate editors who actually manage that study, as well as the editorialist who wrote about that study, and it leads to very unique insights into how that paper is being viewed by the scientific community at large, and also potentially how that information will be implemented in terms of transforming clinical care.

We've added what we call a teaching file. If you think about imagers, imagers learn by seeing images. And the more they can see images, put them in the context of clinical cases, the more they understand what an image means when they see it. So, what we do now is we accept a large number of what we call imaging cases. These are specific unique cases that have a history, and then a short write up about them.

And those are gathered each month, but then they're downloaded into a file. And then, anyone with access to the Journal can then look at, use to learn from, to potentially use for talks to enhance their own education the education of others. And we have found that to be, again, another offering that our readers particularly like.

Dr Amit Khera: And how do you see Circulation Cardiovascular Imaging advancing the mission of imaging, which seems to be ever-expanding, and ever-growing?

Dr Robert Gropler: We're really in the education business. And what that means is that we're educating at a multi-scale level. Just educating a practitioner on what technology can do, how it's helping cardiovascular medicine, yes, that's important. But what we're also doing, is we're educating the scientists as to here as some of the new findings that were coming out because of imaging. And then that, in turn, will help direct them or signal them as to where is the science leading them, and what should be their next steps?

We're also educating the general public as to what can imaging do, and how does imaging change cardiovascular medicine for the better, and what they can expect from that. And we're also educating the regulatory bodies, if you will, that determine what imaging can be done in the clinical environment and so on, and the importance of these imaging techniques.

So number one, I think we always have to maintain that focus, as to that's our goal. Now, that being said, I think the question becomes how do you convey that concept? And where we have to continually evolve.

And I think they were very smart years ago to make it a digital-only journal, as opposed to combined print and digital. So, I think that was actually very savvy. But the digital net component now has to expand. And that means our offerings have to reflect not just that people learn in different ways, that is, we have to have not just, if you will, a didactic or print equivalent component of a paper. But it also should be audio-based, such as this podcast. But they also need to be varied as in terms of the types of offerings, and their brevity or length, if you will.

Dr Amit Khera: Thank you, Dr Robert Gropler, the Editor-in-Chief of Circulation Imaging. We really appreciate your time today.

Dr Robert Gropler: Thank you very much. You have a great day.

Dr Amit Khera: Well, I'm sure you enjoyed this as I did. We really got incredible insight from the Editors-in-Chief of our Circulation family of journals. We learned so much about the broad array of subspecialties that they cover, and all the exciting and innovative things they're doing to really advance the missions of their fields, and also for the authors and for science.

Well, again, I'm Amit Khera, associate editor from UT Southwestern, Digital Strategies editor for Circulation. And next week, you'll have your usual hosts, Carolyn Lam and Greg Hundley.

Circulation June 18 Issue

17 juni 2019 | 25 min

Dr Gregory Hundley: Welcome everyone to the June 18th edition of Circulation on the Run. I am Dr Greg Hundley, Professor of Internal Medicine and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

In today's issue we're deviating from our common format due to some scheduling difficulties. So, rather than our traditional coffee chat in this program I'm going to have a large gulp of coffee and present results from several exciting papers. Then we'll turn over the second half of our program to Dr Carolyn Lam for our feature discussion.

Now, I promise this is a one-time deviation and we will return to our common chat format in early July. But, before I launch into my presentations I did want to introduce what will transpire with Carolyn. She will be discussing an exciting paper from the Adelaide Medical School at the University of Adelaide in Australia.

Some have wondered whether the persistence of a patent arterial venous fistula post-kidney transplant may contribute to ongoing maladaptive cardiovascular remodeling. To address this issue Carolyn will be discussing with authors whether ligation of this AV fistula may reverse this maladaptive remodeling. And like you, I'm excited to listen to that discussion. But before that let me review several of the other distinctive papers on this issue.

The first one is entitled “Individual Treatment Effect Estimation of Two Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.” They are the results from the RE-LY trial. The corresponding author is Professor Frank Visseren from the University Medical Center of Utrecht in Utrecht University.

The study emanates from the randomized evaluation of long-term anticoagulation therapy or the RE-LY trial. In which high dose dabigatran, that's 150 milligrams twice daily, was found more effective in prevention of ischemic stroke and systemic embolism than low dose dabigatran which is 110 milligrams twice daily.

But this occurred at that expense of an increased risk of gastrointestinal bleeds. Importantly however, the absolute treatment effect of dabigatran in both doses, likely differs between individuals. And therefore, individual treatment effect estimation has the potential to identify patients who have a favorable trade off and absolute benefit and harm from dabigatran compared with no treatment, and to select the optimal dose for each individual patient.

So in this study, the investigative team derived and validated a prediction model for ischemic stroke and systemic embolism and major bleeding in patients with atrial fibrillation from three treatment arms of the RE-LY study. They had 11,955 individuals in the derivation cohort and 6,158 in the validation cohort. And they evaluated the patient characteristics of sex, age, smoking, anti-platelet drugs, prior vascular disease, diabetes, blood pressure, estimated glomerular filtration rate, and hemoglobin.

Dr Gregory Hundley: Well, what were the results? Well the five-year absolute risk reduction, for ischemic stroke and systemic embolus minus the five-year absolute risk increase for major bleeding, when comparing the high to the low dose of dabigatran yielded a net benefit in 46% of patients. And therefore, the authors conclude that the absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics.

And perhaps down the road such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine its optimal dose of administration. Well, how 'bout that? And let's go on to the second paper entitled “Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness and Safety, or EMPRISE Study.

And the corresponding author for this study is Elisabetta Patorno from Brigham and Women's Hospital in the Harvard Medical School. So, as a background in a different study to this, the EMPA-REG OUTCOME trial showed that Empagliflozin an SGLT2 inhibitor was found to reduce the risk of hospitalization for heart failure by 35% on top of standard of care in patients with Type 2 diabetes and established cardiovascular disease.

Well, the current study, The Empagliflozin Comparative Effective and Safety or EMPRISE Study was designed to assess empagliflozin's effectiveness, safety, and health care utilization in routine care from the period of time between August of 2014 through September of 2019. And the author's report on the first interim analysis in which they investigated the risk of hospitalization for heart failure among Type 2 diabetic patients initiating empagliflozin vs. sitagliptin.

The investigators used two commercial and one federal Medicare claims data source from the U.S. and identified a one-to-one propensity score matched cohort of 16,443 pairs of Type 2 diabetes patients that were greater than 18 years of age initiating empagliflozin or sitagliptin. The average age of the participants was approximately 59 years.

And almost 54% of the participants were males and approximately 25% had records of existing cardiovascular disease. So compared to sitagliptin the initiation of empagliflozin decreased the hospitalization for heart failure risk by 50% over a mean follow-up of 5.3 months. And the results were consistent in patients with and without baseline cardiovascular disease for both the empagliflozin 10 milligram or 25 milligram daily dose. Or analysis comparing empagliflozin vs. dipeptidyl peptidase-4 inhibitor class all comers.

Thus, in conclusion, in this first interim analysis from EMPRISE, the investigative team showed that compared with sitagliptin the initiation of empagliflozin was associated with a decreased risk of hospitalization for heart failure among patients with Type 2 diabetes as treated in routine care with and without a history of cardiovascular disease.

Dr Gregory Hundley: Well, now we're going to turn our attention to red meat. And this next study was entitled, The Consumption of Meat, Fish, Dairy Products, Eggs, and Risk of Ischemic Heart Disease. It's a Perspective study of 7,198 incident cases among 409,885 participants in the Pan European Epic Cohort. And the corresponding author is Professor Timothy Key from The University of Oxford.

Some of the background here, met analysis of previous prospective studies have suggested that intake of processed meat maybe associated with a higher risk of ischemia heart disease whereas, unprocessed red meat might not. For dairy products and eggs, systematic reviews of prospective studies have reported no consistent evidence that higher intakes are associated with a higher risk of ischemic heart disease.

Other studies have shown that fatty fish consumption may reduce the risk of ischemic heart disease, it is a rich source of long chain N3 fatty acids. And meta-analysis has suggested even an inverse association between overall fish consumption and mortality from ischemic heart disease.

So, hear in this cohort: we're going to evaluate all of these. Accordingly Key, and his co-authors report the relationships of these foods with risk of ischemic heart disease in the European prospective investigation into cancer and nutrition, the EPIC study, and that again is a cohort of a half million men and women from nine European countries followed for 12 years to examine the association between the intake of animal foods and the occurrence of ischemic heart disease.

The author's found that higher consumption of red, unprocessed and processed meat was positively associated with the risk of ischemic heart disease. None of the other animal foods examined were positively associated with this risk. And intakes of fatty fish, yogurt, cheese and eggs were modestly, inversely associated with the risk.

In addition, the red and processed meat were associated with plasma non-HDL cholesterol and systolic blood pressure. And this finding is of interest as possibly these other variables could serve as mediator of the association between red or processed meat and future ischemic heart disease. It is important to note that while these results are of interest to those concerned with the future adverse cardiovascular effects related to the consumption of red meat, one cannot infer causality and other studies would need to be designed to address causal relationships.

The last paper that I'm going to present during the coffee gulp, emanates from the basic science arena. And it is entitled The “Shear-Induced CCN1 Promotion of Atheroprone Endothelial Phenotypes and Arthrosclerosis. And the corresponding author is Dr Fan-E Mo from the National Cheng Kung University College of Medicine.

Dr Gregory Hundley: The matricellular protein CCN1 has been implicated in arthrosclerosis based on its expression in arterial segments with evidence of arthrosclerosis. And this study evaluated the relationship between sheer stress, both laminar and oscillatory at the site of atherosclerotic liaisons and molecular markers of pathophysiologic process involved in the progression of arthrosclerosis.

The authors found that sheer induced CCN1 and its receptor integrin, alpha six, beta one, instigate atheroprone phenotypic changes in endothelial cells via activating NF kappa beta. Because the activation of NF kappa beta further up regulates the expression of CCN1, alpha six, and beta one, atheroprone flow creates a positive feedback to sustain atherogenesis.

In addition, disrupting CCN1, alpha 6 beta one engagement by a specific CCN1 mutation, or by a peptide antagonist unhindered atherogenesis in mice. So what are the clinical implications of these findings? That's something Carolyn would ask me. Well, it appears that CCN1 alpha 6 beta one engagement represents a novel therapeutic target for arthrosclerosis.

These data demonstrate a causative role of CCN1 in atherosclerosis via modulating endothelial phenotypes. And CCN1 binds to its receptor integrin alpha 6 beta one to activate NF kappa beta, thereby instigating a vicious cycle to persistently promote atherogenesis. Perhaps in the future T1 me medics may further be optimized to treat arthrosclerosis.

Well everyone, that concludes the first portion of this June 18 edition of Circulation on the Run and now it's time to move on to Carolyn's discussion of our featured paper.

Dr Carolyn Lam: Cardiovascular disease remains the major cause of death in kidney transplant recipients. And today's featured paper has important implications for the management of this cardiovascular risk following kidney transplantation. I'm so excited to be discussing it, and I'm going to let the corresponding author Dr Toby Coates from Royal Adelaide Hospital tell us all about it, and so happy to also welcome our editorialist Dr Patrick Mark from University of Glasgow.

Toby, could you please tell us what inspired you to do this remarkable study?

Dr Toby Coates: We're very interested in obviously our patients surviving as long as they possible can after kidney transplantation. And we noticed that many of them having had a successful kidney transplant, still had functioning AV fistulas. Now of course the AV fistula, is a connection between the artery and the vein that enabled us to access the circulation after hemodialysis. Which around the world is probably the most, is the most common form of dialysis practice performed.

So many of these patients sustained 20 years down the track after successful transplants still had these very large functioning left to right shunts, on the basis of their dialysis history. So we had a couple of patients who developed quite severe cardiac failure and we noticed that when we ligated the AV fistula, their back got dramatically better.

So, as a consequence of that, we went to look at the ligature and we couldn't find any randomized control trial that told us what the best thing was to do, post-transplant with these fistulas. So we decided that what we would do be use the state of the art cardiac magnetic resonance imaging, or cardiac MRI to assist the cardiac function with myocardium thickness in our patients and then randomize a group of stable transplant patients to ligation or not.

And then follow that up with cardiac MRI six months down the track to see what happened. And so that was the basis of the study that we performed. The first randomized controlled trial of the effect of ligation of the AV fistula on the left ventricular mass, that was the prominent one for trial.

Dr Carolyn Lam: You know, Toby, just to let you know right there, I thought it was so incredibly novel. So I'm a heart failure specialist and we know that shunts are associated with high output cardiac failure, and yet, I personally had never questioned this, so I thought this is incredibly novel and it's important. But please, tell us all about the results.

Dr Toby Coates: We were delighted to say that there was a very significant reduction in the left ventricle mass. In fact, the main decrease was 22.1 grams compared to the control arm in whom the cardiac mass actually went up 1.2 grams. So, then we mobilized the body surface area, the reduction of the left ventricular mass index dropped by 11.8 grams per metered square.

Now, this is quite remarkable for me doing the study because I've never seen an intervention, I've never seen an intervention where every single patient improved with the ligation, every single patient there was an improvement in the cardiac parameters. Never seen anything like it in the pre and post of the ventricular mass it really came down. So that was quite remarkable.

And the second thing that really impressed me at the time, was the improvement in the BMP's, and we measured the brain maturated peptide, and being a methodologist that's clearly something that's of interest to us and we saw a substantial reduction. It's statistically significant reduction in BMP as well.

The patient themselves, some of them recorded quite significant improvement in exercise tolerance afterwards. And we had, as I mentioned before in a couple of patients, not in the study but outside of the study, subsequently when they're presented with profound right heart failure, the ligation of the AV fistula made a huge difference to them symptomatically.

So that was sort of confirming all of the things that we thought along the way. Pleasingly we didn't see any change in kidney function. So, we were concerned that there might have been on the basis of some non-controlled studies in the past, that there might have been a deterioration in the estimated glomerular filtration rate, or eGFR. We didn't see that.

And we didn't see any significant change in the blood pressure either. Which is some of us have previously reported. Closing the fistula itself, is a very trivial procedure. It's usually done as an outpatient, so a day procedure. So it's not resulting in coming to the hospital. And the only complications, really were lots of local redness and some pain, potentially from the fistula where in the ligated.

So, we thought this was remarkable. An outpatient procedure that could significantly reduce the left ventricular mass by 22.1 grams over the six month period that was associated with minimal side effects and complications. And when you think about that, that's sort of equivalent really to taking an anti-hypertensive medication for six months. That magnitude of reduction with ventricular mass which clearly from the patient's point of view is much preferable to adding more medication to an already over-burdened tablet loading in your patients with kidney transplants. So we were very pleased with that result altogether.

Dr Carolyn Lam: Thank you Toby, and we in turn were very pleased to be publishing this in Circulation. Likewise, Patty, if I may, I love your editorial. First, let me tell everybody who's listening out there. Go pick up the editorial and look at the figure. It is so cool. It shows pros and cons of arterial venous fistula ligation in these patients. But could you please share some thoughts Patty? I mean you covered the perspective just so well.

Patrick Marks: I must give the credit to my co-author who actually drew the figure himself. So Chris Eaves rather myself. We were really impressed with the study and we're really delighted to write an editorial for it. It's just one of those studies that I have to say, you know, you kick yourself and you wish you'd done it. With all the world of observational data showing that creation of a fistula appears to be associated with an increase in LV mass obstruction by echo and angio and bicartic MR in smalls studies.

But it's taken a long stat to move from that to actually doing a randomized control of ligating the fistula in people with you know, stable functioning transplants. We were really, really impressed with Toby and his team for undertaking this study. And until we'd gone through the results, they're really very impressive.

The magnitude of reduction LV mass is very impressive and also the changing BMP was really nice to see. One of my comments of the study were, was interesting because as methodologists we are aware of the idea arteriovenous fistula as being the axis for dialysis. And we sometimes feel uncomfortable by ligating this because we know if the transplant was to fail, how much patients need a functioning fistula. And that's the one thing I'm still curious, like and I still offered some comments in the editorial were, that while there's doubt that the cardiovascular benefits demonstrated by Toby's study are really very impressive.

I wondered about the implications out with the study came down the line, you know would there be some of these patients whose kidney transplant function would decline? And there may be regret of losing the access. We mentioned there is some inconvenience, it is an operative procedure to loosen the fistula. So there are some things to think about in the study, but overall, I can't help saying just how impressed I am that they managed to do this trial in a proper randomized, controlled trial form. It's really, really impressive in using the cardiac MR endpoint is it seems quite a secure way of assessing this.

Dr Carolyn Lam: Those are great points, Patty. Toby, any response to that.

Dr Toby Coates: Look it's really very interesting as a transplant pathologist for the last 20 years, one of the biggest, I guess it's a bit of a misconception. When a fistula has been present for 10 or 15 years and still there to come back and try and reuse it for dialysis access after that period of time, in my experience anyway, also very difficult to reuse those fistulas and the surgeons end up having to create a new one anyway.

They frequently become quite aneurismal, they get very large and unsightly and the volume of the shunt is significant and often we find that as an access they don't work as well. So I personally don't have a huge concern about closing them. Now I agree with you, these patients were stable, longstanding and we assessed that the risk is, we need to go back onto hemodialysis was small.

But you are absolutely right, I mean, it is possible that something could have come out of the blue and maybe a patient would be disappointed that that access that they'd had for so many years was no longer available. So that is, the caveat on the study, but thankfully so far out, some of these patients five or six years down the track, we haven't had anybody need to go back on dialysis, so it's been good.

Dr Carolyn Lam: Yeah, it really says to me as well, that patient selection is important exactly like you emphasized, and you, in the editorial Patty. But from a cardiology standpoint, too, are there plans to perhaps do studies with hard, clinical endpoints? What do you think are the next steps? Maybe I'll let Toby go first, then Patty.

Dr Toby Coates: We think now with this study done, the next thing is to have a larger study with significant cardiovascular endpoints. Which I obviously would be cardiac failure and acute coronary events. So the two things that would seem in my mind, and I think that needs to be multi-centered, preferable international if we can.

And one of the really positive things about the highlight from the American Heart Association is that we've had people reach out to us from France and all around the globe saying that they'd be interested in participating, you know in a multi-centered trial. So, I think that's what we need to do, and clearly you don't it’ll have to be a constant endpoint, or not. I'd be interested in Patty's thoughts about that, right if you had some guidelines and some suggestions.

And then obviously would be randomized, controlled trial looking at those hard endpoints with probably some sidearms doing cardiac MRI as well, and potentially more heart functioning tests. So yes, I think this is just the beginning, we do need a hard endpoint trial to really nail this completely.

Patrick Marks: Yeah, I'll just come in there and just come on to that Toby. I completely concur with what you said. I think there's been quite a provocative editorial a few years back, and suggesting that while there's lots of studies in chronic kidney disease, end stage renal disease, kidney transplant patients avoid LV mass, really it hasn't yet been translated into actually leading studies in the integration of LV mass and end stage renal failure haven't really yet translated into mortality benefits.

And I think we need to move to a bigger study. It's really beautiful that you've been able to demonstrate LV mass falls naturally with ligation. And it's impressive that it just happens so consistently across your population in the intervention arm. But we need to move on to a longer trial with hard clinical endpoints. Certainly heart failure, certainly cardiovascular mortality, [be]cause there's plenty of reasons to believe that producing LV mass in these patients might have benefit both for heart failure, whether that's heart failure, heart injection fraction, or whatever, I'll leave that to Carolyn's judgment to help us with that.

But also, if we can reduce LV mass and then we may be able to reduce arrhythmia burden which again is when these things we worry about in end stage renal disease, again, your answer for that is, that in addition to the heart endpoints you should be able to also add in some patient afforded outcomes in a larger study. Or something like an exercise tolerance quota of quality of life.

All this has started has journey from the surrogate endpoint of left ventricular mass into a bigger outcome study and I can't wait to see how you get on with it.

Dr Carolyn Lam: I can't wait either. And I'm sure the audience is sharing all our enthusiasm as well. Thank you so much Toby and Patty. I really learned so much. You heard it right here on Circulation on the Run. Thank you for joining us this week. Don't forget to turn in again next week.

Circulation June 11, 2019 Issue

10 juni 2019 | 21 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summery and backstage pass to the journal and it's editors. We're your co-hosts, I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Gregory Hundley: And I'm Doctor Greg Hundley, Associate editor for Circulation and Director of the Pauley Heart Center at VCU of Health in Richmond, Virginia. Well Carolyn, in the second half of our feature we're going to discuss a randomized clinical trial in lower risked surgical patients related to, the five year clinical echocardiographic outcomes from aortic valve intervention. So Carolyn, do you want to go first this time and discuss on of your favorite papers?

Dr Carolyn Lam: Absolutely! So, are Cardiac Troponin T and I equivalent measures of cardiovascular risk in the general population? Well that's the question Doctor Paul Welsh and colleagues from University of Glasgow aimed to look at. They wanted to compare and contrast the associations of Cardiac Troponin T and Cardiac Troponin I with cardiovascular disease and non-cardiovascular disease outcomes, and also determine their genetic determinants in a genome wide association study involving more than nineteen-thousand, five hundred individuals in generation Scotland, Scottish family health study.

Dr Gregory Hundley: How about that. So this is kind of interesting. So most of us kind of use these two chests interchangeably Carolyn, and I think, I guess we'd consider them to be almost equivalent. So are you going to tell us that they are the same?

Dr Carolyn Lam: Ah-hah! So this is what the authors found. Both Cardiac Troponins T and I were strongly associated with cardiovascular risk, however, Cardiac Troponin I but not T was associated with both myocardial infarction and coronary heart disease. Both Cardiac Troponins I and T had strong associations with cardiovascular death and heart failure, however, Cardiac Troponin T, but not I was associated with non-cardiovascular disease death. They also identified five genetic loci in fifty-three individuals snips that had GWAS significant associations with Cardiac Troponin I and a different set of four loci of four snips for Cardiac Troponin T.

So, the upstream genetic causes of low-grade elevations of Cardiac Troponins I and Cardiac Troponin T appear to be distinct and their associations with outcomes also differ. Elevations of Cardiac Troponin I are more strongly associated with some cardiovascular disease outcomes whereas Cardiac Troponin T, is more strongly associated with the risk of non-cardiovascular disease death. These findings can help inform selection of an optimal Troponin essay for future clinical care and research in these settings.

Dr Gregory Hundley: Very good! So, does sound like there could be a little bit of a difference, depending upon what outcome you're looking for. So, Carolyn I'm going to discuss a paper from Doctor Alison Wright and colleagues at the University of Manchester, and it involves cardiovascular risk and risk factor management in type two diabetes.

So in this retrospective cohort study, using the clinical practice research data link, linked to hospital and death records for people in England, investigators identified 79,985 patients with incident type two diabetes, between the years 2006 and 2013, matched to three 386,547 patients without diabetes, and sex-stratified Cox models were used to assess cardiovascular risk.

Dr Carolyn Lam: Oh I'm dying to know, what did they find?

Dr Gregory Hundley: Well compared to women without type two diabetes mellitus, women with type two diabetes mellitus had a higher cardiovascular event risk than the adjusted hazard ratios 1.2, with similar corresponding data in men, so their hazard ratio is 1.1. And that lead to a nonsignificant relative risk in women with a risk ration of 1.07, however, some important sex differences in the management of risk factors were observed. Compared to men with type two diabetes, women with type two diabetes were more likely to be obese, hypertensive, and have hypercholesterolemia but were less likely to be described lipid lowering medication, ace inhibitors, especially if they had cardiovascular disease. So Carolyn, compared to men developing type two diabetes mellitus, women with type two diabetes mellitus do not have a significantly higher relative increase in cardiovascular risk, but, ongoing sex disparities in prescribing should prompt heightened efforts to improve the standard and equity of diabetes care in women as compared to men.

Dr Carolyn Lam: Nice Greg. Important message. My next one has an important message too. Now it goes to the pediatric population now. We know that brain injury, impaired brain growth, and long term neuro development problems are common in children with transposition of the great arteries. Now does the age at arterial switch operation predict these neuro developmental outcomes in infants with transposition of the great arteries or TGA?

Well Doctor Mike Seed from Hospital for Sick Children in Toronto, Canada and colleges addressed this question by imaging the brains of 45 infants with TGA, undergoing surgical repair, pre and post operatively using MRI. Their main finding was that surgery beyond two weeks of age is associated with impaired brain growth and slower language development in infants with TGA.

Dr Gregory Hundley: Wow Carolyn, this seems like, this could have really important clinical implications for the management of these patients.

Dr Carolyn Lam: Yeah, indeed. Expediting surgical repair could be neuro protective in newborns with Transposition. While the mechanisms underline this association are still unclear, extended periods of cyanosis and pulmonary over circulation maybe factors that inversely impact brain growth and subsequent neurodevelopment if the surgery's not done early. The timing of surgery may have an impact on neurodevelopment in other forms of congenital heart disease, too, therefore. So all of this is discussed in an editorial entitled Correction of TGA, "Sooner Rather than Later?", and this is by Doctors Rollins and Newburger, from Boston's Children's Hospital.

Dr Gregory Hundley: Fantastic Carolyn, well I'm going to discuss a paper from the World of Basic Science from the Ohio State University, Wexner Medical Center from Doctor Douglas Lewandowski. And it involves the preservation of Acyl-CoA and how that attenuates pathological and metabolic cardiac remodeling through selective lipid trafficking. So Carolyn, it has been shown that metabolic remodeling in heart failure contributes to dysfunctional lipid trafficking, and lipotoxicity. Acyl-Coenzyme A Synthase One, or ACLACSL1 facilitates long chain fatty acid uptake an activation with coenzyme A, mediating the fate of the long chain fatty acids. The authors tested wither cardiac Acyl coenzymes A synthase One over-expression aided long chain fatty acid oxidation and reduced lipotoxicity under the pathologic stress of transverse aortic constriction or TAC.

Dr Carolyn Lam: Interesting, I like that concept of metabolic remodeling. So what did they find?

Dr Gregory Hundley: So Carolyn, the studies were performed in both mice and in human subjects, and in mice at 14 weeks, TAC induced cardiac hypertrophy and disfunction was mitigated in MHCACSL1 hearts compared to nontransgenic hearts. This was manifest by retain greater rejection fraction, 65.8 percent versus the nontransgenic hearts of 45.9 percent. An improvement in diastolic E over E prime. Also, functional improvements were mediated by ACSL1 changes to cardiac long chain fatty acid trafficking. In humans, long chain Acyl-CoA was reduced in human failing myocardium and restored to control levels by mechanical unloading.

So, Carolyn, this is the first demonstration on reduced Acyl-Co-A in failing hearts of humans and mice, and suggest possible mechanisms for maintaining mitochondrial oxidative energy metabolism by restoring long chain Acyl-CoA through ASCL1 activation and mechanical unloading.

Dr Carolyn Lam: Awesome Greg! Thanks so much for sharing that paper. Let's go on to our feature discussion.

Dr Gregory Hundley: You bet.

Dr Carolyn Lam: Our feature discussion today is about transcatheter aortic-valve replacement. Could this be the new gold standard for the treatment of aortic stenosis? And yes, I am borrowing from the title of the editorial that accompanies our feature paper. With the editorialists right here with us, Dr Bernard Prendergast, from Saint Thomas' Hospital in London, and we are talking about the wonderful paper for the notion trial and that's a Nordic aortic valve intervention randomized clinical trial, and we're here with the first and corresponding author of that paper Dr Hans Gustav Thyregod from Copenhagen University Hospital, and we also have our associate editor Dr Dharam Kumbhani from UT Southwestern. So welcome gentlemen! And for a start could I ask Hans to please describe the results of the notion trial.

Dr Hans Thyregod: The notion trial as you said is the Nordic aortic valve intervention trial. Designed to compare transcatheter therapy and surgical therapy and patients with severe aortic valve stenosis, patients have to be thirteen years old or older and we didn't really specify any risk profile, as in previous trials. So all patients eligible for both procedures would be enrolled in the trial. And the main result of the trial was that we couldn't find a difference when looking at the composite outcome, which was all-cause mortality, stroke American infraction.

The primary outcome was after one year, in this paper it's up to five years and we could not see any difference. So the range was, in my estimate was 38 percent for transcatheter therapy versus 36.3 percent for surgery. And when looking at the different components of this composite outcome, all-cause mortality, stroke American infraction. We couldn't find any surgically significant difference for any of those outcomes either.

Dr Carolyn Lam: Wow, Bernard, could I ask you to place these results into context for us, I mean the notion trial is after all the first to compare TAVR and SAVR in patients with severe isolated valve stenosis at lower surgical risk, and really has the longest follow-up doesn't it? So please tell us, what are your thoughts?

Dr Bernard Prendergast: So this is yet another notch the remarkable success story of TAVI or TAVR, as you call it in the U.S. We pass our congratulations from the community to Dr Thyregod and the team in Copenhagen for such a ground-breaking study. The wider context is he say is the TAVR have demonstrated remarkable efficacy and safety, initially in operable and high-risk patients, but, more recently randomized control trials in intermediates and lower risk patients. And the important perspective of this study provides is the longer term follow up, because for a number of years we've perhaps considered TAVI or TAVR as a, let’s say a shorter-term treatment for patients in their eighty's and older, who perhaps have a shorter life expectancy. But what the five-year data demonstrates to us is that TAVI or TAVR is as good as surgery, at five years of follow up. With very reassuring outcomes, they maintain durability of the transcatheter heart valve, that's highlighted in the companion paper, which, is published very recently in JACC.

So really takes TAVI into a new territory, which is patients who have at least five years or longer to live and allows us to extend the indication for the procedure into younger patients. Alongside lower risk patients, who have supported by the recent landmark studies published in the New England Journal from Partner Three, and the Core Valve Low Risk trial. So, the information is very reassuring and it's another very positive notch in the journey of TAVI across the spectrum of surgical risk.

Dr Carolyn Lam: Thank you! Beautifully put and Dharam could I just ask you I mean what more do we need? Do you think this is guideline defining stuff now? Or do you have questions?

Dr Dharam Kumbhani: I really want to congratulate the investigators of the NOTION trial, as far as providing us with this longer term follow up in a lower risk population, and so, you know the field is moving incredibly, incredibly quickly and you know as we just mentioned TAVR has now gone from being something that's done in patients that are too high risk to level convention surgery, to now perhaps becoming either one of the main stream options, or the main stream option. And you know time will tell, so I think what this study really helps us is, provide us with a five-year time horizon on follow up, but, to be fair, you know this trial is very helpful in certain ways because it was designed a few years ago. You know it was done with the generation of a valve that is not used much right now for the most part, and you know so it's some of the things like pacemaker et cetera, may not translate to current practice.

Even though the clinical outcomes were similar, it's probably some issues with power as well, but, again not in a clinical way, but, just to kind of say that this trial definitely helps us in moving the field forward and it kind of adds to the growing body of literature that supports that. Going forward I guess one question I would have for this group is, you know as we think about TAVR and surgical aortic replacement, it would seem that we would need even longer term data, based off of detonators to be able to confidently tell patients, there are fairly similar therapies.

And then the other question is, this construct of surgical risk is that we applied telegraphically based on how the evolution of TAVR has occurred, but one wonder, you know with NOTION and other trials we should be thinking about this perhaps from an age perspective as a sort of NOTION trial—those would be my two comments.

Dr Bernard Prendergast: I think that's a very valuable comment, and of course there are other ongoing trials, which, will help to address many of these questions. One important deficit of notion is that it didn't enroll, for example, patients with bicuspid aortic valves. And we know that bicuspid aortic stenosis is far more common in younger patients. So, Hans a few comments regarding the protocol for notion two maybe helpful for our listeners.

Dr Hans Thyregod: Well this was mentioned, the follow up of five years is obviously not a very long time in younger patients with a lower risk profile. We are planning to follow these patients for at least 10 years. And the other comment about the risk profile of the risk certification of patients is also very interesting because the SDS and your scores have been developed for surgical patients and not for transcatheter patients. So we need a whole new transcatheter risk scoring system to help our team determining what treatment would be the best suited for each patient.

And as Dr Prendergast mentioned we are in Copenhagen, and Scandinavia conducting a NOTION II trial, which, will enroll patients younger than the previous low risk trials and also the notion trial. Which, at a mean age, at least for the patient of around 80 years and in notion two patients must be younger than 75 years old. And we are also including patients with bicuspid valve stenosis, and also patients which were not included in the NOTION I trial. Patients with a coronary artery disease, so these patients are obviously also a different patient category and will maybe require a different approach regarding the timing of the revascularization and so forth so there is more research to be done in those areas.

Dr Carolyn Lam: Well exciting. Thank you for sharing that Hans. Dharam could I ask you to just wrap us up with the take home message, it's for our audience right now.

Dr Dharam Kumbhani: For me one of the most interesting findings was that in five years, the clinical performance between TAVR and SAVR were similar, but, more importantly the valve performance, the hemodynamic performance was the same, and perhaps slightly better with the self-expanding design. They are so proud of the self-expanding design that was studied in the study. So that is helpful because as we discussed earlier, I think a lot of the controversy discussions centers around the long-term durability of TAVR compared with surgically aortic valve replacement, so that is a step in the right direction. The same investigators have published that hemodynamic performance elsewhere as well, sot that's I think the number one take home message that, that's very, very reassuring. The second thing is you know this study shows us it adds to the growing body of literature, in lower risk patients so all of this was not strictly a lower risk trial based on contemporary definition.

It was definitely a lower risk population and so, this is the largest pool of patients where they aortic stenosis about 50 percent will have low risk aortic stenosis, low surgical risk aortic stenosis and so this is very helpful in that space and then third you know that this is very exciting that NOTION investigators indeed are the low risk trial investigators, will be extending their follow up with 10 years. So I think in this next decade, most people expect as Dr Prendergast also mentioned, we'll see a gradual change perhaps in how patients with aortic stenosis manage. But, I will add a word of caution, I think in the current era, the way things stand right now, it's probably best in favor to appeal to what the guideline indicates. And for the low risk patients, surgical aorta valve replacement is still the center of choice.

Dr Carolyn Lam: Thank you so much Dharam and thank you Hans for the beautiful paper, and Bernard for that excellent editorial!

Thank you audience for joining us today, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation June 04, 2019 Issue

3 juni 2019 | 26 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, Associate Editor for Circulation and Director of the Pauley Heart Center in Richmond, Virginia at VCU Health.

Dr Carolyn Lam: So Greg, ever wondered if prophylactic use of ICDs would help prevent sudden cardiac death in dialysis patients? Well, guess what? We're going to be discussing it in the feature discussion of the ICD II trial coming right up. First, I hear you've got a very interesting probabilistic paper.

Dr Greg Hundley: Yes. It's very sweet. This is from Renata Micha at Tusk University and it's examining the cost effectiveness of the US Food and Drug Administration added sugar labeling policy for improving diet and health. So Carolyn, in this study, investigators used a validated micro simulation US impact food policy model to estimate cardiovascular disease and type II diabetes mellitus cases averted, quality adjusted life years, policy costs, health care, informal care, and loss productivity in health related savings and cost effectiveness of two different policy scenarios.

First, the implementation of the US Food and Drug Administration added to your labeling policy or just the sugar label. And second, further accounting for corresponding industry reformulation the sugar label plus reformulation. The models used nationally represented demographic and dietary intake data from the national health and nutrition examinations survey and diseased data from the centers for disease control and preventive wonder data base and policy affects in diet disease effects from meta-analysis and policy and health related costs from established sources. Probabilistic sensitivity analysis accounted for model parameter uncertainties and population heterogeneity.

Dr Carolyn Lam: Sweet indeed, so tell us all about probabilistic analysis Greg.

Dr Greg Hundley: Okay Carolyn, so between 2018 and then forecasting out into the future, so this is probabilistic, in the year 2037. The sugar label would prevent 354,400 cardiovascular disease cases, and 599,300 diabetes mellitus cases, gain 727,000 quality adjusted life years, and save 31 Billion dollars in net health care costs. Or 61.9 Billion dollars in societal costs incorporating reduce loss productivity and informal care costs and similar findings were accomplished for the sugar label plus reformulation scenario, both scenarios were estimated with greater than 80% probability to be cost saving by the year 2023.

Thus, the results of this simulation exercises indicated that implementing the FDAs added sugar labeling policy could generate substantial health gains and cost savings for the US population particularly if the new label stimulates industry reformulation. The authors point out that the compliance date for updating the nutrition facts label including the added sugar perversion has been continuously delayed. And the authors believe, their findings highlight the need for timely implementation of this label so as to maximize health and economic gains.

An excellent editorial was written by Elizabeth Magnuson at Saint Luke's Mid America Heart Institute revealing the strengths of this work and explains some of the variants that could occur in the results based on assumptions that were used in the authors micro simulation model.

Dr Carolyn Lam: That is so interesting Greg, thanks. So from policy to guidelines and this time on cardiopulmonary resuscitation or CPR, now we know that an out of hospital cardiac arrest, chest compression only CPR has emerged as an alternative to the standard CPR where we use both chest compressions and rescue breathes. Since 2010, CPR guidelines recommend chest compression only CPR for both untrained bystanders and trained bystanders who are unwilling to preform rescue breaths.

The current study really aimed to describe the changes in the rate and type of CPR perform before the arrival of emergency medical services doing three consecutive guideline periods with gradual adoption of compression only CPR and this was in Sweden. Now these were authors led by Dr Hollenberg from The Center of Resuscitation Science, Karolinska Institute in Stockholm, Sweden and colleagues and basically, they study all bystander witness out of hospital cardiac arrest reported in the Swedish register for CPR from 2000 to 2017. They found that there was a six fold higher proportion of patients receiving compression only CPR and a concomitant almost double rate of CPR before emergency medical services arrival, and these changes occurred over time. Any type of CPR was associated with doubled survival rates in comparison with cases not receiving CPR, and this association was observed in all time periods studied. They also found a small but significantly higher chance of survival after CPR with compression and ventilation in comparison with compression only CPR.

Dr Greg Hundley: So Carolyn, does this mean we should go back to standard CPR?

Dr Carolyn Lam: Well, remember these we observational findings, albeit really amazingly done and nationwide. But the findings really support continuous endorsement of the compression only CPR as an option and that's because its associated with higher CPR rates and overall survival of the no CPR skill. The authors ended up calling for randomized controlled trials, which are really needed to answer the question of whether or not CPR with compression and ventilation is superior to compression only CPR, especially in cases where bystanders have had the previous CPR training. Now, this is discussion in a wonderful editorial by Drs. Hsu and Neumar from University of Michigan Medical School.

Dr Greg Hundley: Very nice, so you're going to tell us a little bit about troponin?

Dr Carolyn Lam: Well, the question is "Is Plasma Troponin I measured by the high sensitivity assay associated with incident cardiovascular disease in the community?" Well, Dr Ballantyne from Baylor College of Medicine and colleagues decided to answer this question by looking at the ARIC Study participants age 54 to 74 years without base line cardiovascular disease and what they found was that elevated high sensitivity troponin I was strongly associated with increased global cardiovascular disease incidents in this general population, and this was independent of traditional risk factors. They also found differences between black and white individuals and between men and women.

Dr Greg Hundley: What kind of differences?

Dr Carolyn Lam: Well high sensitivity troponin I had a stronger association with incident global cardiovascular disease events in white compares to black individuals and a stronger association with incident coronary heart disease in women than in men. The authors also did a comparative association of high sensitivity troponin I vs. troponin T, they found that the high sensitivity troponins I and T show only moderate correlation with each other but were complementary rather than redundant in risk assessment for incident cardiovascular events in individuals without known clinical cardiovascular disease at base line. The bottom line is, adding biomarkers to traditional risk prediction models presents a potentially effective approach for future risk prediction algorithms for cardiovascular disease in the general community.

Dr Greg Hundley: You know, think I might read that paper looking at that complimentary risk assessment. That sounds really interesting Carolyn. Well, I'm going to go back to the world of basic science and discuss a paper from Kun Wang discussing the long non encoding RNA regulation of cardiomyocyte proliferation and cardiac repair. Carolyn, post mitotic cardiomyocytes in the adult heart exit from the cell cycle and cease to proliferate, and that's the basis for their poor regenerative capacity and defective repair in response to say a myocardial infraction. Interestingly, the nonmammalian vertebrates such as our friend the zebra fish, their heart exhibits a robust capacity for regeneration. And it can efficiently regenerate its lost cardiac tissue throughout life due to this retain cardiomyocyte proliferation capability.

Dr Carolyn Lam: Interesting indeed Greg about our friend the zebra fish. So what did the authors find?

Dr Greg Hundley: Okay, in this study, Wang and associates investigated whether long non-encoding RNAs had a role in the regulation of cardiomyocyte proliferation and cardiac repair. Using bioinformatics and initial analysis, the identified a long coding RNA named Cardiomyocyte Proliferation Regulator or CPR that was comparatively higher in the adult heart as opposed to hearts in the fetal stage. The silencing of the Cardiomyocyte Proliferation Regulator or CPR significantly increased the cardiomyocyte proliferation in the postnatal in adult hearts, more over CPR deletion restored the heart function after myocardial injury which was evident from increased cardiomyocyte proliferation, improvement of myocardial function and reduce scar formation. Also, neonatal cardiomyocyte proliferation in cardiac regeneration where markedly suppressed in CPR overexpressing heart cells, therefore CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration in fetal hearts.

So, Carolyn the conclusion of this paper is that the inactivation or silencing of CPR accelerates cardiomyocyte proliferation along with significant restoration of cardiac structure and function after myocardial injury in adult hearts. And as such, further studies may investigate whether the therapeutic inter fashion of CPR could be a useful strategy to trigger the expansion of cardiomyocyte populations and myocardial repair.

Dr Carolyn Lam: Nice Greg, so we've talked about CPR as in Cardiopulmonary Resuscitation to CPR as in Cardiomyocyte Proliferation Regulator, how about that? Well, that's as much as we go for now, let’s get to our feature discussion.

Dialysis patients are known to have a high mortality rate, a large proportion of which have been attributed to sudden cardiac death and yet compared to patients with heart failure, these patients with dialysis have been either excluded or only nominally enrolled in all previous trials of implantable defibrillators or ICDs. Now that's why our feature paper this week is so important, and it is the Cardioverter-Defibrillator in the prevention of sudden cardiac death in dialysis patients that prospective randomized controlled ICD to trial. So pleased to have with us, the corresponding author Dr Wouter Jukema from Leiden University Medical Center as well as associate editor Dr Mark Link from UT South Western to discuss this very important paper. Wouter, congratulations, this is a very difficult, very important to do the study though, could you tell us a bit about what you did and what you found?

Dr J. Wouter Jukema: Actually, you just referred to it as a very difficult study to perform and indeed it was. Many years ago, actually, twelve years ago, we noticed that now a lot of death in dialysis patients was attributed to sudden cardiac death, before we tried to make these type of patients better with all types of medications, but did not really work and suddenly the idea was, that came also from death certificates and death records that they have sudden cardiac death and we said we should monitor it and we should treat it in a prospective randomized study. We initiated the study after careful thoughts and we thought we would do it in 4-6 years but it took us 12. So it was quite an effort to set up this rightly and spread it around the Netherlands and activate a Nephrologist and a Cardiologist to take part in this prospective randomized controlled study in dialysis patients.

Of course, you can easily imagine that you could have great benefit from this ICD devise, but you could also easily imagine that you would have complications of the implication of the device. So explaining that we should show it out, I think was the most important job we had to do and think that was a great effort, and it was not easy to do.

Dr Carolyn Lam: And that in it of itself is very important observation.

Dr Mark Link: So you picked patients without doubts, which is great I mean this is a difficult study, but you also picked with an LDF greater than 35% and traditionally, ICDs are indicated for under 35%, can you give us a little explanation on why you chose the greater than 35% population?

Dr J. Wouter Jukema: Yeah, I think this is perhaps the most important remark on the study, because when we designed the study we had to choose at that time we had guidelines in general that under 35% of injection fraction you were entitled to receive an ICD, however of course almost never dialysis patients were included so there was no formal recommendation on that not to include them or not to exclude them, but dialysis patients have a death rate at that time to sudden cardiac death, anyway regardless of the injection fraction and we thought okay, the patient population that is first at high risk of sudden cardiac deaths so any dialysis patients but also they are entitled to have a meaningful extension of the lives because the prognosis of patients that are on dialysis with an injection fraction under 35% is in general so poor that it would be unfair to start there and most of the Nephrologists also would not allow it anyway, these patients are at the end of life and if you extended for two or three months its useless.

Anyway, so we thought we'd pick the high-risk population and we prove that there were still on high risk but when we could do something meaningful to extend their lives, so we thought we do not pick the worst patients we pick the patients that we think we can really help. We screened them well, we treated them well and we see if an ICD on the patient will benefit them. And that's why we picked the over 35% rage. You need another study to do below 35%, but I don't think that our results are substantiating such an effort.

Dr Mark Link: The population with EFs was 6-50%, which also has a high risk of sudden death in patients with dialysis but it’s still not looking with the population of less than 35%.

Dr J. Wouter Jukema: No, I completely agree, and we acknowledge that in the manuscript, it was always in the manuscript within the revision that was also pointed out to us that it should be more clearly acknowledged, why we choose this patient population and finally, we can of course not make a formal recommendation on dialysis patients with an injection fraction of less than 35%. You can extrapolate data but we have no formal prof of course for this type of population. I fully agree.

Dr Carolyn Lam: Before we go further, could you first describe, what did you find?

Dr J. Wouter Jukema: Basically, the conclusions are the prophylactic ICD therapy in patients on chronic dialysis with an injection fraction of 35% or higher was not associated with a reduced rate of sudden cardiac death nor of all cause of mortality and besides that the preference of sudden cardiac death in this type of patients on dialysis was actually significantly lower compared to its reports from literature, so that's what we very often see of course if you fill out a death certificate, you have to fill out a cause of death and of course in many patients the heart stops, and you say it's a sudden cardiac death. But that's not what this study actually showed and finally it's also no authority that this population was not too healthy to see any benefit, if you look at the results over the years, then you'll see that after five or six years more than half of the patients are dead anyway, but due to all kind of causes and not to a sudden cardiac death.

So, I think that this is from a pathophysiological background, this is also a very interesting study because we now have finally data, real data on sudden cardiac deaths in these types of patients.

Dr Carolyn Lam: Indeed, and Mark, I know that you invited the editorial from Rod Passman, just discussing why did we see the results that we did. Not quite what we expected I suppose, what do you think Mark?

Dr Mark Link: First, I want to congratulate Dr Jukema for finishing this study, this was a massive task and a difficult and long one. I think I was surprised, there has been reported to be a very high rate of sudden death in dialysis patients regardless of their LDF. The ICD is very good at preventing sudden deaths, but not good at preventing other types of deaths, so I would extrapolate to say, well you can prevent sudden death in dialysis patients, you should prolong their life and this study did not show that at all. And I was surprised, and it just goes to what Dr Jukema was telling us, that what's reported on a death certificate as sudden death is not necessarily sudden death and could be other types of death and at the end all death is sudden.

Dr J. Wouter Jukema: I fully agree with that remark because that makes is cumbersome to have the right interpretation of the data, so you have to feel like something and then finally your heart stops.

Dr Carolyn Lam: What seems that most of the reasoning seems to be maybe a lower rate of sudden cardiac death than we expected, but there were also other factors that were considered, for example, if you could clarify by dialysis did you mean both hemodialysis as well as peritoneal dialysis, do you think that made a difference? For example, do you think ICDs work differently in presence of uremic precipitant of arrhythmias vs. not and so on, what do you have to say about those factors?

Dr J. Wouter Jukema: We include on purpose both types of patients, the peritoneal dialysis and the hemodialysis patients because you could easily in-visit that there could be a difference, for instance to fluid or electrolyte sheaths that are more sudden in the hemodialysis patients than in peritoneal dialysis and we did a sub-analysis where we looked at both types, but the results are essentially the same, it doesn't seem to matter a great deal of what type of dialysis you have, the amount of sudden cardiac is lowered and expected. By the way occasionally, of course the ICD did work in sudden cardiac death, was aborted. So, it’s not that the apparatus doesn't function it does, it takes it properly and if functions properly. But finally, it doesn't prolong the life and you will die of something else, mostly infections in general well-being when finally, the nephrologist will say this is end of life you have to stop the dialysis procedures anyway.

Dr Carolyn Lam: Right, great points, now in the last few minutes, I'm dying to ask, what do you think of the next steps from here. Mark, what do you think first? And then perhaps I'll give the last word to Wouter?

Dr Mark Link: I'll start with a question to Wouter myself, the question is what are we going to do now with the individuals on dialysis that are under 35%? I think this study has pretty clearly said that were not going to extend our CDs to people on dialysis with greater than 35%. But we still have a population that currently fits indication for a ICD if their expected longevity is greater than a year. And currently those people are included in the guidelines for ICDs, I think this study gives us some pause about what to do with our population. And many of that population are getting our CDs and I'd be curious to what Dr Jukema thinks about that population and whether that population warrants some randomized trial or whether we should continue with our current guidelines that recommend implantation of an ICD in any individual less than 35%, as long as their expected life span is greater than a year.

Dr J. Wouter Jukema: I think these are excellent questions with excellent remarks, of course, finally, we do not know because we didn't investigate it, I can only imagine the difficulties we would have if we were to do a new additional trial with injection fractions patients less than 35%. I could tell you we had great great difficulty in persuading Nephrologists to take part in the study, because many of them were very reluctant, this is their principal, these are very ill patients, and a lot of them are more or less going towards the end of their lives so you cannot do this when we have Nephrologists telling us that they considered it an unethical study. A lot of them did not want to participate they said, "You shouldn't do this to this patient, they have troubles enough, they suffer from infections and all kinds of things."

Having said this, I do not advocate that you should never implant an ICD in a dialysis patient, I think in our study we also clearly show that in dialysis patients, implantation of an ICD is feasible within acceptable although better complication risk and infection risk, so if you have a patient on dialysis where you feel this patient has a good life expectancy, for instance, he already suffers an episode of arrhythmia, I think you are entitled to discuss this with the patient and have it a try, it might work and prolong their life. So I would not say never do it, I think our studies show that you can do it, yes, it sometimes works but do not expect too much of it. You will never hear me say that in general you should not do it, if you have a clear indication for it you may do it, secondary effect may require a good reason, but primary prophylactic indication, that's a difficult one I think and to do this study in patients that are even more ill, with injection fraction of less than 35%, I feel will be exceeding the difficult.

Dr Mark Link: One other comment I have is the issue of the SUBCU ICD I think changes the equation in a bit because the risk of infection is much lower with a SUBCU IDC in patients on dialysis, did you have any SUBCU ICDs in your study or was it all transvenous?

Dr J. Wouter Jukema: We don't have any data, when we designed and the developed study, the such a device was not even there so we couldn't do that, and during the study we did not adapt that but of course there is also no formal proof yet that it's a lot safer, a lot better, and once again this time of subcutaneous ICD I think you can do it at an acceptable complication rate. But it’s not effective enough, it's not that the patients were dying from infections of their ICD, they were dying of all kinds of infections and malignancies. Infections due to the ICD were facing procedures, real complications were rare.

Dr Carolyn Lam: Great! Thank you Wouter, thank you Mark, what an important study and what a lot of lessons that we learned here.

Thank you very much audience for listening as well, you've been listening to Circulation on the Run, don't forget to tune in again next week.

Circulation May 27, 2019 Issue

27 maj 2019 | 31 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from The National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today?

Dr Greg Hundley: My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes.

As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation.

Dr Carolyn Lam: Interesting, so what did they find, how did they do this?

Dr Greg Hundley: Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription.

Dr Carolyn Lam: And so? What did they find?

Dr Greg Hundley: Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes.

So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings.

So, Carolyn, how about your next study?

Dr Carolyn Lam: Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial.

Dr Greg Hundley: Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us?

Dr Carolyn Lam: Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment.

Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine.

So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group.

Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension.

Dr Greg Hundley: Wow, so we're getting back toward renal denervation? How about that?

Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner.

Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure.

Dr Carolyn Lam: Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes?

Dr Greg Hundley: The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice.

The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis.

So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy.

Dr Carolyn Lam: Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells.

So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz?

Dr Greg Hundley: You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us?

Dr Carolyn Lam: Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice.

Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice.

So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands.

So, Greg, interesting stuff, huh?

Dr Greg Hundley: You bet! Let's go on and here a little bit more about diabetes.

Dr Carolyn Lam: And dapagliflozin coming right up.

Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern.

All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please?

Dr Stephen Wiviott: So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention.

Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke.

And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation.

Dr Carolyn Lam: Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis?

Dr Eri Kato: So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF.

So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints.

There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction.

Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF.

So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events.

And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction.

So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction.

Dr Carolyn Lam: Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined?

Dr Eri Kato: We collected data at the baseline and the heart failure was collected based on the medical record.

Dr Carolyn Lam: So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds?

Dr Darren McGuire: First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction.

And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications.

So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results?

Dr Carolyn Lam: Subodh, I'm going to let you go first.

Dr Subodh Verma: First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE.

I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other.

So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure.

So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents.

But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically.

Dr Carolyn Lam: Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials.

But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find?

Dr Stephen Wiviott: I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke.

In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population.

So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure.

And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI.

And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction.

Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction.

Dr Carolyn Lam: Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next?

Dr Darren McGuire: I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients.

And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes.

Dr Carolyn Lam: Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you?

You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week.

Circulation May 21, 2019 Issue

20 maj 2019 | 26 min

Dr Greg Hundley: And I'm Greg Hundley, Associate Editor of Circulation and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article is going to focus on trastuzumab-induced cardiac dysfunction in breast cancer patients. We will discuss with Stanford investigators their use of pluripotent stem cells that are differentiated to cardiomyocytes and subsequently exposed to toxins to determine an individual's susceptibility to cardio-toxicity from cancer treatment. But before we get to that, Carolyn, do you have a paper that you'd like to discuss?

Dr Carolyn Lam: Well, the first paper deals with cardiac biomarkers and asks the questions, can these biomarkers be useful for the diagnosis and risk stratification of syncope?" Now, this paper is from Dr Mueller and colleagues from University of Hospital Basel in Switzerland. They evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, high-sensitivity cardiac troponin T, and high-sensitivity cardiac troponin I concentrations, alone and against the ones of clinical assessments in more than 1,500 patients presented with syncope to the emergency department in a prospective, diagnostic multi-center study. Now, cardiac syncope was adjudicated in 234 or 15% of patients. What they found was that the diagnostic accuracy from cardiac syncope, as quantified by the area under curve, was 0.77 to 0.78 for all four biomarkers. That was superior to that of the syncope-specific diagnostic score, EGSYS.

Now, combining the four biomarkers further improved diagnostic accuracy to an area under curve of 0.81. Furthermore, using the four biomarkers at cutoffs achieved predefined thresholds for sensitivity and specificity and allowed rule-in or rule-out of 30% of all patients. Finally, the biomarkers predicted adverse cardiac outcomes with moderate to good prognostic accuracy and better than some of the existing syncope risk-prediction scores.

Dr Greg Hundley: Very interesting, Carolyn. Do you think we can now use this clinically? Should we be drawing these biomarkers on patients with syncope?

Dr Carolyn Lam: These results really do imply that these biomarkers look like useful tools for the early rule-out and/or rule-in of cardiac syncope in the emergency department. After all, these biomarkers are readily available, inexpensive, and results of this study suggest that they have potential to simplify diagnosis and to risk stratify in challenging presentations. However, before embracing the concept of ordering cardiac biomarkers routinely for syncope presentation, we really need to read the editorial by Dr Sandhu and Sheldon, in which important perspectives are presented, such as considerations of the certainty of the diagnosis of syncope, the usefulness of the comparative scores, the timing of testing, the potential unintended adverse consequences of testing. These editorialists concluded that, although promising, further work is needed to determine how the use of cardiac biomarkers should be incorporated into a risk-stratification algorithm.

Dr Greg Hundley: Wow, Carolyn. It sounds like we'd get a lot out of that particular editorial. I'm going to switch over and talk about NT-proBNP in patients with pulmonary hypertension. This is a paper from Dr Kelly Chin from UT Southwestern, and the study evaluated the utility of end terminal pro BNP level thresholds and assessing prognosis in pulmonary hypotension using the GRIPHON study. So GRIPHON is a global double blind, randomized placebo control event driven phase 3 study which assesses the safety and efficacy or a Prostacyclin agonist that promotes pulmonary arterial vasodilation.

They performed the study in patients that were 18 to 75 years old with a diagnosis of idiopathic pulmonary hypertension, heritable hypertension or pulmonary hypertension associated with connective tissue disease, repaired congenital systemic pulmonary shunts, HIV infection, drug use or toxin exposure; and the diagnosis of pulmonary hypertension was confirmed by right heart catheterization and by a reduced 6-minute walk distance of 50 to 450 meters.

Eligible patients were permitted to take their other therapies including Endothelin receptor agonists and phosphodiesterase type-5 inhibitors. The patients were categorized into low, medium and high in terminal BNP level subgroups according to two thresholds. First, by just the tertiles within the study overall and the secondly by the ESC guideline cutoff ranges.

Dr Carolyn Lam: Nice, so what did they find Greg?

Dr Greg Hundley: Well first of all both thresholds either the tertile one of the ESC in follow-up NT-proBNP categories were highly prognostic for future morbidity and mortality. And their time dependent analysis the risk of experience a morbidity or mortality even was 92% and 83% lower in the treated patients with a low and medium NT Pro BNP level. And 90% and 56% lower in placebo treated patients with low and medium NT-proBNP levels. So both, whether you're taking that drug of not, the NT-proBNP levels were prognostically valuable. More pronounced treatment benefit of selexipag was seen in the medium and low proBNP groups. There was a positive value for the interaction term.

Dr Carolyn Lam: Wow, sounds like two really important findings.

Dr Greg Hundley: Yes, exactly Carolyn. So first, NT-proBNP levels are highly prognostic for pulmonary arterial hypertension progression. And having NT-proBNP in the low range, by improving to or maintaining low NT-proBNP levels is a clinically relevant treatment goal for those with pulmonary artery hypertension. And of course as we described this was a very diverse well represented group of many different types of patients with pulmonary hypertension. Then second, while selexipag the study drug was beneficial in all NT-proBNP categories, the treatment effect was greater in those with low and medium categories versus the very high. Suggesting that earlier selexipag treatment may be of greater benefit. But very interesting biomarker study that follows up on yours Carolyn.

Dr Carolyn Lam: Indeed!

Dr Greg Hundley: Carolyn what about your next paper?

Dr Carolyn Lam: Well I want to switch tracks now and talk about iron. And the question is, how does intravenous iron repletion augment exercise capacity in chronic heart failure? Even if hemoglobin doesn't change. So, first some background right, now, besides hemoglobin it's important to recognize that iron is an obligate component of the mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. So dynamic phosphorous magnetic resonance spectroscopy is a noninvasive tool that can really quantify the in vivo muscle energetics by measuring the kinetics of phosphocreatine recovery after exertion. These authors use this technique, and these are Dr Okonko from King's College, London British Heart Foundation sender of excellence, school of cardiovascular medicine and sciences. The James Black Center in London and colleagues. And what they did was they tested the hypothesis that intravenous iron repletion in chronic heart failure would enhance skeletal muscle energetics as reflected by a shorter phosphocreatine recovery halftime on phosphorous magnetic resonance spectroscopy imagining of the skeletal muscles. And they looked at 40 patients with chronic heart failure with reduced deduction and iron deficiency in a randomized double blind placebo controlled ferric iron and heart failure trial.

Dr Greg Hundley: So, what did they find?

Dr Carolyn Lam: They found that a single total dose infusion of intravenous iron repleted iron stores and augmented skeletal muscle energetics at 2 weeks post infusion. Enhancements in the skeletal muscle energetics which implied better mitochondrial function were accompanies by improved symptoms despite no change in hemoglobin at 2 weeks. So, this trial really provides mechanistic support for iron repletion in patients with chronic heart failure and its very importantly discussed in an editorial by Peter van der Meer, Haye van der Wal, and Vojtech Melenovsky. And I really suggest that everybody read that.

Dr Greg Hundley: Well, I'm going to talk a little bit about dietary omega-6 fatty acids and the incidence of cardiovascular disease and mortality. And this paper is from Matti Marklund from the Georgia Institute for Global Health and the University of New South Wales in Sydney, Australia. The study focuses on linoleic acid which is an omega-6 polyunsaturated fatty acid that we get from pumpkin seeds, flax seeds, walnuts, soybean oil, canola oil and grapeseed. It's been associated with a decrease in cardiovascular risk, but others have worried about an effect of consumption mainly the downstream production of arachidonic acid which can give rise to eicosanoids that are both pro inflammatory and pro thrombotic.

And it's interesting Carolyn, several organizations suggest replacing saturated fat and carbohydrates with linoleic acid. So this study was really performed to address whether consumption of linoleic acid is associated with future cardiovascular events. In the study, investigators measured linoleic acid as well as arachidonic acid levels and from a global consortium across 30 perspective observational studies from 13 countries they performed multi variable adjusted associations of circulating an adipose tissue linoleic and arachidonic acid biomarkers with incident total cardiovascular disease and subtypes of cardiovascular disease including, coronary heart disease, ischemic stroke and cardiovascular mortality and this was all done as pre-specified analytic plan.

Dr Carolyn Lam: Wow, so what did they find?

Dr Greg Hundley: Well did I put you to sleep discussing all of that?

Dr Carolyn Lam: No! You have to tell me what they found. I'm seriously so interested in this topic because being vegetarian I actually get my source of omega fatty acids exactly from these sources.

Dr Greg Hundley: Okay, so Carolyn, higher levels of linoleic acid were associated with lower risk of total cardiovascular disease, ischemic stroke, cardiovascular mortality. While arachidonic acid was not associated with cardiovascular risks. And so, the clinical implications of the results support the potential benefits of main dietary omega- 6 fatty acid. That is linoleic acid for cardiovascular disease prevention. Now, while the trial is not randomized so we don't have definitive answers, the results do not support any theorized cardiovascular harms of consuming omega-6 fatty acids. And there is an excellent review on polyunsaturated versus saturated fat intake by Thomas Sanders from King's College, London as an editorial to this piece. So Carolyn I think we're safe right now in consuming linoleic acid. So how about a transition to our featured article and learn a little bit more about trastuzumab-induced cardiac dysfunction.

Dr Carolyn Lam: Absolutely!

Dr Greg Hundley: Great.

Welcome everybody, we have a fantastic paper to discuss. We're going to review human induced pluripotent stem cell derived cardiomyocytes and how they can be used to identify individuals at risk of trastuzumab-induced cardiac dysfunction after treatment for breast cancer. We have today Nazish Sayed and also Dr Joseph Wu, both from Stanford University in California.

Welcome gentlemen.

Dr Joseph Wu: Thank you for inviting us.

Dr Nazish Sayed: Thank you.

Dr Greg Hundley: Nazish tell us a little bit about what are these human induced pluripotent stem cells and then also describe your experiment and what were your results?

Dr Nazish Sayed: So, induced pluripotent stem cells is about 10 years ago I knew technology where you can actually turn back the clock by you taking human fiber blast or blood cells and then you can test full reprogramming factors and turn back differentiated cells to pluripotent stem cells will mimic like catalytic stem cells. The catalytics include self-renewal, pluripotency and the most important that they can be differentiated to any cell type in the body. For example, cardiomyocytes or endothelial cells the neuron and kind of mimic these differentiated cells from the same individual from where the IPSCs were derived from.

So, what we did in our study is we used this platform to derive these pluripotent stem cells from patients and then differentiated them into a cardiomyocyte to understand what would these human cardiomyocytes behave in a dish when treated with a Herceptin or trastuzumab and then kind of determine the underlying mechanism for this cardiac dysfunction. It seemed really difficult to model trastuzumab and use cardiac dysfunction as a heart which is the receptor for the trastuzumab is expressed only in humans.

People have usually relied on animal model and for the first time what we did is we used these ideas of cardiomyocytes to model this dysfunction in a dish. Our results were pretty straightforward. We found that the IPSCs cardiomyocytes when treated with the chemotherapy agent showed cardiac dysfunction in the case of decrease contractility. The contraction velocity of these each individual cardiomyocytes is significantly reduced. More with this was also confirmed by having impaired calcium cycling which is very important for the contractility of these cardiomyocytes.

But I think the most important thing which we determined from the study is that individuals who are treated with trastuzumab have a metabolic impairment in these cardiomyocytes which is convenient but however have a severe impact on this contractility and calcium handling in these cardiomyocytes. And that was one of the gist of these papers to figure out the metabolic impairment could be a target where we can improve this cardiac dysfunction in these patients.

Dr Greg Hundley: And so, after you discovered this, I noticed you also did some work with AMPK activators and perhaps would reverse some of the dysfunction. Could you describe a little bit what are AMPK activators and then how did they reverse the dysfunction that you observed?

Dr Nazish Sayed: In our study we characterized these IPS cardiomyocytes from these individuals and then we ran a whole sequencing of them after treatment where trastuzumab to see which of the pathways which could be down regulated or dysfunction when compared to the control patients which are not treated with trastuzumab. And one of the most significant pathways which we found was in PK pathways which was down regulated in the trastuzumab treated IPSC cardiomyocytes. So knowing that the AMPK activators are used for metabolic diseases, for example being diabetes and metabolic dysfunction, we thought that this same thing could be used in a dish where we can take these AMPK activators and simultaneously cotreat cardiomyocytes with Herceptin or trastuzumab to see if we can rescue the phenotype and indeed you can see in our paper we used 4 different AMPK activators with metformin which is a commonly used diabetic drug. Showing the best rescue for that trastuzumab induced cardiac dysfunction.

Dr Greg Hundley: Very intriguing because it looks like you've been able to harvest cells from individuals and then pre-treat them, understand the mechanism of dysfunction, understand who's at risk of dysfunction and then offer therapeutic interventions to perhaps prevent that dysfunction in this patient population. Joe, turning to you now, this is really revolutionary technology it seems to me. Can you describe how long does this process take? Is this something that we see might come into clinical medicine soon?

Dr Joseph Wu: We're really excited about this technology that Nazish has described. I think as you know we've been working on this platform for the past 10+ years. In terms of the timeline, right now it takes us about a month to generate the induced pluripotent stem cells. It takes us another month to expand, propagate the IP itself. It takes us another month to generate the IPS cardiomyocytes. And it will take us probably another month to do all the phenotypic characterization in terms of using these IPS cardiomyocytes to expose them to various chemotherapy drugs and see how the chemotherapy drugs have an effect on these cardiomyocytes.

So, I would say the total timeline is 12 months at this moment. Is it possible that the timeline could be crunched, could be shrunk over time? Yes that's possible, I think the technology is improving month by month, week by week because there are many different labs trying to work on this platform trying to improve the whole process. But right now one of the limitations that as you pointed out is this 4 month time period. And also the cost that's associated with this. But we're hopeful that over time that both the time, the costs can go down so that we can offer this type of platform to help patients diagnosed with cancer, find out what kind of chemotherapy is safe to use, what kind of chemotherapy is not safe to use.

Dr Greg Hundley: So, we're working towards clinical applications but at this point in time it looks like a fantastic platform for understanding, diagnoses and understanding pathways that for patients particularly as they are treated for cancer will experience cardiovascular dysfunction. So, switching a little bit and asking a related question. Patients that receive trastuzumab often also receive doxorubicin. Especially the breast cancer patients. If you looked at this technology trying to understand, and certainly those more at risk for trastuzumab associated left ventricular dysfunction, are the patients that previously received doxorubicin. Have you and your group looked at patients that have also received doxorubicin and then went on to receive trastuzumab relative to those that received trastuzumab alone?

Dr Joseph Wu: I think for these two populations for this particular study, we tried to keep them clean. Meaning that we're looking mostly for trastuzumab treated patients, otherwise it's hard for us to piece out whether the toxicity was due to one medication or the other medication. But what you are asking is very important because as you pointed out many of these patients received both and I think for future studies we should be able to model both medications, meaning that take some IPS cardiomyocytes treated with doxorubicin, treated with Herceptin by itself and treated with both the medications.

In previous studies we have studied using IPS cardiomyocytes the effects of doxorubicin induced cardiac toxicity. In just the assessment, doxorubicin is a very common effective chemotherapy for breast cancer medications and just like Herceptin, the clinicians struggled with the issue, as we cannot predict which patient will develop toxicity. And then granted the doxorubicin induced toxicity has a slight different mechanism compared to perception induced mild cardiac dysfunction that this Nazish had mentioned about. But these are kind of the studies that we're very excited because now for the first time we have a way to model this. Otherwise they alternative would be not possible, for example it would not be possible for us to biopsy breast cancer patients woman's heart to study the cells.

Especially in the case of perception. The receptor that's being studied is not present in animal model cells. For example not present in mouse cardiomyocytes and therefore it would be very difficult to understand the mechanism and this is the reason why the patient specific and disease specific IPS cardiomyocytes become so useful.

Dr Greg Hundley: Do you find another emerging therapy in this entire realm is the immunotherapies? Do you think this technology will be applied to determine susceptibility to immune mediated toxicity?

Dr Joseph Wu: This is a very good question as well Greg. We've been thinking about studying that and as you know, it's a more complicated system because it involves patients’ immune response, the myocardial, to inflammatory infiltrates that happens. So we have a couple projects going on. One is to study direct effect of the immunotherapy on the cardiomyocytes and then the second angle is to take patients who are in full myocarditis and collect their patients urine samples, blood samples and to see if we could expose these IPS cardiomyocytes to the patients urine samples to see what is the effect. For these IPS cardiomyocytes for future studies we're also trying to make it more complicated by generating not just the cardiomyocytes by itself, but generating what we call engineered heart tissues. In which it's a chunk of human heart muscles that would have the patients cardiomyocytes, patients fibroblast, patients endothelial cells and expose them to the patients serum.

But that kind of study would take much longer period of time because the number of people who have these types of immunotherapy induced myocarditis it's relatively low compared to patients who have Herceptin or doxorubicin induced cardio toxicity. This is also part of the reason why we're very much interested in collaborating with big centers throughout the country like York Center to see if we could understand this process better as a team.

Dr Greg Hundley: Excellent. I want to thank both of you for this really elegant discussion and perfect work moving forward. In summary, you've illustrated an ability to withdraw human pluripotent stem cells, differentiate them to cardiomyocytes and then perform tests on them to forecast susceptibility to various treatments used commonly for women with breast cancer. And in this study identifying mechanisms for trastuzumab toxicity. And then perhaps therapeutic interventions using again human cells which has a marked leap as you've identified over doing mouse studies, particularly for studying trastuzumab when the receptors the HER2 receptors in mirroring models differ substantially to those in human subjects.

Dr Joseph Wu: Thank you Greg. And we want to also express our thanks to our collaborators, our colleagues who contributed to the study and most importantly to the patients who helped us with these studies.

Dr Greg Hundley: I want to thank both Nazish and Dr Wu from Stanford and Carolyn and I wish you the best for the coming week and we look forward to speaking with you again next week.

Circulation May 14, 2019 Issue

13 maj 2019 | 23 min

Dr Greg Hundley: And I'm Greg Hundley, Associate Editor of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first.

Dr Greg Hundley: You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.

This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals.

Dr Carolyn Lam: And what did the study show?

Dr Greg Hundley: So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.

So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.

Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.

What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia.

Dr Carolyn Lam: So how did they show or find this fourth category?

Dr Greg Hundley: Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.

During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.

So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients.

Dr Carolyn Lam: Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are?

Dr Greg Hundley: Aren't cilia on prokaryotes? I mean, I think of bacteria.

Dr Carolyn Lam: All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.

Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling.

Dr Greg Hundley: Carolyn, this is so interesting. I had no idea about these cilia. So what did they find?

Dr Carolyn Lam: So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response.

Dr Greg Hundley: So how do we use this clinically, and what does it mean for us?

Dr Carolyn Lam: These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance.

Dr Greg Hundley: Wow, very interesting!

Dr Carolyn Lam: Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.

So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.

They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases.

Dr Greg Hundley: Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart?

Dr Carolyn Lam: Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.

Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.

So, that wraps up our summaries Greg. Shall we move to our feature discussion?

Dr Greg Hundley: Absolutely.

Dr Greg Hundley: Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.

Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience?

Dr Renato Lopes: The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.

We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.

What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.

So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect.

Dr Greg Hundley: Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race?

Dr Renato Lopes: That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex.

Dr Greg Hundley: Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight?

Dr Renato Lopes: This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.

I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.

It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients.

Dr Greg Hundley: Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation?

Dr Brian Olshansky: It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.

One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.

Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.

We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.

Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight.

Dr Greg Hundley: On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week.

Circulation May 07, 2019 Issue

6 maj 2019 | 26 min

Dr Greg Hundley: And I'm Greg Hundley, Associate Editor as well, at Circulation, and Director of the Pauley Heart Center in Richmond, Virginia at BCU Health.

Dr Carolyn Lam: Now, we've heard of the PIONEER heart failure trial and that is a sacubitril/valsartan in acute decompensated heart failure. A very important trial, but was powered on the surrogate outcomes. Now, in today's issue though, we're going to hear a little bit more about the clinical outcomes from the PIONEER heart failure trial, a very important paper, a very important discussion coming right up. Greg, what paper do you have to start us off?

Dr Greg Hundley: Carolyn, I've got another favorite of our little discourse, your next Carolyn's Quiz. Except this time it's essay format, so it's open ended questions. And so here's my question to you. What paper addresses an important issue related to hookah inhalation. So Carolyn, do you know a little bit of the origins of hookah and then how does its use compare to e-cigarettes or conventional cigarettes?

Dr Carolyn Lam: Oh, okay. Well at least the quiz wasn't asking if I smoke hookah. Okay, so hookah, that water pipe smoking pipe, fun stuff. I think, is it a Middle Eastern origin? And frankly I don't know of any data to say whether it is better or worse than cigarette smoking.

Dr Greg Hundley: Yeah, you're exactly right. Hookah, it's a longstanding practice, primarily confined to men from the Middle East. But in the 1990s it was introduced with fruit flavored pre-packaged tobacco products and that ignited a sharp uptake of hookah smoking by young women and also men in the Middle East, and then a migration to our western culture. Now, believe it or not, in the United States and in the United Kingdom, hookah has a prevalence of 15% to 25% among university students. And today, twice as many secondary school children smoke hookah as they do cigarettes, and more adults have tried or currently use hookah than electronic cigarettes.

So, what does this article discuss? Well, it focuses on hookah inhalation byproducts, because the charcoal traditionally is used to heat the hookah tobacco in the water pipe, hookah smoke delivers tobacco toxicants and nicotine plus charcoal combustion products, not only carbon rich nanoparticles and oxidants that may destroy nitric oxide and impair endothelial function, but also large amounts of carbon monoxide, a putative vasodilator molecule that will dilate the arteries independent of endothelial dysfunction.

So, this study enrolled three groups of patients. First, there were 30 26-year-old hookah smokers. Second, there were 20 in which the flavored hookah tobacco product was heated electrically, not by the charcoal. And then finally, 15 age matched cigarette smokers who smoked one cigarette.

Dr Carolyn Lam: Wow, what was the result?

Dr Greg Hundley: Unfortunately, nicotine levels increased similarly with all types of smoking. Now, flow-mediated arterial dilation, a marker of endothelial function, did not become impaired after smoking charcoal heated hookah, but instead increased by about 43%. In contrast, flow-mediated arterial dilation decreased by 27% after smoking electrically heated hookah, compared to the decrease after cigarettes smoking. For hookah smokers, vasodilation increased 138% times more than in the other two groups. Therefore, the acute endothelial dysfunction was masked by those high levels of carbon monoxide that are generated from the charcoal. Remember, carbon monoxide is a very potent vasodilator.

What do we take away from this, Carolyn? With respect to large artery endothelial function, smoking hookah is not as harmless as discussed by an excellent editorial by Naomi Hamburg from the Whitaker Cardiovascular Institute at Boston University School of Medicine.

Dr Carolyn Lam: Oh wow.

Dr Greg Hundley: You know, importantly, the carbon monoxide is blocking our ability to appreciate endothelial dysfunction with traditional measures. So Carolyn, what about your article?

Dr Carolyn Lam: Going from smoking to exercise, this one looking at intensity of exercise that should be performed after heart transplantation. This is a study from Dr Nytrøen and colleagues from Oslo University Hospital in Norway, and they performed a multicenter prospective randomized controlled trial of 81 patients at a mean of 11 weeks only after a heart transplantation. And these patients were randomized to either nine months of high intensity training, which is a four by four minute intervals at 85% to 95% of peak effort, or to moderate intensity continuous training defined as 60% to 80% of peak effort. And the primary outcome was the effect of high versus moderate intensity exercise on the change in aerobic exercise capacity assessed as VO2 peak.

Dr Greg Hundley: So, what did they find here?

Dr Carolyn Lam: First, it's important to note that it is the first study to test this and to show that the effect of nine months of high intensity training in de novo recipients of heart transplants produced a clinically meaningful, significantly larger increase in peak VO2 and muscular exercise capacity compared to moderate intensity continuous training. Importantly, the study also showed that the approach was safe with high adherence and high completion rates. 96% of patients completed the study, during which time the exercise adherence for both groups was 81% and there were no serious exercise related adverse events.

Dr Greg Hundley: Wow. So it looks like we've been hearing about that in training and athletes. Are there any caveats?

Dr Carolyn Lam: Yeah, and that's an important question. High intensity training in this study required one to one interaction with physical therapists, and of course that's not feasible in most cardiac rehabilitation programs. It also requires motivated, medically stable patients who can maintain high exercise intensity ranges. So further research is really required to determine if these initial improvements at peak VO2 and muscular endurance persist in the long-term period post heart transplantation and, of course, whether they're associated with favorable clinical outcomes. All this is discussed in a beautiful editorial entitled "Can a Hit Result in a Home Run?" by Mark Haykowsky, Wesley Tucker, and Peter Brubaker.

Dr Greg Hundley: Carolyn, that's fantastic. In my next study, I'm going to switch over and discuss diabetes and the age of diagnosis of type two diabetes and its association with cardiovascular mortality and risk findings from the Swedish National Diabetes Registry. The study was conducted between 1998 and 2012 and the analysis cohort comprised 318,083 patients with type two diabetes mellitus matched with just under 1.6 million controls. Participants were followed for total mortality, cardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation.

Dr Carolyn Lam: Huge study. Important question. What did it show?

Dr Greg Hundley: Over a median follow up of about five and a half years, patients with type two diabetes diagnosed under the age of 40 years had the highest excess risk for the most common cardiovascular related outcomes. All risk attenuated progressively with each increasing decade. By the time type two diabetes was diagnosed at an age greater than 80 years, adjusted hazard ratios for cardiovascular disease and non-cardiovascular mortality were all less than one. In addition, survival for those diagnosed beyond 80 years was the same as controls, whereas it was more than a decade less when type two diabetes was diagnosed in adolescence.

Dr Carolyn Lam: Okay, so Greg, what does this mean for us clinically?

Dr Greg Hundley: The observations of this study amplify support for preventing and delaying type two diabetes onset in younger individuals and raises questions as to diagnostic strategies, as to whether we should even screen or implement management strategies for those individuals that are diagnosed with diabetes beyond the age of 80 years.

Dr Carolyn Lam: Interesting. Well, for my last paper, I have a basic science paper and this one really provides insights into endothelial dysfunction. It looks at S-Adenosylhomocysteine, which is a precursor of homocysteine, and elevated levels of these are positively associated with the risk of cardiovascular disease and with development of atherosclerosis, but its role in endothelial dysfunction has been unclear. So authors Dr Ling from Sun Yat-sen University in Guangzhou, China and Dr Ke from Shenzhen Center of Disease Control and Prevention in Guangzhou, China, these co-corresponding authors and their colleagues performed a series of elegant mouse experiments and showed that the inhibition of S-Adenosylhomocysteine hydrolase resulted in elevated plasma levels of S-Adenosylhomocysteine, which then induced endothelial dysfunction via epigenetic upregulation of the p66Shc-mediated oxidative stress pathway.

Furthermore, plasma S-Adenosylhomocysteine levels were positively associated with oxidative stress levels and inversely associated with flow-mediated dilation and methylation of p66Shc promoters in patients with coronary artery disease and healthy controls. So, this study really provides a novel molecular insight into mechanisms by which this molecule, S-Adenosylhomocysteine, may be associated with endothelial injury and contribute to the development of atherosclerosis. So that brings us to the end of our summaries, Greg. Let's move on to our feature discussion.

Dr Greg Hundley: Welcome everyone to the second half of our presentation where we have an outstanding interview with David Morrow from Brigham and Women's Hospital and Dr Justin Ezekowitz from Edmonton to discuss a letter that we've received, "The clinical outcomes in patients with acute decompensated heart failure randomized to sacubitril/valsartan or enalapril in the PIONEER HF trial. David, can you remind us just a little bit about, first, your New England Journal study, and then how this letter adds to the prior findings?

Dr David Morrow: I think it's first worthwhile to place a little bit of context in that paradigm heart failure trial, which was a preceding trial in patients with chronic heart failure, who were ambulatory patients, who had to be tolerating a stable dose of an ACE inhibitor or an ARB, and could not have had a current acute decompensation of their heart failure, were randomized to sacubitril/valsartan versus enalapril with a significant reduction in major clinical cardiac events with sacubitril/valsartan. And that finding from that trial has led to changes in guidelines and clinical practice for patients with chronic heart failure with reduced ejection fraction.

But there were several important aspects that still left gaps for our clinical care, in that because of a run in period in that trial, so a period where patients had to tolerate sacubitril/valsartan, the stability of the patients that I just described, it often left practitioners in the position of caring for patients who might not meet those inclusion criteria, particularly those patients who are hospitalized where there is an opportunity, often, to update their care to be consistent with current standards and current guidelines. And so we designed the PIONEER heart failure trial with that in mind, to study specifically patients with acute decompensated heart failure, all patients with heart failure with reduced ejection fraction. And they were randomized within hospital initiation after an initial period of stabilization to either sacubitril/valsartan or enalapril in a double blind, double dummy design.

The primary endpoint for the PIONEER heart failure trial was a biomarker, so NT-proBNP, and we saw that there was a significantly greater reduction in NT-proBNP by four to eight weeks as an average endpoint, by 29% more with the sacubitril/valsartan versus enalapril. And we also saw that the adverse events, the tolerability of the two regimens was similar and the event rates did not differ in the sacubitril/valsartan group.

And so that was the primary result of the trial that was published in the New England Journal of Medicine. We had, in addition, some exploratory clinical end points, one of which was a broad composite which included all-cause mortality, the need for an LVAD implantation, referral for transplantation, heart transplantation, as well as rehospitalization for heart failure. And so, what was new in the letter that we have published in Circulation, is that we specifically looked at the clinical end points and additional exploratory end points, looking at the harder composite of cardiovascular death and rehospitalization for heart failure. And we had particular interest in that because it's being used as a primary end point that was consistent with the paradigm heart failure trial that I described in chronic heart failure. That was really the reason for undertaking this additional analysis.

Dr Greg Hundley: So how did you define rehospitalization for heart failure and what did you find?

Dr David Morrow: Rehospitalization for heart failure, we actually used the same clinical endpoint committee as for the paradigm heart failure trial and used the same definition, which requires that patients had clinical evidence of heart failure, which could include both symptoms as well as biomarker values and evidence of congestion on physical exam. We needed graphic evidence of pulmonary edema. Together, they had to have a clinical presentation that was consistent with heart failure, and then also who have been hospitalized for the management of that decompensation.

And so what we found overall was that there was a significant reduction in cardiovascular death or heart failure with the sacubitril/valsartan over the eight week double blind study period, such that it was a 42% reduction in that end point and an absolute 6% reduction in cardiovascular death or rehospitalization for heart failure with sacubitril/valsartan compared with enalapril.

Dr Greg Hundley: And David, looking at these fantastic figures, for listeners, please take a look at this letter, it looks like the two groups separated early. Can you suggest a mechanism for why that might've occurred?

Dr David Morrow: We agree that it does appear that the separation begins early on. We did not have sufficient statistical power to test individual hypotheses much earlier time points, but the relative risk reduction appears homogeneous over that period. And when we look specifically at 30 days, for example, the relative risk reductions are comparable. So we do think that observation you just made is correct and consistent.

And I think that there's evidence of support for rather early effects on hemodynamic stress. So we have the primary end point with NT-proBNP where we saw that there was separation between the groups that was actually statistically significant on that continuous end point of a natriuretic peptide value already by one week of therapy, which was quite remarkable to us. We had planned as our primary end point the four to eight weeks period where we had expected, based on previous work, that there would likely be a reduction in this slightly different population. But in fact we saw those curves in NT-proBNP separate already by one week. We've also had subsequent work that we presented in abstract form looking at other biomarkers such as troponin and soluble SD2, so biomarkers of wall stress and myocardial injury, and also seeing reductions in those markers that appear also to occur early on.

Dr Carolyn Lam: Justin, can we bring you into this conversation here right now? What do you think are the clinical implications of this particular research letter and then perhaps of PIONEER in general?

Dr Justin Ezekowitz: Thanks Carolyn, and my compliments to Dr Morrow and the team for putting this together as a research letter because that's often a challenge to get to the core information from the study. And I would, again, draw the listeners to get a look at the figures that they put together and especially the way in which they separate early out. And we did ask to be cautious with statistical power about rehospitalization, but it's quite a driving factor for the overall end point and one that shouldn't be lost, because that has the biggest probably clinical implications, that the curves separate early between the groups on an ACE inhibitor versus to sacubitril/valsartan. And given they separate early, one of the clinical implications is, why wait? So why wait for when people have been outside the hospital to change the medication but instead use that as an opportunity when they're in front of you as a clinician to consider switching them over to a newer therapy and consider what they’ve been on from the majority of patients being on an ACE inhibitor or an ARB, but it is the right time when you have them in observation.

The second observation I would make from this study is that although this was done in high quality sites and sites that know how to do clinical research, but also those who take care of patients that are on high quality medications, the baseline medication rate use wasn't perfect. So there's dual opportunity for looking at the baseline medications, which was MRAs and beta blockers, and use it as opportunity and an implication to use all the best medications. And in this case sacubitril/valsartan would be an opportunity.

My final point would be, I think this study is critical from a clinician's perspective, as we've seen many biomarker-based studies where there's a reduction in the biomarker, but the clinical end point doesn't seem to change so NT-proBNP is great, but here is the judicated clinical endpoints. So for me, when I'm treating a patient, that means more to me than the lowering of a biomarker. We've seen other evidence where that doesn't always pan out, and so you are confident now that that is the case.

Dr Carolyn Lam: Well put, Justin. And you had a question, didn't you, for David?

Dr Justin Ezekowitz: Right. One of the questions I was trying to sort through, and we couldn't squeeze this fully into the research letter, was there were some patients who were randomized in the hospital but the overall PIONEER program allowed for up to 10 days, and when you look at the patients and when they were randomized and how they were cared for beginning of the hospital, end of the hostel, right after discharge, was there any difference that you saw across the spectrum of outcome?

Dr David Morrow: Actually, the study drug was initiated in hospital for all patients. We did provide up to 10 days while in hospital for the outer limits of recruitment into this study because we recognized that some hospitalizations for acute decompensated heart failure are quite lengthy, and we wanted to give sites the opportunity to recruit patients who took longer to stabilize in this study than others. So it was starting from 24 hours after hospital presentation up to 10 days as a maximum, but all patients were initiated in hospital.

The median turned out to be at 68 hours and at least three-quarters of patients were recruited and randomized within 98 hours. So the vast majority were early on. Overall, when we look at the consistency of the effects of the primary end points of the natriuretic peptide and a broader composite, we did not see any evidence of heterogeneity based on the timing of randomization relative to presentation. As you pointed out earlier, we have to recognize that the numbers do get smaller across that tier, particularly when we get out to the later window. Still. I would say that the primary results, almost in any trial you should always go by the primary result, and we did not see any heterogeneity to think that there was a different effect in those who were enrolled early or late.

Dr Carolyn Lam: David, can I just chime in and say again, congratulations on this great work. Can I go back to one of the points that Justin made a bit earlier? This being a research letter, could you maybe share with the audience a bit, what's it like to write and be constrained to such few words and a single figure?

Dr David Morrow: Well, as Dr Ezekowitz said, it does present a little bit of a challenge. You have to be very concise. We certainly were fortunate that we could leverage the primary publication for the majority of methods and other design elements that we didn't need to recapitulate. And so I think for, in particular, this type of research where there was something that we felt was quite important scientifically with potentially important clinical implications, but yet still was an additional exploratory end point that we could express concisely, the research letter was a very reasonable format to do that.

Dr Carolyn Lam: I couldn't agree more. But Justin, how about from the editor's point of view? Could you share about the research letter?

Dr Justin Ezekowitz: My compliments to Dr Morrow and his team, as I asked him a lot of questions that required both expanding on the things they had to say while constricting the number of words at the same time, and that's a huge challenge to get findings across. So they were able to meet that challenge. I think one of the key things was really honing down as to what the key messages are, as Dr Morrow just alluded to, you can refer to the main complication or a baseline trial publication for all the other details, but what were the core things that could be demonstrated in a publication that is of a limited number of words, tables, or figures. And I think that's the key is, what is the real hypothesis and question to be answered. And that's the way we focused on all the efforts. I did appreciate that it was not easy not to have a lengthy discussion. So we had a ... in the written discussion we have really just truncated this down to a few key sentences which summarize the overall study, so the reader could pick this up and know what the implications are without actually having to go into a lot of the detail that we've just been speaking about.

Dr Carolyn Lam: Ah, I love it. And thank you so much for this conversation too. That helps us go under the hood a little bit. I'm sure everyone who's listening just wants to pick this up now because it's so concise, so beautiful to read, and just look at the figure.

Thank you everyone for joining us today. Don't forget to tune in again next week to Circulation on the Run.

Circulation April 30, 2019 Issue

29 april 2019 | 24 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor as well, at Circulation, and director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Carolyn, this issue, we've got a super-exciting interaction to follow related to SGL2 inhibitors on 24-hour ambulatory blood pressure in African-Americans, something used to treat diabetes, and maybe a positive effect on blood pressure, but more to come on that. Now, Carolyn, you're also planning to discuss some results from another SGL2 study.

Dr Carolyn Lam: You bet. This time, I'm taking you to Japan for the results of the SACRA study which stands for SGLT2 Inhibitor and Angiotensin Receptor Blocker Combination Therapy in Patients with Diabetes and Uncontrolled Nocturnal Hypertension and this is from Dr Kario and colleagues from Tochigi in Japan. It's a multi-centered, double-blind parallel study of 132 non-obese older adults with type 2 diabetes and uncontrolled nocturnal hypertension, receiving stable antihypertensive therapy, including angiotensin receptor blockers, who were then randomized to 12 weeks' treatment with empagliflozin 10 milligrams once daily or placebo. Clinic blood pressure was performed at baseline in weeks four, eight and 12. Twenty-four hour ambulatory blood pressure monitoring was performed at baseline and week 12 and morning home blood pressure was determined for five days before each visit. The primary efficacy endpoint was changed from baseline in nighttime blood pressure.

Dr Greg Hundley: So, what did they find, Carolyn?

Dr Carolyn Lam: Well, empagliflozin significantly reduced nighttime systolic blood pressure versus the baseline. The reductions in daytime 24-hour morning, home, and clinic systolic blood pressure at 12 weeks with empagliflozin was also greater than placebo. Between group differences in body weight and glycosylated hemoglobin reductions were significant, but small and the changes in antihypertensive medication during the study also did not differ significantly between the groups.

Dr Greg Hundley: Very good. Well, I'm going to switch gears and talk also on the same theme of sugar and diabetes and evaluate the long-term consumption of sugar-sweetened and artificially-sweetened beverages and the risk of mortality in U.S. adults. This is a study by Vasanti Malik from the Harvard School of Public Health. Now, as you know, in epidemiologic studies, intake of sugar-sweetened beverages has been associated with weight gain, a higher risk of type 2 diabetes, coronary heart disease and stroke, but to date, few studies have examined the association between sugar-sweetened beverages and intake and mortality. All right, Carolyn, I'm going to give you a quiz now. Here's the first question.

Dr Carolyn Lam: What?

Dr Greg Hundley That's right, sugar-sweetened beverages are the single largest source of added sugar in the U.S. diet, true or false?

Dr Carolyn Lam: I'm going to guess true.

Dr Greg Hundley: Okay, so all those consumption of sugar-sweetened beverages in the United States has decreased in the past decade. National survey data show a slight rebound in consumption in recent years among adults in many age groups. With the average equivalent being, multiple choice, 2%, 6.5% or 10% of our total energy requirements?

Dr Carolyn Lam: Oh, my goodness. One of the higher ones. I'm just going to go in the middle, 6.5.

Dr Greg Hundley: Excellent, good choice, you're a good multiple-choice taker, 6.5%. So, among younger adults, sugar-sweetened beverages contributed. They're a little bit higher, 9.3% of the daily calories in men and 8.2% in women in the United States. Now, how about other parts of the world, particularly developing countries? The intake of sugar-sweetened beverages, is it dropping, is it flat or is it rising dramatically?

Dr Carolyn Lam: Sorry, Greg, but that one's too easy. It's definitely rising.

Dr Greg Hundley: Yup, you got that right.

Dr Carolyn Lam: I live in those other developing countries, so I've seen so.

Dr Greg Hundley: And it's really thought due to widespread urbanization and beverage marketing. So, now we've got an alternative, artificially-sweetened beverages. And they're often suggested as alternatives to sugar-sweetened beverages and intake levels have increased of these alternative sweeteners in the United States. So, next question. Are the artificially sweetened beverages a better alternative to sugar--sweetened beverages in regard to cardiovascular or all-cause mortality?

Dr Carolyn Lam: Yikes. Okay, so Greg I'm afraid to guess on this one because I have to admit I sometimes, with a sweet tooth, like to take these alternative beverages. I think you're going to be telling us.

Dr Greg Hundley: Well, we don't know. Most of the data in this area is from research and comes from associative analyses utilizing longitudinal cohorts and some studies suggest yes, some studies, no. For example, one in the elderly suggested artificially-sweetened beverages, but not sugar-sweetened beverages were associated with adverse events, but critiques indicated that finding may have related to reverse causation because the elderly patients were switching from sugar-sweetened to artificially-sweetened beverages. So, where are we now? Well this study, in our Journal, examined the associations between the consumption of sugar-sweetened beverages and artificially-sweetened beverages with the risk of total and cause-specific mortality among 37,716 men from the Health Professionals Follow-up Study between 1986 and 2014 and 80,647 women from the Nurse's Health Study from 1980 to 2014, who were free from chronic diseases.

Dr Carolyn Lam: Wow, that's a huge combined cohort. So, come on, what were the results?

Dr Greg Hundley: So, the researchers found after adjusting for major diet and lifestyle factors, consumption of sugar-sweetened beverages was associated with a higher risk of total mortality and cardiovascular mortality and cancer mortality and, thus, the results provide further support for the recommendations and policies to limit intake of sugar-sweetened beverages and to consume artificially-sweetened beverages in moderation did improve overall health. Now, what were the results from artificially-sweetened beverages? Well, they were associated with total and cardiovascular disease mortality in the highest intake category only. So, those consuming large amounts of those daily, but only in the cohort of women from the Nurse's Health Study, not from the men in the Health Professionals Follow-up Study. Artificially-sweetened beverages were not associated with cancer mortality in either cohort.

So, moving forward, the positive association between high intake of artificially-sweetened beverages and total and cardiovascular disease mortality observed among women requires more study and further confirmation and also, we might consider that even though artificially-sweetened beverages could be used to replace sugar-sweetened beverages among habitual sugar-sweetened beverage consumers, higher consumption of the artificially-sweetened beverages would probably be discouraged. Finally, policies and recommendations should continue to call for reductions and limits on sugar-sweetened beverages intake and also address alternative beverage offerings with an emphasis on our favorite, water.

Dr Carolyn Lam: Sweet, Greg! Or maybe not so sweet. Oh, goodness. All right, well my paper deals with related, but not related perhaps, but talking about ketone body, 3-hydroxybutyrate and the cardiovascular effects of treatment with this ketone body in chronic heart failure and this is from corresponding author, Dr Nielsen from Aarhus University Hospital in Denmark and his colleagues. Now, they performed a series of studies. In the first 16 chronic HFrEF patients were randomized in a crossover design to three hours' infusion of 3-hydroxybutyrate or placebo and monitored invasively with a Swan-Ganz catheter and studied with echocardiography and they found that infusion of 3-hydroxybutyrate increased cardiac output by two liters per minute or 40% with an absolute improvement in left ventricular ejection fraction of 8%, and the observed defects were accompanied by vasodilation with a resultant stable systemic and pulmonary blood pressure.

Now, in the second part of the study, they studied eight HFrEF patients examined at increasing infusion rates of 3-hydroxybutyrate and they found a dose response relationship with a significant increase in cardiac output. And, finally, they studied 10 HFrEF patients and 10 age-matched volunteers, randomized in a crossover design to a three hour infusion of 3-hydroxybutyrate or placebo and they looked this time at myocardial external energy efficiency and oxygen consumption using 11-carbon acetate PET and what they found was 3-hydroxybutyrate increased oxygen consumption without altering myocardial external energy efficiency. The response did not differ between HFrEF and age-matched volunteers.

Dr Greg Hundley: Wow, Carolyn, there was a lot of data in that study. So, what's your main take home?

Dr Carolyn Lam: In summary, 3-hydroxybutyrate, this ketone body, demonstrated dose-dependent beneficial cardiac and hemodynamic effects in patients with heart failure reduced ejection fraction without deteriorating mechano-energetic coupling and without causing any safety issues. And what's significant is that this opens the door to modulating circulating 3-hydroxybutyrate as a novel treatment option in patients with heart failure.

Dr Greg Hundley: Right, Carolyn, so I've got an interesting study from the world of basic science that's looking at the role of potassium channels as novel molecular targets and bradyarrhythmia’s and even, perhaps, in atrial fibrillation. This is from Yoshihiro Asano from Osaka University in Japan. So, the acetylcholine activated potassium channel is expressed in the sinus node, atrium, and atrioventricular node and contributes to heart rate slowing triggered by the parasympathetic nervous system. So the potassium, activated potassium channel is a heterotetramer of 2 inwardly rectifying potassium channel proteins encoded by two genes, KCNJ3 and KCNJ5, respectively.

Dr Carolyn Lam: Okay, so what did this study show?

Dr Greg Hundley: What it showed is a selective potassium acetylcholine channel blocker effectively inhibited a mutant potassium channel and up-regulated heart rate and bradyarrhythmias using a zebra fish model. And this is really interesting, Carolyn, because two conclusions are worth considering. First, future studies could determine the prevalence of bradyarrhythmias associated with dysfunctional mutation in this potassium channel. And, second, results raise the possibility that pharmacologic blockade of this channel might serve as a therapy for increasing heart rate and be especially beneficial for bradyarrhythmias in patients with gain of function mutations in the channel and, therefore, genetic testing for KCNJ3 and KCNJ5 in patients with bradyarrhythmias may provide a drug treatment option in lieu of an invasive surgical implantation of a pacemaker.

Dr Carolyn Lam: Fascinating! Thanks, Greg. What a great issue and now onto an even greater feature discussion.

Dr Greg Hundley: Welcome, everybody, to the second part of this interview. We've got a very exciting paper to discuss with you. Remember this is our backstage pass to Circulation and we've got today, Keith Ferdinand from Tulane University in Louisiana and our Associate Editor, our hypertensive expert, Dr Wanpen Vongpatanasin from the University of Texas Southwestern Medical School in Dallas. We're going to be discussing the anti-hyperglycemic and blood pressure effects of empagliflozin in African-Americans with type two diabetes and hypertension. Keith, we're going to start with you. What was your hypothesis for this study? Who's the study population? Review a little bit about your design and, importantly, what were your results?

Dr Keith Ferdinand: Well, my hypothesis was that one of the new classes of medications, the SGLT2 inhibitors, which have a mild diuretic effect and a mild natriuretic effect, may have benefits in self-described African-Americans in not only controlling glucose, but also controlling hypertension. These medicines are approved, of course, as medications for type 2 diabetes, but we had seen in some earlier trials that did not include self-defined African-Americans, that there may be a blood pressure effect. We know that diabetes is higher in blacks, almost twice that seen in the general population and, of course, hypertension and uncontrolled hypertension is disproportionate. So, here's a medication that may be even more beneficial in that population and we wanted to study it.

Dr Greg Hundley: And tell us a little bit about who was in the study and what was your design?

Dr Keith Ferdinand: The design was to be a placebo-controlled randomized trial using empagliflozin starting at 10 milligrams and force-titrating to 25 milligrams versus placebo on the background of conventional anti-hypertensive agents. Everyone was on one or more anti-hypertensive agents. We used the gold standard for blood pressure control with 24-hour ambulatory blood pressure and that was the means by which patients entered the study, although the primary endpoint was changed in hemoglobin A1c, we actually designed and powered the study to see if there would be a change in blood pressure. Additionally, we looked for changes in weight, losing calories with the effects of the SGLT2 inhibitors with glycosuria has translated in some preliminary trials to weight loss. So, this was a study looking at a population. Most of them had diabetes for approximately nine to 10 years, 59 years of age, definite hypertension, obesity, a high risk population, to see if a new class of medications would be beneficial.

Dr Greg Hundley: And what did you find?

Dr Keith Ferdinand: Fortunately, we did find an effect. It did lower the primary endpoint of a change in hemoglobin A1c, but remember it was powered also by blood pressure effect and fortunately, we did see that both with the ambulatory and clinic blood pressure, both at 12 weeks and 24 weeks. The clinic blood pressure was a trend, but the ambulatory blood pressure was positive at 12 weeks and both had a strong difference in terms of confidence intervals for blood pressure lowering. About five millimeters of mercury at 12 weeks and up eight millimeters of mercury at 24 weeks for the change in ambulatory blood pressure which, in a large population would translate into a significant blood pressure lowering, the hemoglobin A1c reduction was also significant. But, although that was the primary endpoint, my concern is as a cardiologist and cardiovascular specialist.

Dr Greg Hundley: And what dose did you select? Did you have to up-titrate this at all and, finally, were there any side effects?

Dr Keith Ferdinand: You know, with the SGLT2 inhibitors, you have an effect both in terms of glycosuria, some osmotic diuresis and some natriuresis, and with the loss of body weight. But the change in body weight really wasn't that much, about 1.2 kilos and the change in blood pressure was discordant with the change in body weight. So, we think that the effects in blood pressure may be from extended diuretic effect, but it may also be from effects on endothelial function that are outside those significantly related to diuresis, per se. Because you're urinating glucose, glycosuria, you would expect the potential for superficial infections, mycotic infections and that was seen. The rates were not prohibitive and not dissimilar to what's been seen in other studies. So, overall, the drug was well-tolerated. It did not have any significant adverse effects outside of a few mycotic infections, which are basically superficial fungal infections and that's been seen in other uses of the SGLT2 inhibitors, but nothing that I think would be unusually disturbing in this population.

Dr Greg Hundley: Outstanding. So, Wanpen, going to switch over to you and ask you to help us put this in the context of treating African-American men, women with hypertension. How do we think about using this new finding? How would we integrate it with other therapies that these individuals already might be taking?

Dr Wanpen Vongpatanasin: Sure, so I think that this study is very intriguing and interesting that empagliflozin to me actually had more prominent benefit on lowering 24-hour blood pressure than the previous study that the true analysis showed the effects of 24-hour blood pressure is much less or almost half of four to five millimeters of mercury and that could be that this was not that significant in African-Americans and maybe this drug is particularly effective and, as you know, African-Americans tend to have more salt sensitive form of hypertension and I wonder if that could explain the results, but I think it's very encouraging because this drug class approved for treatment of diabetes and medication. African-American have higher blood pressures than other ethnic groups and having diabetes makes them prone to having more resistant hypertension. In this particular trial, almost 40% of the patients enrolled is already taking three or more antihypertensive medications, so adding this on top and having that benefit is as good as adding spironolactone, for example, and I didn't see from the manuscript, how many patients are taking spironolactone already, but I would be curious to see that, as well.

But I think that is something that physicians should think about and this drug is already FDA-approved for treating diabetes, so if you have a patient with difficult to control blood pressure and already needed something for diabetes, this could make a lot of sense to use it.

Dr Greg Hundley: Keith, do you have any thoughts on Wanpen's comment regarding the use of spironolactone in the study population?

Dr Keith Ferdinand: No, I don't have those specific data available at the time that we're speaking now, but that's certainly something that I will attempt to look at the database and get more information. But, I think Wanpen is absolutely right. If you look at some of the previous studies, for instance, EMPA-REG, the major outcomes trial that led to the indication of a decrease in cardiovascular death and heart failure, the blood pressure lowering wasn't that robust, maybe 4/2, but here we saw at week 24, 10 millimeters of mercury of blood pressure reduction and if you placebo subtract, which is what I mentioned in my first comments, you're talking about 8 to 8.5 millimeters of mercury reduction and that's a significant reduction, especially for ambulatory blood pressure measurement.

Dr Greg Hundley: Absolutely. So, I'm going to go with each of you separately, but taking this manuscript and this work that Keith, you've performed, we'll start with you. What do you think of the next steps in the research in this area, both from the perspective of using this family of agents in individuals with both diabetes and hypertension?

Dr Keith Ferdinand: What I would hope in the future is another outcome study is done with an SGLT2, any numbers of that class, that they particularly target enough African-Americans to see if this robust blood pressure reduction not only is found again, but also translates to decreased cardiovascular events. You know, NHLBI, for instance and ALLHAT, selectively over-represents African-Americans. They had 35% African-Americans in ALLHAT and the reason for that is you have a population that has a disproportionate degree of hypertension and a disproportionate degree of associated cardiovascular disease and renal disease, so you want to make sure that any medication that's been shown to be effective is effective in the higher risk population. So a future outcome study, regardless of whether they're renal-based or related to heart failure, I hope will target an increased population of blacks to see some of the robust reduction we have, translates in cardiovascular events.

My suspicion is that self-defined African-American versus a genetic factor, describes the phenotype of patients who tend to be more obese, have more salt sensitivity, perhaps subclinical kidney disease and will respond to a medication that has some diuretic natriuretic effects and effects with endothelial dysfunction and sympathetic discharge.

Dr Greg Hundley: Very good, well I heard sympathetic discharge. Wanpen, any comments there? That's your area.

Dr Wanpen Vongpatanasin: I think that definitely needs to be studied. To my knowledge, there was only one small study that published that tried to measure sympathetic nerve activity directly, but unfortunately that study after a very short-term treatment for like four or five days, so I’m sure that there will be more studies to come and also hope that the future study will shed light on any particular markers with surrogate that will identify patients that will respond better, for example, PATHWAY-2 trials that were done to test the effects of spironolactone on resistant hypertension they found that the lower the reading, the more likely you can have better response to Aldactone and I wonder if this might apply to empagliflozin and be something else. I think the fact that the blood pressures continued to decline from the week 12 to week 24 is very, very interesting when the body weight effect doesn't necessarily go down much further. This really tells us there's something else beyond weight and perhaps glucose that would explain this.

Dr Greg Hundley: Very good. Well, I certainly want to thank you both for this outstanding discussion. Keith, we want to thank you for bringing this manuscript to Circulation and identifying this new application for this therapy in African-Americans. Wanpen, thank you also for your time and comments.

On behalf of Carolyn and myself, we really appreciate you listening. Have a great week and we look forward to seeing you next week.

Circulation April 23, 2019 Issue

22 april 2019 | 20 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor as well at Circulation, and director of the Poly Heart Center in Richmond, Virginia, at VCU Health. Well, I'm going to talk about anti-hyperglycemic agents and look at a very important meta-analysis.

Dr Carolyn Lam: Those are the rage: GLP-1 receptor agonists and SGLT-2 inhibitors. But first, let's talk about psychosocial stress and cardiovascular health. So what is the joint impact of multiple stressors on racial or ethnic disparities in cardiovascular health?

Well, this question was tackled by Dr Albert, from University of California San Francisco Center for the Study of Adversity and Cardiovascular Disease and her colleagues. They basically studied more than 25,000 women participating in the women's health study follow-up cohort, and examined the relationship between cumulative psychosocial stress and ideal cardiovascular health as defined by the American Heart Association Strategic 2020 Goals.

As a reminder, this health metric includes smoking, BMI, physical activity, diet, blood pressure, total cholesterol and glucose, and higher levels indicate more ideal cardiovascular health and less cardiovascular risk.

So, they found that both cumulative psychosocial stress and ideal cardiovascular health varied by race or ethnicity. Mean cumulative psychosocial stress scores were higher in Hispanic, Black, and Asian women compared to white women, even after adjusting for age, socioeconomic status and psychological status such as depression and anxiety. The mean ideal cardiovascular health scores remained worse in blacks and better in Asians compared to whites, despite taking into account socioeconomic factors and cumulative psychosocial stress.

Dr Greg Hundley: So Carolyn, how should clinicians incorporate this information in what we do every day?

Dr Carolyn Lam: Although the cumulative psychological stress and socioeconomic status did not fully explain the racial or ethnic differences in ideal cardiovascular health that we saw, clinicians should be informed by these data that psychosocial stressors are social determinants of health that have different prevalence according to race and ethnicity. I think that's what we need to learn. And of course these data support the need for additional work that addresses the joint impact of multiple social determinants of health on cardiovascular disease and in diverse populations.

Dr Greg Hundley: Very good, Carolyn. That was really an interesting article. Well, I'm going to switch gears and talk about the role of red blood cells in promoting vascular calcification. My article is from Dimitrios Tziakas from the Department of Cardiology in Thrace, Alexandropoulos, in Greece.

Now, the presence of extravasated erythrocytes in human atherosclerotic lesions was described several years ago, but little is known about a possible active role of red blood cells during these cardiovascular disease processes. Clinical studies suggest that intraplaque hemorrhage may be associated with the progression of coronary, carotid, and atherosclerotic lesions and degenerative calcific aortic valve stenosis. So, in the present study, the authors examined the contribution of erythrocytes to vascular and valvular lesion progression, focusing on the effects of red blood cells on the osteoblastic transdifferentiation of smooth muscle cells in calcification.

Dr Carolyn Lam: Interesting. So, what did they find?

Dr Greg Hundley: So, lysed erythrocytes, and in particular their membrane faction, enhanced human and murine arterial smooth muscle cell mineralization and vascular aortic ring calcification. Red blood cell membranes injected in the vascular regions of atherosclerotic-prone mice also promoted calcification and red blood cells were found to co-localize with osteoblast like cells in human atherosclerotic plaques, stenotic aortic valves, and abdominal aortic aneurysms. And so, the study demonstrated that intra plaque hemorrhage promotes atherosclerotic and valvular lesion calcification and membranes of extravasated lysed red blood cells appeared to play an important role in the process. The investigators also showed a mechanism, that nitric oxide derived from erythrocyte endothelial nitric oxides synthase is involved, at least in part, in mediating the effects of red blood cells on vascular calcification.

Dr Carolyn Lam: Thanks, Greg. Now back to another, well, clinical paper with the next one asking, do mid-life biomarkers of heart and kidney damage associate with the level of and decline in physical capability with aging? Dr Kuh and colleagues from MRC Unit of Lifelong Health and Aging at University College London used data on 1,736 men and women from the oldest British birth cohort study. And, looked at their walking speed, chair rise speed, balance time, and grip strength. Assessed at ages 60 to 64 and 69 years. They tested the associations between Cystatin C, NT-proBNP, interleukin-6, and E-selectin all at ages 60 to 64 years with their performance at 69 years. And what they found was the lower levels of NT-proBNP in interleukin-6 in middle aged adults were independently associated with better physical capability up to nine years later. And all these associations were stronger than those observed for conventional risk factors: including lipids, blood pressure, and glycemia, and were not explained by the onset of cardio vascular and kidney disease or diabetes.

Dr Greg Hundley: Carolyn, is this saying we should now measure these biomarkers in mid-life?

Dr Carolyn Lam: Ah, before considering the use of NT-proBNP and IL-6 or interleukin-6 for risk stratification, we really do need further research to untangle whether these associations exist because the biomarkers are an integrated measure of accumulated exposures to stressors. Or, whether they are really capturing early an organ damage. Or, whether they are marking additional risk pathways. So, this and more is discussed in a great accompanying editorial entitled "Putting the Measurement of Physical Capacity in Older Adults in its Place". And that's by Dr Kritchevsky from Wake Forest School of Medicine.

Dr Greg Hundley: That's a favorite of my heart, Caroline. The old institution Wake Forest. But, I'm going to switch now and tell you a little bit about plasma ceramides and this is an article from Wei Zhao from the Department of Epidemiology in Population Health at Albert Einstein College of Medicine in Bronx, New York. The study evaluates the role of ceramides and what are those? Well, they're a class of bio-active lipids composed of sphingosines and fatty acids. And are involved in the development of cardiovascular disease. Elevated circulating levels of ceramides have been shown to be associated with increased risk of cardiovascular events, cardiovascular death, and even so, after adjusting for other cardiovascular disease risk factors. Now, interestingly, ceramide metabolism has long been noted to be closely related to HIV infection. But, the relationship has not been fully understood. HIV infected cells may cause enhancement of sphingomyelin volume breakdown and accumulation of intercellular ceramides, whereas intercellular accumulation is associated with enhanced replication of HIV.

So, what did this study do? They evaluated circulating levels of four ceramides species which have been investigated in previous studies of non-HIV populations. And were measured in 737 women and men, 520 HIV infected and 217 HIV uninfected from the Women's Intra-Agency HIV Study and the Multi-Center Aids Cohort Study. And they compared the relationships with the progression of carotid artery disease assessed by B-mode ultrasound over a seven year period.

Dr Carolyn Lam: Interesting approach. So, what did they find?

Dr Greg Hundley: Elevated ceramide levels were associated with anti-retroviral therapy use. Particularly, protease inhibitor use HIV infected individuals. All four ceramides were highly correlated with each other and significantly correlated with total cholesterol and LDL cholesterol. And of note, remember they were measuring four, but C16:0 and C24:1 ceramides rather that C22:0 and C24:0 ceramides were more closely correlated with specific modified activation and inflammation markers and, surface markers of CD4 t-cell activation. Elevated plasma levels of C16:0 and C24:1 ceramides were also associated with progression of carotid artery atherosclerosis. So, in summary, the results of this study provide new information on biological mechanisms that may involve the specific mono-site activation and inflammation beyond cardiovascular disease traditional risk factors like cholesterol levels. For the association between ceramides and CVD, particularly among individuals living with HIV infection.

Dr Carolyn Lam: Fascinating. Thanks, Greg. Now that sets us up for beautifully for our featured discussion.

Dr Greg Hundley: Welcome everyone, to our podcast. My name is Greg Hundley and we've got a very exciting paper for the second part of our program today. With us we have Dr Thomas Zelniker from Brigham and Women's Hospital. And then, also, a guest editor, Dr John McMurray from Glasgow, Scotland. We're going to be discussing a meta-analysis in type 2 diabetic patients. Thomas, can you tell us a little bit about the study population, your design, and what where the outcomes that you saw in this study.

Dr Thomas Zelniker: As you know, the last half decade, members of two drug classes, GLP1 receptor agonists and SGLT2 inhibitors, so our goal was to provide clear context by comparing or contrasting the benefit of these two drug classes, and in particular to investigate the potential heterogeneity in the treatment site between patients with and without atherosclerotic cardiovascular disease. For that reason, we performed meta-analysis of all randomized partially controlled cardiovascular outcome trials of GLP-1 receptor antagonists and SGLT-2 inhibitors. We included data from more than 77,000 patients, nearly 43,000 patients coming from the five GLP-1 receptor antagonist trials and approximately 34,000 patients coming from the three SGLT-2 inhibitor trials. We tried to compare patients with those with known established atherosclerotic cardiovascular disease with those that have multiple risk factors for but no evident ASCVD. And as you can see, our interests included MACE, or major atherosclerotic cardiovascular events, and its individual components, MI, stroke and cardiovascular death. And then we looked at hospitalization for heart failure and progression of kidney disease. The progression of kidney disease was defined as one of the broad composites consisting of new onset of macroalbuminuria, worsening of eGFR, end-stage kidney disease, or death due to renal cause. And then we also had a more narrow kidney outcome which excluded macroalbuminuria.

Dr Greg Hundley: Thomas, did you observe differences in the types of events between the two agents, as they would have impacted hospitalization for heart failure or the progression of renal disease?

Dr Thomas Zelniker: Right. So foremost both trial analyses reduced the risk of MACE, major atherosclerotic events, but the reduction of MACE was actually confined to those patients with atherosclerotic cardiovascular disease. We saw a 40% reduction in patients with known ASCVD, where neither of these groups reduced the risk of MACE in patients with only multiple risk factors but without ASCVD. Now, in terms of the individual components of MACE, both trial analyses reduced the risk of myocardial infarction cardiovascular death but only GLP-1 receptor agonist reduced the risk of stroke. In contrast, as SGLT-2 inhibitors vastly reduced the risk of hospitalization with heart failure by more than 30%, where there was only a non-significant 7% relative risk reduction with GLP-1 receptor antagonist.

GLP-1 receptor antagonists also reduced the broad kidney composite outcome. However, this effect was mainly driven by reduction macroalbuminuria. When excluding macroalbuminuria we found a non-significant relative risk reduction by 8% and this stands in contrast to a very robust relative risk reduction with SGLT-2 inhibitors of more than 45%.

Dr Greg Hundley: Thomas, you mentioned there was a difference in benefit for those with existing cardiovascular disease versus no-known cardiovascular disease upfront. What do you think the reason for that might be, and then did you have the same number of patients in the non-cardiovascular disease group? Did you have enough events in that group? And finally, do you think we might need to follow that patient population a little bit longer in time, to see those events as they didn't have pre-existing cardiovascular disease?

Dr Thomas Zelniker: These are fantastic points. I personally think it's biologically plausible that both drugs and receptors have the same benefit in both patient population to treatment effect may just require more time to become evident in patients with lower risk. You also mentioned a very good point, we had substantially more events in the patient cohort with ASCVD.

Dr Greg Hundley: Very good. So John, we want to turn to you now. Can you help us put those results of this study in perspective? Can you put this into context for us with other published reports using these particular ages?

Dr John McMurray: Certainly Greg, and I'd like to congratulate Thomas on what very important and very timely meta-analysis because, of course, what Thomas and his colleagues have done Greg, is to put all these studies together, to give us what meta-analysis does, which is much more power to look, for example, at components of composite outcomes, and we will in that way compare and contrast the differences and similarities between these two treatments. And as Thomas has mentioned, so interesting differences stand out but there are also some similarities that perhaps were not clear from the individual trials and I suppose the one that would perhaps stand out to me and might not have been realized by many of our readers, is myocardial infarction, that seems to be reduced to pretty much a similar extent by both GLP1 receptor antagonists and SGLT-2 inhibitors.

I think there had perhaps been a view out there from the individual trials, that maybe GLP-1 receptor antagonists have more effect on atherosclerotic events and SGLT-2 inhibitors more effect on heart failure and renal events and to some extent that's true, both agents seem to reduce myocardial infarction to approximately the same extent. Which in itself is interesting, perhaps raises some mechanistic questions. I mean, the differences that stood out is stroke is reduced by GLP-1 receptor antagonists but not by SGLT-2 inhibitors and conversely heart failure which is the opposite, which is by SGLT-2 inhibitors, but not by GLP-1 receptor antagonists in this meta-analysis.

So, I suppose, in summary what this tells us is that these drugs have complementary, perhaps additive cardiovascular benefits. Together, they potentially reduce the whole spectrum of the adverse cardiovascular events that occur in our patients with Type 2 diabetes, especially those who've got established cardiovascular disease.

Dr Greg Hundley: And so, just a last question here, for both Thomas and John, if you're considering in your practice, you have a diabetic patient that's not on these, one of these agents, and they have existing cardiovascular disease, how do you go about considering the addition or the switch to this type of medicine, and what practices do you use to effect that change?

Dr Thomas Zelniker: I guess, looking at patients, so we know that both drug classes have great benefits from MACE, right, but to people on antagonists having also reductions in stroke. So probably the associated risk is in the focus, I would probably rather go with the GLP-1 receptor antagonist. While looking at it from the heart failure perspective, or from the renal perspective, we see obviously bigger advantages attributed to inhibitors.

Dr Greg Hundley: And John, how about you?

Dr John McMurray: I would agree with Thomas' perspective, although I might add just a little caveat which is, of course, that the prevention of heart failure which is what, I think, the clear benefit of SGLT-2 inhibitors is, prevention of heart failure is different to the treatment of heart failure. So, patients at risk of heart failure sadly, an SGLT-2 inhibitor would make sense, but when it comes to patients with established heart failure event, of course we will get that answer because one of the great things about this recent incredible development of new therapies for diabetes, is that now there are now more studies underway including remarkable five trials in patients with different heart failure phenotypes, patients hospitalized, patients in the community, so we will learn a lot more about the use of these drugs, in particular cardiovascular populations.

Dr Greg Hundley: Excellent. I want to thank both Thomas Zelniker from Brigham and Women's Hospital and John McMurray, guest editor from Glasgow, Scotland for helping us work through this just fantastic meta-analysis study pointing us in a new direction for utilizing medications to treat diabetes and those that we see every day, with cardiovascular disease.

On behalf of Carolyn and myself, have a great week and we look forward to seeing you, next week.

Circulation April 16, 2019 Issue

15 april 2019 | 22 min

Dr Greg Hundley: And I'm Greg Hundley, also associate editor of Circulation and director of the Poly Heart Center at BCU Health in Richmond. Carolyn, we've got a really exciting interview to follow our coffee chat and it's evaluating individuals with low complexity congenital heart disease. We often think of those with high complexity congenital heart disease and looking at their cardiovascular events. We're going to hear a little bit about low complexity congenital heart disease.

Now you've got a paper you wanted to talk about first.

Dr Carolyn Lam: Absolutely. You've got to hang on for that because I'm going to delve into chromatin architecture in heart failure, and it's in this paper from corresponding author Dr Foo from Genome Institute of Singapore.

So, as background, the human genome actually folds in 3D to form thousands of chromatin loops within the nucleus encasing the genes and assists regulatory elements for accurate gene expression control. Now, these physical tethers of loops are anchored by the DNA binding protein CTCF, also known as the weaver of the genome and the cohesion ring complex. Now, the role of CTC in binding and changes in chromatin structure in heart failure are not well understood. Well, until today's paper.

What the author said is they undertook an independent analysis of chromatin organization with mouse pressure overload model of myocardial stress or transverse aortic constriction, and a cardiomyocyte specific knockout of CTCF. So, interestingly, they found that the cardiac chromatin architectural in adult terminally differentiated cardiomyocytes was unchanged in pressure overload from transverse aortic constriction. Now this was completely unlike the CTCF knockout model where they verified that there was generation of vast genome-wide loss of genomic insulation and near complete abolition of the CTCF chromatin loops.

Instead of chromatin rewiring on the scale of that knockout, the myocardial stress response appeared to proceed through enhancer H3K27 acetylation epigenetic changes and gene network co-regulation driven largely by fixed cardiac 3D chromatin architecture. In other words, a stable chromatin architecture really set the stage for accurate enhancer promoter interactions required for basal gene expression control and induction of the classical myocardial stress gene response.

Dr Greg Hundley: So Carolyn, are there therapeutic implications here for this?

Dr Carolyn Lam: Now of course, that was preclinical work, but it really opens the door to consider these epigenetic regulators that control disease expression changes and interacting gene sets in heart as potential future targets for novel heart failure therapy.

Dr Greg Hundley: Very interesting. So, I'm going to review and switch gears a little bit and focus on diabetic cardiomyopathy and mitochondria associated endoplasmic reticulin membranes. And this paper is from Shengnan Wu from the Center for Molecular and Translational Medicine at Georgia State University here in the US in Atlanta, Georgia. So as we all know, mitochondria are essential for cellular energy production, but when they're damaged, they become a major source of reactive oxygen species and pro-apoptotic factors. In particular, increasing evidence suggests that mitochondrial dysfunction is a central event in diabetic cardiomyopathy.

Well, the mitochondria and the endoplasmic reticulum are key players that regulate many cellular functions and their structural and functional interactions are essential for cellular homeostasis. The contact points, however, through which the endoplasmic reticulum communicates with mitochondria, they're known as mitochondria associated endoplasmic reticulum membranes, or MAMS. Importantly, MAMS play a pivotal role in calcium signaling, lipid transport, energy metabolism and cell survival, and they've been implicated in a variety of diseases, including Alzheimer's Disease, cancer, lysosomal storage diseases, diabetes, obesity induced mitochondrial dysfunction and other metabolic disorders.

But the role of these MAMS in the initiation and progression of Diabetic Cardiomyopathy is really unknown. So now, FUNDC1 is a highly conserved protein that's exclusively localized to the mitochondria. And this group had previously demonstrated that FUNDC1 was essential for maintaining the structure of MAMS and ensuring appropriate calcium transfer from the endoplasmic reticulum to the mitochondria normal hearts. Moreover, cardiac specific deletion of FUNDC1 induced cardiac dysfunction by inhibiting MAM formation.

Dr Carolyn Lam: Interesting. So that was their prior work? What did the current study show?

Dr Greg Hundley: Right, so what the investigator showed in this study is that high glucose driven inactivation of AMP-activated protein kinase increased FUNDC1 stability, but resulted in aberrant MAM formation, impaired mitochondrial calcium increase, mitochondria dysfunction and then cardiac dysfunction. And additionally, AMP-K activation reverses Diabetic Cardiomyopathy by suppressing high glucose induced MAM formation, mitochondrial calcium increase and mitochondrial dysfunction.

And interestingly, Metformin, an AMP-K activator, used exclusively for Type 2 Diabetes, might be effective in treating Diabetic Cardiomyopathy in individuals with Type 1 Diabetes. So a very interesting mechanistic study providing some information of how MAMS, mitochondrial function and endoplasmic reticulum could be important in understanding how to prevent Diabetic Cardiomyopathy.

Dr Carolyn Lam: Indeed. And you know, that last note that you made on Type 1 Diabetes, also links very well with the next paper that I chose. Which really asks the question, in Type 1 Diabetes, what are the relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes? And this comes from Dr Rawshani and colleagues from the Swedish National Diabetes register who studied more than 32,600 patients with Type 1 Diabetes in their national observational cohort study from the Swedish National Diabetes register, with a mean follow-up of 10.4 years and a mean duration of diabetes of 17.9 years.

They found that the most important predictors for outcomes were HP-A1C, albuminuria, duration of diabetes, systolic blood pressure and low-density lipoprotein cholesterol, or LDL cholesterol. Now, the lower levels of HP-A1C, systolic blood pressure and LDL cholesterol than contemporary target levels were associated with lower risk for outcomes. Albuminuria was associated with a two to four times greater risk of cardiovascular disease and death. And each millimole increase of LDL cholesterol was associated with 35 to 50% higher risk for outcomes.

Dr Greg Hundley: Boy, Carolyn, those are interesting results. So, what do we take away from this in clinical management of patients?

Dr Carolyn Lam: The take home message is that in patients with Type 1 Diabetes, the strongest predictors for mortality and cardiovascular disease, with the exception of age, were mostly conventional and modifiable cardio-metabolic risk factors. And this in turn suggests that increased clinical focus on these risk factors, particularly in primary prevention, may result in the largest relative risk reduction for mortality and cardiovascular disease, even in Type 1 Diabetes. So, future clinical trials may be designed to test these findings.

Dr Greg Hundley: Very good. Well, Carolyn, my next paper, I'm going to talk about five year outcomes after off-pump versus on-pump coronary artery bypass grafting in those over the age of 75 years. And this paper comes from Anno Diegeler from Bad Neustadt in Germany. From June of 2008 to September of 2011, they evaluated a total of 2,539 patients that were 75 years or older, who had been randomly assigned to undergo off-pump or on-pump coronary artery bypass grafting across 12 centers in Germany.

And the primary outcome was all cause mortality at five years, and the secondary outcome included a composite of death, myocardial infarction and repeat revascularization. What did they show in this study? Well, after a median follow up of five years, the hazard ratio for off-pump versus on-pump coronary artery bypass grafting was 1.03, confidence interval 0.81 to 1.19, no difference. The composite outcome of death, myocardial infarction and repeat revascularization, the same. Hazard ratio 1.03, confidence interval 0.89 to 1.18, P-value 0.7.

So, first take-home message, no difference if you had your surgery off-pump or on-pump, if you're over the age of 75. Now, another outcome related to incomplete revascularization. And what was striking I this study is whether you underwent on-pump or off-pump bypass, if you were incompletely revascularized, that was associated with both the primary as well as the secondary outcomes. So, in elderly patients, in summary, greater than or equal to 75 years, the five year survival rates as well as the combined outcome of death, MI and repeat revascularization, was similar for on-pump versus off-pump CABG. And incomplete revascularization was associated with a lower five year survival rate, irrespective of the type of surgery that was performed.

Dr Carolyn Lam: Interesting. Beautifully summarized, Greg. Thank you.

Dr Greg Hundley: Absolutely. And let's head on to that featured article.

Well, welcome everyone to the second half of our program. We are very excited today to have Dr James Priest, from Stanford University School of Medicine. And also our associate editor Gerald Greil from University of Texas Southwestern School of Medicine in Dallas. And we're going to be discussing the article, Substantial Cardiovascular Morbidity in Adults with Lower Complexity Cardiovascular Disease.

So, James, first could you tell us a little bit about what constitutes low complexity congenital heart disease? And then a little bit about your study population, your design, and the results that you found with your study?

Dr James Priest: So, low complexity congenital heart disease really derives from definitions of congenital heart disease in adults that are grown up and have different complexity of lesions. And so high complexity congenital heart disease, you see things that, as people may remember, adult cardiologists may remember from their training. People remember from medical school, things like single ventricle disease, hypoplastic left heart, tetralogy of fallot, transposition of the great arteries. But, non-complex, so our low complexity disease, really constitutes a relatively simple malformation. Things like atrial septal defects, ventricular septal defects, patent ductus arteriosus. Things that are treatable with a single surgery.

You close the hole, you ligate the vessels, you dilate the valve, and the patient is affectively cured. So relatively low complexity diseases that can be treated with typically, a single surgery or minimal interventions to restore completely, or essentially normal, cardiovascular physiology.

So, the study was based upon a very large you know, volunteer data set, the UK Biobank. It comes from the United Kingdom where 500 thousand individuals enrolled, and from those individuals there is genetic information, medical histories dating back to the 1990s, self-reported history. A variety of functional and neuropsychiatric measures. And if you get a group of 500 thousand individuals from anywhere, there's going to be some congenital heart disease in there. And so, we looked to see what types of congenital heart disease were in there. And in fact, there was lower complexity individuals.

And because I spent some time on the research side of things with my adult colleagues, the first thing we looked at were from the common adult cardiovascular outcomes, things people write about in Circulation all the time. Coronary artery disease, atrial fibrillation, heart failure. We know these things are problems in adults with complex cardiovascular disease, but nobody had really looked for the most part in adults with low complexity or non-complex disease. And we were surprised to see such high event rates for these common adult cardiovascular conditions.

Dr Greg Hundley: So, what type of events did you appreciate in the population in follow up?

Dr James Priest: So, we really appreciated about a two-fold rate of let's say, acute coronary syndrome relative to the general population. Up to almost 13 fold risk of atrial fibrillation and heart failure, relative to the general population. So, really substantial and very impactful event rates.

Dr Greg Hundley: Very good. And so, just a couple points of clarification. Do you think that the events you observed, were they related to the congenital heart disease, per se? Or could it have been a result from the surgical procedure to treat that heart disease?

Dr James Priest: So, that's a great question. I think, in some ways, that's the fundamental question that the paper leads to. So, we thought of it in two different ways. You know, one, were these events, and they're perioperative events, for individuals receiving some type of care for their congenital heart disease, during their adulthood? And we performed a sensitivity analysis where we basically looked at those events and then looked for events occurring within a year of adult interventions. And we saw no difference in those event rates. So, they weren't perioperative or postoperative events in adults receiving adult congenital heart disease care.

The second part of the question is really more of an existential question in some ways. You know, is there some fundamental relationship between the care these people received as children? Or the genetic basis of congenital heart disease in the first place that is somehow put people at risk long term for adult cardiovascular disease, acquired adult cardiovascular disease? And I think there's indeed a lot of different ways to try and get at that question and explore that more, which we're currently working on.

Dr Greg Hundley: So, Gerald, I wanted to turn over to you now and, in your practice that encompasses those that are young adults that have this low complexity congenital heart disease, how do you manage them now? And how might the results of this study suggest, potentially, a different management strategy?

Dr Gerald Greil: Usually these patients, they're kind of thought to be cured or only needed minimal follow up in the past. So, if you take a patient with a VSD, rarely during childhood, young adult or even kind of in 20s and 30s, you have any major difficulties. And as a pediatric cardiologist, you rarely experience any major follow up problems with these patients. I think, particularly in the US, and I work actually for more than 10 years in the UK, the problem in the US is how can you organize follow up in these patients?

There're insurance issues, there're issues about moving into different areas, and since these patients were kind of labeled as being healthy and close to normal, they were lost for follow up, particularly in the US. I think this study raises some concerns, we should probably be more careful and cautious and follow these patients up kind of in a lifelong session. And take care of them. This is definitely something, which is a new finding, and what the cause is, how we are following up, that's the question. I guess it could be a good question for future studies.

Dr Greg Hundley: You mentioned future studies. Specifically, what type of future studies do you think we need to perform next? This shows us that the events are occurring, are we ready yet for randomized trials to perform prevention? Do we need studies that have more frequent observation? What are your thoughts there? And I'll get your answer and then we'll come back to James and get his thoughts on the same question.

Dr Gerald Greil: Yeah, I think the major thing is we need close follow up of these patients. And it will be a combined effort between pediatric and specialized adult cardiologists, with a special interest in patients with congenital heart disease. Once again, coming back to it, a closer follow up is a little bit dependent on the medical system, which you have. If you take Canada and the UK, it may be easier in these patients are under close follow up. And this allows large multicenter studies, large data bases like UK Bio Bank are kind of exemplary. And we should try to get something similar within the US or in other countries.

I think that's the lesson what we take from that, we need larger data bases, probably more granular than what we have right now. I mean, James probably can comment in a second about the shortcomings and what can be done better in the UK Bio Bank to allow more detailed conclusions than we have currently from his study.

Dr Greg Hundley: James?

Dr James Priest: I would agree with that. I think as a person who does not, clinically speaking, take care of adults with congenital heart disease, my colleagues and I, or I have the impression from my colleagues that for most of the time, in most of these patients in the Unites States adults who had VSD or ASD repair as a child, they were essentially said, oh, you're cured. And they perhaps had some follow up during childhood, but then were otherwise discharged to live the rest of their lives.

And so, in many cases I'd say the first step before performing any studies is to simply identify who these patients are, and figure out you know, what their risk factors otherwise for cardiovascular disease might be. Now, that being said, I think that was one of the powerful things about the UK Bio Bank study is that there's a large population in which all these traditional cardiovascular risk factors you know, obesity, lipid levels, hypertension, smoking status, all these things were uniformly measured in both the individuals with congenital heart disease, the adults with congenital heart disease. And of course the control population.

And so that allowed us to make some estimates about what proportion of disease was attributable to these traditional cardiovascular risk factors. And what was attributable to other factors related, potentially, to the congenital heart disease. But all those things being said, I think the first questions that I often to tend to receive about these studies from the pediatric cardiologists and the adult congenital heart disease doctors, reflects the sorts of data sets that we're used to looking at.

Well, what sort of an intervention did this person have? Did they have a ventriculostomy? When did they receive their diagnosis and their repair? Details of the surgical care and the perioperative of course, are not available in this data set because it's not a particularly pediatric cardiology focused data set. It's a broad population based data set. And so the relationship specifically the details of their perioperative care and diagnosis are not able to be attained. And so we'll need larger data sets that include that information to fully start to develop those sorts of relationships over time.

Dr Greg Hundley: So, we want to thank our lead author, Dr James Priest from Stanford University School of Medicine, and our associate editor, Gerald Greil from the University of Texas Southwestern Medical School in Dallas. And reviewing this very interesting article on lower complexity cardiovascular disease and its association with an increased risk of cardiovascular events. And thank you both so much for clarifying. It sounds like an opportunity to collect more data through registries, et cetera, that we may need to expand around the world.

Thank you everyone for listening to Circulation on the Run. Remember that's your back stage pass to our journal. And we'll see you next week.

Circulation April 9, 2019 Issue

8 april 2019 | 24 min

Dr Greg Hundley: And I'm Greg Hundley, also associate editor from VCU Health Systems, the Poly Heart Center in Richmond, Virginia.

Dr Carolyn Lam: So arrhythmogenic cardiomyopathy that will make most of us think of right ventricular disease and fatty infiltration of the muscle, but could arrhythmogenic cardiomyopathy really be a bi-ventricular disease? Well you've got to stay tuned to find out more in a fantastic interview coming right up after our little coffee chat. So Greg, what are your picks this week?

Dr Greg Hundley: My first paper is from Chris Lim at NYU in New York. And it's looking at the relationship between Mediterranean diet, air pollution and cardiovascular events.

So, it's unknown whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes. And so, in this large cohort with detailed diet information at the individual level, they had 548000 individuals across six states and two cities within the U.S. and a follow up period of 17 years. And that occurred between 1995 and 2011. And they evaluated whether a Mediterranean Diet modified the association between long-term exposure to ambient air pollution and then cardiovascular disease and mortality risk. And so, the average exposures to parts per billion and nitric oxide air pollution that the residential census track level were measured, and the investigators found that for the particulate matter there were elevated significant associations with cardiovascular disease. So, a hazard ratio of 1.13, ischemic heart disease similar hazard ratio and cerebrovascular disease with also a similar hazard ratio.

For the nitric oxide, there were also significant associations with cardiovascular disease, as well as ischemic heart disease. And then the analysis indicated that Mediterranean diet modified the relationships. Those with a higher Mediterranean diet score had significantly lower rates of air pollution related mortality. These results therefore indicate Carolyn, that Mediterranean diet reduce cardiovascular disease mortality related to long-term exposure to air pollutants in a large perspective, U.S. cohort. Can you believe increased consumption of foods rich in antioxidant compounds actually may aid in reducing the considerable disease burden associated with ambient air pollution?

Dr Carolyn Lam: Oh wow. That is hugely interesting. Gosh, what do we do about this clinically now?

Dr Greg Hundley: Remember, first of all, this is an associate study, so we can't infer cause effect. And what we need next are some more independent studies from other cities around the world, prospective cohorts, examinations of clinical outcomes and randomize interventions. And so, I think the results add to a growing body of literature suggesting that dietary patterns may help reduce cardiovascular events in these high air pollution exposure areas. And how does this work? Well, potentially through augmenting antioxidants and reducing oxidative stress.

Dr Carolyn Lam: That's really cool. So from one region, talking about air pollution to another region that often reports about air pollution and that's China. But this study from China is actually the largest registry study to evaluate sex related differences and hospital management and outcomes of patients with acute coronary syndrome in China.

This is from corresponding author Dr Zhao from Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease. With colleagues of the improving care for cardiovascular disease in China, Acute Coronary Syndrome project, which is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. So, the authors use data from this project and evaluate at sex differences in the acute management, medical therapies for secondary prevention and in hospital mortality in more than 82000 patients admitted for acute coronary syndrome in 192 hospitals across China from 2014 to 2018.

Dr Greg Hundley: What did they show in this study?

Dr Carolyn Lam: They showed that women hospitalized for acute coronary syndrome in China less frequently received acute treatments and strategies for secondary prevention and had a higher in hospital mortality rate than men. Now the observed sex differences in this in hospital mortality were likely due to older age, worse clinical profiles and fewer evidence base acute treatments provided to women. And that's because the sex differences were no longer observed after adjustment for these clinical characteristics and acute treatments.

What this all means though is specifically targeted quality improvement programs may be warranted to narrow these sex related disparities in patients with acute coronary syndrome in China.

Dr Greg Hundley: Very interesting. I'm going to take sort of the next paper and it's looking at a different aspect of acute myocardial infarction. And these papers from Yong Wang from the Division of Molecular and Translational Cardiology at Hannover Medical School in Hanover, Germany.

Now as we know, the heart can undergo deleterious changes and left ventricular geometry and function during that vulnerable period before scar formation has stabilized the infarct area. And so inflammatory cell trafficking from hematopoietic organs like the spleen to sites of tissue injury is coordinated by chemokine chemokine receptor networks. Therapeutically modulating these chemokine chemokine receptor interactions may promote infarct healing by limiting excessive inflammation induced tissue damage or by enhancing the recruitment of angiogenic cell populations to the infarct or the wound. Inflammatory cell trafficking after a myocardial infarction is controlled by a CXC motif chemokine ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor 4. CXC receptor 4 antagonists, mobilize inflammatory cells and promote infarct repair. But the cellular mechanisms are unclear.

So, what do these investigators do? In mouse models, the investigators found that inflammatory cell trafficking between a hematopoietic organs and sites of tissue injury is controlled by CXCL12 and its receptor CXC receptor 4. And bolus injectives of a highly selected peptidic macrocycles CXC receptor 4 antagonist, enhanced tissue repair and functional recovery after re-perfused acute myocardial infarction in mice. And interestingly, the therapeutic effects require a dendritic cell priming and we're specifically mediated by t-regulator cells. Intermittent CXC R4 blockade mobilized the t-regulator cells from their splenic reservoir. Leading to their enhanced recruitment to the infarct region.

Dr Carolyn Lam: So bring it home for us, Greg. What does this mean clinically for MI management in humans?

Dr Greg Hundley: Right. Highlighting the translational potential. What we might infer is that CXC receptor 4 blockade reduces infarct volume and improved systolic function in a porcine close chest model of re-perfuse acute myocardial infarction.

And so, the results of both the mouse experiments and this sort of translational model in pigs should stimulate further research into therapeutic potential of CXC R4 blockade after MI and in other acute conditions were excessive, innate or adaptive immune responses cause immunopathology.

Dr Carolyn Lam: Fascinating. So from one preclinical paper to another, but this time focused on heart failure. And focus specifically on titin. Titin is this giant elastic protein that spans the half-sarcomere from the Z-disk to the M band, and it acts like a molecular spring and a mechanosensor that has been linked to striated muscle disease. Now the pathways that govern tight independent cardiac growth and contribute to disease are diverse and have been really difficult to dissect. And so corresponding author Dr Gotthardt, from Max Delbruck Center for Molecular Medicine and the German Center for Cardiovascular Research and his colleagues aimed to study titin deficiency versus titin dysfunction.

And how they did that is they generated and compared striatum muscles specific knockouts with progressive postnatal loss of the complete titin protein. And that's by removing Exxon 2. Or an M-band truncation that eliminates the proper structure and integration, but retains all the other functional domains. So they then evaluated cardiac function, cardiomyocytes mechanics, and the molecular basis of the phenotype. Now, what they found was that progressive depletion of titin led to sarcomere disassembly an atrophy in striated muscle. And in the complete knockout, remaining titin molecules had increased strain resulting in mechanically induce trophic signaling and eventual dilated cardiomyopathy.

On the other hand, the truncated titin helped maintain passive properties and thus reduced mechanically and do signaling. In other words, truncations versus loss of titin, differentially affected cardiac pathology with atrophy versus dilated cardiomyopathy respectively. And together, these findings really contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications importantly for genotype, phenotype relations that support a personalized approach to the diverse titinopathy.

Dr Greg Hundley: Interesting, Carolyn. All this information on titin. So why is it clinically important?

Dr Carolyn Lam: Well, first of all, tightened mutations are the most common genetic basis of heart disease and the findings are clinically relevant, as I said, for understanding the genotype phenotype relations at the Titin mutation. But understanding the integration of Titin based signaling and sarcomere biology could indeed help personalize diagnostics by improved clinical decisions and maybe identify suitable therapeutic targets for these titinopathy. But that of course requires much further work. Well that brings us to the end of our summaries. Let's go to our feature discussion.

Dr Greg Hundley: Welcome everyone to our second segment of our program. We're discussing an interesting paper today entitled Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. And we want to welcome our coauthors Elijah Behr and Mary Sheppard from St George's University in London. And also, our own associate editor, Sami Viskin to discuss this paper. Mary, can you tell us a little bit about your study design here, the population and the hypothesis and some of your results?

Dr Mary Sheppard: I am a cardiac pathologist of 20 years and I have a special interest in sudden death. Over this time, I've established a national pathology database, where pathologists throughout the country when they have a sudden death, which is likely cardiac and non-ischemic, they will send the heart or tissue blocks insides to me for my opinion concerning the death. We have as a result developed a large number, over 5200 cases which has now built up to 6000. It's the largest pathological series in the world.

And I was also discovering the pathologists were either under or over diagnosing all types of cardiomyopathy but particularly ergogenic cardiomyopathy. And that is why with Chris Miles, our research fellow, we looked in detail at what I had diagnosed, or the pathologist as ergogenic cardiomyopathy and we actually honed are pathological diagnostic criteria for this very important entity. Establishing that left ventricular is five and ventricular and left and ventricular is the norm almost. That right or left ventricular is unusual by themselves and even in 20%, one in five, the heart can look macroscopically normal. So that histology is essential when you're making this diagnosis. You cannot make the diagnosis pathologically without histologically examining the heart.

Dr Greg Hundley: Very good, Mary. And did you also examine some genetic markers in some of the subsets of the patients? And how did you decide who those individuals would be that received the genetic analysis?

Dr Mary Sheppard: A small subset and I will hand over to Elijah Behr, my colleague concerning that.

Dr Elijah Behr: The genetic tissue is only available in a minority of cases. We've developed a pipeline now with the referring pathologists who are increasingly they're sending samples of spleen suitable for DNA extraction that allow us then to do a retrospective postmortem genetic testing or molecular autopsy. But unfortunately, in this particular series we only had a small proportion. I think there were roughly about 24 out of the 202 cases, so just over ten percent. And interestingly, while we didn't necessarily mirror the expected yield of genetic testing that is seen in clinical cases, where you may see about 40% carrying pathogenic variance. We certainly picked up some important pathogenic variance, particularly those that are often associated with highly penetrant and more severe disease. In particular TMEM43 and desmoplakin. These findings may reflect the small size of the sample, but it also may reflect where the greatest risk for sudden death from ergogenic cardiomyopathy lies.

Dr Greg Hundley: Elijah, getting back to some of the patients that experienced the sudden death in the study population Mary was referring to, were there characteristics that were associated with the sudden death? For example, those that might be related to gender or activity?

Dr Elijah Behr: So the majority of the cases were male. The majority has never had prior symptoms. These were unheralded deaths. The majority did not have a family history and I think the majority were addressed, but those that were athletes, we're much more likely to have died during exertion. So as we found with ergogenic cardiomyopathy in general and exertion is a trigger to sudden death. The risk was higher and compared to the athletes in death during exertion was associated with being younger as well. I think exertion and sports clearly play a role in ergogenic cardiomyopathy. It didn't appear to play a role in whether there was left ventricular involvement or not, but certainly a role at more severe presentation.

Dr Greg Hundley: Maybe both Mary and Elijah answering this. You found histopathological evidence of fibrosis and fatty infiltration. How extensive was that? And do you think that could be identified with a test like maybe magnetic resonance imaging?

Dr Mary Sheppard: Yes. Our diagnostic criteria which is illustrated in the addendum is that it was at least two blocks of tissue. We always look at 10 to 12 to 15 blocks of tissue from both right and left ventricle. And at least two of the blocks had to have fibrosis with fat in 20% of the area examined. We did not include inflammation because inflammation is, an important histological criterion in our experience. We were very precise about that because you need that much at least to make the diagnosis. A little bit of fibrosis or a little bit of fat is not sufficient by itself.

Dr Greg Hundley: When you mention a block, for us clinically, how much myocardium would that be? For example, on an imaging test like an echo or an MRI scan.

Dr Mary Sheppard: One to two centimeters squared.

Dr Greg Hundley: So quite a bit.

Dr Elijah Behr: You're looking at probably around two to four millimeters of potential depth of fibrosis. And what we've seen clinically in LV involvement of MRI scans is miss two epicardial late enhancement. Now the question is whether our scans are sensitive enough to pick that up? Given the technology available or a sense to the histopathology and I think that's why maybe some of the clinical studies have tended to miss the true proportion of left ventricular involvement. Because of the relative subtlety of the fibrosis compared to the technological ability to discriminate it. I mean certainly when you look at our cases that were diagnosed previously with cardiomyopathy, either they were arrhythmogenic or dilated, many did have imaging findings if MRI was performed, that would indicate or suggest some left ventricular involvement. But as you know, the task force criteria for arrhythmogenic cardiomyopathy having very much right ventricular focus. An LV imaging findings and LV ECG findings are just not part of those at the moment.

Dr Greg Hundley: Was there a particular location within the heart where there was a predilection toward the findings of fibrosis and fat?

Dr Mary Sheppard: In the posterior basal wall particularly, transmural involves going from the epicardium to the sub endocardium and also the interior walls of the left ventricular were the predilection areas.

Dr Elijah Behr: I think that's what we see on our MRI scans as well. When you look at these patients, that posterior basal area, is the one that tends to light up the most.

Dr Mary Sheppard: It is believed that increased stress in that area gives more damage because of the stretching away from the septum.

Dr Greg Hundley: Very interesting. So Elijah, you had mentioned task force criteria. I want to shift to Sami now and ask, Sami, can you help us put this in perspective relative to the existing task force criteria and then the findings in this study? And how that could lead to subsequent changes down the road?

Dr Sami Viskin: Okay, so it is difficult to place this in the context of the task force because mentioned by Elijah, the taskforce are focused on a disease that is believed to be in the right ventricle. And the study shows that many of the sudden death cases will involve the left ventricle. One of the most important messages of this paper is importance of her forensic examination. And importance of making it for anything examination in the center of expertise. We know of patients that will travel a thousand miles to undergo surgery or an ablation procedure, but families do not think that way when there is casualty or family dies. You may take a postmortem as a given, but in many countries, including my own, most cases of sudden death would not be followed by a post mortem and will not go into center of expertise. And you cannot overemphasize the importance of doing that because then you have to know what you are looking for in the remaining relatives is extremely important.

Dr Greg Hundley: Very good. How about from the perspective as an electrophysiologist? Does this impact in any way how you might evaluate a younger person with syncope?

Dr Sami Viskin: Well, it is difficult to conclude from this paper about how to evaluate patients with syncope because most of the cases in this series don't have symptoms at all. But this paper calls to very interesting investigations by Mario del Mar and others in New York. Looking about the electrophysiology consequences of a disease like right ventricle are like a bit mechanical in [inaudible 00:21:58] The tissues becomes editing the disease, the electrical properties how the patients in brugada can cause malfunction of this sodium channel and create a disease that is more like brugada and dysplasia at the beginning. So, the entire correlation between a morphologic disease and the metrical disease and we used to think they are two different things. And now we see that we can actually put them together and you can go through stages where one disease is before an electrical disease and only at later stages it becomes a morphological evident disease.

Dr Greg Hundley: A fantastic discussion on pathologic findings. Sami making the point that certainly in cases for young individuals having a postmortem examination performed at centers that have expertise such as what Mary's described, can be very important. And then Elijah, helping us to understand with arrhythmogenic cardiomyopathy, number one, findings are not, we shouldn't just be thinking about the right ventricle in isolation, but also the left ventricle. Fibro fatty infiltration, particularly in the posterior basal wall could be an important thing to look for, for those that are performing the magnetic resonance imaging exams. And then lastly, many of the patients in the study like this, the first presentation was of sudden death. And we need to be cognizant that this condition could be prevalent in the population and not necessarily appreciated by some of our current task force guidelines and examinations. So, what an outstanding discussion. And I think for today, we want to thank our authors and our associate editor and wish everyone a great week.

On behalf of Carolyn and myself, we look forward to seeing you next week. Thank you very much.

Circulation April 2, 2019 Issue

1 april 2019 | 24 min

Dr Greg Hundley: And I'm Greg Hundley, also associate editor in Richmond, Virginia at VCU Health.

Dr Carolyn Lam: So, PCI or no PCI for chronic total occlusion. That is a perennial question, and we have the results of the decision CTO trial reported in this week's Journal. In fact, we're going to discuss it right after our little chat here.

So, Greg, why don't you kick us off? What paper did you choose?

Dr Greg Hundley: Yeah, thanks so much Carolyn. My first paper is from Laura Benschop from the Department of Obstetrics and Gynecology at Erasmus Medical Center in Rotterdam, the Netherlands. It's going to focus on placental growth factor as an indicator of maternal cardiovascular risk after pregnancy.

So, as we all know, pregnancy is accompanied by extensive maternal hemodynamic changes that allow for proper placental implantation, growth, profusion, and fetal development and this process requires a tight balance between pro-angiogenic factors like placental growth factor, and anti-angiogenic factors like soluble FMS like tyrosine kinase factors. So, in response to stress, the syncytiotrophoblast will decrease the production of placental growth factor and women with reduced placental growth factor and increased FLT-1, are more at risk of a complicated pregnancy. For example, like preeclampsia and spontaneous preterm birth.

So, angiogenic placental growth factor concentrations can rise during pregnancy, peaking at the end of the mid-pregnancy. And low placental growth factor concentrations during pregnancy are associated with pregnancy complications with recognized later life cardiovascular risk. So here, the authors hypothesize that low placental growth factor concentrations, especially in mid pregnancy, identify not only a subset of women at risk for pregnancy complications, but also women with greater cardiovascular risk factor burden after pregnancy, regardless of their outcome.

So, among 5,529 women, the authors computed gestational age adjusted and mid-pregnancy placental growth factor concentrations and pregnancy complications, like preeclampsia, small for gestational age, spontaneous preterm birth, was obtained from hospital registries.

Dr Carolyn Lam: Cool, and what did they find?

Dr Greg Hundley: So six years after pregnancy, the authors found that women with mid pregnancy low placental growth factors, in the lowest quartile, had larger aortic diameters, left atrial diameters, and LV mass, and a higher systolic blood pressure by an average of 2.3 millimeters of mercury. High mid-pregnancy placental growth factor concentrations were the opposite. They were associated with smaller aortic diameters, smaller left atrial diameters, lower LV mass by 3.9 grams, and lower systolic blood pressure. And these differences persisted after exclusion of women with complicated pregnancies.

So, the results suggest that a woman's response to the cardiovascular changes of pregnancy, measured by pre-mid-pregnancy placental growth factor levels could provide insight into the path of physiological mechanisms leading to future cardiovascular disease in multiparous women.

Dr Carolyn Lam: Wow. That is really interesting. Well, the paper I chose really answers the question, are there racial differences in sudden cardiac death, and why? And this is from corresponding author Dr Guallar from Welch Center for Prevention, Epidemiology, and Clinical Research in Johns Hopkins Bloomberg School of Public Health and Colleagues.

What they did is they compared the lifetime cumulative risk of sudden cardiac death among blacks and whites in the atherosclerosis risk in community study, or ARIC. They evaluated the risk factors that may explain racial differences in sudden cardiac death risk in this general population.

What they found was that blacks had a much higher risk of sudden cardiac death in comparison with whites, with a sex adjusted hazards ratio of 2.12. Known factors explained 65% of the axis risk of sudden cardiac death in blacks compared to whites. The single most important factor explaining this difference was income, followed by education, hypertension, and diabetes. These racial differences were evident in both genders, but stronger in women than men.

Dr Greg Hundley: Hmm. So are there implications, and are there potential strategies that could help reduce this risk in African Americans?

Dr Carolyn Lam: Yeah, this is a really interesting study, and it really implies that efforts to reduce the sudden cardiac risk in blacks should perhaps focus on improving CPR outreach, medical care engagement in response to cardiac arrest, the quality of treatment in medical institutions in predominantly black neighborhoods, and factors such as that. Because remember the single most important factor explaining the difference was actually income and education.

Dr Greg Hundley: Oh, wow. Well, I'm going to switch gears a little bit here Carolyn, and we're going to talk about pulmonary hypertension. And this next paper is going to focus on pericytes. We'll learn a little bit about what pericytes are. So, the paper is from Vinicio de Jesus Perez, who's an assistant professor of medicine and pulmonary critical care at Stanford University Medical Center in California.

What are pericytes? So, pericytes are specialized perivascular cells embedded in the basement membrane of blood vessels, where in conjunction with neighboring and endothelial cells, they support vessel maturation and stability. In the lung, pericytes are mostly found associated with small precapillary arteries, the capillaries, and then those post capillary venules. And it's thought that pericytes are responsible for regulation of vasomotor tone and structural support of these micro-vessels. When the vessels become muscularized, pulmonary vascular resistance increases, resulting in pulmonary artery hypertension.

So recent studies have focused on pericytes in addition to pulmonary endothelial cells, smooth muscle cells, and fiberglass, but not much is known about the contribution of pulmonary pericytes to pulmonary arterial hypertension. Two genes are involved in Wnt planar cell polarity pathway that is responsible for coordinating complex cell movements during tissue morphogenesis. So, in this group, they have produced prior results that show that restoration of the Wnt planar cell polarity in pulmonary arterial hypertension, pericytes could partially restore recruitment to PNVECs and increase vessel stability.

Dr Carolyn Lam: Interesting, and so that was their past research, and what did the current paper show?

Dr Greg Hundley: Right. So Carolyn, what they found is that pulmonary microvascular endothelial cells isolated from pulmonary arterial hypertension patients, and endothelium from pulmonary arterial hypertension tissue have reduced expression of Wnt-5a. Healthy PMVECs produce and package Wnt-5a in the form of exosomes which regulate pericyte recruitment, motility, and polarity.

And so, the overall implication is that promising therapeutic strategies that help can restore the Wnt/PCP, or planar cell polarity pathway, and endothelial pericyte communication could help prevent micro-vessel loss in patients with pulmonary artery hypertension.

Dr Carolyn Lam: Thanks, Greg. So, I'm going to take us to the cath lab for this next paper. And it's the results of the CANTIC study, which aimed to answer the question, does intravenous P2Y12 inhibitor Cangrelor have a role in bridging the gap in platelet inhibition in patients with STEMI undergoing primary PCI. And this is from corresponding author Dr Angiolillo from the University of Florida College of Medicine Jacksonville and Colleagues.

Now, CANTIC was a prospective randomized double-blind placebo control parallel design investigation of the pharmacal dynamic effects of Cangrelor versus placebo in patients undergoing primary PCI, who were also treated with crushed Ticagrelor. So, after diagnostic angiography, patients were randomized to a blinded two-hour infusion of either Cangrelor or placebo. At the same time, 180 milligrams of crushed Ticagrelor was administered to both groups. Platelet reactivity was measured with Verify Now P2Y12 point of care testing, and with vasodilator-stimulated phosphoprotein, or VASP.

Dr Greg Hundley: So what did the trial show, Carolyn?

Dr Carolyn Lam: They found that addition of Cangrelor led to more prompt and potent platelet inhibitory effects, compared with crushed Ticagrelor alone in patients undergoing primary PCI. The significant differences were observed as early as five minutes post bolus administration, and persisted until the end of its two-hour infusion.

Furthermore, after discontinuation of Cangrelor or the placebo infusion, there were no differences in levels of platelet reactivity between groups. And this importantly rules out a drug/drug interaction when Cangrelor and Ticagrelor are concomitantly administered. This lack of drug-drug interaction is important, as it supports a more versatile use of Ticagrelor with respect to timing of its administration in patients treated concurrently with Cangrelor.

Overall, the results are reassuring and demonstrate reduced platelet reactivity, and no high on treatment platelet reactivity with Cangrelor in combination with Ticagrelor in primary PCI patients. Of course, the implications of these pharmacal dynamic findings really warrant investigation in an adequately powered clinical trial.

And that brings us to the end of our summaries. Let's go to our featured discussion.

So PCI, or no PCI for chronic total occlusion, that is a perennial question isn't it? Especially nowadays when procedural results for PCI and CTO have improved in recent years, and PCI strategies have moved towards more complete revascularization. Yet the evidence is clearly lagging behind for us to make decisions on this. And that's why we're so happy that our featured paper today is the DECISION-CTO trial from Korea, and so happy to have the first author, Dr Seung-Whan Lee from ASA Medical Center to tell us about this, as well as our associate editor, Dr Manos Brilakis from UT Southwestern.

So Dr Lee, could you tell us about the DECISION-CTO trial?

Dr Seung-Whan Lee: Yeah, in our trial our multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either one of two strategies; PCI or no PCI or CTO. We did the option for PCI of the other. The primary endpoint as you know the composite outcome of deaths, myocardial infraction, stroke, or any revascularization. As related to quality of life was assessed up to three years. However, because of the slow recruitment, the trial was stopped before completion. We started 208 planned enrollments. For six years 834 patients there were randomly assigned to the CTO PCI versus no CTO PCI strategy.

Among the patients assigned to the no CTO PCI strategy, nearly 20 percent of patient cross over to the CTO PCI. That is our big limitation, as you know. Anyways, the primary end point was assessed per year, and then, finally, we founded the per year risk of the major adverse cardiac events there’s no difference in contributor composite outcome, MI, revascularization, and stroke.

However, in our trial, in some detail, in CTO PCI was success rate around 91 percent. However, complication is very low, .6 percent of patient is complication. Very surprisingly the coheir is up to the three, and no difference between CTO PCI versus no CTO PCI.

I think our main message is our patient is a relatively low-risk population, including the syntax score 20 and the score 22%. The majority of patient preserved LV function and single-vessel disease 25%. The relative low risk population CTO PCI versus no CTO PCI clinical outcome is no difference of the per year from the two groups.

I think that our trial is make the reposition with the medical law in the CTO patient. That’s my summary.

Dr Carolyn Lam: Thank you. Manos, could you maybe paint the background and let us know why this was so important for us to publish in Circulation? Why is it so difficult to do these trials?

Dr Manos Brilakis: This is the largest study on CTO PCI so congratulations on getting this accomplished. I know it was many years and a lot of effort.

I think a couple of things on the background. As Dr Lee said as well, CTO PCI success rates have been improved, and now at experienced centers you can get 85 to 90 percent success fairly consistently.

The complication rates are low. .5 to 3 percent is the average rate. We do have a tool right now. The procedure is mature, and it's time test in the randomized trials.

The question has always been for CTO PCI, "How does it help?" Does it improve symptoms? Does it improve the heart outcomes? Myocardial Infarction? This is what DECISION CTO was trying to answer.

Couple of I think limitations that we should take into account when interpreting the results. The first one is that these were notations with an isolated CTO, but a significant proportion had also multi-vessel disease. They were enrolled before treating the other vessels, which were subsequently treated.

Sometimes it's hard to know how much the residual ischemia or symptoms would be present after the other lesions were treated. That's one thing.

The second is that there was a significant crossover for about 1 in 5 patients that randomized to medical therapy immediately crossed over to the CTO PCI group. And that always uses the power and creates difficulty in interpreting the results.

In my mind, the question still remains, in low risk populations it's possible that CTO PCI doesn't improve symptoms, but the ones that were expected to improve, the heart outcomes dec-MI, would be the high-risk patients with significant ischemia. Ideally, studies in the future should actually look specifically at patients who have high ischemia, significant symptoms when looking at heart outcomes.

Dr Carolyn Lam: Dr Lee, I think you did mention as well in your manuscript that a viability test was not mandatory for patient enrollment. I mean, clearly it was such as work of labor enrolling such patients. If you put even more criteria it would have been impossible, I suppose. Do you have some thoughts there on maybe future studies?

Dr Seung-Whan Lee: Yeah, as you know, the currently ongoing CTO PCI process medical treatment is nobel CTO and ischemia CTO is assessed at the reduction of the ischemia burden in CTO PCI. I think there maybe two studies that give us some answer for the low level of the CTO PCI for the reduction of the ischemia.

So, I think the larger ischemic burden the patient is maybe high risk to make the however we don’t know exactly the cut off… ischemic burden in CTO patient. Usually instable angina any kind…coronary disease…3 years circulation showed more than 10 percent of ischemic burden is really predictive of future cardiac event. However, we don't know exactly the can be applied to CTO patient. We don't know exactly.

Dr Manos Brilakis: Can I ask Dr Lee a question regarding the study and his interpretation as well. Now the study was borrowed for hard end points dec MI. What his is perception, based on the DECISION CTO, and, of course, everything else in the literature and the CTO study with symptomatic benefit...Dr Lee, what is your conclusion about, or your kind of thoughts about, the effect of CTO PCI on improving symptoms, which is a more accepted indication for the procedure right now?

Dr Seung-Whan Lee: As you know, the university trials symptom assessment was done after the no CTO PCI. However, our trial is a pragmatic trial, initial approach to the CTO vessel and the vessels that is patient.

At this moment, I think the other vessel, other no CTO vessel intervention and OMT may improve the patient symptom and then CTO vessel is the intervention including the CI patient completely…improve the symptom status. However, analysis showed up to the 3 year, maybe no difference between two groups in the CTO PCI versus medical treatment.

Our trials of the CTO PCI symptom, we don't exactly the role of the after no CTO PCI. We don't know exactly the CTO based symptom assessment was not done, because of the symptom assessment was done before the intervention.

I think that our trials are more practical, because of the initial…multivessel… CTO. Our trials, maybe, completely vascularization including CTO and no CTO vessel revascularization without the CTO intervention. Sometimes the patient to complain of symptom multivessel with the CTO I think we can wait if we continue the patient symptom…

However, in this trial showed CTO specific intervention trial, because of the symptom assessment was done after no CTO vessel intervention. There is some improvement of the… receptor treatment satisfaction of the angina stability. I think that the CTO intervention is maybe reserved for the symptom control after the medical treatment failure of patient.

I fully agree the symptom control is possible with the CTO PCI.

Dr Manos Brilakis: Wonderful. Thank you. I think that's a critical differentiation that the DECISION CTO is not specific for CTO, but it's multi-vessel disease plus CTO. Thanks for clarifying. That's very important for the leaders and the entire community to understand that part.

One more question, if it's okay. I know that in Asian countries bypass patients are relatively less. I think in the U.S. 50 percent. Any comment on that? I know people get less bypass in Asia than they do in the United States. How may that affect the interpretation of the DECISION CTO?

Dr Seung-Whan Lee: Initially, I introduced my studies to our patients syntax score under 20. As you know, the U.S. Registry shows the syntax score more than I think the 20, and the tester score around 46. Quite different in population, because the risk factor is quite different. U.S. patient is hypertension and diabetic are more prevalent than the Asian patient. Bypass surgery is 40 percent in Asian patients. Bypass surgery is around 102 percent in CTO registry. Quite big difference of the base rank, risk factor, and morbidity.

I cannot apply to U.S. population exactly the same ... Not same situation. We cannot apply directly to the U.S. population. I fully agree with your suggestion, though. Lowest population is maybe ... Our trial is maybe lowest population. We agree.

Dr Carolyn Lam: I'm just learning so much listening to both of your interventionists. What do you think are the take-home messages from this? Maybe, could I start with Dr Lee, and then give Manos the last word?

Dr Seung-Whan Lee: CTO PCI critical outcome, it should be tested as a large random trial. Maybe Manos already mentioned about the high-risk population, because our population is the lowest population. However, in some large random trial with a high-risk population we have consider some random trial because they are not easy.

Maybe not easy to test in high-risk population. However, you must do that, because of the two established CTO PCI law in the current practice.

Dr Carolyn Lam: Manos?

Dr Manos Brilakis: Yeah, I would agree with that. I think the main conclusion regarding the field of CTO PCI is that still right now, the key indication remains symptom improvement. We do have the trials at this point showing that you do CTO PCI in terms of improving mortality. However, CTO PCI is a tool. It's a revascularization tool. Patients who have severe, complex, coronary disease, multi-vessel disease, may be best served with bypass in the first place. Those who have multi-vessel disease that's less complex and don't have significant symptoms after fixing the non-CTO lesions, then they may not benefit from CTO PCI as well. But those who have CTO lesions and have significant symptoms, this is the population for which I think there is general agreement, and I the decision that CTO is good with that, that those patients could benefit from CTO intervention.

Dr Carolyn Lam: Thank you so much for sharing your insights.

Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation March 26, 2019 Issue

25 mars 2019 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia.

Dr Carolyn Lam: A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal.

Dr Greg Hundley: Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.

In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.

During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.

They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished.

Dr Carolyn Lam: Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings?

Dr Greg Hundley: It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.

They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy.

Dr Carolyn Lam: Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"

The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.

What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction.

Dr Greg Hundley: Interesting. How do we apply this clinically, Carolyn?

Dr Carolyn Lam: These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.

However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter.

Dr Greg Hundley: Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.

But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.

So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.

So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury.

Dr Carolyn Lam: Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.

Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.

And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.

And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.

However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively.

Dr Greg Hundley: That's a lot of data, Carolyn. Help me synthesize all that.

Dr Carolyn Lam: This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.

That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked.

Dr Greg Hundley: Very good. That was a very nice summary, Carolyn.

Dr Carolyn Lam: Thanks. Let's move on now to our feature discussion, shall we?

Dr Greg Hundley: Very good.

Dr Carolyn Lam: Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.

The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.

Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.

And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed.

Dr Shreyansh Shah: I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.

As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.

What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.

What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.

While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.

There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy.

Dr Carolyn Lam: Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts?

Dr James Grotta: It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.

I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.

There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.

I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.

And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.

I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.

I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.

Dr Shreyansh Shah: To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.

And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.

And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.

It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving.

Dr Carolyn Lam: Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there?

Dr James Grotta: Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.

It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.

So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.

We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.

We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.

Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.

So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.

Dr Shreyansh Shah: At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome.

Dr Carolyn Lam: Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under.

Dr Graeme Hankey: Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.

And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.

So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.

This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.

And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer.

Dr Carolyn Lam: Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.

Circulation March 19, 2019 Issue

18 mars 2019 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and it's editors. We're your co-hosts. I'm Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center in Richmond, Virginia, VCU Health Sciences.

Dr Carolyn Lam: How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg.

Dr Greg Hundley: Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.

So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months.

Dr Carolyn Lam: Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to.

Dr Greg Hundley: So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.

Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise.

Dr Carolyn Lam: Well, don't keep us in suspense now. What did the study show?

Dr Greg Hundley: So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.

So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.

So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together.

Dr Carolyn Lam: Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.

Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.

Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk.

Dr Greg Hundley: So, Carolyn, how do we use this clinically? I mean, do we measure this in folks?

Dr Carolyn Lam: Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.

So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.

So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median.

Dr Greg Hundley: So should we start checking this in all our patients now, these lipoprotein little A levels?

Dr Carolyn Lam: Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.

Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space.

Dr Greg Hundley: Yeah, so it sounds like another wonderment of PCSK9 inhibitors.

Dr Carolyn Lam: Yeah.

Dr Greg Hundley: Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.

So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored.

Dr Carolyn Lam: Huh, interesting. So, what did they find?

Dr Greg Hundley: Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.

Interesting, Carolyn. Another role for iron in acute MI and more research to come.

Dr Carolyn Lam: Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?

For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come?

Dr William Lewis: The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.

So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint.

Dr Carolyn Lam: Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results?

Dr Jonathan Piccini: I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.

And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well.

Dr Carolyn Lam: Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here?

Dr Jonathan Piccini: It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.

And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well.

Dr Carolyn Lam: Bill, did you expect such remarkable results?

Dr William Lewis: No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions.

Dr Carolyn Lam: That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this?

Dr Jonathan Piccini: That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world.

Dr William Lewis: I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others.

Dr Carolyn Lam: John, before we end, what are the take-home messages for clinicians listening out there?

Dr Jonathan Piccini: I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program.

Dr Carolyn Lam: Thank you so much for sharing that with us.

Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

Circulation March 12, 2019 Isuue

11 mars 2019 | 25 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.

Dr Carolyn Lam: So Greg, are ARNI's now going to be used for functional, mitral regurgitation and heart failure? Well, we're going to be chatting all about that with our feature paper, coming right up after these summaries.

Greg, you've got a biggie to start with, haven't you?

Dr Greg Hundley: Oh yes, Carolyn, I'm really excited about this paper. The senior author Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas and looking at high phosphate diets and their relationship to exercise intolerance. I really felt this was an exceptional study and combining that key that we have, for basic science papers and translation, where we're looking at data from both human and basic science, in both in a single manuscript.

So, this study focuses on inorganic phosphates and they are present in 40-70 percent of the foods, really as a preservative enhancer, in western diets. We see it in colas, meats, dry food mixes, bakery products.

For the human subject component of this study, the investigators examine the relationship between physical inactivity, assessed with ActiGraphs that were worn, and serum phosphate levels. They also obtained MRI measures of cardiac function and participants were recruited from the Dallas Heart Study too.

In animals, they looked at the direct effects of dietary, inorganic phosphate on exercise capacity, oxygen uptake, serum non-esterified fatty acids, and glucose was measured during exercise treadmill tests in mice fed either high inorganic phosphate diets or normal in-organic phosphate diets. And they were on that for 12 weeks.

To determine the direct effect of phosphate on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in the differentiated myotubes were conducted after subjecting those cells to media with high or low phosphate conditions.

Dr Carolyn Lam: So, what did the study show?

Dr Greg Hundley: In the human part, among 1603 participants, higher serum in-organic phosphate was independently associated with reduced time spent in moderate to vigorous physical activity and increased sedentary time. And interestingly, there was no association between serum phosphate levels and left ventricular ejection fraction or volumes.

In the animal studies, mechanistic insight was obtained. Compared to controlled diets, consumption of high phosphate diet for 12 weeks did not alter body weight or left ventricular function, thereby confirming what we saw in the human subjects, but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, fatty acid levels, and led to down-regulations of genes involved in fatty acid synthesis.

So, the take-home on this is that the results of this study demonstrate a detrimental effect of dietary, phosphate excess on skeletal muscle, fatty acid metabolism, and exercise capacity, which is independent of obesity and cardiac contractile function.

And as such, dietary in-organic phosphate may represent a novel and modifiable target to reduce physical inactivity associated with the western diet. I think, Carolyn, we're going to see a large number of epidemiologic studies that are going to really look at this as something we might be able to modify in our diet to help impact some of these sedentary lifestyles and the harmful cardiovascular effects that we find associated with that lifestyle.

Dr Carolyn Lam: Yikes. Remind me again, so phosphates in colas, meats, dried food mixes, and bakery products and so on, the preservative. Wow, you're right; big paper.

Dr Greg Hundley: It's amazing. It's in 40-70 percent of the food products here in the United States. So, wow. Something really striking. So Carolyn, how about one of the papers that you liked?

Dr Carolyn Lam: Moving to related cardio metabolic disease, we know that patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease, there is a tenfold variation in future cardiovascular risk in these patients. The current paper actually analyzes data from EMPA-REG OUTCOME where the authors, led by David Fitchett from St. Michael's Hospital in Toronto, sought to investigate whether the beneficial effects of Empagliflozin, observed in the EMPA-REG OUTCOME trial, varied across the spectrum of baseline, cardiovascular risk.

What they found was that in patients with type 2 diabetes and atherosclerotic cardiovascular disease, the relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalizations with Empagliflozin versus placebo, were consistent in patients with and without a prior, myocardial infarction, with and without a prior stroke, and across sub-groups by the 10-point TIMI Risk Score for secondary prevention at baseline.

Dr Greg Hundley: Does this suggest, Carolyn, that we use these inhibitors in all patients with type 2 diabetes?

Dr Carolyn Lam: Remember the EMPA-REG OUTCOME; all patients had established atherosclerotic cardiovascular disease. This paper really adds to the understanding of the gradient of risk within these patients who had atherosclerotic cardiovascular disease and says Empagliflozin could be beneficial. But remember, there are patients with type 2 diabetes without established, cardiovascular disease and I think there's still equipoise in this primary prevention population.

Dr Greg Hundley: That was great, Carolyn. Now I'm going to grab another sip of coffee and go onto my next paper.

Dr Carolyn Lam: Sure, as long as it's not cola. No phosphates.

Dr Greg Hundley: Right, thank you very much, Carolyn. I'm going to talk about screening for small and medium abdominal aortic aneurysms. This particular study comes from the surveillance of the National Health Service screening program by Dr Earnshaw. Basically, population screening for abdominal, aortic aneurysms has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have a AAA below 5.5 centimeters in diameter, and that's really our current referral threshold for treatment. When they have smaller diameter aneurysms they're entered into an ultrasound surveillance program.

In this study, the investigators looked and reviewed those that had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up to 5.4 centimeter aneurysms, and they were followed. They were looking at the risk of rupture in these under surveillance.

They had a total of 18,652 men and the risk of rupture overall per annum was 0.03% for men with small, abdominal aortic aneurysms and 0.28% for medium size. That was just below the threshold for the 5-5.4 centimeters, which was 0.4% over time. The risk of abdominal aortic aneurysm surveillance is below .5% per year and that is just below our current referral threshold for surgery, which is 5.5 centimeters.

This is a study that really confirms, Carolyn, that the target mark or diameter that we've selected is appropriate.

Dr Carolyn Lam: Nice. These just confirm the current guidelines?

Dr Greg Hundley: Yeah, they do and Gil Upchurch from University of Florida, a surgeon, had a very nice editorial. The point he wants to make is yep, diameter of 5.5 is the threshold, but a couple key points. As patients are coming in for these visits, we need to continue to emphasize to them other factors related to growth of abdominal aortic aneurysms and their rupture. So, tobacco cessation, treatment of your lipids, management of your hypertension.

The other point that he makes, is we really don't need to be operating on those individuals with an abdominal aortic aneurysm diameter of less than 5.5 centimeters. He makes an argument here that's in some countries with fee-for-service reimbursement, up to 30% of AAA repairs are for aneurysms less than this diameter of 5.5 centimeters. This over utilization of resources can add considerable costs to the healthcare system for managing this condition and is unlikely to increase the overall survival of these patients.

A nice study confirming that what we're doing, really in terms of size and diameter, is correct, but also emphasizing this patient population often has a lot of other cardiovascular co-morbidities that we need to aggressively manage. How about your next paper?

Dr Carolyn Lam: From one very clinically, applicable paper to another. This one answers the question, what's the optimal duration of emergency department and post-emergency department rhythm monitoring among patients with syncope. And the authors, led by Dr Thiruganasambandamoorthy and his colleagues from the Ottawa Hospital Research Institute, prospectively studied adults presenting within 24 hours of syncope at six emergency departments. They collected baseline characteristics, the time of syncope, the time of emergency department arrival, and the Canadian Syncope Risk Score, risk category. They followed subjects for 30 days and adjudicated the primary outcome, which was serious arrhythmic conditions and that includes arrhythmias or interventions for arrhythmias and unexplained death.

Their results showed that the overall arrhythmia risk, and the risk after two hours of emergency department arrival from Canadian Syncope Risk Score, low-risk patients, was indeed very low. Similarly, the overall risk and after six hours of emergency department arrival for medium and high-risk patients was moderate and high, respectively. No low-risk patients suffered ventricular arrhythmia or unexplained death and most of the arrhythmias among the non-low-risk patients occurred within 15 days of the index syncope.

Dr Greg Hundley: Carolyn, what's the take home message here?

Dr Carolyn Lam: The results really support brief monitoring in the emergency department for two hours for Canadian Syncope Risk Score low-risk patients, and six hours for medium and high risk patients followed by selective admissions and the results also support a 15-day outpatient monitoring for medium-risk patients at a selected threshold and for all high-risk patients. So very practical advice.

Dr Greg Hundley: Very good. Until next week, I'm going to watch out for phosphates.

Dr Carolyn Lam: Indeed, and let's go on now to our featured discussion.

For today's featured paper, we are discussing the results of the PRIME Study and that is Angiotensin Receptor Neprilysin Inhibitor, or ARNIs, for functional mitral regurgitation. A terribly interesting study. So pleased to have with us an author Dr Sung-Hee Shin from Inha University Medical center in Incheon, Korea as well as our associate editor Dr Victoria Delgado from University of Leiden in the Netherlands.

Sung-Hee, what an interesting study. ARNI or Entresto for functional mitral regurgitation. Could you tell us what inspired this study and what did you find?

Dr Sung-Hee Shin: Our study was the designed to tell if ARNI or functional mitral regurgitation because secondary functional mitral regurgitation was developed as a result of a reduced function. Guideline-directed medical therapy for heart failure would be a mainstay for a therapy.

But despite use of the traditional drugs such as BETA blocker, ACE inhibitor or angiotensin receptor blockers, you know that the functional mitral regurgitation may be common and significant in the person having this functional mitral regurgitation would be related to increased morbidity and mortality.

So, that trial showed that trans-catheter mitral valve repair effectively reduced the function mitral patient and resulted in lower rate of heart related mortality among patients with heart failure and function mitral regurgitation.

In our blind trial, we also tried to tell whether an ARNI is more effective in improving function mitral regurgitation and randomly assigned 118 patients with heart failure and chronic secondary function mitral regurgitation lasting more than six months despite medical therapy and ejection fraction between 25% and 50% to receive either sacubitril/valsartan or valsartan in addition to standard medical therapy for heart failure.

What happened with that change of mitral regurgitation after 12 months which was assessed by means of transthoracic area ways echo. What we observed was that transthoracic area as well as the volume of mitral regurgitation saw a decrease much more effective in the sacubitril/valsartan group than valsartan group.

We also looked at the various other measures of the left ventricle remodeling and showed that the valsartan group had smaller left ventricle volume at 12 months and had a greater reduction of end-diastolic volume index.

Also, among the completers ARNI, for the reduced left ventricle volume and the yearly time than the control group. So, what we think is that these factors might contribute to greater reduction of function mitral regurgitation in patients in the sacubitril/valsartan group.

But our study was a mechanism study, but it was not designed to see outcomes. So further research and data would be necessary to check is this transthoracic echo end point can translate into better outcome in this population.

Dr Carolyn Lam: Sung-Hee, this is just so interesting to have hypothesized this about functional mitral regurgitation. And not only that, I mean, to my mind, this is the largest echo-based studies of patients before and after Entresto that I can think of. It's nice to know, on top of knowing in paradigm that we can improve outcomes in heart failure reduced ejection fraction, that we now can look at the heart and see what happens in so many dimensions.

So, congratulations.

Victoria, were you surprised by these results? And do you agree with the mechanisms that Sung-Hee suggested?

Dr Victoria Delgado: I think that this study is very important because in the field of functional mitral regurgitation, there is still a lack of consensus on how to treat these patients, which are very challenging.

If the patient needs revascularization they will be referred for certain. But it still should be CBR mitral regurgitation and moderate and mile mitral regurgitation are not considered.

I think that we discuss often which is the optimal medical therapy or the guidelines based medical therapy but it's not really consensus because the studies before have not been like this one. That large in order to answer a specifically that question.

I think that this article brings an important message and brings more evidence to our field that there is not that much data. So, I think it's very important for that research, in particularly after the research of the co-op and the mitral trial where it seems that the selection of patients is very important in order to identify the patients that will really benefit from those therapies.

Dr Carolyn Lam: That's such a good point. Going to that selection of patients, Sung-He, you mentioned very carefully the ejection fractions that you allowed up to 50% in these patients. Could you explain how you reasoned the selection of this patient cohort?

Dr Sung-Hee Shin: The reason why we chose the patients we did, the range of ejection fraction condition, was that we thought the reversibility of the left ventricle mortality and function mitral regurgitation might be more pronounced in these patients.

When we considered the fraction condition in mitral regurgitation with ejection fraction used under [inaudible 00:18:17] LV dysfunction, our inclusive criteria of ejection fraction between 25 to 50% might correspond to ejection fraction of 20 to 40% in patients with mitral regurgitation.

We concluded that if a patient had ejection fraction less than 25% because the reversibility of mortality and function mitral regurgitation might be smaller when all the LV dilation is too extreme and advanced heart failure is already established.

So, I just thing how it can be provided to the patient who have functional mitral regurgitation associated with too extreme LV dilation and LV ejection fraction too.

Dr Victoria Delgado: I think, Carolyn, it's a very good point what she explained because we are used to select patients based on ejection fraction, in particularly patients with functional mitral regurgitation, ejection fraction is rather misleading because actually it's just a change of volume in the ventricles emptying in a low pressure chamber which is the left atrium.

The moment that you correct that in mitral regurgitation sometimes then you face, or you see, the true ejection fraction of that ventricle. And if we wait too long, we may end up with ventricles that they don't have any more resource in order to improve ejection fraction after repair of the mitral valve.

So, I think that this study is important to also realize that concept. That ejection fraction in patients with functional mitral regurgitation may not be the most accurate parameter to assess the function of that ventricle.

Dr Carolyn Lam: Yeah. Exactly. And I thought that was a very clever part of the design. I'm glad you explained it and also so glad, Victoria, you invited the editorial by Dr Mullens, who also commented on that. So, just for the audience to understand that ejection fraction up to 50% was included and ejection fraction less than 25% was excluded.

So also, again, very consistent to your prior point, Victoria.

Could I ask you, I think Dr Mullens also spent quite some time talking about the potential mechanisms. What's your take of this Victoria? ARNI for functional regurgitation. How come?

Dr Victoria Delgado: For me, I'm much more from the side of the imaging point of view. When we have patients with functional mitral regurgitation I always try to see which is the capability that that ventricle has to recover.

Actually, first is always medical therapy, but we know that the [inaudible 00:20:59] only, for example, we just reduced the mitral regurgitation, but they don't really improve the function of that ventricle, while if you reduce the loading conditions of the ventricle in terms of blood pressure as well and favoring remodeling of the left ventricle, you can improve the condition of the mitral valve and reduce the mitral regurgitation.

How valsartan plus sacubitril works differently than valsartan alone that I don't think that I have enough knowledge to explain why but it could be that in a way there is more effective with sacubitril on top of valsartan can improve the loading conditions of the ventricle and improve the, or facilitate, the reversing of morbidity of that ventricle, reducing the mitral regurgitation and that, by itself, could also lead to reversing morbidity.

Like a little bit cardiac resynchronization we'd do, for example, in patients with an ejection fraction below 35% and based on the EEG you have the synchronous fraction of the papillary muscle or the walls of the ventricle which could lead to the mitral regurgitation at the moment that you resynchronize that mitral regurgitation can produce, you reduce part of the volume of the load of the ventricle and that can favor that reversing morbidity.

So, I think that this study raises a lot of questions and I think that further research is needed in order to confirm or to know more how these treatments work.

Dr Carolyn Lam: Goodness, that was so beautifully explained and in fact, many clues from Sung-Hee's study and the reversal of left ventricle end diastolic volume index greater with those treated with ARNI, the LA size and so on.

But maybe I should ask you, Sung-Hee, in line with what Victoria said, what are the next steps? Do you already know what are the next studies that you're going to be looking at in PRIME?

Dr Sung-Hee Shin: We're considering mark of monitoring such as NT pro-BNP or using auto imaging models such as echo and cardiac MRI to look at the change of mitral valve regurgitation in more detail.

This kind of study might be very helpful in understanding [inaudible 00:23:15] ARNI in functional mitral patient.

Dr Carolyn Lam: Yes, that's clever, too. And Victoria, before we end could you maybe give us some take home messages?

Dr Victoria Delgado: I think that the take home message from this study is that when we have patients with functional mitral regurgitation, we need to think what we can offer to them. Not consider mitral regurgitation just as a base standard. That it's going to respond only to diuretics. No. We need to do something on that left ventricle to help it to improve the function and to avoid the progress to more reduced function.

It's very important to understand the mechanism of the mitral regurgitation and to use the guidelines based medical therapy trying to go step by step in order to optimize the medication of that patient and later on, see all the potential treatments that are available right now such as cardiac synchronization therapy, which we should not forget, and then surgery if the patient needs catheterization and if the patient needs the benefit from mitral valve plasty or eventually, for example, trans catheter mitral valve therapies.

But we should avoid that the patient goes further down into heart failure with very dilated ventricles and very poor function because then probably we may face a point of no return.

Dr Carolyn Lam: Thank you so much, Victoria. Both you and Sung-Hee mentioned this is a mechanistic study. So many insights. But it's not saying that everybody with functional mitral regurgitation has to be treated this way now. It's calling for more work and it's certainly very, very important study.

Thank you listeners, for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation March 5, 2019 Issue

4 mars 2019 | 22 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Have you heard of long non-coding RNAs? Well, they are definitely the hot topic and our feature paper today discusses the first demonstration of the importance of a linked RNA in atherosclerotic lesions not just in mice but also in humans. You have to listen on, it's coming up right after our copy chat.

Greg, what are your picks upon the journal this week?

Dr Greg Hundley: The first paper I wanted to discuss comes from France, and it's basically looking at ambulance density and outcomes after out of hospital cardiac arrest from Florence Dumas from Hôpital Cochin in Paris, France. This manuscript addresses the geographic disparities and survivorship of out of hospital cardiac arrest and the relevance of the patients characteristics versus whether ambulances are equipped with those trained in basic or advanced cardiac life support. So, what they did they had nineteen neighborhoods in Paris, and the number of BLS trained versus ALS ambulances was collected, and the authors assessed that respective associations of socio-economic characteristics of the patient population and the ambulance resources of these neighborhoods and compared those with successful return of spontaneous circulation or risk as the primary end point and then survival of out of hospital discharge as the second end-point.

So, they had 80754 non-traumatic out of hospital cardiac arrests across the Paris area. 42% at ROSK 9% head survival at discharge, and after accounting for the patient's socio-economic status, greater than one and a half advanced cardiac life support ambulances per neighborhood and greater than 4 basic cardiac support basic life support units per neighborhood were associated with ROSK, but only the 1.5 ALS units per neighborhood were associated with survival.

Dr Carolyn Lam: Oh, interesting Greg. So does this we need more advanced life support units?

Dr Greg Hundley: So, Paul Dorian from St. Micheal's Hospital in Toronto, Canada wrote an excellent editorial, and one point he made related to these ALS units is that it was really a very small 1.3 adjusted odd ratio for survival to hospital discharge, and it's important to note that although the increase in survival was associated with more ALS units, there were many other variables that were likely important and not recorded in this study. For example, including the time to collapse, to calling for EMS, the time from the call to the deployment of that ALS unit to the scene, the time from collapse to the defibrillation, the total "no flow time" sort of in quotation, which is the total duration of collapse until CPR is started and so I think one of the points in this observational study is there could've been many differences that would've associated with the findings, interesting findings how about one of the papers that you liked?

Dr Carolyn Lam: So, the paper that I selected here is a first time that a targeted anti-inflammatory therapy has been shown to reduce hospitalization for heart failure and at-risk patients. So, you know that some clinical inflammation associates with an increased risk of heart failure and associates with the worst prognosis in patients with heart failure, and yet, so far, treatments specifically directed at reducing inflammation in patients with heart failure have not been shown to improve clinical outcomes. That's why today's paper is so special and it's from Dr Everett and colleagues from Brigham and Women's Hospital Harvard Medical School in Boston, and basically, the authors looked at CANTOS and tested the hypothesis that the interleukin -1β inhibitor can canakinumab would prevent heart failure hospitalizations and the composite of heart failure hospitalizations on heart failure related mortality in the CANTOS trial.

Now, remember the CANTOS trial randomized more than 10 000 patients with a prior myocardial infarction and with high sensitivity C-reactive proteins at least two or greater, and they were randomized to canakinumab 50, 150, and 300 mg or placebos. Now, before randomization, these participated were asked if they had a history of heart failure and 22% said yes so the current paper actually looks at this stratification of patients who said they had heart failure, and during a meeting follow-up of 3.7 years, 385 patients had a new heart failure hospitalization event. Now, here's the key: the authors found a dose dependent reduction in the risk of hospitalization for heart failure as well as the composite of hospitalization for heart failure or heart failure related mortality among those allocated to Canakinumab.

Dr Greg Hundley: So, how does this differ from prior attempts targeting inflammation and heart failure? I mean is this ready for prime time thing?

Dr Carolyn Lam: So, we have to bear a few things in mind here you know. CANTOS was different from a previously published randomized controlled trials, which were basically neutral and that was like of infliximab and etanercept so the drug in CANTOS targets interleukin-1 beta whereas the prior ones targeted the TNF-alpha, and also very importantly, CANTOS did not specifically enroll patients with an established heart failure only. CANTOS patients had to have a history of myocardial infarction and there was no data on their ejection fraction or natriuretic peptides at the time of randomization nor at the time of heart failure hospitalization. So, by the way, we don't know whether there's a differentially effect on hep pef versus hep-ref. So, again difference from the heart failure focused trial previously that used an anti-inflammatory agents.

The other thing: although there was a dose dependent reduction in the risk of hospitalization for heart failure no single dose of Canakinumab compared to the placebo had a statistically significant reduction in the risk of heart failure hospitalization. Only the trend was statistically significant so all in all, this was a pre-specified aim of CANTOS to look at heart failure, the data presented here should really be considered hypothesis generally, but really quite promising. And what about you Greg? What's your other paper?

Dr Greg Hundley: We're going to switch gears a little bit and shift over to the Jackson heart study. The large longitudinal cohort from Jackson, Mississippi that's recruited to follow for cardiovascular events, and it's an area of the United States where we have some of the highest cardiovascular disease event rates really across the nation so this study focuses on sleep apnea and is the Jackson's heart sleep study. It's a sub-study of this larger Jackson's heart study that involves 913 patients, and the investigators were looking at the association between sleep apnea and blood pressure control among those of a Black race. So, Dayna Johnson of Emerald University is the first author on the paper. What's nice about this sub-study, this sleep sub-study is that there are objective measures using an in-home type III sleep apnea study. They had clinical blood pressure measurements and then anthropometry as opposed to questionnaire derived data that may have been performed in the larger cohort.

And the study determined these associations between moderate or severe obstructed sleep apnea with controlled, uncontrolled and resistant hypertension. So the analytic sample of the individuals with hypertension was 664, and they had an average age of about 64 years. They were predominately women 69%, obese 58%, College-educated at 51%. Among the sample, about a quarter had obstructive sleep apnea, which was untreated and unrecognized in 94% of the participants. That's an interesting point, just right there.

Overall, 48% of the participants had uncontrolled hypertension and 14% had resistant hypertension. So, multiple medications, often four and still unable to control the blood pressure. So the findings participants with moderate or severe obstructive sleep apnea had 2 times higher odds' ratio of resistant hypertension.

Dr Carolyn Lam: Whoa Greg, that's a huge risk and very important finding. I mean if sleep apnea could be modifiable risk factor perhaps for very important issue among African Americans resistant hypertension. What do you think about clinical implication?

Dr Greg Hundley: One of the things to be considering now is what are we going to do about that cause as you know CPAP is really the preferred treatment for resistant hypertension, but it's efficacy hasn't been really that well studied in African Americans and CPAP tolerance is low so this study highlights for us potentially new mechanisms for resistant hypertension, but we still got to be thinking about what would be our next therapeutic intervention for this particular patient population. And what about your next study?

Dr Carolyn Lam: The next study is about Impella support for acute myocardial infarction complicated by cardiogenic shock. Now, we use it all the time, but did you know that to date, there is no large randomized study actually comparing the use of Impella to other contemporary cardiac support devices and medical treatment in stem related cardiogenic shock. So, Dirk Westermann and colleagues from University Heart Center in Hamburg tried to address this knowledge gap by using a multi-national database of patients with acute myocardial infarction complicated by cardiogenic shock and treated with the Impella device and compared in a matched fashion their outcomes to patients from the IABP Shock II trial, which you would recall is a randomized trial which demonstrated similar outcomes between IABP and medical treatment in myocardial infarction in cardiogenic shock.

So, they looked at 237 matched-pairs so remember this was pairs from this registry of acute myocardial infarction with shock and using an Impella matched with IABP shock patients and what they found was that there was no significant difference in 30-day all-cause mortality. Instead, severe or life-threatening bleeding and peripheral vascular complications occurred significantly more often in the Impella group when they limited the analysis to the IABP treated group as controlled versus Impella that was still the same results.

Dr Greg Hundley: So, Carolyn, there are trying to match patient population from two different studies and they may have confounders in there that we can't account for so why we not able to produce large randomized trials of Impella devices in studies of patients with acute myocardial infarction?

Dr Carolyn Lam: The rate of acute myocardial infarction complicated by cardiogenic shock has really declined in the past decade. Furthermore, clinical signs of shock really appear in half to three quarter of cases several hours after hospital admission so making randomization before primary PCI of the AMI really very difficult. And finally, many interventional cardiologists believe that there's equipoise that has already been reached on the use of these cardiac assistive devices in patients with cardiogenic shock and this was from registry data, and so if interventionists believe this then they also believe its unethical to randomize these patients in trials. Still, I think that current study to date really causes us to pause and to acknowledge that we really need to evaluate this better and prospective randomize trials of Impella treatment are warranted.

Let's now go to our featured discussion, shall we?

For our featured paper discussion today, we are talking about a basic science paper, and we have none other than the best of the best Dr Charles Lowenstein, our associate editor from University of Rochester Medical Center joining us as well as the first author of a really fantastic paper on long non-coding RNA in a specific type involved in arthrosclerosis and plaque formation. This first author is Sebastian Creamer from Goethe University in Frankfurt.

Charlie, could you start us off by telling us what is a long non-coding RNA? We've heard a lot about this in recent times. What's the big deal about them?

Dr Charlie Lowenstein: So in the last decade, scientists have learned that your genome, your DNA inside you, every cell codes about 20,000 genes and those 20000 genes encode proteins, but there are another 20000 genes that encode RNA only, RNA that never turns into protein that leaves RNA are an amazing diversity of different kinds of RNA really short micro RNA, longer RNA that defends the host from viruses and long non-coding RNA that have a huge variety of effects regulating genes, turning genes on and off in proliferation and cell growth and inflammation so long non-coding RNAs are increasingly appreciated as an important part of the genome.

Dr Carolyn Lam: What a perfect set up with that. Sebastian, could you tell us about your study please?

Dr Sebastian Creamer: Our laboratory was interested in non-coding RNAs for some time and previously, we've found that this specific non-coding RNA MALAT1 regulates endothelial cell functions and because we were interested in analyzing this particular RNA in the disease setting it shows at a risk growth so it's because also we saw that when it's regulated by flow and end of previous cells and so we cross MALAT1 deficient mice to Apoe mice and set them on a high fat diet and analyzed and subtracted in both groups. And while we only saw a modest increase in plaque size in MALAT1 deficient mice, we could appreciate a higher amount of inflammatory cells in plaque of aortic roots in those mice, which let us hypothesize that inflammatory responses was appreciated and is a very important contributor to arthrosclerosis in MALAT1 deficient mice. And to test this, we decided to transplant MALAT1 deficient bone marrow in Apoe knockout mice with MALAT1 and interestingly, we saw that now plaques were significantly larger than compared to mice who received controlled MALAT1 white cell bone marrow, and also inflammatory cells were more prominent in those mice.

Dr Greg Hundley: Sebastian, this is Greg Hundley. You also did some experiments in human subjects. Could you tell us a little bit about those too?

Dr Sebastian Creamer: So, because we saw this interesting phenotype, we were very much interested if this also translates into the human setting. Luckily, we got a really nice collaboration receding in Stockholm access to high impact material from patients with arthrosclerosis and what we could see here that MALAT1 expression was down regulated in patients with arthrosclerosis and it also correlated with disease progression. Moreover, in another collaboration, we consolidated those findings with experiments, which showed that human cells have less MALAT1 compared to normal vasculature.

Dr Carolyn Lam: It all sounds so sensible and logical and so on but let me just frame this for our audience. This is actually the first time that it's been demonstrated. The importance of long non-coding RNA in arthrosclerosis. Charlie, could you tell us a little bit about how significant these findings are?

Dr Charlie Lowenstein: Sure. So, I'm really interested in the final figure in this paper because there are lots of interesting human data, showing that MALAT1 expressed more in normal than atherosclerotic arteries and also that MALAT1 expression is correlated with fewer major adverse cardiac events so the whole story is a very nice story saying that the expression of this anti-inflammatory link RNA not only has an effect in mice but it can be extended into the human field of arthrosclerosis and inflammation. It's particularly important because there's a lot of attention in the last decade that inflammation drives atherosclerosis, and in light of CANTO trial showing that anti-inflammatory therapy can actually decrease atherosclerosis and decrease cardiovascular events in humans. This is important cause it shows another pathway, which regulates inflammation. Not only in mice, but also in humans, and in the human atherosclerotic setting.

Dr Carolyn Lam: Amazing. Sebastian, what are the next steps? How far are we away from clinical applications here? What are the next steps to get it in the clinic?

Dr Sebastian Creamer: So, the very difficult thing is that MALAT1 is down-regulated in atherosclerosis and also therapeutic approaches is very difficult in such a complicated disease like atherosclerosis to actually increase the expression of such a long non-coding RNA. What we are currently working on is to decipher more than the clinical malade-1 is actually influencing atherosclerosis so we have lots of hints or some evidence that adhesion of inflammatory substances altered and the bone marrow activity, which is very important in atherosclerosis and also in other cardiovascular diseases like myocardial infarction is altered so we think that malade-1 might actually influence the resolution of inflammation and when it's lacking, inflammation can be resolved. So, we are now putting somewhat mechanistic studies and finally, we hope that we can find another downstream target like micron AB, we talked about in our paper, which we can directly target in the future.

Dr Charlie Lowenstein: So, I agree with Sebastian. I think MALAT1 is going to turn out as one of those major link RNAs that controls inflammation possibly controlling the way in which the bone marrow reacts to systemic inflammation and produces cells and then have those cells home in on various inflammatory targets so I think this is an important observation that's going to have not only implications for atherosclerosis but also for other inflammatory diseases.

Dr Carolyn Lam: Excellent. If you don't mind, I would love to switch tracks a little bit. We find it that very special and we can discuss basic papers with people who can explain it so well because we understand that there's so much work that goes in to these papers and so on. Charlie, could you take behind the scenes a little bit with the editors and tell us what is it that circulation looks for in basic science papers that makes us published?

Dr Charlie Lowenstein: We get a lot of really good basic science papers, and it's a challenge for the associate editors, and the editors to figure out what's right for circulation and let me use this manuscript as a great example because this is a terrific paper. So, this paper is divided into four sections, and these sections are what we look for in any basic science paper that's going to reach an audience of clinicians who are interested in pathways and therapeutics so this paper has a section on mice. There's a gene in mice that's important then the paper delves into cells what's happening with cells and then a little bit of mechanisms and genes and proteins and then this paper takes the observation back into humans and shows that there's some human and clinical relevance so this is not only a great paper, but it is a classic example of what the associate editors are looking for in a basic science paper that's targeted towards clinicians.

Dr Charlie Lowenstein: There's some in vivo work with mice, there's some mechanistic work then they take it back to the humans. Plus, of course like anything that comes into circulation, it's going to be novel, interesting and has some important relevance to human cardiovascular disease. This paper that we're discussing is a great example of a paper that we love to publish in a circulation and it's a real tribute to Dr Dimmeler and her team and to Sebastian that they put this paper together and submitted it to us.

Dr Carolyn Lam: Thank you audience for joining Greg and I today. You've been listening to circulation on the run. Don't forget to tune in again next week.

Circulation February 26, 2019 Issue

25 februari 2019 | 25 min

Dr Greg Hundley: And I'm Greg Hundley, associate editor and director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam: So, Greg, are we any closer to the holy grail of safe ED discharge for acute heart failure based on a risk score? Well, we're going to be discussing that coming right up after Greg and I share about the papers that we'd like to discuss today. Lovely issue, isn't it?

Dr Greg Hundley: Yup, and time to get your coffee and bring it up. My first paper, Carolyn, is from Michael Chu from London Health Sciences Center, and is really investigating the surgical management of thoracic aortic disease, and looking at the impact of gender or sex related differences. Sex related differences have not been thoroughly studied. This group looked at a total of 1653 patients, 30% were women, who underwent thoracic aortic surgery with hypothermic circulatory arrest between the years of 2002 and 2017 across Canada in 10 institutions.

Well, women underwent less aortic root reconstruction, including aortic root replacement, Ross procedures, or valve sparing root operations. But, even with less invasive, the women experienced higher rates of mortality, 11% versus 7%, stroke, and that composite of the thoracic surgeons' adverse events. On multi variable analysis, female sex or women was an independent predictor of overall mortality, stroke, and those comorbidities.

Dr Carolyn Lam: Greg, you know how much I love these papers, so I'm going to repeat that. You're saying the women received less ominous procedures and yet had worse outcomes, and this was independent of the clinical covariances, right?

Dr Greg Hundley: Absolutely. Putting all this together, women underwent thoracic aortic surgery a little bit older, and with larger index aortic aneurysm size than men. Intraoperatively, women undergo fewer concomitant procedures, such as the aortic root repairs, and things that you just mentioned. But nevertheless, women experience significantly worse outcomes identified as an independent predictor of mortality, stroke, and that composite endpoint for mortality, morbidity, after multi variable analysis.

What should we think about this? Well, sex specific considerations are important when considering thoracic aortic surgery and future research should focus on the development of a personalized approach to thoracic aortic surgery with respect to gender. For example, utilization of maybe lower size thresholds for women for aortic aneurysms should be considered, and for earlier interventions, and improved outcomes.

Carolyn, tell me about one of your papers.

Dr Carolyn Lam: All right, so I chose a paper looking at the stroke outcomes in the COMPASS trial. Now, let's remind everybody that the COMPASS trial, where patients with stable coronary artery disease or peripheral artery disease, and randomly assigned to receive aspirin 100 milligrams daily, rivaroxaban five milligrams twice daily, or the combination of rivaroxaban 2.5 milligrams twice daily plus aspirin. Patients requiring anticoagulation with a stroke within a month had a previous lacunar stroke or intracerebral hemorrhage were excluded.

Now, in the current paper, and this is from Dr Sharma from Population Health Research Institute, and their colleagues, basically they looked at a detailed analysis of the stroke by type, predictors, and anti-thrombotic effects in the key subgroups. They found that the combination of low dose rivaroxaban and aspirin prevented stroke and disabling stroke better than aspirin in patients without atrial fibrillation and with stable vascular disease, and without an increasing risk of hemorrhagic stroke; which is really important. This effect was consistent across subgroups of baseline risk, and particularly marked in those with a history of previous stroke.

Dr Greg Hundley: Carolyn, what about that rivaroxaban five milligrams twice daily alone?

Dr Carolyn Lam: There was no significant difference in the occurrence of stroke in the rivaroxaban alone group compared with aspirin. But all of this simply says perhaps low dose rivaroxaban and aspirin may be a really important new anti-thrombotic option for primary and secondary stroke prevention in patients with clinical stable atherosclerosis.

Dr Greg Hundley: Very interesting. I'm going to follow your lead and go into another sort of anticoagulant-related topic on iliofemoral deep vein thrombosis. This paper is by Suresh Vedantham from the Washington University of St. Louis.

Let's talk about just what is the definition? This is a DVT that involves the iliac and/or the common femoral vein with or without involvement of additional veins. It basically obstructs the outflow of the veins. These patients are phenotypically distinct from patients with cath or femoral popliteal DVT because that totally obstructs flow, and they have more frequent recurrence of venous thromboembolic events, and more frequent post-thrombotic syndrome. Well, that's a horrible condition because of that obstruction, it leads to calf muscle dysfunction, edema, subcutaneous fibrosis, tissue hypoxia, and ulceration.

Dr Carolyn Lam: Great background. What did this study show?

Dr Greg Hundley: This is a sub-study of the ATTRACT trial. The ATTRACT trial basically is looking at anticoagulation plus perhaps mechanical intervention, or direct catheter directed thrombolysis therapy versus just anticoagulation alone. This sub-study is 391 patients with acute DVT involving just the iliac or the common femoral veins, and following these individuals for 24 months to compare short and long-term outcomes.

What did the study show? Well, this interventional group did have a reduction in leg pain and swelling, and improvement in quality of life related to that lower extremity. But, no overall difference in overall quality of life, and very importantly, no difference in the occurrence of this post thrombotic syndrome.

Dr Carolyn Lam: That's kind of disappointing. I understand that the ATTRACT study is not the first to look at this, though. That was in an editorial discussing this. Could you tell us about that?

Dr Greg Hundley: Yeah, Carolyn. Jay Giri from University of Pennsylvania just had an incredible editorial. I think if you have an opportunity, listeners, to take a look at that, I highly recommend it. He reminded us of the CaVenT trial, which is basically performed as an open label randomized control trial of 209 patients across 20 hospitals in Norway.

What was different in the CaVenT trial is that at 24 months of follow up, the intervention with thrombolysis and systemic anticoagulation improved iliofemoral patency. It reduced the incidence of this post thrombotic syndrome. In ATTRACT, in this sub-study, it was intravenous thrombolysis, systemic anticoagulation, and mechanical intervention on the vein versus in the other study from Norway, CaVenT, just the inter vein thrombolysis and the systemic anticoagulation.

What Dr Giri points out is that maybe something related to intervention in that vein when you're stripping out thrombus, et cetera, are we damaging the veins in the vessel that prevents reflux, et cetera?

I think really moving forward, you're going to have to personalize this decision in individual patients until we have more data on this subject.

Dr Carolyn Lam: Great learning. I learned a lot from this next paper, too, because I actually chose a basic science paper. This is a paper that uncovers a new fine tuning factor that modulates myocardial infarction induced inflammation. That is a small GTPase called RhoE.

In this study, Drs Chang from Texas A&M University College of Medicine, and Song from Fuwai Hospital in Beijing used three genetic mouse model lines. Those are the global knockout, the cardiomyocyte specific RhoE heterozygous mouse, and the cardiomyocyte specific RhoE over expression mouse. With this combination, they showed that RhoE deficiency causes excessive inflammatory response in infarct animal heart, resulting in enlarged heart, decreased contractility, and increased mortality. The mechanism is that RhoE binds to P65 and P50, which impedes their dimerization and blocks these two proteins from nuclear translocation. Now, over expression of cardiac RhoE inhibits NF-κB, restrains post MI inflammation, and improves cardiac function and survival.

Importantly as you always say, Greg, there is human data. They found that the expression of RhoE was elevated in the infarct patient heart and that patients with a higher expression of RhoE exhibited a better prognosis and better cardiac function recovery.

Dr Greg Hundley: Carolyn, tell me a little bit about the clinical significance of this.

Dr Carolyn Lam: You just wanted to ask me a tough question. I can see it on your face. Basically, I think this is really exciting because RhoE may serve as a new potential biomarker for the assessment of myocardial infarction in patients, and manipulation of RhoE could be a potential therapeutic approach for MI. There.

Dr Greg Hundley: Very good.

Dr Carolyn Lam: That's all the time we have for our little discussion here. Now, let's go onto the feature paper. ...

Over 80% of emergency department patients with acute heart failure are admitted to the hospital. Now, contrast this with the fact that over 80% of all emergency department visits result in discharge. So, why is that many other emergency department based cardiovascular disease processes like for acute coronary syndrome have evolved from high rates of admission to timely and safe discharge whereas decision making in acute heart failure has not experienced a similar evolution. Do we need perhaps a better acute heart failure prognostic score that's validated?

Well, guess what? We're going to talk about this right now in our feature discussion, and a beautiful feature paper that we're so proud to have the corresponding author, Dr Douglas Lee from University of Toronto right here to discuss; along with the managing editor, Dr Justin Ezekowitz, who's associate editor from University of Alberta, and the editorialist, Dr Sean Collins from Vanderbilt University Medical Center. Welcome everyone, and Doug, please, could you just start by telling us about this great paper?

Dr Douglas Lee: We validated, and it's a tool, decision making tool, for acute heart failure patients in the emergency department. We, in this study, wanted to prospectively validate a decision making prognostic tool called the Emergency Heart Failure Mortality Risk Grade, or EHFMRG for short, to see how well it performed in the real world busy emergency department hospital setting.

We studied just under 2,000 patients who came to emergency departments at multiple centers, and asked physicians to rate their prognostic estimation of what's going to happen to that patient in the next seven days. We compared that with the EHFMRG model, which predicts outcomes of seven days and 30 days. We were very careful to ask physicians to provide their prognostic estimates. This is their intuitive guesstimation of the risk of the patient before calculating the score because we didn't want the physicians to be influenced by the score.

What we found was that when we looked at how well physicians' estimates performed, they actually performed quite well. The c-statistic for physician estimated risk was around .7, which is a reasonable discrimination. However, the physicians' estimates were not as good as the EHFMRG risk score, which had a C greater than .8. The mathematical model seemed to do better in terms of predicting what's going to happen to the patient than physicians' estimates.

Interestingly, when we combined the physicians' estimates with the EHFMRG risk score, the c-statistic improved by another 1%, so there's some additive value of having both factors combined.

The other interesting finding was that patients in the lowest risk groups had 0% mortality at seven days, and 0% mortality at 30 days. We may be able to identify, using the score, patients who have a very low risk of events in that seven to 30 day period after emergency department presentation.

Dr Carolyn Lam: Thanks so much, Doug. I have to tell you, I am a fan of the EHFMRG score. In fact, we're trying to study how well it performs in our local situation even here in Singapore.

Justin, you've been thinking a lot about this. I would love for you to share the reactions that we got when we discussed this among the editors.

Dr Justin Ezekowitz: We had a lot of good discussion about this from a number of different aspects. First, it's an in-practice assessment, a physician-based risk assessment, as we survey hundreds of physicians in the ER, which is a busy environment, and get these types of information. That's a very unique piece of this study where, in addition to the just under 2,000 patients and collecting the other data in a robust way, this really does have a potential to contribute to the literature.

A lot of the discussion was about how data rich this is, and that this is an area where unlike acute cardiovascular disease where there are good risk assessment tools and other therapies, it's a really need of a scoring system that was well validated, can be replicated, and both in clinical practice as well as in selective cohorts. Doug, my congrats to your and the other parts of the team that's helped put this together.

One of the questions that came up when we were discussing it was the risk textiles and buckets were very important for people to think about the very low risk, as you mentioned, 0% all the way up through much higher percents for seven day mortality, but how discrepant the risk was of the physicians versus the mathematical model; and a very good reminder of the inaccuracy of sometimes our assessments of risk in practice, especially in acute care.

I wonder if you could comment on what your fence was from the physicians who participated in the study, and then the data of those, the most striking findings of that piece about where physicians make judgements on risk in for that seven-day mortality. Just any comments you may have?

Dr Douglas Lee: We didn't know what to expect because there haven’t been many studies of this type before. What we found in our study was that physicians tended to overestimate the risk of lower risk patients. They thought bad things would happen to healthier patients, just to put it very simply. Physicians also underestimated the risk of the highest risk patients. They thought that the highest risk patients would do well.

We were surprised about that finding, but also, we were not surprised in the fact that it seems to explain some of our earlier findings that in our earlier work, we found that low risk patients are hospitalized, and we think it's probably that physicians are admitting those patients because they want to ensure that they're making a safe decision; and no harm will fall in the patient. Maybe physicians are erring on the side of admitting those patients, even though they know they're a little bit low risk.

At the other extreme, physicians underestimated risk in the highest risk patients. We think it might explain the observation that we made previously that sometimes high risk patients are discharged home, and they die at home after discharge. That may be because patients who look well to physicians, I think there's great value in the clinical experience of a seasoned physician looking at a patient and knowing that, that patient is sick or not sick. But in certain cases, patients may look relatively well, but their numbers would indicate that they're actually higher risk. I think it's that group where we found they're higher risk, but physicians thought that they were healthier than they were. It seems physicians' estimations really have great value, but it seems that they can be improved.

Dr Carolyn Lam: Sean, you discussed this beautifully in your editorial. Share with us your thoughts, and especially thoughts on the question you posed: are we any closer to the holy grail of safe emergency department discharge based on acute heart failure risk rules?

Dr Sean Collins: Doug, kudos to you. Nearly 2,000 patients, nine different hospitals, prospective data collection, as Justin said. I don't think this can be overstated. From a data cleaning perspective, this is truly a labor of love, and to get this done, congratulations to you and your team.

I think the most interesting part of this is this exact disconnect of patients look well who are high risk, and patients may look a little bit unwell who may be low risk, ironically. That's where a risk tool is much needed, as Carolyn said in her introduction to sort of change the dynamic of 80 to 90% of patients are admitted to the hospital. If we even chipped away at 10 to 15% to able to be discharged, it would be a huge win for partly for management for an emergency department perspective.

I think that the importantly, the next steps will be now looking at implementing this in some sort of a randomized manner, somewhat like what you did with asking physicians gestalt about what their level of risk is, but really finding out how does a physician gestalt when it comes to nuance and heart failure. A relative amount of congestion, even when the tool says the patient may be low risk, can they go home? I think that will be the crucial next step to find out how much does this augment and/or detract from physician decision making? We have a long way to go, as Carolyn said. It's just the complete opposite at almost every other disease process, including chest pain, from a discharge perspective. Even a little bit improvement would be great, so I'm looking forward to seeing the next steps, and I'm wondering what your thoughts are about the next steps, Doug.

Dr Douglas Lee: There's actually great value in physicians' clinical judgment. It's been, I think relatively understudied. I'm hopeful that future studies where decision tools or prognostic tools are validated, we can see more potentially, more comparisons with clinicians because we don't have a real great understanding, I think, of how doctors think, especially in an acute setting. More research in this area, I think would be really helpful, especially as we ... As more and more clinical decision tools being published, it would be great to see how well they hold up against good clinician judgment.

In terms of next steps and implementation, when we talk to our emergency colleagues, they have brought up an issue about it's great that patients are low risk, and that we could potentially discharge them from hospital; but where is the receptor to take that patient and to care for that patient once they've left the hospital? Are they going to get good care once they leave the hospital? Are there structures in place?

We're now embarking on testing this in the clinical trial where we will be comparing two strategies. The first strategy will be using the risk score at a hospital-wide level, and then discharging home patients who are in the lower risk categories, and having them follow up, and receive their care in a rapid ambulatory follow up clinic within two to three days after discharge from the emergency. This will be compared to the control, which is not using the risk score, and having usual follow up care. This trial is called the Comparison of Outcomes and Access to Heart Failure Trial, or the COAHFT trial. It is currently ongoing.

Dr Sean Collins: Great point, Doug. As Carolyn suggested with chest pain and heart failure as the interesting dichotomy is that unlike chest pain, when we safely rule somebody out and send them home, we're sort of done with that acute episode. Heart failure, it doesn't end. We've found that they're safe enough to go home, but now they need great collaboration and outpatient support with their heart failure provider, which may be as equally heavy lift as externally validating the EHFMRG score. You bring up a great point, which is we need to have outpatient follow up and collaboration for this to be successful. Thanks.

Dr Carolyn Lam: Awesome comments, guys. Could I switch tracks a bit and maybe just ask Justin to round up by sharing? Circulation, we get a lot of papers about risk scores and so on. There's a bit of fatigue, I think, about scores in all kinds of things. Now, could you maybe tell us, Justin, what makes us look at a paper twice, and in fact, feature this one with a good editorial? I mean it's clearly very clinically applicable. Could you share some thoughts there?

Dr Justin Ezekowitz: Yes, that's a great point. The things that make a risk score like this kind of elevated into kind of a circulation level of manuscript is A) the data quality has to be excellent. There has to be lots of completeness of data, but also capture of elements that we think are quite important. Two, the data science about how it's analyzed and put together, and interpreted, it has to be to the bar that we feel would be robust, and be able ... if somebody could repeat it and replicate it without an obvious challenge to the quality.

The third, I think is the clinical applicability. It's okay to write a data model and come up with all these great risk scores, but if they haven't been thought through about how either a patient will be seeing this, or clinicians behave, or the environment that it has to be deployed in that, that isn't necessarily going to be something that is going to be implemented. Then, the question is: why would somebody do the study in the first place?

Now, it's okay if somebody's forward thinking and saying, 'Look, EMRs are coming, or other EHRs around, so this could be implemented if there was enough impetuous and it's a good enough quality.' That's actually okay, but in the reverse where if you try to implement a model that is too complex, and it's in a hand-off to the environment, it just won't work. We just want to make sure people have thought that next knowledge translation and dissemination approach through.

The final part is things that have a very local impact are, that are very unique to the environment they're in, such as it only would work in your hometown or your own country because of some environment, that's okay. But under that, the much more global focus that, that is, it could be picked up and trans located to any major city, providence, state, or country, because vis vises are global. Those things have a much greater impact because the circulation leadership is global. The patients are global. The clinicians who care for them are also global. People are all looking for very similar situations and can adapt to their own environments.

Dr Carolyn Lam: Awesome, Justin. I don't think any of us could have said it better. Those are the reasons that we're so grateful that you publish with us, Doug. Thank you so much, Sean, for your excellent editorial, too.

Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation February 19, 2019 Issue

18 februari 2019 | 20 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. And I am so privileged to be joined by Senior Associate Editors whom I respect and admire so much. And they are Dr Biykem Bozkurt from Baylor College of Medicine and Dr Sana Al-Khatib from Duke University. And we have three woman discussing the Go Red for Women issue. Yes!

The current issue is the third Go Red for Women issue and boy, is it a bonanza issue. It tackles a wide spectrum of topics relating to cardiovascular disease in women, including prevention, risk stratification, myocardial infarction, pregnancy, heart failure, cardiac arrest, sudden cardiac death, and in so many wonderful formats; from original papers to systematic reviews, state-of-the-art papers, in-depth reviews, a research letter, and even frame of reference papers.

So, let’s get digging into this issue, shall we? And Biykem, we could start with you because I'd like to start with three original papers that really set the scene. The first discussed temporal changes and the very contemporary data from 2001 to 2016, describing cardiovascular risk factors and their treatment. And then the second focuses on young females with acute myocardial infarction. And the third on older women. Could you take us through these papers Biykem?

Dr Biykem Bozkurt: Lets first start looking at the sex differences through the Anne Haines Survey which enrolled more than 35000 patients. And they examined the trend all the way back from 2000 to 2016. Now the good news is the improvement in hypertension diabetes hyperlipidemia in woman were similar to men. So that's the good news. But BMI increased more in women than in men and overall, the ability to control blood pressure and diabetes hyperlipidemia appear to be a little bit better for women than in men.

But the concerning trend becomes apparent when we look at another paper that examined the twenty-year trend in young adults. Now, the first message is, and this is important for both genders, the proportion of the hospitalizations that are attributable to young patients, and young patients are defined as ages between 35 and 54 in this study, and this study was from Erik, increased from 1995 to 2014. So young patients appear to be having more in life compared to before, compared to 1990s and the 2000s. And that was actually partly due to the increasing prevalence of comorbidities, such as hypertension diabetes among young patients.

Now, interestingly among young patients, young women presenting with [inaudible] had a lower likelihood of receiving guideline directed therapy which, of course, sound familiar to our audience because we have the disparities of lower treatments and lower access to care in women with MI presentation compared to men. And unfortunately, again this will sound like the former news, the pre-hospital mortality was quite high in young women and has declined less in young women, compared to men.

So, the Erik study highlights the disparity for young women compared to young men. And then we have to recognize that most young patients in my hospitalization attributed to young patients is increasing. So this is probably a population that we need to be aware of. Regarding the older patients, there is a publication from the Opach Study looking at the sedentary behavior and cardiovascular disease in older women. And they looked at more than 5500 patients aged between 63 and all the way up until 97. And they looked at sedentary time and they looked at the duration of sedentary time all the way over eleven hours in some of the patients. And of course the higher the sedentary time was, the worse the cardiovascular disease risk was amongst the older women. So now we are recognizing that among older women, the post-menopausal or elderly women, the risk of cardiovascular disease rises with sedentary lifestyle.

And I think these three papers highlight the overall trend that we tend to see, maybe, better emphasis for comorbidity control. But at the same time we are now starting to recognize that in younger patients, especially in younger women the risk of MI is on the rise. And in older women, activity and remaining active and not having too much sedentary time are important to prevent cardiovascular disease.

Dr Carolyn Lam: Oh, Biykem, thank you for framing that so beautifully. So some good news, some bad news, and certainly some things we should be looking out for. You know, in another patient group that we always need to touch on when we talk about the Go Red for Women issue is pregnant women, or post-pregnancy. Could you comment, perhaps, on the systematic review that we have?

Dr Biykem Bozkurt: This is a very comprehensive, systematic review looking at the cardiovascular disease morbidity and mortality in women with a history of pregnancy complications. And they provide detailed systematic review and method analysis. It's becoming more apparent that the spectrum of cardiovascular disease ranges all the way from preeclampsia to arrythmia to pericardial myopathy. And we're recognizing this continuum both in the peripartum period, at the same time as the future risk. So those with preeclampsia and premature birth and delivery are associated with lifetime risk of cardiovascular disease. So, I think this paper is providing the right overview and a very comprehensive meta-analysis recognizing that pregnancy led to complications and morbidity and mortality in women.

Dr Carolyn Lam: Indeed. And it does just add so nicely to this issue, you know? Letting us know that we should watch out for the young women. We should watch out for the sedentary older women. And we should watch out for women with a history of pregnancy complications. But let’s switch tracks now. Sana, there was an amazing autopsy paper, actually, relating to sudden death in women. And as well as another original paper focusing on out of hospital cardiac arrest that is really very interesting. Would you like to tell us about those two?

Dr Sana Al-Khatib: Oh absolutely. I would love to. As someone who has devoted her life to the study of sudden cardiac death and you know, identifying factors, prevention. I really like that the paper looking at the risk of cardiac death in women and men. This study, Carolyn, was conducting in Finland, and the aim of the study was to determine autopsy findings and causes of death among women in a large population of sudden cardiac death.

They also were able to classify some EKG characteristics in men and women cardiac death victims. That really added helpful information. To do that, they systematically collected clinical and autopsy data from sudden cardiac death victims in Northern Finland between 1998 and 2017. So they actually had data on close to 5870 SCD victims. The findings were very interesting because they found that victims were significantly older than that. You know, so when they provided the median age it was 70 years for women versus 63 for men. So that was a significant difference there. And when they looked at the most frequently identified cause of death, they found that it was ischemic heart disease in both factions. Seventy two percent in women verses seventy six percent among men. And what was really striking about this was that the seventy two percent presence among women was higher than what had been reported in other theories.

They also reported that women were more likely to have lung ischemic cause of sudden cardiac death than men. It commented on the fact that primary myocardiac fibrosis was more likely to be found in woman victims rather than in men. And then they were able to identify some EKG factors stating that, in general, women were more likely to have a prior normal EKG than men. But that it increased the marker for sudden cardiac death with the presence of MDH with the polarization changes that were more commonly seen in women.

So, I thought that the findings were really interesting. They sure to be advance the field.

Dr Carolyn Lam: I couldn't agree more. Sex differences in sudden cardiac death. I don't think many people could tell you they knew much about it at all before this paper. And what about at a hospital cardiac arrest?

Dr Sana Al-Khatib: So, the other paper, which was really interesting, was a study that really looked at the public perception on why women receive less bystander CPR than men in out of hospital cardiac arrest. And this was an observation that was made a long time ago, Carolyn. So what's interesting for these investigators to be able to shed some light on this observation. What they did was they conducted a national survey of members of the public. And they were able to get 548 people to respond. Not a very high response rate, but pretty good for getting qualitative research studies. About fifty percent of the responders were women, so it was important to note that. And there was a good geographic distribution of the people; this was done in the U.S. And after they corrected their data, and they analyzed their data, the major thing emerged in terms of why the public perceived that women received less bystander CPR. The findings were really interesting.

The first finding was that people were concerned about being accused of sexual assault if they were to do CPR on the woman, which was interesting. Some actually were concerned that women were too weak or too frail. If they were to ever do CPR, might they cause any bone fractures, any injuries to the woman because they're more fragile, so to speak, than men. And their last theme was misperceptions about women in medical distress. What that meant was they felt that, well, you know, are women actually victims of sudden cardiac death? Yes, definitely, women can have sudden cardiac arrest and some people said, "Well, sometimes women can be overly dramatic and so maybe those presentations were not real presentations of sudden cardiac arrest," which I thought was really interesting.

I felt these were really interesting insights into why women don't receive CPR as much as men, and hopefully future interventions can be targeting these misconceptions or these concerns that the public has about doing CPR on women.

Dr Carolyn Lam: Isn't that so intriguing. The misconception that women are either too shy, too frail, or too dramatic. Oh my goodness. Anyway, that was all the original papers, which were fantastic. But I have to admit that one of the things that I love most about the Go Red for Women issues is that it talks about women in cardiology. And Biykem, you've always been such a huge mentor to me. And what I love about this issue is that there are a few papers, aren't there, that actually focus on the importance of this mentorship. Could you tell us about that?

Dr Biykem Bozkurt: It's a very important concept that I think is underlying a few papers in our issue. The first one is women in cardiology and perhaps the lack of increase in the representation of women in cardiology. Even though women make up about half of our medical graduates, among practicing cardiologists women comprise less than about twelve to fifteen percent of the population. That perhaps disparity hasn't changed in the last two decades. We tend to sometimes compare our profession to the surgical field, and I think gender inequality appears to be a little bit similar to general surgery and orthopedic.

But the paper by Ziman underlines the following: Even though our gender inequality is similar to the surgical field, to look at the temporal trends there has been a significant rise in female representation in general surgery. And actually, among medical trainees, about one third of the medical trainees, not fifty percent like us, one third of the medical trainees are in surgical fields after they go to medical school. But the female representation has been steadily increasing in the surgical fields; about three-fold out of cardiology. Whereas female representation cardiology has the main slot, so the surgical fields are doing a better job in either welcoming, supporting, and mentoring their female trainees than the cardiology field.

This is an important concept for us to recognize, and usually the disparity reasons are perceived to be gender and lifestyle and/or personal preferences. That doesn't appear to be the case. Perhaps the better role models and better mentorship could eliminate this disparity and this is underlined in the Olmein Mein paper by Ziman.

Another paper by Sharon Hunt also underlines this concept. She portrays the woman needed in cardiac transplantation from a historical and personal perspective, and underlines the following: We tend to have a large number of woman leaders in advance heart failure and cardiac transplantation. And part of this may be attributed to the fact that women have been part of the fabric, part of the readership, part of the group that has developed the field and has been practicing. And thus, there has not been a nation or incorporation of the women in the field. And thus, since they've been involved in the practice from the beginning, they have been seen as a natural partner. Even though cardiac transplantation is quite demanding, requires bedside presence, and hours which are usually used as a reason for women not to go into certain fields, such as interventional. In transplant, we don't seem to have that much disparity for women. Women tend to select this field on one of the reasons in Sharon Hunt's piece is identified as being part of the team from the beginning, and having good role models and mentors.

And finally, there is a research letter that identifies if the corresponding author is a female author. There is a large representation of co-authors. This is a very interesting finding by Ouyang stating that even though the female to male senior authorship rates have not been different over the years, if the senior author or the corresponding author is a female there tends to be a higher number of co-authors. This may suggest that female corresponding authors are able to mentor or include their partners or team members. Or vice versa, female co-authors may feel more invited and incorporated as a team. So, this paper also underlines that women in leadership positions connected to cardiology may serve as positive role models to recruit and retain talented junior female investigators.

Dr Carolyn Lam: Ah, indeed, indeed, indeed. So many topics that come close to my own heart. But Sana, among the numerous other papers here, we have two state of the art papers, two in-depth reviews, there are three frame of reference papers. Which one, or ones, stood out to you?

Dr San Al-Khatib: One important paper, Carolyn, you certainly mentioned is an online paper that was titled "Why are Young Black Women as High Risk for Cardiovascular Disease". I personally like this paper a lot because it highlights such an important issue that has great impact on public health. And sometimes the population of young black women may go unrecognized in terms of their risk of cardiovascular disease and what have you. So really the On My Mind paper tackles what are these things that are driving the worsening cardiovascular disease trends in this patient population. And what can we do about it? And they talk about how the awareness of heart disease and the leading cause of death among these women is actually more among black patients. And so, they talk about the need to really implement multi-level strategies to try to address this, raise awareness, identify disparities in care. They even also call for really investing in black women scientists.

And so, this was such a really good paper and I'm sure that the readers will enjoy it as much as I have.

Dr Carolyn Lam: Oh, thank you so much for that, Sana. That really, really makes for such a rich issue with such a lot of different papers. We're running out of time, so we don't even have the opportunity to really discuss, but I want to mention these so that the listeners will look out for them. Beyond the papers we've already discussed, we have state-of-the-art papers on cardiovascular care in women veterans and the management of cardiovascular disease in women with breast cancer. We even have two in-depth reviews. One on sex differences in advance heart failure therapies and a second on the role of breast arterial calcification in cardiovascular risk stratification in women. And finally, there's a research letter on the size of thoracic aortic aneurysms in women. So many papers, such a beautiful, beautiful issue. I just want to thank you both Sana and Biykem for leading this beautiful Go Red for Women issue.

Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation February 12, 2019 Issue

11 februari 2019 | 22 min

Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Is income volatility a new cardiovascular risk factor? You have to stay tuned to hear all about that. But for now, join Greg and I over a nice little coffee chat, because we're picking up the journal right here and I'm going to tell you about our two top picks this week. Greg, you go.

Dr Greg Hundley: Well my top picks, Carolyn, is really pertaining to senescence and senescent cardiomyocytes. Remember that? Senescence is a situation where there's a mismatch between energy demand and supply and so that facilitates the cells transitioning toward failure. They lose their ability to function. In other parts of the body, they lose their ability to divide.

And these investigators assessed altered calcium transfer from sarcoplasmic reticulum to the mitochondria, because that's being casually linked to the pathophysiology of aging in heart failure. Because the advanced glycation end products or AGEs accumulate through life, the authors thought that maybe this intracellular glycation would be occurring in aged cardiomyocytes and their impact on the sarcoplasmic reticulum and mitochondria. So, their study, they investigated both mice and humans and the found that ryanodine receptor glycation was associated with more pronounced calcium leak in mice and also interfibrillar mitochondria directly exposed to sarcoplasmic calcium release from aging mice had increased calcium content, compared to those with younger ones.

Now we're starting to implicate a mechanism by where senescence could be important in these mice. But of course, in Circulation in these wonderful basic science papers that we have, they also cover a translational human component. And what these group found is that there were higher levels of advanced glycation end products and reduced glyoxalase 1 activity present in left atrial appendages, from those patients that underwent surgery greater than 75-years-of-age, compared to individuals that were younger. And also, elderly patients exhibited hyper glycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity due to less respiring mitochondria.

Dr Carolyn Lam: Wow Greg, that was a huge summary and how nice to link aging or senescence with AGE or advanced glycation end products. Seriously, that was new to me. Okay look, bring it home. What are the clinical implications?

Dr Greg Hundley: What these investigators have done is now identified a previously unknown pathophysiological mechanism that may facilitate the transition from healthy, towards failing cardiomyocytes and the implication is that if you could disrupt that process, maybe you could halt the aging of cardiomyocytes. You got to be careful though I think with senescence, just as we know from the general literature. Senescence is a defense mechanism in cancer therapy, but it's a protagonist if you will, in aging. More to come in this field, but very exciting research.

So Carolyn, tell me about your first paper.

Dr Carolyn Lam: Happily, Greg. I'm going to take us to the cath lab and talk about functional assessment of epicardial coronary artery disease. This paper from Dr Koo and colleagues of Seoul National University Hospital, is the first to validate the physiological relevance and prognostic implication of all available novel resting pressure derived indices of coronary stenosis. This includes indices like resting full cycle ratio or RFR and diastolic pressure ratio or DPR, and they compared this to instantaneous wave free ratio or IFR and fractional flow ratio or FFR.

What they looked at was more than a thousand vessels in 435 patients and showed that all the resting ... Just the resting. Not hyperemic but resting pressure divide indices, closely correlated with each other and showed excellent agreement and the same discriminatory ability for no FFR. All the indices also showed a similar pattern of changes to different anatomical and hemodynamic stenosis severity, regardless of the target vessels and importantly showed similar diagnostic performance for myocardial ischemia, defined by gold standard PET derived CFR and hyperemic myocardial blood flow.

And finally, they showed that all these indices showed significant association with the two year vessel oriented composite clinical outcomes.

Dr Greg Hundley: So, do we still need to do adenosine infusions in the cath lab?

Dr Carolyn Lam: That's exactly what they're trying to drive at, because the major advantage of these resting indices, for example RFR over IFR, is that IFR doesn't require identification of a specific landmark or a specific time point during diastole. They may be simpler to perform and this first study showing their physiologic relevance and prognostic implication may enhance adoption of invasive physiologic assessment in daily clinical practice, which we know is important and a clinical benefit.

Dr Greg Hundley: Excellent. I tell you, it would sure save time if we could use indices like that.

Let me tell you about my next paper. This is from Renato Lopes, from Duke University Medical Center, in Durham. Also, one of your affiliates. In all of our cardiovascular/metabolic clinical trials today, cardiovascular death is a very important outcome. But what happens when, in doing a study like that and you have an undetermined cause of death, the US Food & Drug Administration Guidance indicates that deaths due to undetermined causes should be rare in well-run clinical trials.

And so what this group did is they looked at 127,049 enrolled participants from nine trials and they looked at how deaths were adjudicated. And across nine clinical cardiovascular trials, in different therapeutic areas, the proportions of deaths adjudicated as related to undetermined cause ranged from 7-to-22% and overall, had an average of 16%. Interestingly, in multi-variable analysis, death due to undetermined cause, was associated with the therapeutic area and the year of publication of the study, and then also several patient factors including: gender, age, the region of enrollment, and time from enrollment to death.

Dr Carolyn Lam: Gosh, this is so enlightening. Greg, having been on CECs and struggle with the adjudication, I really like this paper as well. But please, tell us all, why should we be concerned about this?

Dr Greg Hundley: Great question, Carolyn. First we might think about, if you're reading a study, the proportion of deaths due to undetermined cause should really fall within this range. And have a mean of maybe 16%. Second, what if there are higher rates due to undetermined cause? Well, that may indicate there are issues with the trial quality. And then finally, researchers, whenever they're doing a study, should really report on the proportion of deaths where cause was unable to be determined.

And there was a great editorialist, David Morrow, from Brigham and Women's Hospital, and really pointed out, you've got a couple factors here that lead to why there's undetermined cause of death. Maybe the documents are missing, or you're in a clinical situation where a subject lives alone, found dead, there's no autopsy. Uncertain duration. Sometimes there are limits on the study personnel; their ability to actually go out and acquire the data so that the team, like what you're on, can actually adjudicate the information. And a point that's made is really ... He used the word, doggedness, but with which he consistently worked toward and tried to get those medical records and pursue them, because that is very important.

When we think, well what's the importance of a study like this? It's valuable to those that perform studies, because as we're working with our study coordinators, we need to make that information known to them. If we don't collect the exact cause of death in these important cardiovascular interventional studies, we may end up with an improper result. And also, for the investigative team. A really important study I think, providing guidance for the first time now about what we should expect in undetermined cause of death, when we're looking at cardiovascular trials.

Dr Carolyn Lam: Indeed, and from talking about doing the trials to talking about a very important trial, I want to take you to The Partner 2 Trials and talk about the cost-effectiveness of Transcatheter Aortic Valve Replacement, or TAVR, compared to surgical aortic valve replacement, in patients at intermediate surgical risk.

Now we already know that TAVR is cost-effective, although not cost-saving. But cost-effective compared to surgical aortic valve replacement in those at high surgical risk. But this paper refers to intermediate surgical risk. And the analysis is from Dr Cohen and colleagues from Saint Luke's Mid-America Heart Institute, and it's an analysis of the Partner 2A Randomized Trial and the SAPIEN 3 Intermediate Risk Registry.

In summary, they found that TAVR was projected to lower total costs by $8,000.00 to $10,000.00. And to increase quality adjusted survival by 0.15 to 0.27 years, compared to surgical aortic valve replacement over a lifetime horizon.

Dr Greg Hundley: Wow! Carolyn, I've got two questions for you. First of all, how does TAVR save those costs? And number two, was this true for everyone? Were there any caveats or special subgroups that this was really applied to?

Dr Carolyn Lam: The cost savings in a TAVR cohort looked like they were driven by both a shorter length of stay during the index hospitalization, as well, as less resource utilization during follow-up. And that would be in the form of fewer hospital days, as well as fewer rehabilitation and skilled nursing facility days.

As for the caveats, you see that the authors did acknowledge that the long-term durability of the valves involved like the SAPIEN XT and the SAPIEN 3 valves is still unknown, and so lifetime costs associated with TAVR, may be higher than we assumed, owing to the need of more frequent repeat valve procedures for example.

Now if though, the long-term data demonstrate comparable late mortality with TAVR, and the surgical aortic valve replacement, these findings are really significant, because they suggest that TAVR may become the preferred treatment strategy for patient populations. Not only based on clinical outcomes, but even based on economic considerations.

Dr Greg Hundley: It looks like that long-term information is going to be really critical here, so we'll look for more in this area.

Dr Carolyn Lam: For sure. Wish we could keep chatting, but I think we need to move to the featured discussion.

Dr Greg Hundley: And now to the very fun segment of our discussion this week at Circulation on the Run. This is Greg Hundley, from VCU Health. Director of The Pauley Heart Center. And today we have a fantastic paper from Adina Zeki Al Hazzouri from Miami, transitioning to Columbia University. And also, our Associate Editor, Dharam Kumbhani from the University of Texas, Southwestern.

Today's paper, Adina is going to discuss is, Associations of Income Volatility with Incident Cardiovascular Disease and All-Cause Mortality in a US Cohort. And what she's done is worked with the Coronary Artery Risk Development in Young Adult Study, we also know that as, CARDIA. And it's really a prospective cohort conducted in urban centers, in Birmingham, Alabama, Chicago, Illinois, Minneapolis, Minnesota, and Oakland, California. The goal here was to asses a block of individuals, younger, aged 23-35 years, identified in the time window of 1990-to-2005 and then followed subsequently to look at income volatility.

Adina, we're so excited to have you here. And can you tell us a little bit more about your study.

Dr Adina Zeki Al Hazzouri: Sure, the motivation for the study is the fact that we know that income volatility is on the rise. And what I mean by, income volatility, is the sudden and unpredictable change in income. And in the health researcher, we actually do not know as much, what is the effect or the influence of income volatility on health outcomes, and it is really common, most of us do experience these sudden or unpredictable changes in income. Whether they're little dips or little jumps in income. So they are really common, and I think it's really important to try to understand what would be their effect on health outcomes.

We were really interested in specifically understanding their effect on all-cause mortality and incidents of cardiovascular disease events, so we took advantage of an ongoing perspective cohort study. The cardio study that you just mentioned. And what is really nice about this study is they were really relatively young back in 1990 when we first had the measure of income. They were between ages 23-and-35. And they were followed for over 20-years, so we had repeatedly over 10-years, or 15-years, repeated measures of income. And then we were able then to look in the subsequent 10-years for incident events, cardiovascular events and all-cause mortality, and what is also interesting in this study is that these individuals, given that their age range, so that they are in the peak of their working years, which makes it even more interesting in terms of applicability and inference of those findings that we're making in this study.

We looked at, as I said, income volatility and we defined it basically as what is the standard deviation of these percent changes in income that you experience between the different visits in the study, which were on average, five years apart. And once we defined that, then we looked at it with outcome and what we really found was that those who experienced high volatility had around a two-fold increased risk of cardiovascular disease, as well as all-cause mortality.

We also looked at another measure of income volatility which is the number of income drops, so how many times you've dropped significantly, which we defined as a drop of more than 25%. And that is lower than your average income throughout the study period. And we found similar results.

Dr Greg Hundley: Adina, what could be the cause of this? What do you think as an investigative group, is the mechanism behind this finding?

Dr Adina Zeki Al Hazzouri: There could be various mechanisms playing roles here. Stress is obviously one of the important mechanisms. If you think about the instability of income, that instability in income could result in daily stresses, maybe inability to pay for bills. Also, that resulting in inflammation in all the stress pathway.

Also, you could think potentially having this instability could also maybe hinder access to care, maybe coping mechanisms related to stress could alter adherence to treatment. Whether maybe someone has to take daily medications, having those dips or changes, sudden changes in income, could alter your adherence to those medications and then subsequently influence your risk for cardiovascular disease.

Also, you could think access to health insurance. The social support, though it's not very well evidenced, but maybe if you've had always stable income, or low income, you're more likely to have more resilience. However, when you have these unpredictable changes, or sudden changes in income, you may not have that coping mechanism or support ready for you to deal with those sudden changes.

These are some of the pathways that we think of that could potentially be playing a key role here.

Dr Greg Hundley: Very good. Now let's turn to Dharam, our Associate Editor, from University Texas, Southwestern. Dharam, boy, surprising findings. A young cohort. I mean, they were 23-to-35 and in the next 10-years of their life they start to experience hard cardiovascular events. I mean, fatal and non-fatal myocardial infarction, and also, all-cause mortality. How do you put this in perspective, related to the workforce, and what do you think this means for this young population moving forward?

Dr Dharam Kumbhani: At the outset we obviously want to congratulate Adina and her group, for this really, very interesting study in cardiovascular EPY and broadly intersects in health economics and health policy, as well for obvious reasons.

Very interesting construct as you pointed out and what does this mean for younger subjects who experience these income volatility very early in their life. I think, just like any other EPY study, I think the perspective is helpful, because although the hazard ratio for these income volatility is two or higher, the absolute incidents rates are, again putting that in perspective is important, and so the absolute incident rates for example is somewhere between two-to-five, per 1,000 persons. So overall that impact, that's just helpful to understand what effects this would have.

Hopefully, that helps. But obviously, very interesting analysis and brings up a lot of questions. I think one thing I may add to what was just mentioned is ... And this was highlighted very nicely by the editorialist, Dr Spatz, and her colleague from Yale. About how this is globally in the financial toxicity space, and there are a number of these indicators that are now being carefully studied like in this study, such as wealth shock and as I said, financial toxicity. And how they actually have an impact on cardiovascular outcomes.

One of the feelings when you read a paper like this or when you read studies like this, and in fact this was one of our initial concerns as well, is to what extent you may have a component, or significant component of reverse causality. Your, "Patients who are sicker in some way," or have those culpabilities, be the ones that have these events is their relationship with other socio-economic indicators such as employment and how that would affect income volatility as well.

I think the authors have done a really terrific job responding to that. And again, it shows an association obviously we know that, that doesn't imply that it's cause[owed], but it's a very interesting association. And that it's helpful to speculate both on the mechanisms, which were just outlined, and also what this means from a health policy standpoint. What that would mean for researchers in the cardiology community, or policy makers, things like that. So I think this is a very nice analysis and definitely brings up a lot of discussion points.

Dr Greg Hundley: And a very important paper on multiple fronts. One, we've identified an issue in young, healthy individuals that could significantly contribute to adverse cardiovascular events. And then number two, I really liked your point on how this could impact public health policy, and maybe even how we need to think about reducing stress and how we design aspects of the workforce moving forward, so individuals don't suffer from these conditions.

I want to thank, Adina Zeki Al Hazzouri, from Columbia. And our Associate Editor, Dharam Kumbhani, for these excellent comments. We look forward to seeing you next week.

Circulation February 5, 2019 Issue

4 februari 2019 | min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, from National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg Hundley, associate editor for circulation from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam: What does cardiac autoimmunity, glycemic control, and cardiovascular disease risk and Type I diabetes have in common? Well, you've got to wait for our feature discussion. This one's such a hot one, don't you agree, Greg? We could hardly finish talking.

Dr Greg Hundley: Absolutely, and Myra, you're just going to love listening to her.

Dr Carolyn Lam: Yep, but stay tuned. First, we're going to discuss a couple of papers each. Greg.

Dr Greg Hundley: Thanks Carolyn. So, the first paper I've got is from Professor Van Rein at Leiden University Medical Center. And basically he's getting at the issue of bleeding in patients with atrial fibrillation. So this is a retrospective cohort that evaluates different anticoagulation strategies for atrial fibrillation. They examined 272,315 patients that had a median age of 75 years and followed them longitudinally over time. These individuals experience 31,459 major bleeding events, and what he did is he evaluated whether they were not taking anticoagulant therapy, whether they were on a vitamin K antagonist, a DOAC, antiplatelet therapies, and then all combinations of the above, including single, double and triple therapy.

What he observed is relative to taking a vitamin K antagonist alone. The hazard ratios range from 1.13 to 3.73 in those that were receiving dual antiplatelet therapy of vitamin K antagonist plus antiplatelet therapy, a DOAC plus antiplatelet therapy, and then of course triple therapy, which had that highest hazard ratio.

Dr Carolyn Lam: But were there particular combinations within these groups that had particularly high bleeding risk?

Dr Greg Hundley: Well, yeah, Carolyn. As we might expect, triple therapy was the worst, but those that were receiving triple therapy, there were two subgroups that were particularly susceptible to having a bleeding episode. First, those that were greater than 90 years of age, and second, those that had CHADS-VASc 2 scores greater than six. Of course, these are very complicated patients, often particularly that latter group. So there are clinical implications. I mean, clearly, this isn't a randomized trial, but what we should take away from this is that if we have one of those two patient groups, age greater than 90, CHADS-VASc score greater than six, that we ought to minimize the time that those individuals are on that triple therapy.

Dr Carolyn Lam: Talk about and bleeding, I've got a paper, and it's on the performance of the ABC scores for assessing the risk of stroke and systemic embolism or bleeding in patients with atrial fibrillation. This is a study that actually looked at the performance of these scores in an external cohort, which actually hasn't really been done. Now, as a reminder, the ABC score is actually the age biomarker clinical history stroke score, which helps to estimate the risk of stroke or systemic embolism. The ABC bleeding risk score incorporates biomarkers along with the clinical variables to estimate the risk of bleeding.

All of these were tested in the ENGAGE AF-TIMI 48 trial, which was that multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS-VASc 2 score of two and above. Now, this was from Dr Morrow and the TIMI study group in the Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts. Basically what they found was that the ABC stroke and ABC bleeding risk scores performed well in stratifying the risk for stroke or systemic embolic events or major bleeding in this multinational trial.

Compared to the CHADS-VASc score, the ABC stroke score provided both correct upward and downward reclassification of the stroke systemic embolism risk. Compared with the HAS-BLED score, the ABC bleeding score resulted in a predominantly correct downward reclassification of the bleeding risk.

Dr Greg Hundley: So, this new ABC score, do we integrate it with HAS-BLED? Do we integrate it with CHADS-VASc 2? How do we use this clinically?

Dr Carolyn Lam: So first of all, there are some important remaining unanswered questions, and this was really nicely discussed in an accompanying editorial by Dr Hylek from Boston University School of Medicine. Among this, first of all, the ABC scores need to be validated in patients outside of a clinical trial. Remember, this was a clinical trial cohort. Then there are questions about the timing of measurements of the score, the different settings, hospital and otherwise. Do these scores perform equally well across different vascular beds and in diverse patient populations at the same thresholds used?

So, all these things still need to be addressed. And really, in Dr Hylek's words, the work has just begun.

Dr Greg Hundley: This is an issue with the theme that might be bleeding, and I'm going to talk about a study from Professor Huisman from Leiden University again, and this is the RE-VERSE AD study. Again, patients that are receiving dabigatran and that may have a GI bleed or patients that are on this therapy and unexpectedly need an emergent surgical procedure, this investigative team evaluated the utility of idarucizumab on reversing that anticoagulant dabigatran. So what did they do? They administered 2.5 milligrams of idarucizumab twice separated by 15 minutes.

And again, the study population was uncontrolled GI bleeding or those in need of an emergent procedure. The types of GI bleeds that were involved in this study, a third were upper GI bleeds, a third lower, and then a third, it was either unknown, or there was a mixture of both upper GI or lower GI bleeding. So how do we know that dabigatran is effective? We use a DTT time, and 98% of those with an elevated diluted thrombin time had that reduced after receiving these two twin 2.5 milligram doses at a time point of four hours after administration.

Dr Carolyn Lam: Okay, but were there any complications?

Dr Greg Hundley: Yeah, there were. So first of all, something to think about is that this is a high-risk group. In this study, 14.6% of the cohort actually later died either from the bleeding or what have you. Then another thing we need to be thinking about is when we reversed this anticoagulant, do patients experience thrombotic events? So what this group reported is 4.4% did within 30 days. What were those? Myocardial infarction, deep venous thrombosis, and subsequent PE. Then also at the 30-day time point, one patient experienced an ischemic event.

Another question is once you've administered this, you've gone through the procedure. You stopped the GI bleeding, or you've had the surgery. In this particular study, 66% of those individuals had restarted their DOAC. Those events occurred on top of that. So, interesting information. Looking at administration of idarucizumab, and we'll be using this I think frequently as DOACs are used more frequently in the population, particularly dabigatran, so some important data in guiding us on what we might expect when we administer this therapy.

Dr Carolyn Lam: I think going back to atrial fibrillation though, this is my other selected paper, and it's actually results from the GARFIELD-AF Registry. It's from Dr Bassand from University of Besançon in France, and colleagues, and basically, they looked at the early risks of death, stroke, systemic embolism and major bleeding in patients with newly diagnosed atrial fibrillation in the GARFIELD-AF Registry. They basically found that the rates of all three major clinical events was significantly higher during the first month than in the subsequent period set following up to 12 months.

The leading causes of early death were heart failure, sudden death, acute coronary syndromes, infection or sepsis, and respiratory failure.

Dr Greg Hundley: So, what's the take-home message here?

Dr Carolyn Lam: This is observational, so the key thing to understand here, it's a registry. It's observational. We can't really tell chicken from egg with regards to its newly diagnosed AF verses events, which comes first, which causes what. But nonetheless, the increased hazards of an early event and especially cardiovascular mortality in these newly diagnosed AF patients really point to the importance of comprehensive care for such patients and really should alert physicians to detect warning signs of possible early mortality in these newly diagnosed patients.

Dr Greg Hundley: Very good, Carolyn.

Dr Carolyn Lam: I think that wraps it up. Let's hop to our feature discussion, shall we? I'm so super excited about today's feature paper because it may explain that strong link between hyperglycemia and cardiovascular disease in type one diabetes and all by revealing a potential novel pathway that may have been hiding in plain sight. And yes, I'm stealing the words of editorialists and our associate editor, Dr Naveed Sattar from University of Glasgow, and we're all so pleased to have with us the corresponding author of today's feature paper, Dr Myra Lipes from Joslin Diabetes Center in Boston, Massachusetts. Myra, start us off by telling us a little bit about your study please.

Dr Myra Lipes: Sure. So we were interested in examining the role of whether chronic hyperglycemia could trigger cardiac autoimmunity in type one diabetes, because chronic hyperglycemia is associated with subclinical myocardial damage, and we had actually previously observed just unexpectedly in a young adult cohort that ... Actually from Italy, where unexpectedly, we noticed that patients with the poorest glycemic control expressed cardiac antibodies. There's a lot of interesting people who are autoimmune-proned may overreact to injury of certain tissues.

So, type one diabetes, it's a classical autoimmune disorder. So we examined, really tested this hypothesis, in stored samples from the DCCT/EDIC study, and this is a very landmark study where patients were randomized to tight glycemic control, intensive glycemic control. Then another group had just conventional control, and this was done over an average of six and a half years. So during this time, the samples were stored. Every year samples were stored from participants, and this was quite a rich data set that is publicly available. So we studied the development of autoimmunity in two groups that had very distinct separations of the A1C level.

We specifically excluded people who developed kidney disease or cardiovascular disease events during the study. So this is a cohort that had relatively recent onset type one diabetes. They're relatively healthy, and again, groups were matched with cardiovascular risk factors at the beginning and the end of this DCCT period. And of course with our studies, we've also looked genetically because your HLA immune response genes can influence susceptibility to autoimmunity.

These patients were actually matched in HLA genotypes. So what we found was that patients with poor glycemic control, there was expression over time. You could see a time course relationship between expression of antibodies over time on the levels of the antibodies that were different in the two A1C groups. The number of antibodies were different in that with the high group expressing more antibodies, more different types of antibodies. These are antibodies ... might say antibodies as like proteins in the blood, and they're actually directed against parts of the myocytes, the myofibrillar complex, and a major target is cardiac myosin heavy chain.

We saw the different parts of the myosin heavy chain retarded, and the presence of two or more antibodies, different types of antibodies, different regions of the myosin to different isoforms. Also, we saw antibodies, the troponin, troponin I. So the number of antibodies with different ... with almost a complete absence of antibodies in a tightly controlled group. I might mention the A1C average was 6.5%, so this is a very tightly controlled group whereas the poorly controlled group is at the opposite extreme, the average A1C during DCCT. The mean updated A1C was about 10%.

So, it was a very clean group, two different groups, and we could see that the number of the types, the number over time, very different in the two groups. In fact the profiles of these antibodies were almost very similar to patients with Chagas cardiomyopathy. That was our positive control group. Chagas cardiomyopathy is possibility to be a form of chronic myocarditis directed against cardiac myosin. So the profiles are almost indistinguishable. So on one hand, you have relatively healthy patients with type one before glycemic control, and that was very unexpected that this would look pretty similar.

But very interestingly, and I might say unexpectedly, we saw ... It was very clear that the people with the highest titers of antibody and the most different types of antibodies, particularly two or more, were subsequently ... We noticed that those patients were at high risk for developing CVD events. And that's while the number of events was slow, we noticed that all the patients, some 60%, had two or more antibodies and developed cardiovascular events. Perhaps one more striking example is a single patient in the study could die of cardiovascular death, had a positivity for all five antibodies at highest titer.

Then we looked at coronary calcification just to measure subclinical atherosclerosis. We noticed that the same numbers, two or more, and also the same antibody specificities that were the highest predictors of CVD events were also predictive of coronary ... had detectable coronary calcification. In addition, we looked at the levels trying to find mechanistically what could explain the link between cardiac autoimmunity and an increased risk for atherosclerosis. We looked at CRP, high sensitivity CRP levels.

Again, these were measured about a decade after the antibody samples were obtained, and we saw that the positivity for multiple antibodies was also associated with markedly elevated ... subsequently elevated high sensitivity CRP levels with levels of six versus something like 1.4 in a group with one or less antibody. So these were very intriguing findings, suggesting a role for autoimmune pathways as a susceptibility to cardiovascular disease in type one diabetes.

Dr Greg Hundley: Myra, that was absolutely incredible description of the study and all the particulars of the findings. I wonder if I could ask both you and Naveed, where do you see the next steps moving forward with this research in the future? Number one. And number two, is this in any way can be used to segregate patients that may need, for example, really aggressive glucose control with an insulin pump or something of that nature?

Naveed Sattar: I think we left this study as beautifully described as you see by Dr Lipes. I think the context ... We looked at this from editorial perspective ... is that most people don't realize if you have a middle-aged person with type one, their hazard ratio for cardiovascular risk is about somewhere between four to six fold for men and women respectively, which is much higher than type two. It's often thought that it's the area under the curve for hyperglycemia. But what this paper throws up is actually maybe there's another pathway, which we just didn't understand that this wasn't a permanent autoimmunity closing subclinical myocardial disease and inflammations.

But potentially, for me though, there's a saying in British that one swallow does not make a summer. So, it would be nice for other groups to replicate this. I think the findings are, as they stand in isolation, fantastically well done. But it would be lovely if other groups had accessible samples, and I knew of several groups that have up towards tens of thousands of samples, maybe even not 10,000. Certainly 10,000 or so plus or minus samples for type and prospective outcomes to potentially validate the findings and extend them.

And really, if the antibodies do help protect people at higher risk in a meaningful way and improve beyond what we can already do, then you're right. Absolutely. If we can pick up early people who are going to have substantially higher risk, you would want to potentially improve glycemic control, potentially pumps, CGM, closed-loop systems or more intensive statins or lower blood pressure targets or other types of antihyperglycemic agents, which seem to be being tested in type one as well. So that's really one example.

And for me, the other thing would be really nice is to pull up any inflammation. Is this high systemic inflammation? Is it IL-6 level? Is it something else? What about troponin and BNP levels, et cetera. I'd be interested to hear what Dr Lipes thinks and how do you think to take it forward as well.

Dr Myra Lipes: So, this is something Dr Sattar said and I completely agree. Actually, right now, we're looking at the DCCT cohort as a whole for already. It's relatively small compared to the population-based studies. But there's 1,400 patients, and the subjects had CMR studies that were published in Circulation. So we're going to actually study next whether we see CMR evidence of systolic dysfunction and looking at the broader DCCT cohort. So, those studies are underway. But of course the ultimate test would be looking at if there were samples available from the Swedish NDRs, Scottish registry.

I think it's something that's not often done prospectively. So that would be incredibly exciting, and that's the important thing. I'd say with type one diabetes, for screening for type one diabetes, the use of autoantibodies and particularly two or more different types of islet autoantibodies, and this is just putting things in a broader context, is the entry criteria for type one diabetes prevention trials and something cardiologists wouldn't be aware of but this particular thing. So in decades, people, researchers, in the field has spent decades optimizing islet antibody assays.

So by analogy, it would be really important to standardize assays so that they can be done in Sweden and Scotland and so that other groups could confirm this, and I'm confident that this could be done, since the setting up of our assays was really built on the experience of people of developing standardized assays and rigorous cutoff points for antibody positivity. So it would be really important to work internationally to try to tap into this.

Dr Carolyn Lam: Oh, my goodness. Myra, Naveed, these are such insightful comments. I think as Greg said earlier, I think we could go on forever discussing this paper, but I'm so sorry. Our time is up. Before we go though, I must point all readers to look at figure five of this marvelous paper. It puts together the whole schema of how autoantibodies can play a role both in myocardial and atherosclerotic cardiovascular disease and type one diabetes.

Thank you so much. Greg and I loved having you. Listeners, don't forget to tune in again next week.

Circulation January 29, 2019 Issue

28 januari 2019 | 22 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts of Circulation on the Run. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I am Greg Hundley, also associate editor from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam: So, have you ever wondered in patients with atrial fibrillation and stable coronary artery disease beyond a year of coronary stenting, can you safely just continue on oral anticoagulation without antiplatelet therapy? Well, if you've ever wondered that ... I sure have. I'm sure you have too, Greg. Our feature paper this week does discuss this, so you have to stay tuned. But for now, Greg, what are your picks from this week's issue?

Dr Greg Hundley: I've got a couple to discuss. The first is Patrick Hsieh from Taipei, Taiwan, and really is evaluating the gut microbiota and how that affects cardiac repair after myocardial infarction. I mean, who would've thought to chase an idea like this? But what this investigative team did is they had mice, so this was a basic science experiment, and they treated them seven days prior to ligation of their left anterior descending artery that would induce a myocardial infarction. They treated them seven days prior with ampicillin, metronidazole, neomycin, and vancomycin. What were they trying to do? Totally obliterate any bacterial load within their GI system. Then, they ligated that coronary artery, and at 21 days, they looked at histopathologically what was happening.

And you know what they found? Those where they wiped out the bacterial load, they had increased cardiovascular events. And importantly, myocardial rupture was very high in this group of mice. Also those mice, they had reduced heart rate, and mechanistically what had occurred is there was a reduction in our immune monocytes that were trying to infiltrate the peri-infarct. They weren't there. They were not in those peri-infarct zones. And so, the thought here is that removal of the favorable microbiota in the gut can actually be harmful in the setting of myocardial infarction.

Dr Carolyn Lam: Fascinating. So, microbiome as our pals. But wait a minute. I mean, how can you say it's from elimination of the microbiome versus some kind of effect of the antibiotics itself?

Dr Greg Hundley: Yeah, that's a great question, Carolyn. The way they did this is they took another group of animals, and they supplemented them with lactobacillus probiotic, like the stuff we get in the grocery store. And those animals, they did not suffer any of the adverse cardiovascular effects. So, it really points to an important role of our gut microbiota. You know, and what do they do? They basically ferment these carbohydrates that we ingest, and produce short chain fatty acids that are a substrate for these mononuclear cells to help infiltrate those infarct zones. So, really exciting basic science question that this group examined.

Dr Carolyn Lam: I love that you picked a basic science paper, and I love that you made even me understand it so well. Okay, but what I have is a clinical trial. So, it's the REDUCE-MVI trial, which is the first randomized trial comparing maintenance treatment with ticagrelor or prasugrel after a primary PCI. So, this is from Dr van Royen and colleagues. They're from Radboud University Medical Center in the Netherlands. Basically, they figured that despite successful restoration of epicardial vessel patency with primary PCI, coronary microvascular injury does occur in a large proportion of STEMI patients, and of course, adversely affects outcomes. Now, ticagrelor has been reported to increase plasma adenosine levels, which may have a protective effect on the microcirculation. So, the authors randomize 110 STEMI patients following revascularization to maintenance therapy with ticagrelor versus prasugrel, with the primary outcome being microvascular injury at one month as determined by the index of microcirculatory resistance in the infarct related artery.

What they found was that there was no difference in the extent of microvascular injury and in the extent of infarct size by cardiac MRI at one month after the primary PCI. The attributed pleiotropic benefits of ticagrelor through the adenosine metabolism pathway actually could not be confirmed in the STEMI population, as plasma adenosine levels were actually not increased in the patients treated with ticagrelor.

Dr Greg Hundley: So, what does this mean for the use of adenosine and its role?

Dr Carolyn Lam: I suppose you're also asking, you know, is the adenosine hypothesis really out here? This is a study that really suggests we have to question it, but there are some limitations that we perhaps should keep in mind when we think about this. So first, before primary PCI, all patients were loaded with ticagrelor because this was standard of care in the participating centers. That, of course, could have modified microvascular injury already at the index event. Now, a second important thing is that the study may have been underpowered. There was a greater than anticipated variability in that primary outcome of index on microcirculatory resistance.

The relatively low rates of risk factors, the small infarct size, the preserved ejection fraction could all have influenced this IMR values, as well as the potential effects of the pharmacological intervention. And furthermore, the natural recovery of microvascular dysfunction over time may have diluted the positive effects. And of course, selection bias is inevitable in a trial. And so, you know, although this really questions the adenosine hypothesis, there are still caveats to these results.

Dr Greg Hundley: Very good. So, Carolyn, I've got another study to sort of go over, and this is from Dan Modin from the University of Copenhagen. And it's really addressing this issue. We all in the fall, do we all get our flu shots? And could that be helpful in patients with heart failure? You know, the ACC, the AHA, and the ESC all suggest flu shots, but there's actually no guideline to recommend. So, what did these investigators do? They looked in Denmark, and from the period of January of 2003 to June of 2015, they identified 134,048 subjects. And they looked at the vaccination status for those with a diagnosis of heart failure that were greater than 18 years in age. 55% percent of these were men. And then, they also looked at ICD-10 codes for cardiovascular events.

Now, they examine the dates of when you had your vaccination, how frequently, what were your comorbidities cardiovascular-wise, medication use, etc. And what they observed is that those individuals that had more than one vaccination ... So, basically annual vaccinations for a three year period, they had an 18% reduction in all death, and a 19% reduction in cardiovascular death.

Dr Carolyn Lam: So, is this all heart failure patients? Are there specific subgroups that we should be targeting?

Dr Greg Hundley: At our institution, they really get on us. If we don't have our flu shots in September, I mean, they threaten to withhold everything, or maybe October. Well, interesting that you asked that question. Those individuals that had flu shots in the September to October window did much better than those individuals that had their vaccination November, December, or actually later in January. And the second group that benefited were the individuals that actually had annual vaccinations. So, if periodically you say, "Oh, I'm going to get it this year, but then I'm not going to get it two years from now." Not so good. It was those individuals that had those vaccinations annually.

Dr Carolyn Lam: You know, Greg, it's making me question too, because here I am in a tropical island. We actually don't have seasons. So, what does that mean for us? That's one thing. And then, do we need even randomized trials now?

Dr Greg Hundley: Yeah, I think you're right there, Carolyn, because first of all, you know the investigators targeted this because 50% of heart failure exacerbations are actually triggered by some sort of respiratory infection. So, that was kind of the thought behind this. But we do have to be careful about looking at this longitudinal data and making predictions or developing guidelines. A couple of reasons why. It could be that those that come in for annual vaccinations at the time points, well, maybe they also come in for more frequent heart failure visits with their doctor. So, it's not cause and effect.

And in fact, there was another study, Get with the Guidelines heart failure study, and it actually showed no association. So, more work really needs to be done in this area. And just to point out quickly, there is a current randomized trial going on called Invested, and it's looking at different types of vaccinations, trivalent versus quadrivalent. They're underway in those with heart failure. And so, there's a lot more work in this area. But it was interesting getting it that old "get your flu shot," and it looks like at least longitudinally in cohort studies could be beneficial. And if you are going to do it, do it every year and get that September, October. So, Carolyn, what about your next paper?

Dr Carolyn Lam: So, Greg, my second paper is another trial. It's the radio sound hypertension trial, this time focusing on renal denervation. In fact, it's the first trial to compare three different techniques and technologies for catheter-based renal denervation. It's from Dr Lurz from Heart Center Leipzig in Germany. And what they did is, they randomized 120 patients with resistant hypertension to three arms. Either one, radiofrequency, renal denervation of the main renal arteries. Two, radiofrequency renal denervation of the main renal arteries and the side branches and accessories. Or three, an endovascular ultrasound-based renal denervation of the main renal artery. The primary endpoint was change in systolic daytime ambulatory blood pressure at three months. In the end, endovascular ultrasound-based renal denervation was the winner over radiofrequency ablation of the main arteries, with or without ablation of the side branches.

Dr Greg Hundley: Carolyn, does this mean that renal denervation is coming back? Are we going to actually start thinking about this as a viable option to treat those with longstanding hypertension?

Dr Carolyn Lam: Greg, this was exactly addressed by an editorialist, Dr Ram from UT Southwestern and Apollo Hospitals and Apollo Medical College in India. Beautiful editorial. Basically, even with the publication of these new data, it is difficult to predict whether renal denervation is firmly back on track. You see, some caveats should be mentioned, including that in this trial, only patients with large renal arteries were chosen for this study. And patient enrollment was rather selective.

For example, out of 1,884 patients screened, only 120 patients met the inclusion criteria. And then, importantly, in a few patients, the reduction in systolic blood pressure was really impressive, close to 40 millimeters mercury. But the majority of responders had a more modest effect, and in about 30%, there was no change in blood pressure.

So, one of the ultimate things we need to learn to do is to identify the so-called hyper-responders from the non-responders. So, lots more work needs to be done in renal denervation.

That brings us to a close of our little chat. Can't wait for our feature discussion coming right up.

Our feature paper today deals with a very important topic in a very frequently encountered group of patients. And they're the ones with concomitant stable coronary artery disease and atrial fibrillation. You see, these are patients at high risk of both ischemic and bleeding events, and therefore, it's critical to identify the right antithrombotic regimen with the optimal benefit ratio, since this is going to be lifelong therapy. Now, interestingly, despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation with and without antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond one year of coronary stenting. I mean, Greg, I didn't even realize that we didn't have a randomized control trial. Did you?

Dr Greg Hundley: Absolutely, Carolyn. And, you know, this is an important issue, because we have a lot of patients coming to the cath lab that have atrial fibrillation, and what is going to be the recommended anticoagulant and antiplatelet combination? And so, it's really time for a randomized trial.

Dr Carolyn Lam: I know, and luckily for us, that's exactly what this issue's feature paper does. And I'm so pleased to welcome to the show Dr Satoshi Shizuta from Kyoto University Graduate School of Medicine, Japan, as well as associate editor Dr Shinya Goto from Tokai University in Japan. We're so proud to be publishing the OAC-ALONE trial, even though we understand it was a difficult trial. Tell us, what were the results?

Dr Satoshi Shizuta: As you know, the results were somewhat inconclusive because of pretty much a combination of patient enrollment. Initially, we scheduled to enroll 2,000 patients during 12 months, but patient enrollment speed was extremely slow, much slower than expected. So, we extended the patient enrollment period from 12 months to 38 months. But finally, we could only enroll 696 patients, about one-third of the initially planned patients. The result was around 50% rate of primary end point during 2.5 years of follow up. And the hazard ratio of [inaudible 00:15:01] strategy, as compared with OAC plus APT was 1.16 with a 95 confidence interval of 0.79 to 1.72.

So, in conclusion, our study failed to establish no inferiority of OAC-ALONE to combination therapy of OAC plus antiplatelet therapy in patients with AF and stable coronary artery disease beyond one year after stenting in terms of primary endpoint of death, MI, or stroke. So, this study was underpowered and inconclusive. So, future larger studies require to establish the optimal antithrombotic regimen in this same patient population.

Dr Carolyn Lam: Thanks so much. Shinya, you've been thinking about this, too, and the performance of such a difficult trial. Did you have anything to add or to ask?

Dr Shinya Goto: So, first of all, I would to congratulate Satoshi and the group. They have completed a very interesting randomizing trial. As Greg mentioned, there is two kind of patient who lead to coronary artery disease and atrial fibrillation, especially after, you know, one year after stenting. So, taking a look at coronary artery disease with atrial fibrillation, we don't have the established standard of care yet. So, Satoshi know, it is a long-time study. So, I understand the rich colored nature of the patient in this kind of trial. So, what is the most difficult point increased to encourage the patient in this long-term trial?

Dr Satoshi Shizuta: We think that difficulty reflects substantial reluctance of most cardiologists to withdraw antiplatelet therapy, single antiplatelet therapy from stented patients, even the patients treated with oral anticoagulation for atrial fibrillation. So, that is the most important point.

Dr Shinya Goto: You have already showed in this paper myocardial infarction recurrence of stents thrombosis. Not a huge problem in this kind of patient population, you know? Stroke is a bigger problem, mortality, not including cardiovascular is also the problem. So, you have suggested, you have a strong kind of mind, is it? And single antiplatelet therapy necessary after stenting. Your results are underpowered but still suggest how always you know would be enough in stable CAD patients with atrial fibrillation.

I would congratulate you again.

Dr Satoshi Shizuta: Thank you.

Dr Greg Hundley: Satoshi, I have a quick question. So, in the randomization process, how can you achieve the physicians managing the patients to administer the anticoagulant therapy to guideline levels, particularly when they are also prescribed antiplatelet therapy? I noticed that in the editorial on this manuscript that was a concern, and suggesting that in future studies that the therapy really be defined, and not so much open label administration at the discretion of the prescribing physician. What are your thoughts on that?

Dr Satoshi Shizuta: I agree with you, but in this kind of study, randomizing whether or not to withdraw a drug is very difficult to conduct. Financial support is limited, and in such situation, double blind placebo controlled trial is very difficult to conduct. As you know, several years ago, a loose trial was published in the Lancet. And also in the loose trial, the study design was open level, and also in the PCI and [inaudible 00:19:48], I think the study design was not blinded but open. In this paper figure two, our control level was set as a dependent based on the Japanese guidelines. In the Japanese guidelines, target IR was set as 1.6 to 2.6, a little bit lower than Western golden standard for elderly patients older than 50 years. And same 2.0 to 3.0 in patients younger than 70 years.

And in that criteria, as you can see, if you get 2A of paper, the therapeutic range was extremely high. 76% in the OAC-ALONE group, and also 73% in the OAC plus APD group. We can clearly understand that the intensity of oral anticoagulation was different between the two groups. Most of the OAC-ALONE group, OAC was controlled with ionine level higher than 2.0. On the other hand, in the OAC plus APD group, the ionine level was mostly controlled between 1.6 to 2.2 or .5 or so. So, this is a great big limitation of the study. But even in this limitation, the bleeding events, there was numerical excess in the OAC plus APD group. And, regarding the TEMI major bleeding, there was a trend toward increased major bleeding in the OAC plus APD group. If the intensity of OAC was the same, of course, I am convinced that even in this underpowered sample five, the major bleeding will be statistically higher in the OAC plus APD group.

Dr Carolyn Lam: Thank you so much Satoshi for really taking us under the hood, and showing us all the myriad of considerations that occurred to perform this trial.

This is Greg and Carolyn. Thank you for joining us on Circulation on the Run. Don't forget to tune in again next week.

Circulation January 22, 2019 Issue

21 januari 2019 | 25 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts of Circulation on the Run and if you don't know what this show is about, well, you have to listen to the previous episodes in January please.

I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley: I'm Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: So Greg, before we pick up our coffees and begin discussing a couple of the paper, let's just tell everyone that this feature paper, they have to listen to because it is the results of the cardiac amyloidosis section, or sub-set of the APOLLO study. Have to listen to this one. But how about the other papers in today's issue Greg?

Greg Hundley: Right Carolyn, the first one I'm going to start with is from Alexander Fanaroff at Duke University and the DCRI. And basically, this particular paper was looking at the procedural volume and how that might affect outcomes with those that are performing PCI. So they divided the cohort into those individuals that had less than 50 PCIs per year, 50 to 100 and then greater than 100 PCIs per year. So, this is looking at our national cardiovascular data registry within the United States, and of course, as you know, that's linked to Medicare claims data for those that are over 65 years in age. So they had 723,644 PCIs performed by 8,936 operators. And the surprise in this study was that those low volume operators, less than 50 PCIs per year had a one year rate of 15.9% of MACE as opposed to those that were high volume operators that had 16.9% MACE rates. That was significant at a P value of .004.

Dr Carolyn Lam: Wait a minute, this seems different from prior reports. Are you saying that those with low volume operators actually had lower mortality?

Greg Hundley: Yeah, exactly. And you've pointed out something, cause previously what's been shown is that high volume operators have lower 30 day and in-hospital mortality rates. And that was actually confirmed in this study. But out of a year it was really the low volume operators in unadjusted results had lower rates of all MACE.

A very nice editorial by Dharam Kumbhani from UT Southwestern points out that high volume operators do tend to take on more serious cases, those with higher numbers of cardiovascular risk factors. And so, when they did adjustments and accounted for all those risk factors, actually the event rates were the same. Still though, they're the same. And so what could be going on? And the editorialist and also the authors of the paper point out, "Hey, maybe we shouldn't just be focusing on PCI volume per operator, but other quality metrics to look at outcomes. And so this really builds in to the whole quality discussion. Adherence to therapy with the patients in your health care system. What about operator longevity? An operator that may have been doing this for 10 years but has a lower volume, maybe that could come into play. So future studies I think, certainly all over the world in this field, this paper's going to direct us to focus more on other quality issues and not just procedural volume.

Dr Carolyn Lam: So, quality versus quantity. Interesting.

Well switching gears to a paper that I thought was nice, it is from Dr Lubitz from Massachusetts General Hospital in Boston and colleagues, and they sought to answer the question of whether refining a phenotypic classification of heart failure would facilitate genetic discovery. So, to do that, they defined all cause heart failure among almost 500,000 participants in the UK bio-bank and performed a GWAS study and then later refined the heart failure phenotype by classifying individuals with left ventricular dysfunction but without coronary artery disease as having nonischemic cardiomyopathy and then repeated the GWAS. And basically they found that the GWAS in the all cause heart failure yielded multiple genetic signals for known heart failure risk factors, such as coronary artery disease and atrial fibrillation.

However, after refining the heart failure phenotype to a nonischemic cardiomyopathy sub-set, this enhanced the detection of genetic loci associated with dilated cardiomyopathy, which appeared to operate independent of the traditional heart failure risk factors. So that was pretty interesting.

Greg Hundley: So where do we go from here with that Carolyn? I mean, what is this telling us and how are we going to move forward with this information?

Dr Carolyn Lam: I think the clinical implications are first that common genetic variants associated with both clinical and sub-clinical heart failure, because they looked at left ventricular dysfunction, these genetic variants may be leveraged to improve heart failure risk prediction and prevention. But obviously future studies are warranted to investigate the prognostic and therapeutic implications of these findings.

Greg Hundley: Very good. Well I'm going to take us back into the cath lab again and we're going to address fractional flow reserve. And remember, typically, we get fractional flow reserve measures using guide wires, and that's kind of a tough thing to do sometimes in terms of adding links to the procedure, etc. So what these investigators did, they had 10 centers in the United States, Europe and Israel. And this was William Fearon from Stanford University who did this study. And they looked at 301 subjects and they had 319 evaluable vessels. Now what did they compare? They looked at guide wire derived fractional flow reserve versus angiographic derived. Simply, just when you're doing the injections, looking at how quickly that contrast flows down the coronary arteries.

And so, in this study the mean fractional flow reserve value was 0.81 and 43% of the vessels they studied had an FFR less than or equal to that magic number of 0.8. Interestingly, the angiographic obtained FFR measures were 94% sensitive and 91% specific for identifying the guide wire derived FFR. That's really incredible. And importantly, the accuracy of this contrast measure was 87% for FFR values between 0.75 and 0.85, that magical threshold.

Dr Carolyn Lam: Well that is impressive, suggesting that we don't need guide wires. I mean, is that true for all patients? All vessels?

Greg Hundley: Right, so that's sort of the kick here, this is really interesting new data but let's look at the patients that they studied. First of all, they were relatively stable I would say. They had either angina or maybe even unstable angina and non-ST elevation MIs. But no ST elevation MIs. The average stenosis by angiography that they looked at was about 63% and then, very importantly, you have to look at the exclusion criteria. So things that, other conditions within the heart that are going to impact FFR were excluded. So, all their patients had an EF greater than 45%. Nobody had a CABG. Nobody had a chronic total occlusion. Nobody had a heart transplant, aortic stenosis, no heart valve surgery, no left main. It couldn't have had a recent stent within 12 months. It couldn't have had severe diffused disease, no collaterals, no in-stent thrombosis or stenosis. So this technique I think could be useful when you've got that patient perhaps with stable angina, single vessel disease, stenosis severity of 50 to 60% and none of these other conditions, preserved EF etc. But for many of the patients that we send to the cath lab, this technique, we still need a little bit more development. We don't know its utility. You've got another paper?

Dr Carolyn Lam: I've got another few papers because I'm going to drag you out of the cath lab right now and into the ICU. And we're talking about cardiogenic shock and it's really nice that we have these three papers in today's issue. One's an original paper and two are On my Mind articles. Now the original paper talks about the randomized shock cool trial. This is from Dr Thiele from the heart center Leipzig in University Hospital in Germany. And it is an un-blinded, randomized trial of 40 patients with cardiogenic shock undergoing primary percutaneous coronary intervention. And without a classical indication from mild therapeutic hypothermia, but randomized one-to-one to mild therapeutic hypothermia for 24 hours versus control. And basically the mild therapeutic hypothermia did not show a substantial beneficial effect on the primary outcome of cardiac power index at 24 hours or on any other of the hemodynamic parameters. And there was also no difference in the short and long term outcomes. So a neutral trial.

But taking a step back and just talking about these patients with cardiogenic shock and all the different ways that we have now to keep them alive, I really want to highlight these two On My Mind papers. One is by Drs Gill, Grunau and MacRedmond from University of British Columbia. And they really talk about the need to define limits for extracorporeal cardiopulmonary resuscitation. In a very similar vein, Drs Mulaikal, Nakagawa and Prager from Columbia University also wrote a beautiful piece on ECMO, ECMO as a bridge to no recovery. And when is enough enough? So really, really interesting conversations and discussions regarding what is death, when do we have to put a time limit perhaps to these therapies? And yet not limit the potential life-saving effects of these. I really strongly encourage our listeners to read these papers and also to stay tuned because coming right up, a very important paper on the APOLLO study in our feature discussion.

For today's feature paper we're discussing the results of a sub-study of the APOLLO study. Now this deals with cardiac amyloidosis, a super, super hot subject. And we have super, super hot guests today on the show. The first our corresponding author, doctor Scott Solomon from Brigham and Women's Hospital as well as our associate editor doctor Justin Ezekowitz. Welcome both, and let's just plunge straight into it. So Scott, tell us, tell us about this APOLLO sub-study.

Scott Solomon: APOLLO is a study of patients with hereditary transthyretin amyloidosis and, as you know, that hereditary transthyretin amyloidosis is an inherited disease caused by mutations of the transthyretin gene and these mutations cause the transthyretin protein to misfold and then accumulate as amyloid fibrils which go to the nerves and go to the heart. And we know that this can cause severe polyneuropathy and cardiomyopathy, partly depending on which mutation the patients have. And we, as cardiologists, are aware that when amyloid infiltrates the heart it can increase cardiac wall thickness, it can cause increase in chamber stiffness, it can result in severe diastolic dysfunction and these patients, often with cardiac involvement of amyloid, have a really markedly reduced life-span and really poor quality of life.

The APOLLO study was a study of a new agent that is designed to reduce transthyretin, it's a transthyretin knock-down agent. It's basically an RNAi therapeutic, it basically is a small, interfering RNA that basically blocks the production of transthyretin and this is one of several approaches that are currently being considered for amyloid disease. And APOLLO is primarily designed as a study to look at neuropathy. The primary end-point was a neurologic scale to look at neuropathy, but it was also designed to secondarily look at some cardiac end-points, especially in the patients who were felt to have cardiac involvement.

Dr Carolyn Lam: Cool. And so your current paper deals with that cardiac amyloidosis sub-set, but it was pre-specified, it was planned, right?

Scott Solomon: Yeah, it was a pre-specified sub-group. In fact, what we did is we actually did echocardiograms on everybody in the study and then defined a pre-specified cardiac sub-population that was comprised of patients who had a very high likelihood of having cardiac amyloid involvement, and so this was patients who had a baseline left ventricular wall thickness of 13mm or greater and no history of either aortic valve disease or hypertension. And so this was a group that we thought most likely had evidence of cardiac involvement. And just so it's clear, we did echocardiography on everybody in the study and in this paper we reported in both everybody and in the pre-specified cardiac sub-population. So we looked a number of things in these patients including various measures of cardiac structure function including wall thickness, left ventricular mass, ejection fraction, cardiac output, atrial size, volumes and myocardial strain which, as you know, has been particularly useful in assessment of patients with amyloidosis. And we also looked at reduction or improvement in Anti-proBNP which, as you know, is a very good measure of the severity of heart failure in patients.

And so, of the 225 patients who enrolled overall in the APOLLO study, 126 were part of this pre-specified cardiac sub-population. And in this group of patients, we've observed a reduction in left ventricular wall thickness of about a millimeter. And this was statistically significant in the patients who were treated with patisiran compared with placebo. We also saw an improvement in global longitudinal strain and improvement of cardiac output and an increase of left ventricular end-diastolic volume. In this case an increase in end-diastolic volume is actually a good thing because these patients often start out with smaller end-diastolic volumes because of the increased wall thickness. Those improvements in echocardiography were really paralleled by dramatic improvements in Anti-proBNP and we started out with patients with abnormal Anti-proBNPs in the range of about 800. These were significantly reduced, highly significantly reduced with a P value of about seven times 10 to minus eighth at both nine and 18 months, so pretty dramatic relative reduction in Anti-proBNP in the patisiran group compared to placebo.

Dr Carolyn Lam: Super exciting, and it really adds to mounting evidence isn't it? That we're sort of reaching a really effective treatment for these patients and who knows how common they are. But Justin, you've been thinking a lot about this, what are your thoughts?

Justin Ezekowitz: This is a terrific paper, and this is a groundbreaking therapy. Scott, this really has something for everybody, for example functional Anti-proBNP and echocardiographic measures of improvement and also less deterioration which I think is also holding it in its tracks. The question is, if you have 126 patients in the cardiac sub-group, whether or not this is really prime for clinical integration, as to start using this therapy broadly or do we need to really broaden the scope and do larger outcome studies with this therapy for these patients, recognizing some of the gaps in any clinical trial design and implementation. So what are your thoughts on that?

Scott Solomon: First of all, it's important to remember that the APOLLO study was designed primarily to look at the neurologic outcomes, not the cardiac outcomes. The cardiac outcomes were technically considered exploratory and, in fact, although really pretty impressive in this group, this wasn't really how the study was designed. And so the current indication for this particular therapy. Patisiran is for the improvement in the neurologic outcomes, not for the cardiac. So I think that there will need to be additional studies that will look more specifically at the cardiac effects, although I think these are among the most impressive findings we've seen with any agent that is interfering with transthyretin. And just to put this in context, there are a variety of ways in which amyloid can be affected and one of the other approaches to this disease has been not to reduce the production of transthyretin but to stabilize transthyretin.

And you may be aware of the ATTRACT trial which was presented at ESC and published in the New England Journal, which was actually an outcomes trial in patients with cardiomyopathy secondary amyloid and they used a drug which is a TTR stabilizer and showed a significant reduction in cardiac events and mortality. And I think that in the context of that study, this is extremely exciting as well because it says that there are multiple potential approaches to affecting transthyretin and potentially improving outcomes in patients with cardiac amyloidosis. There are other approaches that also are being tested. In fact, another therapy that works in a similar way to patisiran is atersin which is an agulo nucleotide anti-sense molecule. And so, I think that it's such an exciting time now in this field because there almost certainly will be several different approaches to transthyretin amyloidosis.

So, I think, Justin, to succinctly answer your question I don't think we're quite ready yet with patisiran but stay tuned because there will be more trials for sure. The other thing that we have to realize is that this study was done in mutant or hereditary amyloidosis but there's a very broad group of patients out there with wild type amyloidosis and there's no reason to think that a therapy like this won't work there as well. So that has to be tested too.

Justin Ezekowitz: I think, Scott, that's a true way to put it. I think one of the other questions is the substantial difference between the trials and sub-groups of the trial between the three major therapies you just described about wild type versus hereditary. It does make you wonder if either one individual therapy or a combination of the therapies might give the right way to precisely manage these individuals according to their phenotype, neurologic status or cardiac status.

So, I maybe just want to draw you on one other point which is that you used global longitudinal strain as one of your outcomes and it sounds like, and from all the data we've seen, it looks like GLS will be the way to go for earlier phase two and other types of studies. What are your thoughts based on experience?

Scott Solomon: Well in general I'm a big fan of global longitudinal strain because I think it is, in many respects, more robust than our standard measures of cardiac function like ejection fraction, it's not volume dependent the way ejection fraction is. In particular in amyloid heart disease, as you know, global longitudinal strain can be quite abnormal and, interestingly, it can be quite abnormal in a very specific pattern. And patients with amyloid is typically sparing at the apex, so the apical strain is relatively normal compared to the strain at the base of the heart. And this is kind of interesting and we've certainly been looking at this as well in amyloid heart disease but I agree that this global longitudinal strain as a measure of potential benefit for a therapy has a lot of potential.

Dr Carolyn Lam: You know, that's just so amazing. I just have one last question for both of you. Where do you think the field is going? Do you think it's going to be a race to treatment or a race to diagnosis? I shudder to think of the number of cases we're missing, what do you think Justin?

Justin Ezekowitz: Carolyn you just brought up a great point which is, one is our diagnostics need to improve and be broadly applicable and implementable in any health care system, so I think that race has to speed up and become more cost-effective and efficient to know who indeed we need to screen closer. That's point number one but number two is the therapies ... the race has to be focused around what will be the best way to treat patients rather than the cost-effectiveness initially, but then once we identify the three or four different agents that work with different groups and how you can combine them, then the consideration has to be how we can apply these more broadly to the groups that really haven't had a therapy that has had a meaningful impact trajectory.

Dr Carolyn Lam: Scott, what do you think?

Scott Solomon: Well I would add that one of the most exciting things I think in this area, Carolyn, and this is going to interest you I think because of your own interests, is that there's probably a lot of amyloid out there that we don't know about. Especially in these patients that we're currently calling heart failure with preserved ejection fraction. There's some data from Mayo clinic and from groups in Europe suggesting that 15 to 20% of patients with HFpEF, might actually have wild type transthyretin amyloid. And that means that we've got to get better at making this diagnosis, especially where our suspicions are high. Because we might all of sudden have a targeted therapy for some of these patients, so I think that's one area where things are really exciting. And then with respect to which of these therapies is going to be beneficial, I mean I think that we're still in the early stages, it's very possible as Justin said that even a combination of TTR stabilizers and knock-down agents are going to provide the best benefit. But I think we're going to see a lot of very interesting studies in the next several years in this field. It's really great to have a potential molecular target, and targeted therapy for a type of cardiomyopathy and I think this is one of the really few areas where we have that as this point. So I'm extremely excited.

Dr Carolyn Lam: Thank you so much for publishing your paper with us in Circulation.

Well audience you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

Circulation January 15, 2018 Issue

14 januari 2019 | 27 min

Dr Carolyn Lam: Hello. We're here at the American Heart Association meeting in Chicago where circulation has 19 simultaneous publications this year. And that is a huge increase from six in the past to 19, all thanks to the man next to me.

But first, let me introduce myself. I'm Dr Carolyn Lam. I'm associate editor from the National Heart Center and Duke National University of Singapore. I'm the voice you hear on 'Circulation On the Run'.

I'm so pleased to be here in person today with Dr Dharam Kumbhani. He's associate editor from UT Southwestern and he also leads the simultaneous publications for this journal. So big applause for this amazing bonanza this year.

Dr Dharam Kumbhani: Thank you.

Dr Carolyn Lam: Next to him, we have Dr Sana Al-Khatib and she's from the Duke University. And finally, Dr Gabriel Steg from University of Paris. Wow! Okay, we've got 19 papers to chat about. No, I'm just kidding. We're going to talk and focus on the seven simultaneous publications that were late-breaking science.

Why don't you start us off, Dharam. We will first start with the interventional trials, and there were three of them. I'd love you to chat about the first of them, but even before that, maybe, tell us what it's like to get a simultaneous publication. Because I think people underestimate the amount of work it takes to do that.

Dr Dharam Kumbhani: Thanks a lot, Carolyn. I think under Joe's leadership the whole space of simultaneous publications in late paying clinical science has really been a big endeavor for him and for the journal. We just have an amazing team that's able to work on this in very quick order. So, for the viewers, I think it's a very involved process, but it's a very gratifying process.

We work very closely among the associate editors, the senior editors, and then the circ staff, and we have very rapid turnaround time. So we owe a lot of gratitude to our reviewers who frequently will turn these reviews in within 48 hours. Our goal has been that we respond back with a decision usually within five to seven days. So it's been very gratifying.

Then it moves onto the next set of revisions, et cetera. But even among the papers that we are unable to accept for circulation, it's just a quick turnaround time for the authors so they haven't lost as much time and can potentially look elsewhere.

It's been a really gratifying process. It's been a great, great team effort. I appreciate everything you said, but really I don't deserve all that credit. It's been a great team effort.

Dr Carolyn Lam: No, it's been rumored there's a lot of lost sleep on your end, so thank you, thank you Dharam for this. And maybe you could open with the ISAR-TEST 4, that's been [crosstalk 00:02:47].

Dr Dharam Kumbhani: Yeah, well thank you. I think we had some really interesting interventional trials and Dr Steg will discuss a couple of them as well.

ISAR-TEST 4 was a very interesting trial. It is one of the first 10 trials that gets to the 10-year mark, so this is just the 10-year follow-up results of that. It was about a 2500 patient trial. It was done in Germany, multiple centers. Really they were trying to assess the space that they were trying to ... Or the knowledge gap that they were trying to fill was the durability of the bioabsorbable polymer stents.

Specifically, they were looking at a bioabsorbable polymer sirolimus-eluting stent, the Yukon stent, and then they compared that with durable polymer stents including Xience or the everolimus-eluting stent and then Cypher, which is no longer available in the U.S., but that's a permanent polymer sirolimus-eluting stent.

The primary results were published and presented a long time ago. There was really MACE events at one year and it showed non-inferiority for this bioabsorbable polymer stent back then. So, then they had, incredibly, 83% of the cohort that they were able to follow-up out of 10 years. And what they showed is that ... I don't want to necessarily get into the numbers and the details as much, but what they showed is that this bioabsorbable polymer sirolimus-eluting stent tended to have similar outcomes to Xience, which we accept as state of the art current generation stent, permanent polymer. And it did better than the Cypher stent, both in terms of MACE events and stent thrombosis.

So suggesting that, the big advance in the field for this is ... This is a long-term follow-up of the stent. It suggests that outcomes may be similar in this patient population. Although only 12% were really enrolled with an MI in this patient population. Most of them were stable or less sick ACS patients. And they show fairly good outcomes out of 10 years, comparable to Xience and better than Cypher.

I think it was interesting. Gabriel, what is your take [crosstalk 00:04:57].

Dr Gabriel Steg: I think it's important. There's been a tremendous interest in international community on trying to tease out which are the best types of stents and beyond brands, try to understand the type of stent, the coating, the drug that you put on it, whether the polymer is durable or not durable. I think these types of fairly well done, large randomized trials with long term flow are critical.

A lot of the focus in the interventional community originally was on lumen size, late loss, angiographic parameters short term. And now the field has matured, and we've moved to clinical outcomes, patient-oriented outcomes, long term follow-up. And it's important because we've learned from long term trials such as PROTECT that the result at one year may not predict what happens at five years, and sometimes you have surprises.

So, it's really important. We owe it to our patients because these are irretrievable devices. Once you've implanted them, they are there. We talked about Cypher being out of the market, but there are more than a million patients who walk every day on this plant with a Cypher in their coronary artery, so we better know what the long-term follow-up is.

Dr Dharam Kumbhani: Yeah, that's a great point.

Dr Carolyn Lam: Wow. And then thanks also for the discussion that allows me, as a noninterventionist, to realize ... It's hard to keep track of what's happening with all the different types of stents and polymers and so on. But could you then summarize for the field, does that mean that these biodegradable ones are now ... Do I sound ignorant when I say that? That they are now really in the game. Is that what it does?

Dr Dharam Kumbhani: This whole bioabsorbable field, there are nuances. So this really is testing a bioabsorbable polymer where -

Dr Carolyn Lam: Oh!

Dr Dharam Kumbhani: So, with every stent you have a stent, you have the polymer, and then you have the drug.

Dr Carolyn Lam: Thank you.

Dr Dharam Kumbhani: And so, the polymer and the drug go away, and then you're left behind with a bare metal stent. And that's this Yukon stent.

Dr Carolyn Lam: Got it.

Dr Dharam Kumbhani: The one that has been in the press a lot more is the bioabsorbable scaffold where the stent and the polymer and the drug, everything in theory should be gone at a certain period of time. So this is ... It's an important distinction though. Because I know that it's very confusion when you just say bioabsorbable and it's unclear if you're talking about the polymer or you're talking about the stent, itself. But this really was a bioabsorbable polymer issue, so you're left behind with a bare metal stent at the end of it.

Dr Carolyn Lam: Got it, crystal clear, and thank you. That's cool. That's super.

Dr Sana Al-Khatib: I agree, for an electrophysiologist too.

Dr Carolyn Lam: But now, let's go into the AMI field. There were two trials that really spoke to acute management patients coming in with an AMI and with cardiogenic shock, for example. Gabriel, could you tell us a little bit about the IABP-SHOCK II trial, as well as the really talked about a door-to-unload IMPELLA Trial.

Dr Gabriel Steg: The IABP II trial is a randomized trial looking at the benefit, or lack thereof, of intraaortic balloon pump in patients with cardiogenic shock and acute MI. It's been standard practice since the '60s to offer IABP pumping to patients with cardiogenic shocks and AMI.

So, literally more than a million patients have been implanted with IABP, but the reality is when we look at the randomized trial evidence of benefit there was none. They were very small trials, inconclusive, underpowered. Professor Thiele from Germany and his colleagues deserve enormous credit for having had the courage to really do what needed to be done. A proper randomized controlled trial, of course open label.

And what they found in IABP II, which they already reported a few years ago, was that there was no acute benefit of IABP on survival short term, or for that matter on many of the secondary clinical outcomes looked at in this trial. They subsequently reported one year mortality.

What they did here is they gathered follow-up on almost all of the cohort at more than six years. And they found that the long term survival is identical for patients who received an IABP and those who did not. So I think this nails the issue. But there's another thing we learn. The mortality at six years is staggering, it's close to 60%. And although a large fraction of the patients die in the first 30 days, you still have an additional 10% of patients who die between the first year and six years.

So there still remains a very sick patient population for whom we need to investigate new strategies. I don't think it's going to be necessarily mechanical. We have to think of all of the strategies we do to prevent and mitigate cardiogenic shock to build up. And that's gets us to the second trial that I'll talk to you about in a minute.

Dr Sana Al-Khatib: I have a quick question about this. Did they provide any information about modes of death in these patients?

Dr Gabriel Steg: Yes. They did capture information about that. Off the top of my head, I'm unable to provide information, but yes they did capture that. The German system allowed them to retrieve information about causes of death and it's a closed system. It's a national trial, so they were able to get enormous follow-up.

Dr Sana Al-Khatib: Because this information can help us inform what interventions are needed next.

Dr Gabriel Steg: Yes. That's really important.

Dr Dharam Kumbhani: To your point about ... You use a very interesting word, the last nail. That's actually how Dr Hochman addressed her editorial. She wrote a really nice editorial-

Dr Gabriel Steg: The leading expert in the field.

Dr Dharam Kumbhani: And so, I'm interested in your thoughts. The use of balloon pumps for shock, there's a discrepancy between the American guidelines and the European guidelines. Last year the European guidelines were updated. It is really such a practice changing guideline in that it now lists routine use of balloon pumps in cardiogenic shock-

Dr Gabriel Steg: Class III.

Dr Dharam Kumbhani: -as a class III indication. Going through training, that was all you had when someone came in with shock, you would throw in a balloon pump. So that's really quite a practice changing event.

Dr Gabriel Steg: Yeah. These investigators are embarking on new studies with ECMO and I think it's going to be fascinating to see whether ECMO, which also gets increasingly used worldwide, whether there is evidence to acutely support or not whether this is useful. I think they are doing the proper thing. They are doing the right thing, randomized trials. And we could commend them because these are really difficult trials.

Dr Carolyn Lam: Absolutely.

Dr Gabriel Steg: In the acute MI setting, shock patients, ECMO, IABP, that's really difficult. They are brave investigators, they are good investigators, and I think they provided the community with a clear answer.

Dr Carolyn Lam: And exactly the kind of papers that we like publishing at circulation, isn't it? Now what about the door-to-unload?

Dr Gabriel Steg: That is actually a good segue with door-to-unload because if we can't properly treat shock once it's there, can we do something to prevent shock? Can we do something to preserve myocardium? One of the experimental findings that is very clear is that if you unload experimental myocardial infarction, if you unload the left ventricle you reduce infarct size.

Dr Gabriel Steg: So, investigators have been trying to translate this experimental finding into the clinical arena using the Impella device. There's enormous interest, particularly in North America for Impella use in acute MI patients with larger infarcts with the idea that if you can unload the left ventricle, you might be able to mitigate the extent of the myocardial infarction, and therefore avoid cardiogenic shock and probably improve prognosis.

Although this is a very attractive theoretical concept, it still deserves to be tested. And so, if you want to test it you have to unload the ventricle as soon as possible, ideally before reperfusion, which means that you're going to have to delay reperfusion for the time of implanting the device and unloading the ventricle. And so what the investigators did in this trial is to study whether delaying proposedly by 30 minutes reperfusion, to unload the ventricle for 30 minutes prior to reperfusion, was feasible and reasonably safe.

It's a small trial. It's really a pilot trial. By no means does it test the proof of concept of the device or the theoretical issue, but it shows that it's feasible. There doesn't seem to be a massive increase in total time to reperfusion because just by change the group that was not delayed had a longer time to PCI, so eventually things are sort of evening out.

They looked at MRI size of infarcts at follow-up. There was no obvious difference, but of course it could still be tied to errors. We're not totally sure about this, but it certainly paves the way for doing a proper proof of concept randomized trial, testing unloading versus no unloading with a true control group. And I think that's what investigators are looking forward, but I understand there's immense interest for this concept in international community, particularly in the United States and I'm quite curious to see what this future trial will look like and what the results will be.

Dr Carolyn Lam: Yeah, indeed. Gabriel, I noticed you were very careful to frame it, to say what the trial was trying to address and what it wasn't. And there's been quite a bit of buzz after that.

Do you agree with everything Gabriel has said and what have you heard?

Dr Dharam Kumbhani: I think he was incredibly eloquent in outlining the premise of the trial and what it really showed. I think the one thing that ... And this was brought up in the very nice editorial by Dr Patel from Duke as well, is it would've been really nice to have a control arm which didn't have any unloading. Because these are not patients with shock, that just directly had primary PCI. And then comparing infarct size.

So, I think that was one of the pieces of information that would've been helpful to then put this in perspective. When you have an infarct size of 8% or 10%, how does that compare in the same patient population in their testing? You're absolutely right about the need to do difficult trials like this, where a lot of times it's just assumed to be true and is embraced in clinical practice.

As I gave the example about the balloon pump earlier, where as a Fellow you saw someone in shock and your reflex was to put in a balloon pump. And so, I think testing these very difficult patient scenarios, as well as just in terms of trial execution, it's amazing to have two trials on that.

Dr Gabriel Steg: If I may come back to this?

Dr Carolyn Lam: Yes.

Dr Gabriel Steg: It's funny because we've been using the IABP for years, thinking this is what we should do in shock. Now our German colleagues have proven that IABP doesn't work. So a lot of investigators have reverted, saying "Well, we should use Impella." But where is the evidence showing that Impella is beneficial?

Dr Dharam Kumbhani: That's right.

Dr Carolyn Lam: That's right.

Dr Gabriel Steg: We have none, so I think that's a trial that deserves to be done.

Dr Dharam Kumbhani: And ECMO. Yeah, exactly.

Dr Carolyn Lam: Yeah, ECMO. Exactly. And, you know, going back to door-to-unload, it's important to prove safety in order to go to the next step, which is exactly how you frame-

Dr Gabriel Steg: I think it shouldn't be over interpreted.

Dr Carolyn Lam: That's how it should be, exactly, received by the community. So that's great. Now let's switch gears a bit.

Sana, in EP world, the EP guided noninvasive radio ablation of VT. Fascinating stuff. What are your thoughts?

Dr Sana Al-Khatib: I absolutely agree, definitely. This was a phase two study that the authors did. They enrolled 19 patients, so it was a small study, but it was really helpful. Remember, there's a major clinical need there. These are patients who have an ICD, who have recurring ventricular tachycardia, that have been treated with at least one antiarrhythmic medication, at least one catheter ablation procedure, and then what do you do with those patients? This is actually a clinical scenario that comes up frequently and we absolutely need to be looking for more therapies for those patients.

So that's what that study was about, trying to explore new ways to treat these patients. To be able to do it noninvasively, I think is fascinating. That's what ... They enrolled these patients. Patients had to have failed these treatments, antiarrhythmic medications, prior catheter ablation, and they underwent noninvasive imaging to really localize the source of the ventricular tachycardia, where it's coming from, and then they subjected them to stereotactic body radiotherapy to ablate those sources of ventricular tachycardia.

And, of course, the results were fascinating because they showed on the effectiveness side that this seemed to be very effective because if you look at the reduction in the burden of ventricular tachycardia, and a couple of their patients actually had significant PVCs and PVC induced cardiomyopathy, there was a significant reduction in the rates of these arrhythmias in these patients with this intervention, which was great to see.

In fact, to be specific, about 94% of these patients, so 18 out of the 19, had significant benefit. And in about 89% of the patients there was more than 75% reduction in the arrhythmia. So these are actually really interesting findings, especially in a patient population where we really don't have other options. Now of course you're going to ask me about the safety. What are the safety concerns?

Of course, this was a primary endpoint for the authors. They did look at safety up to 90 days and they found that there were two significant adverse events that occurred in those 90 days. One was heart failure and one was pericarditis. The concern, of course, with radiation is what else can we expect especially if you follow the patients longer? So certainly we need more data. The authors acknowledged that beautifully and I think their intent is to launch a multi-center randomized clinical trial. I don't know if it will be randomized, but at least a multi-center clinical trial to see if they can replicate those findings. So that was very interesting to see.

Dr Carolyn Lam: Yeah it was. Thanks, that was really exciting.

So, some exciting trials in my world of cardiometabolic disease too, and I want to highlight two. The CARMELINA trial and the CAMELLIA-TIMI 61.

First the CARMELINA trial. This was a secondary analysis of CARMELINA and this was ... CARMELINA, if I can remind everyone, is a cardiovascular outcomes trial, randomizing about 7000 patients with type 2 diabetes and atherosclerotic cardiovascular disease, and/or chronic kidney disease. Randomizing them to the DPP-4 inhibitor linagliptin 5 mg a day versus placebo, following up for a median of about two years.

We know that type 2 diabetic patients are at risk of heart failure and there's always been a bit of a question mark when it comes to DPP-4 inhibitors and their risk for heart failure. And so this secondary analysis looks specifically at the hospitalization for heart failure and related events in CARMELINA. The important thing is that all these were prospectively centrally adjudicated events, and this was a pre-specified post hoc analysis.

And the summary of it all is that linagliptin was not associated with an increased risk of hospitalization for heart failure or the composite of cardiovascular death in hospitalization or the related outcomes. Importantly, the authors did also sensitivity analyses and interaction analyses to show that the results were consistent whether or not patients had a history of heart failure, which was in 27% of patients, regardless of the baseline ejection fraction that was measured within a year of starting the drug, and also regardless of renal function. So EGFR or urinary albumin to creatinine ratio.

This is really important because this trial adds to the growing perhaps understanding of DPP-4 inhibitor heart failure risk. The whole question mark actually came with SAVOR TIMI and that was saxagliptin. But since then there's been three other trials that have showed no heart failure risk. EXAMINE, TECOS, and now CARMELINA. So, an important addition and I think it should reassure us.

And then from diabetes and heart failure risk, which is always very hot, but now obesity. The CAMELLIA-TIMI 61 trial looked at renal outcomes in this trial. Now what was this trial? It was actually testing lorcaserin, and that is a selective serotonin 2C receptor agonist, in about 12,000 obese or overweight patients.

Basically, the primary results showed that it did not increase any ... It met it's CV safety outcomes with weight loss and so on. But this time they looked at renal outcomes. Because obesity has been known to be associated with hyperfiltration of the kidneys, you get albuminuria and it's apparently worsening of kidney disease. So what we need to know is pharmacological weight loss going to be associated with improved renal outcomes?

And basically, that is what CAMELLIA-TIMIA 61 showed. Their renal outcomes were new or persistent albuminuria and then the standard doubling of EGFR or end-stage renal failure, renal transplant or renal death. And that was improved by lorcaserin. Along with that, there was the anticipated reduction in weight, HbA1c, and BP. It does look like, from these late breaking results that we have another tool in our toolbox.

Dr Sana Al-Khatib: And for the clinicians out there, which patients should they be thinking to use this medication in? What kind of obesity are we talking about? At what point do you introduce that?

Dr Carolyn Lam: This is common garden, just defined by BMI that was above 27. And I don't think they're saying to use it in patients with renal dysfunction, but to sort of say to look and see whether weight loss also associates with renal function improvement, and it does. It's reassuring.

Dr Sana Al-Khatib: Yeah, okay.

Dr Carolyn Lam: And then ... Okay, let's round up with that last trial. A very interesting one because it's pragmatic mobile health and wellness. Tell us.

Dr Dharam Kumbhani: It's really a monumental effort. This is ... I'll be brief, but it's really a phenomenal trial from an epi standpoint and implementation standpoint. This is from India. It was coordinated by the Center for Chronic Disease Control and the Public Health Foundation of India where, as everyone knows, India is now the diabetes capital of the world and chronic diseases have very quickly overtaken other infectious causes as the number one cause of mortality and morbidity.

This was a big undertaking, really collaboration from three continents, but it was a community based plus a randomized trial. They had 40 community health centers and what they were trying to see is primarily for hypertension and diabetes. That if you implemented a structure and typically using this mWELLCARE tool, which is basically an electronic medical records storage facility and then it also has inbuilt clinical decision support.

And really for hypertension and diabetes management, but also, they had tobacco and alcohol screening, abuse screening, and also for depression. So what they really wanted to do ... A very ingenious endeavor and they try to see if doing this systematically on a clustered randomized fashion if that would actually influence patient outcome. They had a little over 3000 patients and they followed them for 12 months.

Unfortunately, the trial, itself, as far as the primary endpoint, which was change in systolic blood pressure and hemoglobin A1c, they had pretty significant reductions in both arms, about 12 to 13 millimeters, which is amazing from a population health standpoint, in both arms not statistically significant, and in hemoglobin A1c also by 0.5% in both arms.

Just suggesting that having this more frequent interactions with the medical health system, itself, was driving a lot of this benefit. So although the trial, itself, was negative for the primary endpoint, I think it's a huge step forward for the management of chronic disease epidemiology and burden in developing countries.

Dr Gabriel Steg: Neutral.

Dr Carolyn Lam: Ah, true.

Dr Dharam Kumbhani: Fair point.

Dr Carolyn Lam: We've discussed this whole array of seven trials and they are difficult trials. I mean, talk about another difficult type of trial to do, cluster randomized pragmatic trial. It's amazing the breadth of simultaneous publications we've had this year. Thanks again to everyone for introducing this and thank you for joining us today.

Circulation January 8, 2019 Issue

7 januari 2019 | 23 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Caroline Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley: And I'm Greg Hundley, Professor at the Pauley Heart Center of Virginia Commonwealth University Health Sciences in Richmond, Virginia.

Dr Carolyn Lam: In case you guys missed us last week, this is how our new podcast is gonna work. Greg and I are going to invite you for coffee with us, almost with a journal in hand, and we're gonna chat about the week's issue, highlighting two original papers each, that we thought were awesome. And don't you worry, the feature discussion is still there, authors will join us for a feature discussion right after our coffee.

And for this week, the feature paper speaks about the MOMENTUM 3 trial, and talks about the important analysis of stroke outcomes in this trial. But before that, I think Greg, you've got a couple of papers don't you?

Greg Hundley: Absolutely Carolyn. So the whole issue, I think we're gonna pick out several stroke papers, really a stroke theme. The first paper is Ankit Maheshwari. He looked at the utility of P-wave morphology on the 12-lead electrocardiogram, to help predict ischemic stroke in patients with atrial fibrillation.

Now, how did he do this? Basically, they looked at a large cohort of individuals from the ARIC study, and these were patients that developed atrial fibrillation. And electrocardiograms had been recorded prior to their Afib episode.

So, what were they looking for in P-wave morphology? Well, they were looking for changes in Lead three. They were looking for changes in V1. They were also looking for extension of that P-wave. So a prolonged duration. And what they observed, is that that abnormal P-wave, could forecast abnormal atrial remodeling, that might be an indicator of future stroke.

Dr Carolyn Lam: Huh, interesting. But is it really reproducible? Did they validate it somehow?

Greg Hundley: Yeah, so that's great Carolyn. You know, in papers like this, you like to take a finding in one large cohort, but then you've got to reproduce it. So they went to the MESA Study. Remember now, Mesa are individuals without cardiovascular disease. ARIC are patients with cardiovascular disease. And the finding was reproducible in MESA. Also, what the authors did, is they looked at the relevance of this EKG finding to our existing CHADS-VASc2 scoring system.

And what was really smart by these investigators, is that if you added the information from the abnormal P-wave morphology to the CHADS-VASc2 score, you could forecast stroke. Now you say, well CHADS-VASc2 is already pretty reliable, but what about those patients that have a CHADS-VASc score of one right? We're always kind of wondering, do we anticoagulate them? Do we give them aspirin, et cetera. Well if the P-wave morphology was abnormal and they were at higher risk for stroke, that could sway you as a clinician, to go ahead and prescribe anticoagulation for that group of patients.

And something very simple, just from the 12-lead EKG before the patients went into atrial fibrillation. You've got a paper that also is sort of focusing on stroke. You want to tell us about that?

Dr Carolyn Lam: Yeah, one big data to another big data series. This time, it's Get With The Guidelines Stroke series, and this paper is from Dr Menon from University of Calgary in Canada. Where they described the door to treatment times for endovascular therapy in acute stroke. What is that? Well that's a time interval from when the patient arrives in the emergency department or the door, to the first pass of the treatment initiation and endovascular therapy. And basically they found that the median door to first pass time was 130 minutes. Only 3% of patients achieved a door to first pass time of less than 60 minutes.

In multivariable analyses, older age arrival during nonregular hours and a history of diabetes, were all associated with the longer door to first pass time. And finally, among hospitals with an annual endovascular therapy case volume of 40 or less, every five unit increase in that volume was associated with a 3% reduction in this door to first pass time.

Greg Hundley: It sounds like that could be really useful information for stroke centers, you know, that are managing these patients acutely. How do you think these results are going to impact that Carolyn?

Dr Carolyn Lam: Great question. So first thing is, I think it provides some benchmark times for this in hospital workflow, and it obviously shows areas of improvement. For example, improving workflow during nonregular hours, or increasing the experience of a center, and basically emphasizes the point that efforts on streamlining workflow and saving time, need to continue so that the full potential of endovascular therapy is realized.

Greg Hundley: Oh wow, that's outstanding. I'm gonna transition sort of to a basic science paper, also trying to help manage patients with stroke. This one is looking at the safety of all of the dehydrogenased right stem cells. Well, what the world is that. In animals, what has been shown previously, is this particular cells type, that's harvested from your bone marrow, can be infused into the carotid artery, and those animals experience smaller neurologic deficits after stroke. And so with that encouraging result in animals, these investigators sought to test the efficacy of this type of therapy, well not really the efficacy, but the safety of this type of approach in those patients that have sustained actually quite a large stroke.

You had to have a relatively large neurologic deficit to qualify for this study. And just quickly, the way this works is these cells enter up through the bloodstream and they modulate inflammation. By modulating inflammation, that facilitates healing in the stroke patient.

Dr Carolyn Lam: Yeah, but wow. I mean bone marrow, biopsy and isolating the cells and so on. How is the study done?

Greg Hundley: So, the key here is you've had your stroke, you're still in the hospital with a large neurologic deficit. And so day 11 to 17, you undergo a bone marrow biopsy. Then the cells are purified, and they're reinfused into your carotid artery by the way.

And so, what was the study trying to do? Well, it was actually looking at the safety off all this. And what would the concern be? You're infusing these cells into the carotid artery. They go into the cerebral microcirculation, and those that are working in this field, are concerned is that going to promote more emboli? Is that going to promote thrombus? Extend the size of the infarct in the brain, et cetera?

So, the investigators performed MRI's and neurologic exams. And what they found is the neurologic findings in the patients really didn't change, so there was no benefit. But the study wasn't set up to look for a benefit. And there were four patients that had a little bit of an enlargement of the stroke observed on MRI. So, a lot more to come in this basic science realm, but it's interesting to see investigators thinking about this in a whole different way, where we're harvesting one cell type from your body, and then infusing it up into the brain to sort of help rescue the situation.

Dr Carolyn Lam: Well, another paper dealing with stroke. This time, a Mendelian randomization study to explore whether genetically determined circulating levels of cytokines and growth factors, may be associated with stroke. And this was done in the mega stroke GWA data set and validated in the UK biobank, and it’s by Dr Dichgans and colleagues from the university hospital, Ludwig Maximilian University of Munich. They basically found, that a genetic predisposition to higher circulating levels of monocyte chemoattractant protein one, was associated with a higher risk of stroke. The associations also found for the etiology of the stroke subtypes, and especially for large artery stroke and cardioembolic stroke. In fact the genetically determined levels of this monocyte chemoattractant protein one, was also associated with higher risk of the related phenotypes of coronary artery disease and myocardial infarction.

Greg Hundley: So, how do you bring this to practice in the clinic Carolyn?

Dr Carolyn Lam: So, this is still some steps away, but I do think that it very nicely supports the idea that inflammation as part of the pathogenesis of stroke, and of course additional work is needed to determine whether targeting the specific monocyte chemoattractant protein one, or it's downstream effectors, may be a meaningful strategy to lower stroke risk. So, terribly interesting.

Greg Hundley: Yeah, you know it sounds like hitting inflammation or targeting that, is a real theme here from the basic science group. Well this is great Carolyn.

And now, I guess we'll transition over to our feature article.

Dr Carolyn Lam: Absolutely. So, we're here to discuss the long-term results of the MOMENTUM 3 Trial, and that was a randomized controlled trial of the HeartMate 3 versus the Heartmate II left ventricular assist device. And this time, with a focus on stroke. The outcomes that's just so important to our patients. Greg and I are incredibly pleased to have with us, the authors, Dr Mandeep Mehra from Brigham and Women's Hospital, as well as our senior associate editor, Dr Biykem Bozkurt, to discuss this paper.

Mandeep, perhaps just set the scene by telling us what this secondary analysis found?

Dr Mandeep Mehra: This analysis is really focused on the issue of stroke, as you pointed out. I'd like to just lace into context what this is important. Ever since the advent of left ventricular assist device therapy from the 80s and early 90s, to now, one of the major Achilles' heels, whether we have used pulsatile flow devices or non-pulsatile flow devices, has been the very constant occurrence of a high incidence of stroke, beyond the stroke rates were predominantly as compared to ischemic strokes. Then with the newer devices, we actually saw a reversal, where we began to see more ischemic strokes as opposed to hemorrhagic strokes, almost an equal parts at this time point.

And this has been one of the critical reasons why we have not been able to expand the therapy beyond the very, very sick patient.

Greg Hundley: Very nice. And another particular in the results here is, you didn't really see a difference in stroke rates, either hemorrhagic or ischemic strokes early, but you did start to see a difference after 180 days. Why do you think that's the case?

Dr Mandeep Mehra: That's a great point Greg. We really saw no difference in the first 30 days. When we analyzed this data, we divided it into a perioperative, a first 30-day time point. Then, we looked at the short-term time point up to 180 days or six months, and then beyond that to the two year end point. What became very clear is that most of the gains that we saw in the stroke rate, began to appear after the first 30 days, did not quite reach statistical significance at six months, but really the differences became heavily pronounced after six months, all the way out to two years.

So, first point that I would make Greg, is that we did see differences beyond 30 days, it's just that they didn't reach conventional statistical significance. The second thing is, the more important point that you make, asking why that was the case. We actually think that the reason behind that, is that the first three months or so after that implant, really is a period of chaos in these patients, where the hemocompatibility, which is essentially the interface between the device as well as the patient, is attempting to be established. And it's very similar in a way as we see in heart transplantation Greg, where the real challenge in heart transplantation is between rejection and infection.

And in the case of left ventricular assist device is the challenges between bleeding and thrombosis. It turns out that three months, whether it be transplantation or whether it be left ventricular assist devices, seems to be this period of chaos and adjustment, during which the patient and the device are starting to get to know each other.

And this is why we think that most of the gains occurred after this period of chaos was overcome.

Greg Hundley: No, it's really interesting that after accounting or adjusting for all the anticoagulant drugs, antiplatelet drugs, even the other medical therapies that were applied, you found these results. I mean, maybe also bring in Biykem here to answer the question, what is this machine doing that's providing such a benefit?

Dr Biykem Bozkurt: The two-year results being quite impressive for the HeartMate 3 are truly encouraging. Because I think we truly see a concordance benefit beyond 180 days, especially the nondisabling strokes, giving the hope to the providers that we can further perhaps enhance the field by focusing on optimization of anticoagulation strategies, prevention of atrial fibrillation, and maybe even consider our algorithms or pathways for stroke. Because, in this protocol, even though the stroke management was not standardized, and I'm sure that the data will not yield that information as to which centers were able to approach the stroke management in a perhaps evidence based approach, the sobering facts are regardless of the device, at two years, approximately half of the patients died. Even the non-disabling stroke patients had increased mortality compared to no-stroke patients.

And if you examine evidence-based approaches, only one-third of the hemorrhagic stroke patients had reversal of anticoagulation, and a very small percentage ... actually, none of the patients had device intervention for the ischemic stroke. That raises the question of yes at two years the HeartMate 3 results are very promising. But, can we further even advance the field by doing evidence based standardized pathway driven stroke treatment approaches.

The other very interesting finding from this trial is, in ENDURANCE trial, which was another trial with centrifugal device, HVAD device, there was an association of the stroke rates with inadequate control of blood pressure and anticoagulation, which was not noted in this trial. Maybe Mandeep can comment on do we truly have the adequate power to be able to infer whether blood pressure control and/or appropriate anticoagulation management strategies will matter?

Dr Mandeep Mehra: Biykem you've said it really well, and I'd like to just make some additional points with respect to the question. So, first of all Greg you're absolutely correct, that we tried to search for anything that would predict this reduction in stroke with the HeartMate 3, and it turned out that all we were left with is the device itself. So, it really begs the question, what is it about the device or it's interface that may have resulted in this.

And of course, some of what I'm about to tell you will be speculation, but it may actually carry some water. So, for example, the HeartMate 3 is very unique in one other aspect, and that is that, even though it's a small profile device, it's engineering principles are such that it allows for very wide blood flow pathways. And in fact, despite its small profile, the blood flow pathways allow for 20 times more red blood cells to travel through the primary and secondary pathway, than other devices.

What it means is that as blood is going through this device, it is exposed to very low sheer stress. And in return, the benefit that we see very clearly with this device in a very, very important way, is the fact that we see almost no denovo pump thrombosis developing with this device. Certainly, if the device doesn't carry some small quad risks in it, that cause problems with the device, it's probably also not causing the production of smaller non-device malfunction producing thrombi, which may with other devices, actually develop and cause strokes.

So, we think that particular engineering enhancement, may play a very important role in reducing this stroke rate that we have observed.

The second very important point that Biykem brought up, is this notion about the management of ... whether it be with anticoagulants or with blood pressure management. And for a moment let's dwell on the blood pressure issue. One of the striking things with the other centrifugal device, the HVAD device, is that the ENDURANCE Trial showed a significantly higher stroke rate with that device. And in fact, in a subsequent study, the ENDURANCE Supplemental Trial, when blood pressure was tightly, tightly controlled in the device, there appeared to be a small signal in reduction in strokes, although it still did not meet the non-inferiority endpoint, compared to the HeartMate II in the second supplementary trial that was done with that device.

So, what's unique about this? Well, we can very clearly say maybe we just didn't have enough ability to show a difference in this particular trial, we didn't analyze it the right way, because we didn't have a blood pressure intervention or low or higher permissive blood pressures in this trial. But I would say that there's one other issue that I think may have played a very important role in this, and that is the HeartMate 3 is intrinsically developed with a fixed pulse algorithm. And in fact, the HeartMate 3 has a capacity where the magnetically levitated rotor upregulates itself and then downregulates itself every two seconds, and creates an internal pulsatility.

Now, engineers developed that pulsatility to really decrease stasis, so that the pump wouldn't thrombose. But we often see that it provides sufficient peripheral pulsatility, not to the pulse pressures that we would normally like to see, but certainly to some degree, where the vasculature can perceive or transduce some degree of pulsatility. Why that may be important is, that it may actually allow for preservation of baroreceptor function in these patients, which tends to be lost in continuous flow pumps.

And how important that is for blood pressure regulation and its vascular effect, may be something that needs to be looked at into the future. But it's certainly a very, very intriguing issue for us to examine.

Dr Biykem Bozkurt: Mandeep, one final question or comment. Do want to comment on the stroke rates of HeartMate II compared to former trials. Because that comes as a common query as to why in MOMENTUM 3 the stroke rate in HeartMate II, appear to be higher than the former trials.

Dr Mandeep Mehra: So very quickly, I'll tell you they're not. So, if you look at the 2009 randomized trials, randomized patients with a HeartMate II versus the HeartMate XVE trial, the two-year stroke rates with the HeartMate II in that trial were 19%, exactly what we observed at two years in this trial.

Other trials have shown exactly that same number. The only trial in which there appeared to be a difference in those numbers, was in the ENDURANCE Trial, where the two-year rate of any stroke was 12%, and was a little lower in the HeartMate II than what we observed. However, I will caution you that if someone dies before having a stroke, then they die without a stroke. And so, stroke can sometimes we underestimated if the population that is enrolled, such as a transplant ineligible population at very high risk, is dying more often than having the chance of a stroke.

So, I actually do not think at all that there was any difference whatsoever compared to prior trials. And even when you look at the ENDURANCE Supplement Trial, which is probably the most contemporary comparison of HeartMate II stroke rates, with MOMENTUM 3, the ENDURANCE Supplement Trial was only a one year trial, and the stroke rates even at one year were right on target with what we observed at the HeartMate II group in MOMENTUM 3. So, frankly that criticism is probably an unfounded criticism.

Dr Biykem Bozkurt: Thank you.

Dr Carolyn Lam: Wow, thank you Mandeep and Biykem, for really helping us go under the hood with this paper. I'm heart failure trained as well, but I learned so much, I'm sure our listeners did as well, and I'm sure you agree too Greg.

Thank you so much for joining us today. Don't forget to tune in again next week.

Circulation January 2, 2019 Issue

31 december 2018 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the run, your weekly podcast summary and back stage pass to the journal and its editors, and welcome to a whole new podcast format in 2019. Ha-ha, I bet that surprised you. Well guess what? This new format promises more interaction, more discussion and a whole lot more fun, and that's because to begin with, you don't have to listen to me talk to myself half the time anymore. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore, and I am simply delighted that Santa gave me a partner on this podcast, and co-hosted with me, and my gift is none other than Dr Greg Hundley, associate editor from the Pauley Heart Center, at Virginia Commonwealth University Health Sciences. Welcome Greg.

Dr Gregory Hundley: Thank you so much Carolyn. How exciting is it to start this new year with this exciting format, where we'll take several of the key manuscripts from Circulation and discuss them? Picking five each time, and as you've alluded to, we're not going to get rid of that favorite format, where we take a select paper and interview and work with the authors.

Dr Carolyn Lam: Exactly. In fact, maybe I could liken it to welcoming everyone to join us over a cup of coffee, each week, with the journal in the hand and we're just going to discuss it, and never forgetting that feature paper with the authors, and this week's paper is huge. I love it. We're actually going to be talking about blood pressure control in the barber shop. But before then, here's the articles that we've chosen to discuss. So Greg, you got your coffee ready? Shall we start?

Dr Gregory Hundley: Absolutely Carolyn, and let's get going first with Gorav Ailwadi, from University of Virginia, his paper evaluating the utility of MitraClips in those with secondary mitral regurgitation. This is really a follow-up from the EVEREST study. It's not a randomized trial, but it's a longitudinal look over time, at 616 patients. Interestingly, those individuals that had class three or four heart failure, that had the MitraClip, the left ventricular volumes got smaller in a year, the hazard ratio for events became less. The magnitude of mitral regurgitation went from 4+ down to 2+. Exciting findings.

Dr Carolyn Lam: Interesting, but you know Greg, these all sound so positive. Why is it so different in the Mitra FR study?

Dr Gregory Hundley: Absolutely Carolyn. So, as you know, Mitra FR, that was a randomized trial. So, this study doesn't compare, the EVEREST study in this issue, doesn't compare with conventional medical therapy, that's number one, and Mitra FR did. Also, the Mitra FR patients were a little bit sicker. The ejection fraction really was 15 to 40 percent, and in the EVEREST study, much higher, average 45 percent. In fact, many had a normal EF. So it really raises a lot of questions as to whether or not this finding will hold up in future randomized trials, which we'll be looking to see the results.

Dr Carolyn Lam: Indeed, and it was really nicely discussing the accompanying editorial wasn't it, which I really enjoyed. Well, the paper I picked out Greg is from Dr Gatzoulis from The Royal Brompton Hospital, and it's actually the MAESTRO trial. Now, MAESTRO is a randomized control trial of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. Short and long of it, macitentan did not show superiority over placebo on the primary endpoint of change in baseline to week 16 in exercise capacity. And there was also no relevant trends observed for the secondary endpoints.

However, among the exploratory endpoints, macitentan did reduce Nt-proBNP in the main cohort, and improved pulmonary vascular resistant index, and exercise capacity, in a hemodynamic sub-study. Importantly also, there were no specific safety concerns with macitentan.

Dr Gregory Hundley: Sounds really interesting, Carolyn. But how did this compare with prior studies that have really focused on endothelin?

Dr Carolyn Lam: Great question. So, MAESTRO's only the second randomized control trial of an endothelin receptor antagonist in Eisenmenger Syndrome. BREATHE-5 was the first, and this used a different endothelin receptor antagonist that was bosentan, also in Eisenmenger Syndrome, and actually found that bosentan reduced pulmonary vascular resistance as its primary efficacy endpoint, without worsening systemic pulse of symmetry.

So, very different trials in terms of endpoints, as you can hear, but also importantly, different populations that were enrolled. MAESTRO enrolled a more heterogeneous population with more complex forms of Eisenmenger, including patients with Down syndrome, had a broader WHO functional class inclusion, and allowed the use of pre-existing therapies such as PDE5 inhibitors.

Dr Gregory Hundley: That's really spectacular, Carolyn. Very interesting findings for something that these vasoconstrictors, vasodilators, often very harmful. Switching over, I've got sort of another paper that is also working on vasodilation, but comes really from the world of basic science. And it's from Ingrid Fleming from Goethe University in Frankfurt, Germany, examining how does hydrogen sulfide, a common gas that we have in the environment, it smells terrible, we worry about sulfuric acid and acid rain, but how does this promote vasodilation in the system?

And so, in this basic science study, they unlocked sort of a key that this hydrogen sulfide is produced by cystathionine gamma-lyase, CSE. And why is that important, and what does it do? Well, production of H2S by CSE goes and inhibits human antigen R, or HuR, that regulates cellular proliferation and growth. And so, basically these authors have unlocked a mechanism by which hydrogen sulfide can be protective.

So, what's interesting Carolyn is that patients can have elevated levels of L-cysteine, increased expression of CSE, so you've got the components and the manufacturer of H2S, but they still have low arterial levels.

Dr Carolyn Lam: Hm. So, how can this be addressed then? How can we raise that H2S?

Dr Gregory Hundley: That's what's so clever that the investigators found out, Carolyn. They found a slow-release oral active drug, a sulfide donor called sodium polysulthionate, H2R, or sulfhydration, and can inhibit atherosclerosis development or progression when these levels are low.

Dr Carolyn Lam: Indeed. sodium polysulthionate. Awesome, Greg! That is so cool. Honestly I just loved your explanation of that. Okay. Well, I've got another paper to share. And this is from Dr Bress and colleagues from University of Utah School of Medicine. And this one is really interesting because these authors estimated the number of cardiovascular disease events that could be prevented, and the treatment-related serious adverse events that could occur over ten years, if U.S. adults with hypertension were achieving the 2017 ACC/AHA guideline recommended BP goals, compared to their current blood pressure levels, as well as compared to achieving the older 2003 JNC7 goals, or the older 2014 JNC8 goals.

Now, basically they found that achieving and maintaining the 2017 guideline blood pressure goals over ten years could prevent three million cardiovascular disease events, a greater number of events prevented compared to prior guidelines, but this could also lead to 3.3 million more treatment-related serious adverse events.

Dr Gregory Hundley: So, Carolyn, hasn't a main concern of this type of work been that these new guidelines over-extend the reach of our treatment?

Dr Carolyn Lam: That's a real concern that I've also heard. The lower blood pressure thresholds used to define hypertension in the 2017 guidelines could indeed lead to more diagnoses. However, this paper helped because remember that the recommendation for anti-hypertensive drug treatment in patients with the pre-treatment blood pressure of 130-139 systolic, or 80-89 diastolic, was limited to those at high cardiovascular disease risk. So not everyone, but only those at high cardiovascular disease risk.

And so, treatment under the 2017 guidelines, by these data, would lead to more health gains, while only extending treatment to 5.4% more adults with hypertension compared to JNC7. So, this paper really modeled these things out with important contemporary U.S. adult populations using a national representative, a sample of U.S. adults, and NHANES, as well as REGARDS, and they also used estimates of benefit from the recent large meta-analysis of 42 blood pressure-lowering trials.

So, important data that I think are going to be reassuring to a lot of people managing these patients. Well Greg, that really brings us to the end of our little chat. Now, let's move to our future discussion, shall we?

Could cutting blood pressure in a barber shop be the long-term solution to hypertension in African-American men? Well, the future paper of this first issue in 2019 really talks about it. Greg and I are so delighted to have with us the authors of the paper, Dr Ciantel Blyler, and Dr Florian Rader from Cedars-Sinai Medical Center, as well as our associate editor, Dr Wanpen Vongpatanasin.

So, Ciantel, can you just perhaps start by telling us what you found.

Dr Ciantel Blyler: So, what we're talking about today are the 12-month results as a follow-up to our 6-month results that we published earlier this year. So, we took 319 African-American men in Los Angeles County, and randomized them to two groups. One group saw a clinical pharmacist who worked with them to reduce their blood pressure, and the other group just worked with their barber to talk about blood pressure, and encourage usual follow-up.

And, as we saw at the 6-month mark, blood pressure really improved in the group that was able to work with the clinical pharmacist. So, we saw an almost 29 mm Hg drop in the intervention group, as compared to only 7 mm Hg in the control group.

Dr Gregory Hundley: Ciantel, Florian, that is really exciting results. What is a collaborative practice arrangement, and how did you affect that in Los Angeles?

Dr Ciantel Blyler: So, collaborative practice is actually widespread in the United States. California is one particular state that is kind of ahead of the curve with respect to collaborative practice between pharmacists and physicians. But what it essentially allows a pharmacist to do is to prescribe, monitor, and adjust medications underneath a physician's supervision. So, a document is drawn up, medications are selected, and an algorithm so to speak is put together so that a pharmacist can treat a patient independently of a physician needing to be there.

Dr Greg Hundley: Very nice. And did you find in the pharmacist-led group that these patients were taking a different anti-hypertensive regimen, or were they more compliant? What do you think was the reason for the discrepancy in this magnificent blood pressure drop in this group of hypertensive men?

Dr Florian Rader: So clearly, there were a lot of differences between the two groups. First of all, we had a protocol with our favorite blood pressure medications that we use clinically here in the hypertension center at Cedars-Sinai. Essentially it is long-acting calcium channel blocker, specifically Amlodipine, longer-acting angiotensin receptor blockers, or ACE inhibitors, and a third line, usually a thiazide diuretic, and also a longer-acting one, not the usual Hydrochlorothiazide, but specifically Indapamide that we used for this research study.

Dr Greg Hundley: And do you think that there was more compliance in this pharmacist-led group?

Dr Florian Rader: One would expect that. First of all, I think that seeing the clinical pharmacist, more frequently being reminded of taking the medications, having feedback by actually seeing the blood pressure numbers in the barber shop, I think would help. But then, in addition, we choose these medications not only because they affect it, but also because they're easy to take. They're once-a-day medications with very high continuation rates in larger studies, so they're just easier to take than other medications that are oftentimes prescribed.

Dr Greg Hundley: It sounds like also, there might have been a trust factor. Because you're seeing the same person over and over in a very nice environment. Was that a factor?

Dr Ciantel Blyler: Absolutely. I think there's a different level of trust that's established when you meet somebody on their own turf. So I think the fact that we met men in barber shops where they felt comfortable, where many of them had been going to the same barber for over a decade, it made all the difference in terms of establishing a rapport, and gaining their trust with respect to having them take medications. So, I think that was a huge part of why we saw increased adherence, and really sort of a commitment to the program.

Dr Greg Hundley: And we certainly recognize how harmful hypertension is in individuals of Black race. How does this group in Los Angeles translate to perhaps other Black men in the United States? Particularly, for example, in the South.

Dr Ciantel Blyler: I think the program could translate really anywhere. I think what makes it so tailored to African-American men is this notion of going into a barber shop, which is a very important place in the Black community. So, again, sort of going back to what I said earlier, most of these men had been seeing the same barber as frequently as almost every two weeks for over a decade. So, it really helps increase the frequency with which we could interact with the men, and it helped with continued follow-up and adherence to the program.

With respect to the area of the country again, I think it translates.

Dr Carolyn Lam: I've got a follow-up question to that, if you don't mind. So, I'm here listening all the way from Singapore, and I'm just so impressed, and frankly just enamored by this study. And wondering what is the barber shop to my local Chinese guy? I'm actually wondering if it's the kafei dian and that stands for coffee shop, and I'm also wondering what about the women? Wanpen, do you have any insights that you want to share?

Dr Wanpen Vongpatanasin: I believe that even Dr Victor had thought about the beauty shops, that is a barber shop study in parallel, and this could very well work very well. Who knows, we could be going to massage parlor, anywhere, that when we feel relaxed and be ourselves, we go out our way, out of our regular activity, and it could really be a neat idea. And for a study, I'm not sure I could do something out of the box. I would say it must have been successful as this approach, and partly it could be because of the additional pharmacists engage likely. So, I think this is a perfect combination.

Dr Greg Hundley: Wanpen, you had mentioned Ron Victor. Maybe Ciantel, Florian, and Wanpen, you used to work with him. What did Ron mean to this study? Ron Victor unfortunately passed away this past Fall.

Dr Florian Rader: Ron hired me almost seven years ago now straight out of fellowship. He was personally my mentor. He taught me all the tricks when it comes to the work of the management of hypertension, so personally I owe him a lot. Regarding the study, he's been thinking about this for a long time, this approach to hypertension management. He's tried it in Dallas. It worked partially, but not very well because he didn't have a pharmacist, and he didn't have somebody that made it their goal to lower blood pressure no matter what.

And in this study, we had somebody like that, the clinical pharmacist. So, Ron Victor has thought about this for a long time, has done a lot of analysis of the Dallas hypertension study, and figured out why it didn't work out in Dallas, and really cooked up a recipe for this trial, and the results speak for themselves.

Dr Greg Hundley: Wanpen, do you have anything to add about Ron? I think he was your mentor as well.

Dr Wanpen Vongpatanasin: Absolutely. I trained with him actually from the internship until fellowship, and I owe my career to him. And actually, I see this idea stemming from the Dallas heart study when he did the survey, and realized that if you just wait for patients to show up in the clinic, that you're not going to get anywhere, because African Americans have higher blood pressure at a younger age, and are more susceptible for target organ damage. And as we all know, by the time many presented with, they already have end-stage kidney disease or cardiovascular disease by the time first presentation. So, to avoid it, we have to go into much earlier, not wait until they come to the healthcare facility, and I'm glad to see that this idea is really becoming widely successful more than anyone can imagine.

Dr Carolyn Lam: What a beautiful tribute. What a poignant note. Thank you, all of you, for your great input, and for publishing this amazing paper with us at Circulation!

Thank you, listeners, for joining us today on Circulation on the Run with Greg Huntley and me. Thank you, and don't forget to tune in again next week.

Circulation Fellows-in-Training Podcast

24 december 2018 | 23 min

Dr Amit Khera: Welcome to Circulation on the Run, your weekly summary and backstage pass to the journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas. And I have the privilege of standing in for Dr Carolyn Lam, your usual weekly podcast host. Today we have a special treat. It is our semiannual fellows and training FIT podcast. And the additional part of this treat is we have three very special FITs today. These are our assistant editors for social media for Circulation. And really I want to introduce you just a moment, but I want to thank these three for their hard work and efforts. It really is them that helped bring our social media to life. And importantly for us, we really have a commitment to enhancing fellow education involving fellows in our editorial process and really making sure that the journal is appealing to fellows in training. So we really rely on these three to help us understand what best resonates and what is most helpful for fellows in training. So without further ado, Jainy Savla from UT Southwestern. Welcome Jainy.

Jainy Savla: Thanks for having me on the podcast today.

Dr Amit Khera: And we have Daniel Ambinder from Johns Hopkins University. Hi Dan.

Daniel Ambinder: Hey Amit. Thanks for having me on the podcast today.

Dr Amit Khera: Absolutely. And finally we have Jeff Hsu from UCLA. Hi Jeff.

Jeff Hsu: Hi Amit and hi everyone. Very glad to be here.

Dr Amit Khera: Well, Jainy, I'm going to start with you. You've been with us on the social media side the longest. I think it's maybe almost a year or a bit more that you've been working on these efforts. And again, very much appreciate all of your hard work and insight. Tell us a bit about yourself.

Jainy Savla: So I'm currently a research fellow at UT Southwestern. So I completed my general cardiology training and I've been doing some extra research training in one of our basic science labs there.

Dr Amit Khera: So not surprisingly with your background, do you select an article? So we've asked them each to select one article as they've been working through the social media side and see all of our articles come through. Each to select one that they found was interesting and perhaps summarize for us what it included and what appealed to them. So Jainy, tell us a little bit about the article you chose and why you chose it.

Jainy Savla: So, I chose one of the articles that was published in April of 2018 from the Molkentin team lab. And this is a basic science article that focused on which types of cells contribute to heart regeneration. They hadn't thought that there was cardiac progenitor cell that could contribute to the development of new cardiomyocytes. And more recent data has shown that maybe that's not quite the case. So what this study did was used a lot of fancy lineage tracing models to try to figure out which types of cells we're actually contributing to the development of new cardiomyocytes. So importantly, what came from this was that one of their models, they were able to delete two transcription factors that are necessary for cardiomyocytes to develop from these progenitor cells. But they found that when they did that, they even got a higher number of cardiomyocytes that formed. And then what they were able to show in this paper was that actually comes from fusion of leukocytes to cardiomyocytes. And then interestingly, they found a role for one of these transcription factors and the development of endothelial cells. So that was kind of a new, not known function of one of these genes that was previously thought to be just contributory to cardiac development.

Dr Amit Khera: It's really a fascinating article when you think about it. Most of the science we publish are people bringing to light new discoveries and certainly there was a component of that here. But in many ways, it was kind of a different article where there had been this a prevailing thought about these c kit positive cells and here they're actually had gone through, refuted what people had thought was happening with these in this de novo cardiomyocyte formation. So you'll see that very often where people's articles or work is headed out to sort of maybe refute or set right what's happening in the literature in the field. Can you comment on that as to that type of article and how that appealed to you in this study?

Jainy Savla: That is interesting because previously it has meant that these cells can be used as a therapeutic option in human patients. But some of them were recent data showed that perhaps the new cardiomyocytes weren't actually coming from these cells, but it was hard to say. So the nice part about this paper was really they used a lot of important lineage tracing models to really show where these cells are coming from. And it helped clarify some of the, I guess, more confusing science that had been in the field since there were a few papers that showed these cells were contributary and then a few papers that have shown that maybe they weren't. So I think that's really helpful, particularly when you're talking about things that could be potentially used as therapeutic agents in human. And also the interesting thing is that while these cells themselves may not be useful to perhaps harvest and give to someone, you could potentially alter these cells and then they produce cells that fuse with cardiomyocytes. Or could you use this a different way? So I thought that was also interesting about this article.

Dr Amit Khera: Great points in it. It does remind us again that in our enthusiasm for rushing things to clinical practices in some things in this field, the importance of rigorous basic science to really understand the molecular underpinnings. And as you mentioned, there's some new insights here that could be used for clinical therapeutic purposes in the future. So definitely an interesting article and glad you enjoyed it and brought it to our attention. I'm going to ask you a bit of a different question. You again have been working with this in the social media side for longer. You've seen this now for some time about the different articles that come through. I know you and I've had several conversations about our different platforms, Twitter or Facebook, and how they're different and how we engage with them and how we engage with the audience. Can you tell us a little bit just reflecting now on your time and working with social media from a journal perspective, kind of what you've learned? What are some interesting observations over this year?

Jainy Savla: Definitely one interesting observation is just that their general usage of these social media platforms has increased significantly since I've started doing this. And you can see this with when we get articles that are accepted, how many authors have Twitter handles that they'd like to be tagged in some of these posts. And that's just gone up significantly since I've started doing this. And that also changes sort of what the comments we get on some of the posts and the back and forth discussions that we're seeing on these platforms. And then the second thing I found really interesting over time is that the way people use Facebook is really different from the way people use Twitter. And you can follow the discussions that people have linked to our posts a little bit better on Facebook. And then on Twitter, there's also a lot of similar discussions about these posts. But they kind of manifest in different ways and it's really interesting to see how that plays out.

Dr Amit Khera: I think those are fantastic points. And from a fellow's perspective, how do you think fellows are engaging with social media now compared to maybe, I don't know, when you started your training a few years back. What have you seen in a positive light?

Jainy Savla: I mean in general, there are more fellows on Twitter now than when I was a first-year fellow. Even myself, I've got my Twitter account when I was in fellowship. I didn't have one prior to that. I mean it's interesting because people are able to showcase their work a little bit better I think with these types of handles whereas before maybe you wouldn't know that even one of your own co fellows had published something. So it's kind of nice to see people use that kind of as a networking tool in some ways or to showcase some of their own work, which is something that when I was a first year and I didn't have a Twitter handle and there weren't as many fellows on Twitter, I didn't really notice some of the work that's being done by some of my colleagues at my level.

Dr Amit Khera: Those are great points and I'll stoplight some of the things you just said talking about it being a way for fellows to really showcase their work, to help with networking and in some ways, it's sort of the great equalizer. So I think it's really a valuable platform specifically for fellows. Well thank you Jainy. I'm going to move on to Daniel and hear a little bit from Daniel. Tell us a bit about yourself.

Daniel Ambinder: I'm currently a second year cardiology fellow at John's Hopkins Hospital and I plan on doing interventional and structural cardiology in the future.

Dr Amit Khera: Great and certainly a lively and growing field and so many exciting things happening. Well, it's interesting you chose an article today that is more of a clinical article and obviously quite different than the last one we heard, but equally as interesting. Tell us a little about the article you've chose and why you chose it.

Daniel Ambinder: I was very excited about this article that was published in Circulation back in July 2018. So, it's by Dr Borlaug and Reddy on how to diagnose HFpEF and what they did was they took patients with clinical dyspnea and they used invasive human dynamics to kind of assess whether or not they had HFpEF. And by doing so they were able to generate a list of clinical and eco based guidance to help us kind of identify patients with heart failure with preserved ejection fraction. So they came up with this amazing little table which was featured in Circulation and on Circulation twitter, where they have a chart that basically goes through several clinical variables including weight and hypertensiveness, atrial fibrillation, pulmonary hypertension, being elderly. And filling pressure is based on echo cardiographic information. And by that they were able to generate a score and give you a probability of if your patient has HFpEF or not.

And the reason why I really enjoyed reading this article and also posting this article was because going through internal medicine and not being so fundamentally aware of echo and kind of what goes into understanding left ventricular filling pressures, it was challenging to make a diagnosis of heart failure with preserved ejection fraction. Do you just basically say, "My patient has lower extremity swelling but normal EF? They have heart failure with preserved ejection fraction and [inaudible 00:09:32] on the [inaudible 00:09:33]. And so I thought that this would be really helpful to the medical community at large. And in fact, shortly after we posted it, I saw that our cardiology console fellow is actually utilizing this exact table to help one of the medicine teams manage a patient with lower extremity swelling and come to the diagnosis of heart failure with preserved ejection fraction. So that is why I chose this article for today.

Dr Amit Khera: That's a great article and I thought you summarized it very well. And it is a field. HFpEF you'd see a lot of articles in Circulation on this topic. We have many people that are interested from an editor’s level but also from a society level. This is a huge problem, but we know very, very little. And I'm sure you know that as well and this was a wonderful tool. Just shows you're sort of the beauty and simplicity. Although if you read it, the message were pretty rigorous and they had a lot of great work that they did to develop it. But I love that the H2 HFpEF, how they basically came up with it h for heavy and the f from fibrillation. So I thought that was incredibly creative and a very simplistic but useful score. So, you said your, tell us about yourself. Have you used the H2 of the HFpEF score yet?

Daniel Ambinder: Absolutely. I use it in clinic on a daily basis. And I actually pull up the Tweet in my office and show the patients why I think that they have heart failure preserved ejection fraction, especially since many of my patients start to get really nervous when you start talking about heart failure. But then they don't understand that they have a normal functioning heart. They can't really put those two together. And so going through this chart and going through the etiology, or at least what we know about heart failure with preserved ejection fraction, turns out to be quite helpful.

Dr Amit Khera: And the basis of this study goes back to hemodynamics. This obviously is a cohort where they had done invasive hemodynamics to essentially diagnosed HFpEF based on pressure. So as you, as someone who's going interventional and structural where we are really seeing kind of the rebirth or refocus on hemodynamics again, tell me a little bit like what you're learning in terms of hemodynamics and how you think that importance in today's practice of cardiovascular medicine.

Daniel Ambinder: One of my passions is spending as much time as I possibly can in the cardiac ICU. And we're fortunate to meet many different patients that come in with very different kinds of cardiogenic shock for other hemodynamic compromise from other types of shock. And I have found it extremely helpful to think about either using a virtual Swan or by actually getting the measurements with a PA catheter to kind of identify where the break in the system is to hopefully provide our patients with the ability to turn them around in a fast manner before they develop metabolic compromise from prolonged hypoperfusion.

Dr Amit Khera: Great summary of how you're using hemodynamics and the training. And I'm going to pivot. The last question for you is when we first met I think several months back and we're communicating about your interest in social media, one thing that was really interesting and fascinating was the great work you're doing on Twitter on your own account where you essentially, if I think you told me this right, you sit on your iPhone and basically in this matter of a very few minutes would construct cases and teaching points on Twitter. So tell me a little bit about that, about using Twitter for medical education and learning cardiology and cases. And I know you're passionate about that. So tell us a little bit more about that.

Daniel Ambinder: Back in May, last year, I had been in my first year of cardiology fellowship. And I was really kind of obsessed with grabbing as much imaging and cases as I could to construct them into teaching stories to share these important stories that I encounter with other people. And so also share the aha moments that I have when I'm learning from my mentors about a new clinical condition or even a clinical condition that I've encountered many times. We never thought about any unique way. And so I was putting these all together and developing somewhat of a library of cases. But I would share them with the residents that I was working with at the time. And then Dr Erin Michos was one of my mentors at Hopkins. She's an echocardiographer and she kind of exposed me to the Twitter community where you're really able to just start reaching out to different people and share the same insights that I had saved on my drive on my computer. And so I started constructing these cases, putting that together and developing them and then associating them with like a few bullet pointed tidbits of pearls that I can put on Twitter. And I quickly realized what an amazing community Twitter have to offer in terms of cardiology and in terms of the medical education community at large.

At first, I realized you can't put out content and not expect to participate in a conversation. It has to be two ways. You have to really engage with others and others will engage with you. And then just a couple months later, it's really grown that you can post a case, post the teaching pearl and in about 24 hours it can be viewed thousands and thousands of times, really internationally. And generates just so much great conversation. So it's been really a tremendous way to communicate with the world, especially within the cardiovascular world.

Dr Amit Khera: Well thanks. I think there's so much learning that can happen and I think the work you're doing with cases and with others. And I know when I've gone on Twitter, even in just two minutes you can see really fascinating things and learn a lot. So keep up the good work and appreciate your efforts there. I'm going to switch gears and finally finished with Jeff Hsu from UCLA. Jeff, tell us a bit about yourself.

Jeff Hsu: I'm a fellow at UCLA. So I actually finished my general cardiology fellowship pretty recently and now I'm a research fellow in the STAR program here. I'm also enrolled in the PhD program at UCLA in the Department of Physiology and planning to defend in the next few months. So right now, very stressed out about that. Starting in July, I'll be starting advanced fellowship in advanced heart failure and transplant here at UCLA.

Well excellent and best of luck to you in your PhD defense. Now you also chose a very interesting article that again, all of yours are a bit different. So tell us a little about the article you chose and why you chose it.

When I chose this article, I was really excited by a few weeks ago. It was published in the December 4th issue of Circulation called Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells. So this came out of the lab of Joe Wu at Stanford and the co first authors is Ning Ma, Joe Zhang and Ilanit Itzhaki. But I think the beauty of this article is that it really addressed this frustrating clinical scenario in question that we often encounter nowadays in this era of genome sequencing. And now that we're sequencing a lot more people, since the cost of sequencing has come down a lot, we were finding a lot of these mutations that we don't know what to do with, so I think Dr Wu's lab really try to address this question using the disease model with the cardiomyopathy. So, leveraging Dr Wu's expertise in using human induced pluripotent stem cells or iPSCs, they found a patient who is actually healthy but apparently had this mutation in this gene called MYL3 or myosin light chain 3. And so this patient had a variance of uncertain significance in this gene.

Now, notably, this patient, again had no clinical phenotype, was very healthy and the patient's family members over three generations were all healthy too. But had this mutation that based on in silico analyses was thought to be likely pathogenic. So using cells from this patient that they reprogrammed into cardiomyocyte, they tested various properties of these cells from the same patient to see whether or not they thought this mutation is actually a pathogenic mutation. So again, using these reprogrammed cardiomyocytes, they tested a variety of things including gene expression, sarcomere structure, and cell contractility, action potentials, and the handling of calcium. And they saw that even with this mutation, there were no abnormal findings in vitro in their system.

Now just to prove that their cell culture system and this in vitro model of testing the pathogenicity of certain mutations actually works, they actually took cells from a patient who did have the clinical phenotype as a result of a known mutation that causes hypertrophic cardiomyopathy. And found that when testing those cells in vitro, they did demonstrate abnormal phenotypes in all the parameters I mentioned before. So I thought this is really exciting. I thought this is a great way to address, potentially answer whether or not we think these variants of uncertain significance that we often encounter are indeed pathogenic because we are often just left in this situation where we don't know what to do with this information. But this potentially at least is a proof of concept for this protocol where we can finally take advantage of the ability to take cells from our patient and actually test them in the lab to see whether or not either various treatments work or whether or not these mutations that actually will results in pathology down the line. So I thought overall this was a great paper that was a great summary of how we can take the bedside to the bench actually. And I'm just really looking forward to the future where we can maybe then bring it back to the bedside.

Dr Amit Khera: Well thanks. I think that's an excellent choice and a great summary. And this article really hit all of the kind of timely and cutting-edge topics in the era genomic medicine and precision medicine have really kind of individualized treatments. And when we get stuck, these VUSes, these are a nightmare. And also this is sort of proof of concept for extending this to other treatments and other ways to test drugs and therapies. I've heard Joe, we talk about this before and use the word disease in the dishes. He did I think in the article itself and it's exactly that. I mean the potential here is profound. I'll pivot this into the next question for you. For our roles, one thing we do is we interact a lot with media and I interact a lot with them to help translate, I guess, the articles that we have to things that would be able to be digestible for media and for lay individuals. It was interesting because it's hard for us to do that with basic science and most of the time we have some difficulty in translating that. But this one translated pretty well and I think we had done some various press releases and things because it really showed the potential of modern medicine and kind of the excitement of it.

But that gets to the question I have for you, something we have discussed as well, your interest in basic science and some of the challenges of taking basic science articles and digesting them down to a couple hundred-word tweet. Even as beautiful as all the pictures are, and in this article I think there's six figures, but each panel is 10 pictures or 10 figures by themselves. And how do we digest basic science articles down to make them really appeal to people on social media and help people understand that may not be in the fields or in basic science that are clinicians, if you will. I know you've thought about that a little bit. Tell me a little bit about your thoughts on that.

Jeff Hsu: Jainy, Dan and I have this challenge on a weekly basis, figuring out how to summarize great articles such as this one into a short tweet. And I think that is a big challenge particularly for basic science articles on social media to make it appeal to a broader audience because the audience you're seeing on Twitter and Facebook, again, they're not just basic scientists. If you want to catch people's attention, you need to find a way to really understand the big picture of the question you're answering in your basic science research. So I think that is a challenge. You're challenged to make your science appealing to a broader audience. But I think again, that's one of the advantages of social media is that you can appeal to a larger audience and have a wide range of people engage with your research and understand your research. So it is something that we work on is to try to pick out the figure that best represents the science that was done in these basic science articles.

It can be quite challenging because a lot of times one picture won't do it justice. So it's tough to distill a full article in one picture. It is helpful when some articles do have a summary, a graphic or figure where they typically reserve their last figure for either a cartoon or some type of schematic that really explains either the mechanism or pathway that they explored in their article. So what we've found is that these articles that do have some of these illustrations or summary figures, they seem to engage a larger audience on Twitter and social media. So personally I find it more appealing when I do see these summary figures. So if there is one recommendation, I would have the basic science researchers, especially trainees is in this age of social media, try to come up with an illustration or summary figure for your research. I think it helps you figure out what is truly important with the research that you've done and helps you communicate this research to a broader audience. And I've seen a lot of people take advantage of a graphic designers to really help them illustrate their research. And I found that to be very effective in articles I've read on social media.

Dr Amit Khera: Thanks Jeff. That's a great point and great suggestion. And certainly these days the most effective communicators are those they can translate their complex science into easily digestible bites and can think of ways to portray them in ways that sort of summarize, like you said, be it summary figures or otherwise. And it's a challenge and also talent. And you all are certainly perfecting that. Well, I think we've had an excellent conversation. I have to tell you, I'm so excited to get the chance to spotlight you all. You do excellent work each day. Every week you're working hard and coming up with great ideas and suggestions and we really value having your input as fellows and training and as a colleague.

Thank you for joining us today on our FIT podcast. Amit Khera standing in for Carolyn Lam. We look forward to seeing you for our next edition of Circulation on the Run. This program is copyright American Heart Association 2018.

Circulation December 18, 2018 Issue

17 december 2018 | 23 min

In today's feature discussion, we will be doing a deep dive into the LEADER trial results, looking at new results of liraglutide and its effects in patients with type two diabetes, with or without a history of myocardial infarction or stroke. All of that coming right up after these summaries.

In today's issue, five groups of investigators in two original basic research articles and three research letters tackled the same biological question, and all reached the same conclusion that cells in the heart expressing the SCA-1 cell surface antigen do not become cardiomyocytes to any meaningful degree, and instead become endothelial cells. Among the original basic papers, first author Dr Vagnozzi, corresponding author Dr Molkentin from Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, and their colleagues use the inducible recombinase method and generated a constitutive recombinase at the SCA-1 locus. They found that cardiac resident SCA-1 positive cells were not significant contributors to cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells generated cardiac vasculature throughout development, during aging, and following injury with trivial contribution to the cardiomyocyte population.

In the second paper from co-first authors, Drs Zhang and Sultana, with corresponding author Dr Cai from Indiana University School of Medicine and colleagues, these authors engineered a series of genetically altered mice to identify and track SCA-1 positive cells in the heart, and found that SCA-1 positive cells were purely of the endothelial lineage. Together with three research letters, these five papers add to the growing body of evidence that in adult mammals, our new cardiomyocytes arise from preexisting cardiomyocytes and rarely, if at all, from adult cardiac stem cells.

Could metformin be cardioprotective in patients with type one diabetes? Co-first authors Drs Bjornstad and Schafer, corresponding author Dr Nadeau from University of Colorado School of Medicine, and their colleagues hypothesized that adolescents with type one diabetes have impaired vascular function, and that metformin may improve insulin resistance and vascular dysfunction.

To test this hypothesis, they studied 48 adolescents with type one diabetes and 24 non-diabetic controls using MRI of the ascending and descending aorta, as well as assessment of carotid intima-medial thickness by ultrasound, brachial distance ability by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic euglycemic clamp. The adolescents with type one diabetes were randomized one as to one to three months of 2000 milligrams metformin or placebo daily, after which the baseline measures were repeated.

The authors detected early signs of cardiovascular disease with MRI in these adolescents with type one diabetes compared to controls. They further found that three months of metformin therapy improved insulin sensitivity as assessed by gold standard hyperinsulinemic euglycemic clamp, both in normal weight and obese adolescents with type one diabetes. Moreover, metformin improved carotid intima-medial thickness and aortic wall shear stress and stiffness. Thus, metformin may hold promise as a cardioprotective intervention in type one diabetes.

What are the clinical genetic and environmental determinants of varicose vein formation? Co-first authors Drs Fukaya and Flores, corresponding author Dr Leeper from Stanford University, and colleagues applied machine learning to agnostically search for risk factors of varicose veins in nearly half a million individuals in the UK bio bank. They found that greater height appeared as a novel predictor of varicose vein disease in machine learning analyses, and was independently associated in multi-variable adjusted Cox regression. Using Mendelian randomization, they demonstrated that greater height had a causal role in varicose vein development. A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development, and skeletal/limb biology, and discovering a strong genetic correlation between varicose veins and deep vein thrombosis. The knowledge greatly expands our understanding of disease pathophysiology, and may help future improvements in the management of varicose veins and their associated complications.

The final original paper describes the effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events, and all-cause mortality in patients with type two diabetes and chronic kidney disease. First and corresponding author Dr Mann from Friedrich Alexander University of Erlangen in Germany and their colleagues performed a post hoc analysis of the LEADER trial comparing the liraglutide's treatment effects in patients with and without kidney disease.

As a reminder, LEADER was designed to recruit a subgroup of at least 660 patients with an estimated glomerular filtration rate, or eGFR, less than 60, approximately 220 patients with severe renal impairment, eGFR less than 30, and at least 440 patients with moderate renal impairment with an eGFR of 30 to 60. The authors found that the liraglutide reduced the risk of major adverse cardiovascular events, and all-cause mortality compared with placebo in patients with chronic kidney disease defined as an eGFR less than 60, and also in patients with albuminuria defined as a urinary albumin to creatinine ratio above 30.

The overall risk of adverse events did not differ between the liraglutide and placebo treated patients either with or without chronic kidney disease in the LEADER trial. In summary, these results show that liraglutide added to standard of care reduced the risk of major cardiovascular events and all-cause mortality in patients with type two diabetes and chronic kidney disease. Furthermore, these results appear to apply across the chronic kidney disease spectrum that was enrolled.

And that brings us to the end of our summaries. Now for this week's feature discussion.

Cardiovascular outcome trials have transformed the world of treating patients with diabetes. And for our feature discussion today, we're going to be talking about a new analysis from a very important trial, the LEADER trial of GLP-1 receptor agonists, and that's the liraglutide. I'm very proud to have the corresponding author of this paper with us, Dr Subodh Verma, and he's from St Michael's Hospital and University of Toronto, and our senior associate editor, Dr Gabriel Steg, from University of Paris. Actually, Gabriel, I'm actually going to start with you for once because I recall perhaps something you may have written about cardiovascular outcome trials.

Dr Gabriel Steg: Yeah, it's really funny. I'll try to take it graciously. You know, I wrote a frame of reference in Circulation a few years ago, wondering whether we were doing good by doing all these large outcome trials for safety with new anti-diabetic drugs, because there had been not one but two, three, four, five, six trials that were essentially neutral, enrolling more than 107 patients and participants at the expense of millions of dollars, and not much came out of it. And this was published in circulation. I was very happy until the next trial comes up, and this is EMPA-REG. And the next one is LEADER. And we have two trials that literally transform our vision of anti-diabetic agents as major agents for cardiovascular prevention. The trial we're going to discuss today, which you wrote about, is one of these trials. And I think I have to revisit my own writings and probably eat my hat.

Dr Carolyn Lam: So indeed, that's a great segue. Thank you, Gabriel. And Subodh, tell us then, what did you look at this time in LEADER? And maybe start by saying a little bit about LEADER, and the rationale for doing this particular sub analysis.

Dr Subodh Verma: Right. So, as Dr Steg mentioned, these were FDA-mandated studies to look at safety and potential efficacy of newer antihyperglycemic agents. The entire premise was that cardiologists and cardiovascular specialists were not really getting that excited about antihyperglycemic therapies in people with diabetes, because there was no data that they did much. And as Dr Steg mentioned, even the data leading up to some of these trials were disappointing, suggesting that they're safe, but they neither reduce nor increase events.

So, I think EMPA-REG and LEADER really changed the calculus in many ways of how we look at cardiovascular risk reduction with antihyperglycemic agents. LEADER was a trial that was 9,340 patients. These are patients that were at high cardiovascular risk, but unlike EMPA-REG that only enrolled people with prior to ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a position of enriching the population with this spectrum of patients with cardiovascular disease and risk factors.

So, some were in so-called high risk primary prevention who had not had established ASCVD, but had multiple risk factors such as uncontrolled hypertension or chronic kidney disease. Some had evidence of ASCVD, but had not had a prior myocardial infarction. And some, in fact, had had a prior MI stroke or PAD. So, it was a broad population of patients that was enrolled. And the primary result, again, for the primary outcome of MACE, demonstrated a significant reduction in favor of liraglutide versus placebo. And then for the individual components of that primary outcome, they were all statistically significant, or at least went in the right direction. Importantly, CV death was reduced by 22% with liraglutide versus placebo.

I would like to emphasize that in this day and age, and Dr Steg has nicely set the stage, we have started thinking about how do we think about cardiovascular phenotypes of patients. You know, is a drug more likely to reduce heart failure? More likely to reduce ischemic events? And with LEADER, we found that in fact the trial actually reduced mostly ischemic events, and was really not that beneficial on heart failure related outcomes.

So, that was the broad positive outcome from LEADER. They've led to guideline changes worldwide that patients with diabetes should be prioritized to receive an agent that has shown benefit, particularly if they have cardiovascular disease. And one of those agents was empagliflozin. The other was liraglutide. But, secondary prevention is a pretty crowded space, and not everybody can get everything, and not everybody should get everything, and not everybody can afford everything. So, I think leaders like the two of you here are often thinking about, how do you risk-stratify these populations, and how do we start thinking about people who are at greater risk, people who can actually derive benefit? And I think that's the smart and thoughtful way of doing this. And is there a certain threshold at which point the therapy loses its ability to reduce cardiovascular events, at least in the short term?

So, in that theme, in that vein, what we looked at here was an analysis of people in LEADER who truly had a prior ischemic event. And the work that Dr Steg and others have done in REACH registries, etc. clearly establish that that's a population of patients, type two diabetes and a prior ischemic event. You don't really need many more calculators beyond that. That's the highest risk population. And then, the next level is really type two diabetes with a ASCVD. And we know that from REACH as well, that that's the next level of risk. And then, what about people who have type two diabetes just by itself? Which certainly are much higher risk than people who don't have diabetes, but we didn't have a non-diabetic group to compare to.

And what we find is that the higher the baseline risk defined by this, the greater is the absolute risk reduction. The P value is consistent for ... You know, this is non-significant for heterogeneity. but specifically, people with a prior ischemic event derive benefit. People without a prior ischemic event who've had ASCVD derive significant benefit. But, in fact, we found that the curves were almost superimposable for people who did not have prior ASCVD. And that's not to say the GLP-1 receptor agonists should not be used in diabetes in the absence of cardiovascular disease, because they're great glucose lowering agents. They cause hypoglycemia, they cause weight loss. And potentially, within longer exposure times, cardiovascular benefit may actually emerge. And we've heard data from Dr Gerstein's study called Rewind that is positive, that will be presented next year. Harmony Outcomes was a study that was presented recently that also showed a benefit. So, whether in the primary prevention group we see a benefit in the future remains to be seen.

Dr Carolyn Lam: Oh, that's a great, great summary. But Subodh, you know, it's become a bit of what do we define as a primary and secondary prevention anymore, you know? And the patient that already got type two diabetes. Now, in this paper, it's very nice. As you said, has a history of myocardial infarction and stroke. And maybe I could just clarify to the audience, you couldn't just pick up the primary paper and see that because the way the inclusion exclusion criteria were designed in LEADER, you can't just pick up the sub-groups. So, this specific analysis, so carefully and wonderfully done, was absolutely needed. But then you know, what do you think? What's primary and what's secondary prevention anymore?

Dr Gabriel Steg: Well, I want to commend the authors for doing the careful stratification of diabetic patients they've done in the paper, and particularly for pointing out that it's one thing to have had an event where you actually ruptured a plaque and had a traumatic event. And it's very different from merely having plaque in one of your carotids or your arteries, and which is, of course, in turn very different from the majority of diabetic patients who have neither an event, nor diagnosed plaque or established plaque. And when we think about preventing cardiovascular and diabetes, we have to remember that the outer circle, the broader circle of diabetic patients who haven't had disease is the largest component.

Dr Subodh Verma: True.

Dr Gabriel Steg: And these are the patients whom we treat every day with the hope of eventually keeping them from harm, safe from harm, or with therapies that are new and potentially beneficial. And I think your research very clearly shows that there's a gradient of benefit. The sicker the patient, the greater the benefit in preventing MACE. And as long as you get to more healthier phenotypes of diabetes, then there is less of a benefit. Which doesn't mean that we shouldn't use these agents. As you point out, they're very convenient and effective agents for glucose control. But then, their cardiovascular benefits are more uncertain. And I think this is the key message from this analysis, and it's a great analysis.

Dr Subodh Verma: Thank you. I appreciate that. I totally agree that for the doctor in the trenches, particularly the cardiologist who's just trying to get their feet wet with antihyperglycemic therapy, you know? Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at low dose, and maybe a new way of doing surgery or putting an LVAD. But it's very hard to get their attention when it comes to antihyperglycemic therapy. So, defining for them the population that matters the most, where the greatest risk and risk reduction can be achieved, I think is quite important from a clinical standpoint. And I think most cardiologists will agree that type two diabetes and a prior ischemic event is a high-risk population. Type two diabetes in a prior ASCVD is a high-risk population, and the magnitude of CV death reduction here is something meaningful for them to pay attention to.

Dr Carolyn Lam: Yeah, indeed. That's what I love best about this paper. It's actually asking the question the way a cardiologist would, exactly like you had both put. So, what do you think is the next step now? Do you think we need to look at this primary prevention type two diabetics with no established cardiovascular disease? Do we really need to? Is it that we need a method analysis, which you can talk about? Or, is it that we need longer follow up? Or, what next?

Dr Subodh Verma: I think that first of all, we have to get rid of the terminology, and maybe as a heart surgeon, I can be a little bit provocative and just say it. I wrote an editorial to the Declare Study that was just published yesterday in The Lancet called "Pumps, Pipes, and Filter: Do SGLT2 inhibitors cover it all?" Then I made a strong statement there that this nomenclature of primary and secondary really is artificial because it only captures ischemic risk, and does not capture risk of heart failure or renal disease. So, in a patient, as you've asked, Carolyn, who has type two diabetes, whose renal function is 54 or GFR is 55, who's not had a prior MI ... Is that patient primary prevention? Maybe from an ischemic standpoint, but he's clearly secondary prevention from a renal standpoint.

Dr Subodh Verma: So, I think we need to just think about all disease as a spectrum, and not as an artificial cutoff that, if you've had an ischemic event, suddenly the world changes for you there. Because, that gradient I think is probably what we need to somehow appreciate as to where that risk lies. The patient who's 40 who's had no risk factors, you know? The Rashami paper from the New England Journal that looks at risk factor control and diabetes make a very compelling story that if you control your five risk factors, you actually don't have an excess risk of cardiovascular events in diabetes, at least from MACE. The story is whether anybody can have those five risk factors controlled. But, early on in diabetes, with diabetes duration not being that significant, with risk factors not being that significant, I think maybe that's not the population to go after. But certainly, waiting for ASCVD to develop and then start therapy is also not the right way of doing it, so ...

Dr Carolyn Lam: Interesting. I really wonder what new guidelines are gonna show. Gabriel, any other perspective?

Dr Gabriel Steg: Well, first of all, I love the editorial. I thought the title was fantastic, and you summarize here what we need to think about when we think about diabetes; not solely the pipes. As an interventional cardiologist, I'm very interested in the pipes.

Dr Subodh Verma: Me, too.

Dr Gabriel Steg: Not solely the pump, but also the filter. And there's more than the heart and vessels in the complications of diabetes. So I thought it was a great, great title. My view is that we still need to remember that if we take the lifetime perspective, a healthy youngster with type one diabetes, a relatively healthy patient in his fifties with type two diabetes, their probability of dying from cardiovascular disease is enormous. Even though risk calculators will give them a relatively low probability over the 5 year or 10 year term, eventually that's what's gonna get them. And therefore, we still have progress to make. We are fortunate to have lived an incredible period in the past few years where we've had emergence of new risk preventive therapies in diabetes. That's incredible. It's an epiphany. But, it's not over. We need more information, more trials in other populations. We need to look at renal function and heart failure. So, it's a great time to be doing clinical trials in diabetes.

Dr Subodh Verma: Right.

Dr Carolyn Lam: And indeed, a great time to be publishing in circulation. We've been really doing a lot of publications in the cardiovascular outcome trials in diabetes here.

Dr Subodh Verma: And it's being noticed. There's no doubt about it.

Dr Carolyn Lam: I hope so. And, maybe a time for a new frame of reference, because what you just said was diametrically sort of in contrast.

Dr Subodh Verma: I would emphasize one more point, and that is, you know in atherosclerosis, the dominant mechanism has been LDL, right? And Dr Steg here is changing the landscape of that with Odyssey Outcomes and many other strategies. But again, in Circulation, Dr Bhatt, and I, along with the LEADER investigators, recently presented and published a paper showing that liraglutide's benefit is seen independent of LDL cholesterol, and all the way down to people with LDLs of below .5. So, the point is that this mechanism of benefit of GLP-1 seems to be complimentary to LDL lowering. And therefore, I think it offers great hope that you can actually reduce the ischemic burden in diabetes, not just by ultra-low LDL, but by potentially additional mechanisms as well.

Dr Carolyn Lam: Absolutely. And then now, because I have to have the last word here on this show, let's not forget heart failure outcomes in diabetes. I think it's underestimated. I think it's really important. Okay, and with that, thank you gentlemen for joining me today.

You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation December 11, 2018 issue

10 december 2018 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. What are the long-term effects of oxygen therapy in patients with suspected acute myocardial infarction? Well, to find out, stay tuned for our discussion of our feature paper this week, coming right up after these summaries.

The first two original papers demonstrate that, similar to neonatal mice, one day old and two-day old neonatal pigs are capable of mounting a cardiac regenerative response following myocardial infarction, which is characterized by restoration of contractile function, cardiomyocyte replenishment, and minimal fibrosis. Now, interestingly, this regenerative capacity is lost after the first two days of life.

The first paper is from co-corresponding authors, Drs Yeh and Cook from National Heart Research Institute of Singapore and National Heart Center, Singapore, and the second from co-corresponding, authors Drs Zhang and Zhu from the University of Alabama at Birmingham.

These authors report collectively that proliferation of preexisting cardiomyocytes appear to be the primary source of cardiomyocyte replenishment in neonatal pigs with markers of cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis elevated following injury in the one day and two-day old hearts, but not at later time points.

Furthermore, cardiomyocyte DNA synthesis was increased following neonatal pig myocardial infarction. Cardiomyocyte proliferation significantly decreased after this two-day window, which was associated with a marked reduction in telomerase activity.

Heart failure with preserved ejection fraction may look different in the young compared to that in the elderly. First author, Dr Jasper Tromp, corresponding author, myself, Carolyn Lam from the National Heart Center, Singapore and Duke National University of Singapore, and our colleagues from the Asian Heart Failure Registry studied more than 1,200 patients with HEF PEF from 11 Asian regions and found that 37% of our Asian HEF PEF population was under 65 years of age. Younger age was associated with male preponderance, a higher prevalence of obesity, and less renal impairment, atrial fibrillation, and hypertension. Left ventricular filling pressures and the prevalence of left ventricular hypertrophy was similar in the very young of less than 55 years and elderly HEF PEF of more than 75 years of age.

Compared to age matched controls from the community without heart failure, the very young HEF PEF patients had a three-fold higher death rate and twice the prevalence of left ventricular hypertrophy. Thus, young and very young patients with HEF PEF display similar adverse cardiac remodeling as their older counterparts, but very poor outcomes compared to controls without heart failure.

Obesity may be a major driver of HEF PEF in a high proportion of HEF PEF in the young and very young.

How important is hospitalization for heart failure as a complication of diabetes? In the next paper from first and corresponding author, Dr McAllister from University of Glasgow, the authors examined the incidents and case fatality of heart failure hospitalizations in the entire population age 30 years and older resident in Scotland during 2004 to 2013.

Over the 10-year period of study, among 3.25 million people, the coot incidence rates of heart failure hospitalization were 2.4 per thousand-person years for those without diabetes, 12.4 for those with type two diabetes, and 5.6 for those with type one diabetes. Heart failure incidents had fallen over time for people with and without diabetes, but remained around two times higher in people with diabetes than those without diabetes. Heart failure case fatality was higher in people with type one diabetes. Duration of diabetes and glycated hemoglobin was associated with increased risk of heart failure in type one and type two diabetes. Thus, clinicians should be aware of the importance of heart failure and diabetes, especially in type one diabetes where this is under appreciated.

What are epigenetic mechanisms contributing to ischemia reperfusion injury? Co-first authors Dr Yu, Yang, and Zhang, co-corresponding authors, Dr Xu from Nanjing Medical University, Dr Sun from Fudan University, and Dr Ge from Fudan University, and their colleagues evaluated the potential role of megakaryocytic leukemia one, or MKL 1, as a bridge linking epigenetic activation of NAD pH oxidases, or NOX, to reactive oxygen species production and cardiac ischemia reperfusion injury in mice. They found that genetic deletion of pharmaceutical inhibition of MKL 1 attenuated cardiac ischemia reperfusion injury in mice. MKL 1 levels were elevated in macrophages, but not in cardiomyocytes in vivo, following cardiac ischemia reperfusion injury.

MKL 1 recruited the histone acetyltransferase, MOF, to activate NOX transcription in macrophages. Pharmaceutical inhibition of MOF attenuated cardiac ischemia reperfusion injury in mice, and pharmaceutical inhibition of NOX one or four attenuated cardiac ischemia reperfusion injury as well.

These findings provide a novel link between MKL 1-mediated epigenetic regulation of gene expression in macrophages and ischemic heart disease. This opens the door to small molecule compounds targeting the MKL 1 MOF NOX access as a novel therapeutic strategy against ischemic heart disease.

Is the time from last hospitalization for heart failure to placement of a primary prevention ICD associated with patient outcomes? First and corresponding author Dr Ambrosy from the Permanente Medical Group in San Francisco performed a post hoc analysis of Medicare beneficiaries enrolled in the national Cardiovascular Data Registries implantable cardioverter defibrillator, or ICD registry, all with a known diagnosis of heart failure and an ejection fraction of less than 35%, undergoing a new ICD placement for primary prevention.

They found that older patients, currently or recently hospitalized for heart failure, undergoing initial ICD placement for primary prevention, experienced a higher rate of periprocedural complications and were at increased risk of death compared to those receiving an ICD without recent heart failure hospitalization. Additional prospective real world pragmatic comparative effectiveness studies should be conducted to define the optimal timing of ICD placement.

The final original paper presents result of the VERDICT trial, a large scale randomized controlled trial evaluating the value of very early invasive strategy conducted within 12 hours of diagnosis on long term clinical outcomes in patients with non-SD elevation acute coronary syndrome. First and corresponding author Dr Kofoed from University of Copenhagen and colleagues studied 2,147 patients who were randomized and found that an invasive strategy performed within 4.7 hours after diagnosis was not associated with improved outcomes, compared to an invasive strategy conducted within two to three days.

However, in the pre-specified subgroup of patients with a GRACE risk score of more than 140, a very early invasive treatment strategy did appear to improve outcomes, compared to a standard invasive treatment strategy. And that wraps it up for our summaries. Now, for our feature discussion.

For our feature discussion today, we are talking about oxygen therapy for patients with suspected acute myocardial infarction. Something that seems so benign, something we've taken for granted, and yet now we now question since the Detox AMI trial. Well, for today's feature paper, we have a follow-up of this trial, and I'm so pleased to have actually our associate editor, but also author of this paper, Dr Stefan James from Uppsala Clinical Research Center, and the guest editor for this paper, Dr David Morrow, who's from Brigham Women's Hospital and Harvard Medical School. So, thank you both for being here.

Stefan, could I just ask you to start by taking us back. How was Detox AMI first conceived? What made you even question oxygen therapy? And then, perhaps then, tell us about what this new paper adds.

Dr Stefan James: I think that's so interesting because I think we all learned in medical school that for myocardial infarction, you should always deliver oxygen. That's sort of the first choice. And the other sort of first choice that we learned was morphine. Some of the other important things that we learned was to give not only oxygen but morphine, and nitroglycerin, and perhaps aspirin. And by those four, only aspirin is really the agent that has been proven beneficial to patients.

But we thought for many years actually about this oxygen hypothesis, or we were interested in trying to understand, is it really helpful to give patients oxygen? Or are we in fact harming patients? Because there is, as you may know, there is a metanalysis performed long ago with small trials on the fibrinolysis era that showed actually a threefold increased risk of dying in those patients who had received oxygen in randomized various small trials, and their animal experience actually suggesting that oxygen is also hazardous. You don't think about that so often, but it's really an agent that constricts arteries, and so as the arteries close by a clot in myocardial infarction, there is no way the oxygen that you breathe in your nose can reach the suffering myocardium. It actually contracts the arteries, and may make the infarct larger than it would be otherwise.

Dr Carolyn Lam: I love that explanation. Alright, so what did you find in the current analysis of longer term results?

Dr Stefan James: So, we performed this, the main oxygen trial that we call Detox. We built it upon our national registries, and so we decided to include not only MI patients, but patients who were suspected of MI, in order to be able to enroll patients before the diagnosis was clear. We didn't want to wait for troponins, so we enrolled patients in the ambulances, in the emergency departments, in the cath labs, or in the wards, patients who had suspected myocardial infarction.

Most of them, eventually, did have myocardial infarction, but a proportion did not have myocardial infarction. They had other diseases that resembles MI and have breathing problems. And we selected the cut point of 90%. We said if they are below 90%, they're hypoxic, and it would be unethical to withdraw oxygen, if you were hypoxic. So, we sort of arbitrarily selected the cut point of 90%. And then, we randomized patients to receive oxygen or do not receive oxygen.

We considered to do double blind, but in order to do a double blind, you need to provide air on a mask. And air is not available in ambulances or in the emergency department. We cannot put a mask without anything in it because then it will feel more difficult to breathe. So, we had actually oxygen versus nothing, and we enrolled all patients coming to the cath labs, and emergency departments, and ambulances in Sweden. And thanks to the infrastructure that we have built on the national registries, we were able to enroll these to conduct this large trial, larger than any other trial, 6,600 patients.

In the main study, we found no benefit, and fortunately, no harm of providing oxygen for our primary end point, which was all caused death. But we realized that we were little bit underpowered actually to really clearly rule out that there was any benefit on the primary endpoints. And so, we said, we probably need a longer follow-up, and we probably also need other important measures such as heart failure. Because we thought that oxygen may, if it works, it may reduce the infarct size and may result in a lower risk of heart failure in the long-term. We don't believe that we will reduce the risk of re-MI because we're not interfering with atherosclerosis or plaque ruptures, but we may interfere with the development of heart failure.

So, in this particular paper, we said, longer follow up in order for patients to possibly develop heart failure and increase their risk of heart failure hospitalizations. So, in this paper, we used as a primary endpoint of this analysis, death or hospitalization for heart failure, post MI. And with this way of calculating events, we are more sure that we are not underpowered for this evaluation.

Dr Carolyn Lam: Right. And the results?

Dr Stefan James: The results were completely neutral. There was no benefit at all in any sub group. It doesn't matter if you were ST elevation MI, or no ST elevation MI, or no MI, or high risk prior MI, prior heart failure, respiratory disease, there is no benefits and no harm, which is good. And those results are supported by our findings on troponin levels. So, we checked troponins repeatedly. I shouldn't say top troponin, but the highest measured, we did not find any difference between the two groups in Troponin elevations. And we did not find any difference in LVEF and in Echo performed during the initial hospitalization.

So, I think both of those results support the primary endpoint of death and repeat hospitalization for heart failure.

Dr Carolyn Lam: So David, you've thought a lot about this, and also framed it so nicely when we were just talking a little bit earlier. What do you think is the real significance of this paper on so many levels?

Dr David Morrow: Yeah, I think there are many levels. I think it's such important work because it takes something that we are still doing in many hospitals every day for patients and is difficult to study because it's become part of standard of care, as Dr James pointed out, and so the authors are to be congratulated for being able to study this intervention. And I think in additionally because it is a therapy that's not associated with high cost, has been part of our care for so long, it's not one where there is the support for a large type of randomized trials. So, the ability to perform this with relatively low costs by nesting it in a registry is important, not only for this particular test, but also as a model for future research of so many interventions that we make right now where they started in a time where our threshold for a need for data was much less.

Dr Carolyn Lam: Yeah. Indeed. That's wonderfully put. I am also really struck. It's the importance of the message, but also especially about how you do a pragmatic registry-based randomized trial. The ability of Sweden to do this, it's just rock the world, right? Because we really need solutions like that for our clinical trial world, which has to be sustainable somehow. Could you maybe take us behind the scenes a little bit? I mean you did already in your description. I didn't realize there were so many considerations when you're planning this, but how easy or difficult is it to do a trial like this?

Dr Stefan James: We call the entity RRCT. We call it registry based randomized trial, but being aware that there is no strict definition of what is a registry based randomized trial. So, sometimes for some simple interventions like strategies, we can use only the registry for collection of baseline variables, procedure variables, and also outcomes. The registry can really do everything. The only thing we need to add is a randomization, so then we just program into the registry, which is used live in front of the patients.

So, when I enter a patient in the registry, the personal identification number collects me to the population registry that supports directly back to me name and gender of the patient, and then I enter all the baseline characteristics anyway in the registry. And then, there is a question that comes up that screens my patients. So, the system proposes to me to randomize patients who are eligible because I programmed the inclusion/exclusion criteria. So, it proposes to every doctor in the country, this is a patient that is eligible potentially for this trial and just click randomize, and that's the trial. Everything is completed by that. No extra tests, no visits, no follow up, no telephone calls.

That's the basic, very simple format that can only be used for a strategy, like a device or a strategy. But many of the questions we have in medicine are really regarding strategies. How long should you treat? How often do you need to come back? Sort of strategies. Then, when we've tried to expand this to pharmaceutical agents, and oxygen was the first pharmaceutical agent that we wanted to try. You may not consider oxygen as a pharmaceutical agent, but it is in fact. But it's not manufactured by any companies, and we are still, in this trial, wanted to keep all-cause mortality as the primary end point because that's very reliable. That's indisputable, and in our country it's absolutely 100% correct. If they registered dead, they are dead. There's no question.

The next level we did in the validate was a true pharmaceutical agent manufactured by a company, [byobatterin seprin 00:18:31]. A little bit more complex because you need to be careful about making sure that the patients are receiving the pharmaceutical agent in the right manner, in the right time point. We need to be a little bit careful about collection of side effects, and complications, and so on, but it also worked very well in that trial. If they validated, we did actually adjudicate events because in the primary end point we had it where it was more complex primary endpoint, including myocardial infarction. If you include myocardial infarction or bleeding events, that needs to be defined in a certain way according to protocol. You need to adjudicate. If you really need to rely on the outcome assessment.

We're not trying to take this type of study to the next level, to use it for typical oral pharmaceutical agents. Our largest trial now running is the spirit HFPF lactone versus no treatment in patients with HFPF. And again, this is a pharmaceutical agent that is a very inexpensive. There's no company that would sponsor such a trial, but we think it's a really important question. There's so many patients that suffer from HFPF, and in order to do that trial, it has to be simple and inexpensive.

So, that's running. We hope to be successful. There are, of course, many challenges. Like any other trial, it's difficult to write a protocol. You have to be very dedicated and detailed for any trial. So backstage, this is not easier than any other trial, but for the investigator, it is much easier. That's the reason we have succeeded to reach out to every hospital in the country, and every physician seeing these patients are investigators. And many of them have never done any trials before. They have no experience with research, but still they should be able to randomize and do the trials because it seems to be so easy for them and for the patients. That's the whole idea.

Dr Carolyn Lam: Yeah. I'm just enamored by the whole concept, and of course, a lot of people I think are wishing that we could institute that in all countries as well. Trust me, a lot of conversation has occurred about that in Singapore, for example, where population based capture is possible. But, as you said, it's not that easy. It's got to be well thought out. Protocols still have to well thought out. Investigators still need to be trained, and so on.

Dr Stefan James: We want the investigators to feel that it's easy, that it's attractive to participate. Not for money, just because it's so easy and so interesting to be part of such an experiment.

Dr David Morrow: I think testing some of those therapies that are commonplace that they're used to, and our nature of practice is this is the perfect type of setting than more complicated interventions where you may need to train the investigators more in order how to implement to them, and apply the therapy correctly. That's the new trend, is ... I think the key issue is that in order to reliably test things where mortality is not the acceptable outcome that you could power adequately for, it's really the endpoint collection in the safety collection, and because of the robust medical record systems you have, you're able to do that. And we're so far from being able to do that reliably in the United States right now that it's not possible to do that. Unless we have specific well-constructed registries, which we do in some areas. I think we're learning, and hopefully we'll get there, but we're far behind [crosstalk 00:21:55].

Dr Stefan James: [crosstalk 00:21:55] Yeah, but even-

Dr David Morrow: [crosstalk 00:21:57] Nationals-

Dr Stefan James: Even if you're not able to do a registry based, I think we all should consider in all trials to do it as easy as possible and really try to ask ourselves, what is the most important reason we're doing this trial? Sometimes we need to collect a lot of extra information because we need to understand the mechanisms or the side effects. If that's the case, I don't think at this trial methodology is not suitable. You shouldn't perform it that way. It needs to be the more traditional, more conservative, more expensive and burdensome way, but for many therapies, a more simple approach, more pragmatic approach is preferable.

Dr Carolyn Lam: Well, thanks again for diving into that because it gives us a real, to me at least, even greater appreciation for this paper when you understand the amount of work that's gone into it. But may I just end by saying, what do you think is the take home message for clinicians now? David, for example, you started by saying everyone's still doing it? I fully agree.

Dr David Morrow: Yeah. I think it's a very simple message, and that we know that oxygen is not effective in patients who have an oxygen saturation above 90%. And there's really no rationale to use it.

Dr Carolyn Lam: Perfect. Has this been put in practice in Sweden already?

Dr Stefan James: It has been. One of the virtues of running these registries is that we can also check the adherence to the results, so we can check that this is not used anymore.

Dr David Morrow: And since the investigators are your entire country, they all learned actually from participation in these trials.

Dr Stefan James: Exactly. Exactly.

Dr David Morrow: There's more of an investment in it already.

Dr Carolyn Lam: That's amazing. So, thank you again for sharing. Thank you for publishing this in circulation and for helping us to do that.

You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation December 4, 2018 Issue

3 december 2018 | 25 min

Our featured paper this week reports the five-year clinical outcomes and valve durability in the largest available cohort to date of consecutive high-risk patients undergoing transcatheter aortic valve replacement. You must listen up for this discussion, coming right up after these summaries.

The first original paper describes a personalized risk assessment platform that promotes the implementation of precision medicine by helping us with the evaluation of a genomic variant of uncertain significance. A genomic variant of uncertain significance is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded and thus cannot be definitively annotated. These variants therefore pose critical challenges to the clinical interpretation and risk assessment. New methods are therefore urgently needed to better characterize their pathogenicity.

Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author Dr Wu from Stanford University School of Medicine and colleagues recruited a healthy, asymptomatic individual lacking cardiac disease clinical history and carrying hypertrophic cardiomyopathy associated genetic variant in the sarcomeric gene, MYL3, which has been reported by ClinVar database to be likely pathogenic.

Human-induced pluripotent stem cells or IPSCs were derived from the heterozygous carrier, and their genome was edited using CRISPR/Cas9 genome editing to generate karyo-specific IPSCs. Extensive essays, including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic IPSC-derived cardiomyocytes, and together, the platform was shown to elucidate both benign and pathogenic hypertrophic cardiomyopathy-functional phenotypes.

Thus, this paper demonstrates for the first time the unique potential of combining IPSC-based disease modeling and CRISPR/Cas9 genome editing technology as a personalized risk assessment platform for determining the pathogenicity of a variant of unknown significance for hypertrophic cardiomyopathy in a patient-specific manner.

Transcatheter aortic valve replacement is increasingly being used for the treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement. The next paper provides real world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated transcatheter vs. surgical aortic valve replacement.

Co-first and corresponding others, Dr Werner and Zahn from Clinical Ludwigshafen in Germany compared clinical characteristics and outcomes of more than 7,600 patients with intermediate surgical risk who underwent isolated transcatheter or conventional surgical aortic valve replacement within the prospective all-comers, German aortic valve registry between 2012 and 2014.

Multi-variable analyses reveal that factors that were associated with performing transcatheter instead of surgical aortic valve replacement included advanced age, coronary artery disease, New York Heart Association class three or four, pulmonary hypertension, prior cardiac decompensation, and elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area.

Unadjusted in-hospital mortality rates were equal for transcatheter and surgical aortic valve replacement, whereas unadjusted one-year mortality was significantly higher in patients with transcatheter aortic valve replacement. After propensity score matching, the difference in one-year mortality was no longer significant. Thus, this large registry analysis suggests that both transcatheter and surgical aortic valve replacement are reasonable treatment options in a real world population with aortic stenosis and intermediate surgical risk.

The next paper demonstrates a key role of vascular endothelial growth factor receptor 1 in hemorrhagic telangiectasia type 2. Now, this is an inherited genetic disorder where haplo-insufficiency of the activin receptor-like kinase 1 gene, ACVRL1, results in blood vessels that are prone to respond to angiogenic stimuli, leading to the development of telangiectatic lesions that can bleed.

First author, Dr Thalgott, corresponding author, Dr Lebrin from Leiden University Medical Center and colleagues used ACVRL mutant mice and found that vascular endothelial growth factor, or VEGF receptor 1 levels were reduced, causing increased VEGF receptor 2 signaling that promoted sprouting angiogenesis, correcting the abnormal VEGF gradient, by expressing membranal-soluble VEGF receptor 1 in embryonic stem cells or blocking VEGF receptor 2 with antibodies in mutant mice, normalized the phenotype both in vitro and in vivo.

Importantly, VEGF receptor 1 was reduced in the blood and skin blood vessels of patients with hemorrhagic telangiectasia type 2 compared with H match controls, demonstrating an important role of VEGF receptor 1 in these patients and explaining why their blood vessels might respond abnormally to angiogenic signals. These findings support the use of anti-VEGF therapy in hemorrhagic telangiectasia type 2.

The next study suggests that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease following acute rheumatic fever. First author, Dr Kim, corresponding author, Dr Wicks from Walter and Eliza Hall Institute of Medical Research and University of Melbourne and their colleagues analyzed the immune response to group A streptococcus in peripheral blood mononuclear cells from an Australian Aboriginal acute rheumatic fever cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing.

They then tested the widely used immunomodulatory drug, hydroxychloroquine for its effects on this response. They found that group A streptococcus activated persistent IL-1 beta production and selective expansion of a specific group of T helper 1 cells that produce GMCSF. Furthermore, hydroxychloroquine limited the expansion of these group A streptococcus-activated, GMCSF-producing T helper cells in vitro.

Gene transcriptional profiling of peripheral blood mononuclear cells from patients with acute rheumatic fever showed dynamic changes at different stages of disease. Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis where GMCSF plays a pivotal role, the authors therefore proposed that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart fever following acute rheumatic fever.

The next paper identifies a new anchoring B genetic variant in unrelated Han Chinese probands with ventricular tachycardia. In this paper from co-first authors, Dr Zhu, Wang and Hu, co-corresponding authors, Dr Hong from Second Affiliated Hospital of Nanjing University, Dr Mohler from Ohio State University Wexner Medical Center and colleagues, the authors identified the first anchoring B variant, Q1283H, localized to the ZU5C region in a proband with recurrent ventricular tachycardia.

Knocking mice with this variant showed an increased susceptibility to arrhythmias associated with abnormal calcium dynamics. The variant was associated with loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed after depolarization-mediated trigger activity, and arrhythmogenesis. Furthermore, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias, representing potential therapies for anchoring B variant-associated arrhythmias.

Does variability in metabolic parameters affect health outcomes? First author, Dr Kim, corresponding author, Dr Lee from Seoul Saint Mary's Hospital College of Medicine and Catholic University of Korea and their colleagues used nationally representative data from the Korean National Health Insurance system, consisting of more than 6.7 million people who are free of diabetes, hypertension, or dyslipidemia and who underwent three or more health examinations from 2005 to 2012 and were followed to the end of 2015.

Variability and fasting blood glucose and total cholesterol, systolic blood pressure and body mass index was measured using the coefficient of variation, standard of deviation, variability independent of the mean, and average real variability. They found that a high variability in fasting glucose and cholesterol, systolic blood pressure and body mass index was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Variabilities in several metabolic parameters had additive associations with the risk of mortality and cardiovascular outcomes in the general population.

These findings suggest that treatment strategies to reduce fluctuations in metabolic parameters may be considered another goal to prevent adverse health outcomes.

How much exercise over a lifetime is necessary to preserve efficient ventricular arterial coupling? First author Dr Hieda, corresponding author Dr Levine from Texas Health Presbyterian Hospital Dallas and University of Texas Southwestern Medical Center and colleagues studied 102 seniors and grouped them based on their 25 years of exercise training history. The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure and stroke volume index.

They found that there was a graded dose-dependent improvement in ventricular arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Their data suggested that the optimal does of lifelong endurance exercise to preserve ventricular arterial coupling with age appeared to be at least four to five sessions per week. The sufficient lifelong endurance exercise was effective for maintaining the normal dynamic Starling mechanism, left ventricular compliance, and arterial compliance with aging, all of which may lead to favorable effect on cardiovascular stiffness or function.

And that brings us to the end of our summaries this week. Now, for our feature discussion.

Transcatheter aortic valve replacement is taking over the interventional world. It's really rapidly growing, and we're increasingly using it for the treatment of aortic stenosis. It was initially used for inoperable and high-risk patients but now is indicated even in the treatment of intermediate-risk patient, and even low-risk patients are being enrolled into current trials.

So, with TAVR being used for low- and intermediate-risk patients, the longer-term results of this treatment involved your abilities becoming more and more important. Well, gratefully, we have today's feature paper, and it describes the five-year clinical outcomes and valve durability of the FRANCE-2 Registry.

I'm so pleased to have with us the corresponding author, Dr Martine Gilard from University Hospital of Brest in France, we have our editorialist, Dr Anita Asgar from Montreal Heart Institute, and we have our associate editor, Dr Dharam Kumbhani from UT Southwestern.

Martine, congratulations on this largest cohort of high-risk patients and long-term outcomes. Could you please tell us what you found?

Dr Martine Gilard: Yes, and I'll just quote, actually, to have a follow-up of five years. We have 1,200 patients arrive at five years after rotation of TAVI. Each patient was a high-risk patient because it was at the beginning of each treatment, and in this time, it's only the high-risk patient was implanted with TAVI, and actually, we can follow this 1,200 patients, 50% of these patients of these patients have an echography because when we analyze these patients, we have an echography at five years, and the patients who have not echography at five years, the only difference is the age.

It's very old patient. It's very difficult to make this echography on this patient to come back in our center, so it's why there is not all the patient who have an echography at five years.

But our patients who have an echography, we can see that it's a very, very good result at five years. There is always the same area, just after before, of the valve. There is the same gradient. There is not a sign of deterioration.

As you know, we have some guidelines published last year about how we asked to define deterioration of the valve, surgical or TAVI, and if we apply this new recommendation, we saw that in this largest cohort, at five years, there is only 13% of patient who have some sign of deterioration, and of these patients, we never need to make another valve in valve because the deterioration was not so important, and patient leave with this valve like that. There is no necessity to make a new valve in valve, so at five years of this very high-risk patient treated by TAVI, there is no necessity to implant a second valve because the valve deterioration. It's a very, very important message.

Dr Carolyn Lam: Thank you, Martine. Indeed, an important message. And Anita, you wrote a beautiful editorial about it. First, could I ask you to frame the issue? I mean, is there any reason we would expect the durability to be any different from a surgical replacement?

Dr Anita Asgar: I think that's a great question, Carolyn, and I congratulate again Martine and her team for doing a fantastic job to add some very important results to the clinical literature on TAVI. Five years is relatively early to see structural valve deterioration, so in a sense, it's not surprising, and we would consider this sort of medium-term follow-up rather than really long-term durability, but very reassuring that in a high-risk population of patients, that TAVR performs very well in this population of patients and as mentioned, is very low to the dynamic structural valve deterioration.

One question I have for Martine is, as you mentioned, there was only about 12% that had some evidence of structural valve deterioration hemodynamically, but this didn't result in another procedure, and I wonder if you could explain a little bit about that, whether it's the hemodynamic dynamic value, and yet there's a clinical indication for re-intervention. How do you incorporate the two?

Dr Martine Gilard: It's actually hemodynamic deterioration, there is some form of regurgitation. However, there is no need or clinical indication to make another intervention. So, if you compare this research to the bioprostheses surgical paths, the only one who have, at five years, no need to make a re-intervention appearing rotated, which is a valve, a surgical valve we have a longer bioprostheses surgical path.

So, if we compare this best bioprostheses surgical valve, we have sustained results at five years. At five years, we have no need to make a re-intervention because the deterioration was not so important or as needed for clinical evidence as a need to make a new intervention.

Dr Anita Asgar: So, there were some increased rates of heart failure in those patients with structural valve deterioration in your paper, and I know that in the paper you did mention that this is not an adjudicated outcome, and there wasn't a VARC definition for heart failure, but what's your interpretation of increasing heart failure events in these patients with structural valve deterioration?

Dr Martine Gilard: We have no real definition about that. We know that there is another registry. We say that there is an increasing of heart failure, and during the follow-up, and the result of this heart failure increase in mortality. There is an increasing of heart failure, but the number of these patients, there is more. So I don't know if this due to because patient is a high-risk patient, or it's because of the TAVI, but it's very difficult actually to have a real explanation about that.

Dr Carolyn Lam: Thanks, Anita and Martin. Dharam, could you share some of the thoughts and the discussions that were going on behind the scenes with the editors when we saw this paper?

Dr Dharam Kumbhani: Professor Gilard, this was a really excellent paper. We really appreciated you sending it to us, and I think for us, the fact that this was a very large cohort, the largest published cohort that has gotten to five years in a TAVR population, in a multicenter study, and having very good follow-up up to five years, with these patients is always this competing hazard that you want to know what the valve is doing at five years from an echocardiographic and hemodynamic perspective, but there's such a high competing hazard of death, just given the population that you're enrolling, and still, you had one of the largest echo follow-ups on these patients, so we want to congratulate you on the study and really a monumental endeavor, and so really great, great work there.

And I think this is, exactly some of the questions that I think we had and I'm sure that the audience would have as well, I guess the one other question I have, and it's not really a question about your paper. So the median Euro score is 21 in this study, approximately 21, so that's obviously gonna, consistent with the patients that are being enrolled at that time between 2007 and 2012, which were predominantly high-risk and inoperable patients. Can you talk to us a little bit about the landscape of, how is TAVR practice in France as a society or from the regulatory standpoint, what are the benchmarks that you have achieve as you move towards low-risk now? Because intermediate-risk, I'm assuming is a [inaudible 00:20:16], so could you talk to us a little bit about the landscape there?

Dr Martine Gilard: Yes. In France, it's difficult because we have the authority to follow, not immediately, the ESC recommendations, so actually in France, we are allowed to implant only patients with high risk, patients with complication of surgery, and actually just since one year, patients with automatic risk, but we have no authorization to implant patient with low risk.

However, the most important fact is the heart team, and if they write. Because we need to have something written, and if they write, if they explain that it's necessary to implant a patient at low risk because of some point while not including the risk score or it's very difficult to explain, for example, frailty or something, we can implant a patient with low risk.

But normally actually, it is only for complication or high risk and for intermediate risk like the recommendation of the ESC.

So the rate of implantation in France increased because we implant only 2,000 people per year, but actually, in 2017, we have implanted 10,200 patient, and this year, we think that we implant 12,800 patients, so as the number of patients increase, the number of patients who have a very high risk decrease because there is a futile indication, and we have a lot of futile indication, so we doesn't implant patient while too high-risk, and we select the most majority of patient implanted in France was high-risk but also intermediate-risk.

Dr Dharam Kumbhani: So, you think you're implanting more intermediate, like that is a bigger population that is getting TAVIs right now in France?

Dr Martine Gilard: Yes, exactly.

Dr Carolyn Lam: How about perspectives from Montreal? What do you think the implications of this findings from today's paper in relation to the types of patients that you might perform this in now?

Dr Anita Asgar: For us, this is exceptionally reassuring, and as Martine has said, I mean, we have transitioned as well away from that very inoperable cohort C type of patient to more your higher-risk patient or intermediate, and to be honest, everyone over the age of 80 in Canada essentially is getting a TAVR.

Dr Carolyn Lam: Oh, wow.

Dr Anita Asgar: Because regardless of their risk, and we've been very aggressive with that because trying to get patients back to an appropriate quality of life is very important, and to seeing this very reassuring data is telling us that, as she has already mentioned, we have reached the standard, at least in midterm follow-up as the gold standard of surgical valve replacement, and so structural valve deterioration is not as big a concern.

I think we still however need longer-term data when we're looking at lower-risk patients, and lower-risk patients, let's remember, are not 60-year-olds. They're the 75-year-old, perhaps. But we're still gonna need some more data, but it's very reassuring, and patients are asking for it and are really advocating on their behalf to have a less invasive approach, and I think we can say now with more certainty that we know after five years, your chance of structural valve deterioration is actually quite low, and so I think that's very helpful from our point of view.

Dr Carolyn Lam: I love that, Anita, and it's so consistent with the title of your editorial, "Closing in on the Finish Line". Love it, love it, and recommend all listeners pick it up and have a good read. Dharam, I want to leave the last words to you. What do you think are the implications of this paper?

Dr Dharam Kumbhani: Well, I think that, as Anita said, this is very encouraging results that, in this kind of extreme and high-risk patient cohort, that there appear to be no medium- to long-term signals of structural valve degeneration, that the biggest hazard from this procedure is all upfront, and after that, it's pretty much, it's as we have seen with surgery, that after that, the actuarial rates come back to what you would expect.

If they didn't have aortic stenosis and then they would die from whatever causes they had. Now obviously, that wasn't tested, but it seems like looking at the curves, that that seems like what's going on, so I think they've done a great service to our TAVR community in terms of showing us these results in very large, multicenter cohorts from France.

Dr Carolyn Lam: Thank you so much for joining us today. Thank you, listeners. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation November 27, 2018

26 november 2018 | 22 min

Dr Carolyn Lam: Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. We will be discussing accelerated diagnostic protocols for chest pain, a very, very important issue in Cardiology with very important new safety and effectiveness data on one such protocol provided in our feature paper this week. Coming right up after these summaries.

Our first original paper this week identifies a new link between specific gut bacteria and atherosclerosis. Co-First authors, Dr Yoshida and Emoto, corresponding author, Dr Yamashita, from Kobe University Graduate School of Medicine, and colleagues recruited patients with coronary artery disease and controls without coronary artery disease but with coronary risk factors. They then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples. Subsequently, they used atherosclerosis prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Their analysis of gut microbial profile in patients with coronary artery disease showed a relative depletion of bacteroides vulgatus and bacteroides dorei compared to controls with coronary risk factors. Gavage with live bacteroides vulgatus and bacteroides dorei decreased fecal and plasma lipopolysaccharide levels and protected against atherosclerosis in apoE deficient mice. Fecal lipopolysaccharide levels in patients with coronary artery disease were significantly higher compared to controls. These findings suggest that bacteroides treatment may serve as a novel and effective therapeutic strategy for suppressing lipopolysaccharide-induced inflammatory response in coronary artery disease.

The next paper identified a potential novel molecular target in the treatment of myocarditis. Co-First authors, Dr Chen and Zeng, Co-Corresponding authors, Dr Song from Fuwai Hospital in Beijing, and Dr Yang from Shenzhen University School of Medicine, and their colleagues aim to elucidate the role of BCL2 Like protein 12 in the pathogenesis of biased T Helper-2 response in myocarditis. Using a combination of mouse models of myocardial inflammation and human hearts from patients undergoing heart transplantation, the authors found that CD4 positive T-cells isolated from hearts in myocarditis at the end stage of heart failure expressed high levels of BCL2 Like protein 12, which was required for the development of aberrant T Helper 2 polarization in the heart. Thus, BCL2 Like protein 12 may be a novel target in the treatment of myocarditis, as well as other T Helper 2 biased inflammatory processes.

Could vaccination against LDL be a way to prevent atherosclerosis? Well, the next paper brings us one step closer to this dream. First author, Dr Gisterå, corresponding author, Dr Hansson from Karolinska School University Hospital and colleagues developed T-cell receptor transgenic mice to study LDL autoimmunity in a humanized hypercholesterolemic mouse model of atherosclerosis. A strong T-cell dependent E-cell response was induced by ODL leading to production of anti-LDL IgG antibodies that enhanced LDL clearance and ameliorated atherosclerosis. Results show that anti-LDL immuno-reactivity evoked three atheroprotective mechanisms, namely 1) antibody-dependent LDL clearance, 2) increased cholesterol excretion, and 3) reduced vascular inflammation, thus targeting LDL-reactive T cells may enhance atheroprotective immunity, and vaccination against LDL components may be an attractive way to prevent atherosclerosis.

MicroRNAs regulate nearly all biological pathways and dysregulation of MicroRNAs is known to lead to disease progression. However, are there cell type specific effects of MicroRNAs in the heart? Co-First authors, Drs Rogg and Abplanalp, corresponding author, Dr Dimmeler from Goethe University Frankfurt, and colleagues assessed MicroRNA target regulation using MicroRNA 92a3p as an example. Their data showed that MicroRNAs have cell type specific effects in vivo which would be overlooked in bulk RNA sequencing. Analysis of MicroRNA targets in cell subsets disclosed a novel function of MicroRNA 92a3p in endothelial cell autophagy and cardiomyocyte metabolism. These findings may have clinical applications for the fine tuning of autophagy and metabolism to mitigate tissue damage in patients with cardiac disease.

The next paper establishes a mechanism by which cardiac inflammation may be initiated in response to hemodynamic stress, but in the absence of significant cardiomyocyte cell death. Co-First authors, Drs Suetomi and Willeford, Co-Corresponding authors, Drs Brown and Miyamoto from University of California San Diego, and their colleagues used conditional cardiomyocyte-specific calcium calmodulin-regulated kinase Delta all CaM kinase II Delta knockout mice to demonstrate that cardiomyocytes generate inflammatory chemokines and cytokines and are the initial site of NLRP3 inflammasome activation. They further identified a causal role for CaM-Kinase II Delta-mediated activation of NLRP3 inflammasome and inflammatory responses in macrophage recruitment, cardiac fibrosis, and development of heart failure induced by pressure overload. Their elegant mouse experiments revealed sites and mechanisms of proinflammatory gene and inflammasome activation within cardiomyocytes which could serve as targets for early intervention or disease prevention.

Are there different metabolomic effects between PCSK9 inhibitors and statins? First author, Dr Sliz, Corresponding Author, Dr Würtz from Nightingale Health Limited in Helsinki, Finland, and their colleagues quantify 228 circulating metabolic measures by Nuclear Magnetic Resonance Spectroscopy for over 5300 individuals in the PROSPER Trial at six months post randomization. The corresponding metabolic measures were also analyzed in eight population cohorts, including more than 72,000 individuals using a specific PCSK9 inhibitor SNP as an unfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Scaled to an equivalent lowering of LDL cholesterol the effects of genetic inhibition of PCSK9 on these 228 metabolic markers were generally consistent with those of statin therapy. Alterations of lipoprotein lipid composition and fatty acid distributions were also similar. However, discrepancies were observed for very low-density lipoprotein or VLDL lipid measures where genetic inhibition of PCSK9 had weaker effects on lowering VLDL cholesterol compared with statin therapy. Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation, where a statin treatment weekly lowered this marker of inflammation. Thus, if VLDL lipids have an independent causal effect on cardiovascular disease risk, the observed discrepancy on VLDL lipid lowering could contribute to differences in cardiovascular risk reduction between statins and PCSK9 inhibitors for an equivalent reduction in LDL cholesterol. Moreover, these results exemplify the utility of large-scale metabolomic profiling with genetics and randomized trial data to uncover potential molecular differences between related therapeutics.

The final original paper this week demonstrates a novel biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases. Co-First authors, Dr Mosley and Benson, co-corresponding authors, Dr Wang from Vanderbilt University Medical Center and Gerszten from Beth Israel Deaconess Medical Center, and their colleagues employed a virtual proteomic approach linking genetically-predicted protein levels to clinical diagnosis in more than 40,000 individuals. They used genome-wide association data from the Framingham Heart Study to construct genetic predictors for more than 1100 plasma protein levels. They validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in more than 41,000 genotyped individuals in the eMerge Cohort. They tested associations for each predicted protein with more than 1100 clinical phenotypes. These associations were validated using directly-measured protein levels and either LDL cholesterol or subclinical atherosclerosis in the Malmo Diet and Cancer study. Using this virtual biomarker strategy the authors identified CLC1B and PDGFR Beta as potential circulating biomarkers of atherosclerosis and validated them in an epidemiologic cohort. Thus, these results demonstrate that a virtual biomarker study may efficiently identify potential biomarker disease associations, and that wraps it up for our summaries. Now for our feature discussion.

Accelerated diagnostic protocols for testing are used everywhere. They're designed to improve the quality and value of chest pain risk stratification. However, many of them lack sufficient prospective safety and effectiveness data. We're so pleased to have a paper today that provides such important data on one of these accelerated diagnostic protocols for chest pain, and it's the HEART Pathway. To discuss this, I've got the corresponding author of today's featured paper, Dr Simon Mahler from Wake Forest School of Medicine, as well as our Associate Editor, Dr Deb Diercks from UT Southwestern. Simon, could you start by just telling us, what is the HEART Pathway?

Dr Simon Mahler: Sure. Yeah, it's an accelerated diagnostic protocol. It's based on an accelerated diagnostic protocol called the HEART Score. We use a modified version of the Heart Score. We actually use a HEAR score, and that stands for the history, EKG, Age, and risk factors. That is combined with two troponin measures at 0 and 3 hours. We also factor in whether or not the patient has had prior coronary artery disease or has an acute ischemic EKG. So, to be low-risk you have to have a HEAR score of 0-3. HEAR is an acronym. You get points for each of those categories. If you have less than 3 points that's a low score. You have to have a low score, a non-ischemic EKG, no history of prior coronary disease, and two troponins less than a 99th percentile at 0 and 3 hours to be considered low risk and recommended for early discharge. If you don't meet any of those criteria then you are considered non-low risk and appropriate for further in-hospital evaluation.

Dr Carolyn Lam: That's great. Could you just tell us what you did to give us some real-world safety and effectiveness data on this.

Dr Simon Mahler: Yeah, so we had done a single-site randomized controlled trial. That was published in 2015 in Circulation: Quality and Outcomes, and really showed some promising results. We received some funding to do an implementation trial. So, this is the results of our implementation study. It's a before and after study. What we did was we sought to implement a HEART Pathway as a clinical decision support tool, integrated fully into our electronic medical record so that when providers see the patient with chest pain and order a troponin they interact with a HEART Pathway tool that guides them through the HEART Pathway risk assessment and then provides real-time decision support regarding their treatment and disposition decisions based on whether or not the patient has a low-risk assessment or a non-low-risk assessment. The design of the study was we collected data on all patients with chest pain and troponin order for one year while we worked on how we were gonna build this tool and embed it, and then we had three month watching period where we built the tool into the electronic health record across our three sites. Then, we had one year where we were post implementation where we collected data and looking at the difference in outcomes, particularly looking at both safety and utilization outcomes before and after use of the HEART Pathway.

Dr Carolyn Lam: That's just such a clever design. Just give us a summary of the results before I ask Deb to chime in here.

Dr Simon Mahler: There's a few really important things that we found. Probably the most important thing was the safety data that came out of this study. We had some good safety signals on prior studies. They didn't have enough sample size to really have a good precision around the safety point estimate, so in this study we had over 4000 patients in our post-implementation cohort, and about 31%, 30.7%, of those patients were classified as low-risk by the HEART Pathway. Among those patients that were classified by low-risk, the rate of death and MI, the composite outcome at 30 days, was 0.4%. Typically for these accelerated diagnostic protocols we want them to have an adverse cardiac event rate less than 1%, so a finding of 0.4% with a confidence in our role that doesn't extend beyond 1% that was a really important finding that really confirms the safety of this strategy.

The other thing that we found which was interesting was that the use of the HEART Pathway was actually associated with detecting more myocardial infarctions during the index visit, which means that possibly the HEART Pathway use improved the recognition of those patients that were presenting with MIs. It's possible that without using the HEART Pathway some of those cases may have been missed. Finally, we were able to demonstrate that use of the HEART Pathway as a clinical decision support tool was able to decrease hospitalizations and some other utilization metrics such as stress testing and possible length of stay.

Dr Carolyn Lam: Oh, that's awesome, Simon. I said it earlier. I'm gonna say it again. Thank you so much for publishing this wonderful work with Circulation. I really think that implementation, science, and decision support tools you've got that all in this paper, just beyond even the actual topic. Deb, take us behind the scenes a little bit with how we reacted as editors to this paper, please.

Dr Deb Diercks: Well, I think that overall, we were really excited about this paper. It really does add a real, real context to something we were really discussing and wondering about. I think one of the great things about the implementation, and Simon, please comment on this, is the diversity of the places that you actually used this in. I mean, most of us when we look at papers there's always a fear that it won't be able to be generalized to real-world practices. Correct me if I'm wrong, but you really applied it to just a wide variety of Emergency Departments that really support that this could be used anywhere.

Dr Simon Mahler: Yeah, I think that's a really important point, that we did this across our system so that included a large academic busy Emergency Department that sees over 100,000 patients per year, all the way, basically to a smaller 12,000 per year, essentially almost a free-standing Emergency Department at the time that we started our study; it now has inpatient bed capacity, and then a suburban/rural hospital, as well, with about 30,000 patient visits per year. We extended beyond kind of the typical kind of comfort zone of large academic centers and into smaller community Emergency Departments as well.

Dr Deb Diercks: One of the things that this manuscript nicely articulated is that you kind of break it into the HEAR and then the troponin.

Dr Simon Mahler: Right.

Dr Deb Diercks: Things change in the US with troponin. How do you think that's gonna impact how you guys apply this Pathway in the future?

Dr Simon Mahler: It's a big topic of discussion right now, what to do with these Pathways. Are these Pathways still needed with the availability now of high-sensitivity troponins in the United States? I think that for many years as we've kind of followed data coming out of Europe we've been anxiously awaiting the arrival of these tests in the U.S., and there's a lot we can learn from the European data so far. Most of that data suggests that the high-density troponins are best used still in the context of a Pathway or an accelerated diagnostic protocol.

I think that this particular study was conducted just using contemporary troponins, particularly given the time frame of the study in which we were accruing patients from 2013 through 2016, but I think it's still gonna be highly relevant, because I think that best practices are gonna still require us to use some sort of structured framework with high-sensitivity troponins. Now, it does remain to be seen a little bit what the best Pathway is gonna be to incorporate that. My take on this is that I believe that clinical decisions support tools or decision aids integrated with high-sensitivity troponins is going to be the best way to go. I'm a little bit skeptical about troponin-only approaches.

Dr Deb Diercks: That's a great summary. I don't think it's time to throw out all the value of that risk stratification tool, and I think your study showed that how it can easily be incorporated into what we do in a manner that doesn't really negatively impact the work flow, which I think is so important.

Dr Simon Mahler: You know, we did a smaller study where we looked at the performance of the HEART Pathway with high-sensitivity assays. We studied it with both the Roche troponin high-sensitivity troponin T and the Abbott high-sensitivity I, and at the 99th percentile it actually made very little difference in terms of the performance of the HEART Pathway. What the potential advantages of incorporating high-sensitivity assays is that you probably no longer need a 0 and 3 hours, evaluation can be condensed. I think there's a lot of really interesting questions that availability of high-sensitivity troponins has created, and I think that there's gonna be a lot of emerging evidence over the next few years about new Pathways, and what are the best ways to fully take advantage of these higher-sensitive assays because, frankly, most of the decision aids that are currently in use they were developed using contemporary troponins, and they may not fully take advantage of high-sensitivity troponins. We may see modifications of our Pathway, and it will interesting to see kind of how things evolve as we study the impact of high-sensitivity troponin.

Dr Carolyn Lam: Wow, exciting work ahead. Just one last question regarding the future. So, you followed up the patients in your study for 30 days. Am I wrong? Any plans to follow them up longer, and do you think such data are needed?

Dr Simon Mahler: Yeah, we actually followed them for a year. Our primary analysis was through 30 days, and so we do have one-year data on all of our patients, and so we'll be doing a secondary analysis looking out to a year. Yeah, you can look forward to that coming up hopefully in the next six months or so.

Dr Carolyn Lam: That is awesome. Thank you so much, Simon. Thank you so much, Deb. Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2018.

Circulation November 20, 2018 Issue

19 november 2018 | 23 min

Is there a unique lipoprotein profile for incident peripheral artery disease as opposed to coronary or cerebral vascular disease? Well, you're just gonna have to wait for our feature discussion to find out. That's coming right up after these summaries.

Our first original paper this week tells us that gene variance known to be associated with idiopathic and peripartum cardiomyopathy are also associated with preeclampsia. First and corresponding author Dr Gammill from University of Washington and colleagues studied 181 participants with confirmed preeclampsia from the Preeclampsia Registry in BioBank. Saliva samples were collected for DNA isolation and whole exome sequencing was performed to detect rare variants in 43 genes known to be associated with cardiomyopathy.

Results were compared with data from two controlled groups, unrelated women with a gynecological disorder, sequence using the same methods and instruments, as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium.

The results showed that women who developed preeclampsia are more likely to carry protein altering mutations in genes associated with cardiomyopathy, particularly, the TTN gene which encodes the sarcomeric protein titin. Thus, detecting these gene variants may allow more specific diagnosis, classification, counseling and management of women at risk.

Prior trials have shown that nonsteroidal anti-inflammatory drugs or NSAIDS confer cardiovascular risk. Now this has been postulated to be due to enhanced formation of methyl arginines in the kidney that would limit the action of nitric oxide throughout the vasculature. However, the next original paper in this week's journal suggests that this may not be correct. First author, Dr Ricciotti, corresponding author, Dr FitzGerald from University of Pennsylvania Perelman School of Medicine and colleagues, used multiple genetic and pharmacological approaches to disrupt the COX 2 pathway in mice and analyze plasma from patients taking NSAIDS.

However, they did not observe an increase in methyl arginines. In contrast, they did observe an increase in plasma asymmetric dimethylarginine or EDMA in mice-rendered hypertensive by infusion of angiotensin II at a dose that also caused renal impairment. After a four week washout period following the infusion of angiotensin II, blood pressure, creatinine, and ADMA levels all fell back to normal levels.

Celecoxib-treated mice also exhibited increased ADMA and plasma creatinine in response to infusion of angiotensin II and their levels also returned to normal thereafter. Thus, it seems likely that the previous reported elevations in ADMA reflected renal dysfunction rather than a direct consequence of COX 2 deletion or inhibition. The authors end by suggesting that the most plausible mechanism by which NSAIDS confer a cardiovascular risk, is by suppression of COX 2 derived cardioprotective prostaglandins such as Prostacyclin rather than by enhanced formation of methyl arginines.

The next original paper identifies new targets with the potential to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia. Co-corresponding authors, Dr Ola and Eichmann from Yale University School of Medicine and colleagues looked at SMAD4, which is a downstream effector of transforming growth factor-beta/bone morphogenetic protein family ligands that signal via activin-like kinase receptors.

The authors generated a tamoxifen inducible postnatal endo-fetal specific SMAD for a mutant mouse and showed that SMAD4 prevented flow-induced arterial venous malformations by inhibiting casein kinase II. The uncovered pathways provided novel targets for the treatment of vascular lesions in hereditary hemorrhagic telangiectasia related juvenile polyposis patients carrying SMAD4 mutations.

The next original paper provides important data for the accurate diagnosis of long QT syndrome. Long QT syndrome can be a challenging diagnosis partly because the optimal method for QT assessment is not unequivocally established. QT experts advocate manual measurements with a tangent or threshold method.

In today's paper, first and corresponding author, Dr Vink from Academic Medical Center University of Amsterdam and colleagues, aimed to assess similarities and differences between these two methods of QT interval analysis among 1,484 patients with a confirmed pathogenic variant in either KCNQ1, KCNH2 or SNC5A genes from 265 families. Both QT measurement methods yielded a high inter and intra reader validity and a high diagnostic accuracy.

Using the same current guideline cutoff of QTC interval 480 milliseconds, both methods had similar specificity but yielded a different sensitivity. QTC interval cutoff values for the QT measured by the tangent method was lower compared to that measured by the threshold method. Plus, values were different depending on the correction for heart rate, age, and sex.

The authors provided an adjusted cutoff values specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for long QT syndrome at www.QTcalculator.org has been made available as an aid in the interpretation of the QT interval.

The next original paper demonstrates for the first time that thrombin mediated signaling may play a role in diet-induced atherogenesis. Co-first authors, Dr Raghavan and Singh, corresponding author Dr Rao from University of Tennessee Health Science Center and colleagues, used a mouse model of diet-induced atherosclerosis and molecular biological approaches and explored the role of thrombin and its G protein coupled receptor signaling in diet-induced atherosclerosis.

They found that thrombin-induced CD36 expression and foam cell formation required protease activated receptor 1, G alpha 12, Pyk2, GAB 1, and protein kinase C theta dependent activating transcription factor 2 activation. Thus, inhibition of thrombin G protein coupled receptor signaling could be a promising target for the development of new drugs in reducing the risk of diet-induced atherogenesis.

The next study provides insights into the long- term association of LDL cholesterol with coronary heart disease mortality in individuals at low tenure risks of atherosclerotic cardiovascular disease. First and corresponding author, Dr Abdullah, from VA North Texas Medical Center and UT Southwestern Medical Center and colleagues studied more than 36,000 subjects in the Cooper Clinic Longitudinal Study cohort who are at low tenure estimated risk of atherosclerotic cardiovascular disease. In other words, a low tenure risk of less than 7.5%. They've followed these patients for more than two decades.

Results showed that LDL cholesterol and non-HDL cholesterol at or above 160 milligrams per deciliter were independently associated with a 50 to 80% increased relative risk of cardiovascular disease mortality. The associations between LDL cholesterol and cardiovascular disease mortality were more robust when follow up was extended beyond the traditional 10 year estimated risk period.

The associations remain significant in those with an estimated tenure atherosclerotic cardiovascular disease risk of less than 5%. These data suggests that LDL cholesterol levels at or above 160 milligrams per deciliter in individuals deemed to be at low tenure atherosclerotic cardiovascular risk are associated with worse long term cardiovascular disease mortality. These findings, along with other observational data and data extrapolated from clinical trials, support further consideration of appropriate LDL cholesterol thresholds for lipid lowering interventions in individuals categorized as low short-term risk.

The final paper this week uncovers a novel therapeutic target for the prevention and treatment of thoracic aortic aneurysms. First author, Dr Nogi, corresponding author Dr Shimokawa from Tohoku University Graduate School of Medicine and colleagues, used genetically modified mice to show a pathogenic role of the small GTP binding protein, GDP dissociation stimulator in the development of angiotensin 2 induced thoracic aortic aneurysms and dissection. Down regulation of this protein contributed to dysfunction of aortic smooth muscle cells and hence oxidative stress, and matrix metalloproteinase activities in the pathogenesis of thoracic aortic aneurysms and dissection.

Local over expression of this small GTB binding protein GDP dissociation stimulator around the thoracic aorta inhibited aortic dilatation and rupture in deficient mice. And that wraps it up for this week's summaries. Now for our feature discussion.

Atherosclerosis has been considered a systemic process, meaning that when we see a disease in one vascular bed, we assume that that's a risk marker for disease in other vascular territories, and that they share pathophysiology, they share risk factors. However, if we think about it, the prior studies have all been sort of focusing on coronary and cerebral vascular disease, but today's feature paper changes that a bit because it addresses a key knowledge gap in peripheral artery disease risk, and interestingly suggests that there may be a unique lipid profile that's related to peripheral artery disease.

This is gonna be an exciting discussion and I have the first author, Dr Aaron Aday from Vanderbilt University Medical Center currently. We have our editorialist, Dr Parag Joshi from UT Southwestern, and our associate editor, Dr Anand Rohatgi from UT Southwestern. Welcome gentlemen and Aaron, could we start with you sharing about your study?

Dr Aaron Aday: So, as you mentioned, a lot of the previous epidemiologic data on atherosclerosis have been primarily in coronary artery disease and stroke, and when we looked at peripheral artery disease or PAD, there seemed to be some subtle differences. So for instance, total cholesterol on HTL cholesterol seemed to be the strongest risk factors for future peripheral artery disease and in terms of LDL cholesterol, the data are somewhat mixed. Some have found a weak association, some have actually found no association. And so building on that, we wanted to see if using nuclear magnetic resonance spectroscopy, we could elucidate more details about the litho protein pathways associated with peripheral artery disease.

And we did this in the women's health study which is a prospective cohort study of women free of cardiovascular disease, the baseline, they were aged 45 and older. And what we've found in terms of the standards with their profiles, we again found that there was no association between LDL cholesterol and future peripheral artery disease, whereas certain standard lipid measures like HDL cholesterol were strongly associated with PAD, and then using the Endemol spectroscopy tool, we found that actually, small LDL particles and total LDL particles were concentrations of both of those markers, were strong risk factors for future PAD and other measures like total HDL particle concentration were even more strongly associated with future PAD than coronary artery disease.

So essentially the signature associated with future peripheral artery disease, had some important differences than that for a composite of coronary artery disease and stroke.

Dr Carolyn Lam: Aaron thanks for that. That's beautifully described and just so intriguing. Parag, could you tell us how should we be thinking about results like this?

Dr Parag Joshi: It's a great paper and it really highlights a new and unique approach in that we ... Peripheral artery disease as an isolated incident event is fairly understudied I guess we could say and so, this is a really nice paper to start choosing out some of the risk factors for that. I think overall, when we think of peripheral arterial disease in general, I think historically, we've thought of it as similar pathophysiology, you know LDL particles and perhaps other particles depositing in the arterial space. But this does highlight some important differences that might exist and I think one of those seems to be that maybe this is more a signature of elevated remnant lipoproteins or triglyceride rich remnant lipoproteins, small dent LDL particles, low HDL, that sort of metabolic syndrome type patterns that we look at as a high risk factor that may be more contributory to peripheral artery disease than coronary disease, or at least more specific to peripheral artery disease.

I guess one of my main questions about that from your work Aaron is, how can we be sure this isn't just a pre-clinical marker of diabetic patients which we know have this type of pattern?

Dr Aaron Aday: Sure, it's certainly a possibility. I think what's notable in the cohort, at least a time enrollment. And there was a very little diabetes and actually there was a much greater prevalent of metabolic syndrome. So in my mind, it may be more of a metabolic syndrome specific marker rather than necessarily down the diabetes pathway, but it's certainly something that needs to be explored further.

Dr Parag Joshi: I wonder whether women's health studies such a healthy cohort that I wonder if this is picking up some signal before the answer to diabetes or as you said, metabolic syndrome, you know which certainly suggests an insulin resistance pattern and we know the association of diabetes with peripheral artery disease is stronger and so I wonder if this may be a sort of earlier way of picking that up.

Dr Aaron Aday: It may be. I think one thing to notice is the outcome of peripheral artery disease that we're using. So it is symptomatic disease. So, we're not picking up a lot of ulcers that are developing in the future, it's more the claudication and then people who've undergone revascularization. Certainly diabetics have both of those as well but I think that may suggest it's not fully unexplained by developing diabetes than peripheral artery disease further down the line.

Dr Parag Joshi: Yeah that's a great point.

Dr Carolyn Lam: Yeah great questions, great thoughts. Anand, what about you? Did you have questions too?

Dr Anand Rohatgi: I think from my perspective and thinking about it for circulation and its readership, we found this really interesting for several reasons. Number one, I think is, as you all have discussed, peripheral arterial disease just is not as well characterized and you can see that here in over 25,000 people, add about a 100 a bed, so I think in younger folk, it takes a lot of people to study, to be able to really understand kind of the pathophysiology of peripheral arterial disease.

The other thing that they think they really shed some light on is how this is happening in women in particular and in women, of course as we know have been understudied in all cardiovascular diseases, but in particular, diseases like this which are less common. It's really insightful to see that these lipid abnormalities in women are contributing to peripheral arterial disease more so than your typical LDL cholesterol management and interestingly enough, most of the women who had PAD events in this study, did not have other cardiovascular events.

They really just had PAD events exclusively and I thought that was really intriguing, and the use of this advanced lipoprotein testing, this NMR modality has been very useful in terms of biology and research, and I think that's the case here where we really go under the hood Carolyn, as you said, and get kind of deep dive, the lipid metalobles on abnormalities. And I think Parag and Aaron hit the nail in the head that this is really capturing an insulin resistance of phenotype and what I really liked about this is, instead of studying people who are 70, 80 years old and a lot of things are sort of clustering, a lot of diseases are clustering and they're manifesting all at the same time, it's very hard to tease apart the effective age.

Here, we captured women in their 50s and middle aged, just as they have kind of gone through menopause and this adverse metabolite's phenotype starts to rise in women. And then we could follow them over time and see what the natural history of that is, and the women who have this phenotype go on to have this devastating consequence, this peripheral arterial disease. One of the questions I had then, Aaron for you is, what do you think the implications are from these findings? Does it mean that in terms of diagnostics, we should be doing more advanced testings looking at LDL and HDL type particles with NMR or some other mortality? Does it change therapies with new therapies beings studies right now? What do you think the implications are from your work?

Dr Aaron Aday: That's important right. I think you mentioned this and I see the inter marked tool in this study, is really a way to try to dig further into the biology of peripheral artery disease as a form of atherosclerosis. I think that we already know patients who are extremely high risk or PAD, those are patients with diabetes, smoking history, metabolic syndrome et cetera., and as you can see in a patient population in 28,000 middle aged women who are pretty healthy, we only had just over a 100 PAD events.

So, I think even if you were to scale this up in terms of cost, I'm not sure that that would necessarily be a viable option for patients, but I think it does suggest that truly focusing on LDL in a very high-risk patient population, meaning patients with PAD, or we may not be fully addressing their risk. And so I think this is a need to highlight that important gap, think about other therapeutic options and we'll soon have ongoing trials, triglyceride low in therapy that may be particularly beneficial in this patient population and so that's how I see this being used.

Dr Anand Rohatgi: That makes a lot of sense and particular because in middle aged women like this, your standard risk score algorithms will not really capture that they're at increased risk, even if they smoke, just because they're women and they're younger and so, I think this really is a call to arms to more refined risk assessment in these women.

Dr Parag Joshi: Aaron, do you think there's actually a difference in the biology in the peripheral arteries compared to the coronary and cerebral vascular beds, or is there data to kind of look at that or maybe histopathological data to look at that?

Dr Aaron Aday: We know there's a lot of overlaps, so I don't wanna suggest that PAD is not a former atherosclerosis. I think one limitation is that the primary animal model for PAD is the hyperCKemia model. That doesn't fully recapitulate what's happening in a limb with PAD and so I think that has been one limitation in understanding the biology. But I think what we're starting to see in some clinical trials that have come out in the last couple of years or starting to see a somewhat different signal for therapies in patients with PAD so for instance, in 48, we actually saw that there was a greater benefit to LDL lower [inaudible 00:21:00] inhibitors than for coronary disease. We now have the compass trial results, again, more events, higher risk among these patients but for their benefit, add on River Oxodine therapy, we've seen lymph events or lymph signals in the SGLP2 inhibitor trials. So, I think we're starting to get a sense that there may be something else on top of the traditional ascariasis biology that may be a potential target on down the road.

Dr Parag Joshi: I think it's really a fascinating biological question of how these different territories might actually differ in their pathophysiology. I think it's a really a nice time to look at this. Also I think, Anand and Aaron both mentioned ongoing trials. The omega 3 fatty acid trials I think reduce it, will be soon to be presented and hopefully published in the next month or so. It would be nice to see if they evaluate peripheral events in that group, I'm sure they will.

Dr Carolyn Lam: Indeed, these have been just such great thoughts and discussion. Nothing really much to add there. I suppose I could say something cheeky like for the first time, and I never thought I'd say it on the podcast, I feel kind of bad that there are no men included in this trial but anyway, I just learnt so much from this. I just wanna thank you gentlemen for a great discussion.

Thank you, listeners, for joining us today and don't forget to tune in again next week to Circulation on the Run.

Circulation November 13, 2018 Issue

12 november 2018 | 25 min

This week's feature discussion focuses on first and man pilot study results of pericardiotomy and its influence on left ventricular diastolic reserve with volume loading. Very fascinating implications for heart failure with reserved ejection fraction, coming right up after these summaries.

Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. But what are the underlying mechanisms and potential therapeutic approaches to this? Well, in today's paper from co-first authors Drs Sun and Yao, corresponding author Dr Chang, and colleagues from UT Southwestern Medical Center, the authors examine the status of cardiac autophagy and its role during sepsis pathogenesis using a rodent lipopolysaccharide-induced sepsis model. They've found that forced overexpression of Beclin-1 in the heart promoted autophagy and mitophagy, protected mitochondria, improved cardiac function, and alleviated inflammation and fibrosis after a lipopolysaccharide challenge. Whereas, haplosufficiency for Beclin-1 resulted in the opposite effects. For the more injection of a cell permeable Tat-Beclin-1 peptide improved outcomes in lipopolysaccharide-challenged animals. Thus promoting Beclin-1-dependent signaling may be a novel and effective intervention to alleviate organ dysfunction caused by maladaptive autophagy during severe sepsis.

The next paper presents important experimental data that causes us to consider the potential cardiovascular hazards of anti B-cell activating factor immunotherapy, which is currently approved for the treatment of autoimmune systemic lupus erythematosus. You see, genomic data has shown that B-cell activating factor receptor pathway is specifically essential for the survival of conventional B lymphocytes, which is a key driver of coronary heart disease. However, in today's paper from co-first authors, Drs Tsiantoulas and Sage, corresponding author Dr Binder and colleagues from Medical University of Vienna, the authors reported an unexpected finding that B-cell activating factor neutralization increased atherosclerotic plaque size and complexity despite efficient depletion of mature, conventional B lymphocytes. Furthermore, the authors provided evidence suggesting a novel B-cell independent anti-inflammatory property of B-cell activating factor. They showed that the expression of the alternative B-cell activating factor binding receptor, transmembrane activator and CAML interactor in myeloid cells limited atherosclerosis thus showing novel atheroprotective pathways. Thus, these results introduce a new perspective with respect to the potential cardiovascular hazards that may be associated with the long term blockade of B-cell activating factor in chronic inflammatory settings. There is a need for more refine therapeutic approaches targeting the B-cell activating factor pathway.

Vascular smooth muscle cells are known to possess remarkable plasticity undergoing fundamental phenotypic switches from a differentiated to a dedifferentiated state in response to vascular injury or remodeling. However, what are the underlying cellular processes by which vascular smooth muscle cells maintain their cell identity? Well, in today's paper from co-first authors Dr Yao, Yu and Li, corresponding Dr Wang from Fu Wai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking University Medical College. The authors applied single cell RNA sequencing to analyze disease human arteries and identified histone variant H2A.Z as a key histone signature that maintains vascular smooth muscle cell identity. H2A.Z occupied genomic regions near vascular smooth muscle cell marker genes and it's occupancy was decreased in vascular smooth muscle cells undergoing dedifferention. H2A.Z expression was dramatically reduced at both messenger RNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescued injury-induced loss of vascular smooth muscle cells identity and new intima formation. Together, these data introduced dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions and implied that H2A.Z may be a potential intervention known for vascular diseases.

What is the causal role of body mass index and cardiovascular health in young adults? In the next paper from first and corresponding author Dr Wade from University of Bristol in United Kingdom and her colleagues. The authors used a combination of conventional multivariable regression analyses, Mendelian randomization and subsample recall by genotype methodologies. Recall by genotype is a novel approach that exploits the random assortment of alleles through meiotic cell division at conception to inform genetically base recall and enables the collection of precise phenotypic measures in smaller studies while maintaining statistical power and ability for causal inference. The authors use these methods to estimate the causal effect of body mass index on gross level and detail cardiovascular health in healthy participants from the Avon longitudinal study of parents and children at age 17 years as well as in an independent sample from the same cohort study at age 21 years.

Their results showed that higher body mass index was likely to cause worse cardiovascular health specifically higher blood pressure and higher left ventricular mass index even in youth. Higher body mass index also resulted in increased cardiac output in the recall by genotype study which appeared to be solely driven by stroke volume, as neither the Mendelian randomization nor the recall by genotype analyses suggested a causal effect of body mass index on heart rate. These consistent results support efforts to reduce body mass index from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using a recall by genotype methodology.

Older adults undergoing aortic valve replacement are at risk for malnutrition, however, what is the association between pre-procedural nutritional status at midterm mortality? First author, Dr Goldfarb, corresponding author Dr Afilalo from McGill University in Montreal, Quebec, reported results of the FRAILTY-AVR prospective multicenter international cohort study conducted between 2012 and 2017 in 14 centers in three countries. This study included patients 70 years and older who underwent transcatheter aortic valve replacement or surgical aortic valve replacement. The mini nutritional assessment short form was assessed by trained observers pre procedure with scores seven or less out of 14 being considered to be malnourished. The short performance physical battery was simultaneously assessed to measure physical frailty. The authors found that malnutrition was associated with higher one-year mortality and 30-day adverse events following aortic valve replacement via a transcatheter or surgical approach. While malnutrition and frailty were interrelated, the integration of nutritional assessment resulted in improved predictive value for frail patients. Clinical trials are needed to determine whether pre and post procedural nutritional interventions can improve clinical outcomes in these vulnerable patients.

Do newer generation ultra-thin strut drug-eluding stents improve clinical outcomes over contemporary thicker strut stents? First and corresponding author, Dr Bangalore from New York University's School of Medicine and colleagues search PubMed, Embase and Central and identified 10 trials that randomized more than 11,650 patients and evaluated three newer generation ultra-thin strut drug-eluding stents, that is defined as a strut thickness less than 70 microns, versus thicker strut second generation drug eluding stents and reported clinical outcomes. They found that newer generation ultra-thin strut drug-eluding stents were associated with a 16% reduction in target lesion failure, which was a composite of cardiovascular death, target vessel myocardial infarction or ischemia-driven target lesion revascularization evaluated at one year follow-up. Ultra-thin strut drug-eluding stents reduced the risk of target-lesion failure driven by a reduction in myocardial infarction and also a qualitatively lower rate of stent thrombosis compared to contemporary thicker strut second generation drug-eluding stents.

Ambient air pollutants are known to be associated with increased cardiovascular morbidity and mortality, however, what is the association between air pollution and cardiac structure and function? First and corresponding author Dr Aung from Queen Mary University of London and colleagues performed a cross-sectional analysis of a large population free of preexisting cardiovascular disease in the UK Biobank population study. They found that higher past exposure to fine particulate matter and nitrogen dioxide were associated with larger cardiac biventricular volumes. Proximity to major roads, a surrogate for chronic air pollution exposure, was additionally associated with higher left ventricular mass. These associations between ambient air pollution and at first cardiac phenotypic changes, in individuals without prevalent cardiovascular disease, suggest that air pollution should be recognized as a major modifiable risk factor which needs to be targeted by a public health measures.

The final original paper this week is the first study to demonstrate a causal link between atrial fibrillation and the NLRP3 inflammasome, which is an innate inflammation signaling complex. Co-first authors, Drs Yao and Veleva, corresponding author Dr Li from Baylor College of Medicine and colleagues assessed MLRP3 inflammasome activation by immunoblot in atrial whole tissue lysates and cardiomyocytes from patients with paroxysmal or long-standing persistent atrial fibrillation. They found that NLRP3 inflammasome activity was increased in these patients. To determine whether cardiomyocytes specific activation of NRLP3 was sufficient to promote atrial fibrillation, they established a cardiomyocyte specific knock in mouse model which expressed constitutively active NLRP3. These mice developed spontaneous premature atrial contractions, an inducible atrial fibrillation, which was attenuated by a specific NLRP3 inflammasome inhibitor. Cardiomyocyte-specific knockdown of NRLP3 suppressed atrial fibrillation development in these mice. Thus, these results establish a novel pathophysiological role for cardiomyocyte NLRP3 inflammasome signaling with a mechanistic link to the pathogenesis of atrial fibrillation, and suggests that inhibition of NLRP3 may be a potential novel atrial fibrillation therapy approach.

And that brings us to the end of our summaries.

Now for our feature discussion.

Is pericardiotomy going to be our next treatment for heart failure with preserved ejection fraction or HFpEF? I have the first and corresponding author of a very intriguing research letter. Dr Barry Borlaug from Mayo Clinic in Rochester, Minnesota, joining me today to tell today about his great paper. Barry, welcome back to the show. You are amazing. Congratulations on yet another wonderful publication. So, could you set us up. Those of us who don't think about this every day. The hemodynamics of what pericardiotomy does. Tell us what was the rationale of doing this study?

Dr Barry Borlaug: You know, it's interesting. We think about intracavitary pressures on the left side ventricle and the left atrium causing congestion and pulmonary hypertension. We think that this is all related to left ventricular issues, but about 30 or 40% of the pressure is actually related to external restraint on the heart as mediated by the right ventricle across the septum and the pericardium and external pericardial contact restraints. In animals, we've known since back in the late 1970s, that with the chest open, if you open up the pericardium, which we know in HFpEF, on average, is shifted up and to the left. It's stiffer. This effect really comes into play more at higher heart volumes. It doesn't have as much of an affect at lower heart volumes like might be absorbed with rest. It's even been rumored that in some species like greyhounds, illicit dog racers, would actually cut away the pericardium so these dogs could race better. It's actually been shown that they can experimentally, in a paper in the 1980s, that they can exercise the higher peak VO2. They have a higher cardiac output response, because the heart is better able to utilize the Frank-Starling relationships to augment ventricular filling and ejection at fuller pressures.

Dr Carolyn Lam: Oh my goodness. I didn't know that latter fact about the racing dogs. Could I ask you something? We've talked about this before back in the day. When you say the left side the filling pressures go up when there's pericardial restraint, remember we used to talk about a parallel shift upwards versus true intrinsic stiffening ... diastolic stiffening. You still do mean that parallel shift upwards, right?

Dr Barry Borlaug: That's right. If it was purely an increase in stiffness, we would expect it to sort of rotate, pivot from the bottom left up, but what we see, and in human data, we published a number of years ago, most of the increase in LV end-diastolic pressure is a parallel shift upward in the diastolic pressure volume relationship. That really suggests that there's an increase in restraints on the heart. That's why we think that that's an important target and it's possibly more remediable to treatment since we're having such tough luck changing the viscoelastic properties of the left ventricle, not that we shouldn't be doing that, but this might be something different that we could do that might give us a little bit more of a benefit in terms of filling pressure reduction.

Dr Carolyn Lam: True. True. But the way you describe it too, it does mean that we may be talking about, I hate to say this but, specific subsets or types of HFpEF, where that may play a bigger role and I'd just like to bring the audience to your incredible paper that I think that I've cited a gazillion times already on the obese HFpEF phenotype. Do you want to remind everyone about that because I think there you really [inaudible 00:16:30], didn't you that ventricular interdependence played a big role.

Dr Barry Borlaug: So, in people with obese HFpEF, which is now becoming by far one of the most dominant. Oh God. We did a study that compared them to non-obese and we see that the obese patients have a bit more plasma volume expansion, a bit more cardiac remodeling, right heart enlargements, increase of LV mass and an increase in epicardial fat. What all this does is increases the total heart volume in the pericardial space. Because the pericardium doesn't appear to grow as much as the heart volume, this increases the coupling between the right and left heart. Some people, perhaps like the obese phenotype of HFpEF, might be more poised to derive benefit from approaches to therapeutically remove this excess pericardial restraint.

Dr Carolyn Lam: Okay, now you just have to get down to telling us what you did. This was a first in man pilot study. Drum roll everybody. You gotta listen up. This was so cool.

Dr Barry Borlaug: This physiology just got us thinking that maybe we could do this to help our patients with HFpEF. First we tested this in dogs, then with pigs with features of HFpEF and it seemed to work there so the next step was to show that it might work in people. We took people that were already going to get their pericardium open, so people that were referred for cardiac surgery. We wanted to choose people that had risk factors for HFpEF and diastolic dysfunction but maybe not necessarily diagnosed HFpEF.

Dr Barry Borlaug: We took people who were referred for aortic valve replacement for AS, coronary artery bypass grafting or both and consented them ahead of time, put catheters into them to measure hemodynamics and then we measured resting hemodynamics with the chest open, but pericardium intact, because the changes that we see occur predominantly when there's an increase in volume load to the heart, we then had to stress the system. Now we can't have them exercise cause they're under general anesthesia with an open chest. You achieve that by elevating their legs and giving them a little saline bolus, so we had a pressure at rest, pressure with saline load.

Then we asked our surgeons to open the pericardium, which they do obviously to gain access to the heart for cardiac surgery and we repeated the same assessments and intervention. What we saw was that the resting filling pressures, again these people did have diastolic dysfunction, the resting pulmonary wedge pressure was about 16. With the volume load maneuver, it increased to 25 when the pericardium was intact. After we had opened the pericardium, the increase in wedge pressure, which was our primary endpoint, was reduced from an increase in nine millimeters of mercury down to an increase of only three millimeters of mercury. So that verified our hypothesis that the pericardium contributed and that we could prove total cardiac diastolic reserve, if you will, just by removing that pericardial restraints.

Dr Carolyn Lam: Wow. I love the figures, by the way, that you've drawn as always they illustrate that so beautifully. And listeners, this is a research letter, so there's that one central figure that you must get your hands on right away. Now Barry, I think the first question is this wasn't really HFpEF patients right? Let's be very clear with the audience who these were though and then you did a subset analyses though, a further analysis that showed this may apply more to people with higher wedge at rest. Could you elaborate?

Dr Barry Borlaug: Absolutely. While these people, and Carolyn, I think you know as well, I think a lot of people probably have HFpEF that they have a sort of occult HFpEF, that's not been diagnosed maybe because unfortunately, not everybody else thinks about this diagnosis. When you look at the charts very carefully, and found out about 13 of the 19 patients complained of significant dyspnea based on chart review. Of those 13, 10 had other indicators that according to current criteria would give them the diagnosis. When we looked at this at this very post hoc, sort of exploratory subset, we actually saw that these patients, even though they didn't necessarily have a clinic diagnosis of HFpEF, that these patients actually responded even more favorably to the effects of pericardiotomy in their greater reduction in the increase in wedge pressure. When we plotted in the figure that you mentioned, we plotted the change in the increase in wedge pressure, it was really the patients that had the greatest increase with volume loading initially that derived the most benefit. That makes sense because those were the people where the pericardium and the restraint is the becoming most operative, when the heart is most distended and congested.

Dr Carolyn Lam Maybe one quick last question. What next Dr Borlaug? Gosh, you just keep coming up with one thing after another with the animals. I noticed that it was a non-invasive pericardiotomy. I'm reading between the lines here. What are you going to do next? Do you think this is ready for prime time?

Dr Barry Borlaug: As usual, you're reading correctly between the lines. We have filed a patent awhile back for this and we have a device that can achieve a pericardial modification or an anterior pericardiotomy without the need for open heart surgery, so that you don't crack the sternum. It's done from a subxiphoid approach and we've actually just received some funding to start doing this under an IDE, which we will need to work with the FDA. We hope to do and start testing this in patients that have HFpEF and then look at the acute hemodynamically affects. Then we'll also begin to explore the safety and potential efficacy using other indices like imaging, exercise capacity and things like that.

Dr Carolyn Lam: That is just so cool. I think that one of the immediate take home messages for me now though is when we see patients who we think have HFpEF, have a low threshold to look for evidence of constriction. I would say that we may miss the diagnosis of people who legitimately have constrictive pericarditis and may need to benefit from this. I think it's one of those hidden diagnosis, so that's one thing. And then the next thing, if I could just ask you, are there any patient populations that you say should not undergo this? And I say this because I remember back in the day again, when we were experimenting with dog models, this is just gestalt okay, but I thought that the dogs who had right-sided heart failure, severe right-sided heart failure, needed that pericardium to lean on, and if you released it, the dilatation on the right side would just be inexorable because there is no pericardium to rein them in. Do you get what I mean? I don't know. I'm just curious if you have any patient population right now that you're already thinking I'm not going to include in my trial.

Dr Barry Borlaug: Yeah. That's a very important point, Carolyn. We would not want to apply or test initially certainly this therapy where eccentric cardiac remodeling is a problem because we know that there is a little bit of eccentric dilatation even in people after a regular cardiac surgery with pericardiotomy. Marty Molenter showed that, in a paper back in the 1980s, you have a patient who already has some dysfunction, we would hypothesize that they may get a bit worse, so we would not want to test this in people with the right ventricular dysfunction, right ventricular enlargement phenotype of HFpEF. We would not want to give this to people with HFrEF. Remember with HFrEF, we wanted to do just the opposite. We tested this years ago with the ACORN trial or older studies wrapping the latissimus dorsi around the heart to cause reverse remodeling so this is really something that would maybe work more for people with smaller stiff hearts, HFpEF, where that concern that they're going to dilate and get low EF heart failure either on the left or on the right side. We would want to focus more on the small hearts and away from those people with dilation.

Dr Carolyn Lam: That is so great. Thanks so much Barry for letting us under the hood. Congratulations once again. These are just great papers. Keep them coming. Well listeners. I'm sure you enjoyed that as much as I did. Don't forget to tune in again next week.

Circulation November 6, 2018 Issue

5 november 2018 | 23 min

James de Lemos: Welcome everyone to Circulation on the Run my name is James de Lemos, I am the executive editor for Circulation based at UT Southwestern in Dallas and I will be filling in for Carolyn today as we discuss this year's surgery themed issue. I would like to welcome Dr Marc Ruel, the chairman of cardiac surgery at the University of Ottawa and a long-time editor of the Circulation of surgery themed issue, as well as Dr Tim Gardner, professor of cardiac surgery at The University of Pennsylvania and our leader at Circulation on the editor team for issues related to cardiac and vascular surgery. Marc and Tim, welcome and thanks for all your tremendous work in this issue.

Dr Marc Ruel: Thanks James for having us.

Dr Tim Gardner: Thank you. Glad to be here.

James de Lemos: Why don't we start Marc with your thoughts on how this issue comes together, how it came to be, you picked the papers and how we ended up with this terrific issue.

Dr Marc Ruel: It’s been a really important year for surgery and for this issue, as some of you may know the supplement which used to be the old designation of this issue has been changed to the surgery themed issue in about 2014 or so where the new Circulation leadership and what we tried to do every year is to bring the very best, not only of cardiovascular surgical science but also of clinical care and pearls around clinical and surgical care. So, I think this year we have had probably more than 60 submissions sent to us. Tim and I have looked at those very closely and you as well, James, we really wanted to get the feedback and the approach from not only cardiac surgeons but also from cardiologists and cardio vascular care specialist around those. We've tried to select the best of science and also some papers that we feel would be very useful with regards to providing new clinical pearls for surgeons and anyone in the circle of care around cardiovascular surgery.

Dr Tim Gardner: If I could just add, James, of course we have other papers that have been submitted by surgeons that are published or that deal with cardiac surgical or vascular surgical topics during the year, this particular issue is very much focused on cardiac surgery but throughout the year we have plenty of submissions of manuscripts by surgeons about surgery about surgically related topics and so on. So, I am actually kept quite busy reviewing and commenting and consulting on manuscript submissions of Circulation. There are plenty of papers over the course of the year that relate to surgical topics.

James de Lemos: Wonderful, I think you will see, as we talk about these papers, really that what Marc and Tim are talking about in terms of papers that are broadly relevant to cardiac surgeons and cardio vascular providers really rings true. Let’s walk through the issue, its set up like most of our issues begins with a couple of opinion pieces, a brief frame of reference, articles about important topics. Marc, do you want to talk about the Domanski paper, talk about revascularization for ischemic cardiomyopathy?

Dr Marc Ruel: Absolutely, we've asked experts, namely Mike Farkouh and Micheal Domanski, to provide us where their thoughts regarding the optimal treatment on patients with LV dysfunction and severe coronary disease. What many of us would call an ischemic cardiomyopathy, which may be construed as a misnomer or as an accurate term, I will not debate on this today, but certainly it remains a very vexing clinical problem. I think we could all agree that the last niche where we still see very high in terms of treatment for coronary disease this is probably mortality and kind of an inability to provide for a tangible result.

Once LV dysfunction has set in and the present of CAD the outcomes are poor, and it took years and literally almost ten years for the STICHES trials to show a benefit for surgical treatment. This is relatively all study now and it has to be put in context and I then that Mike and Mike are doing this extremely well in terms of providing the caveat, for instance, STICHES at its inception added had a 5% mortality rate around CABG, so we know that the modern outcome are probably better than that. It’s very difficult to actually decipher what sound be the mainstay of treatment for each challenging patient and I think the frame of reference provided by Dr Farkouh and Domanski is extremely useful in helping with that.

James de Lemos: Tim we have another frame of reference that is also provocative. Trying to make a case that we think about in patients with hypertrophic cardiomyopathy with obstruction early surgical procedures to relieve the obstruction. Do you want to tell the readers a little bit about this opinion piece and what your thoughts on it are?

Dr Tim Gardner: Sure James, this is a really nice frame of reference article from both doctors Martin and Barry Maron and then their European contributor Paolo Spirito and the point of their opinion paper is that the surgical art for managing this very difficult obstructive cardiomyopathy syndrome has reached the point where we really shouldn't wait until patients are in extremist or in class 3 or 4 status in term of syndromic problems and can consider earlier surgery for these patients. They make the very important point which I think we have to except is that for patients to do well with this operation they need to be in a center where there is experienced surgery and experienced surgeons, but the point is now that the state of the art for managing obstructive cardiomyopathy is as such that good result are obtained and patients should be offered this surgery when appropriate, but earlier, in order to avoid the challenges of end stage cardiomyopathy and difficulty relieving the obstruction, so this is a really important opinion piece. It’s great to see our cardiology colleagues who are experts in this field make this point based on well published data from centers like the Mayo Clinic.

James de Lemos: Moving now to the original articles, we've got 5 original articles, maybe Marc we can start with your thoughts on 2 articles related to revascularization, one in coronary disease and one identifying a really novel approach for treating type A aortic dissection with malperfusion.

Dr Marc Ruel: I think that's well said James, the first of these original papers will be likely somewhat controversial. The first author is Dr Bo Yang and essentially it is a series from Michigan where they look at just shy of 600 patients with acute Type A Aortic Dissection, of whom 135 were identified to have malperfusion syndrome. Essentially defined by the authors as something slightly different than malperfusion per say but really malperfusion accompanied with evidence of necrosis in one of the organs.

Their approach has been new and somewhat controversial in that they have brought these patients first to the interventional radiology suite in order to fenestrate in many cases or at least open the culprit artery or the culprit perfusion territory that leads to malperfusion syndrome and then depending on how the patient is doing they would then proceed to open repair as soon as 24 hours afterwards or they may wait longer in someone where there is no sign of improvement yet prior to moving to the ER, so they have found this has not only improved the results with regards to in hospital mortality after operative repair type A aortic dissection, but also to allow them to better discern or differentiate should I say between patients in whom malperfusion may lead to a futile situation and who then may be avoided from undergoing a very complex and difficult OR so would argue this is probably the first such large organized, well documented series of such an approach and I think it will lead to some head scratching, this being said it must be remembered that the goal standard for Type A aortic dissection is dealing with the intrapericardial aorta first and hoping that the perfusion gets better from this and everyone knows that the results of this approach are not fantastic.

We know that even in the best centers, including the latest data from Germany such an approach has about a 20% mortality rate so clearly there are ways that we can improve with Type A aortic dissection and this paper may be a strike in the right direction.

James de Lemos: The other revascularization paper addresses that, I would say also a quite controversial topic which is how many atrial grafts are optimal in patients that are undergoing surgical revascularization?

Dr Marc Ruel: This is a paper from Toronto where the Ontario ICES database was used and several papers actually dozens and dozens of papers have come out previously from this well established and well allocated database. Steve Fremes who is the senior author and one of his trainees, Dr Rocha and the team of authors got together and decided to look at the impact of 3 versus 2 arterial grafts in patients undergoing cabbage with regards to survival. They have very nice, very compelling follow up information and they basically carry out 2 exercises.

First, they wanted to see if the 3,000 patients or so had 3 or more arterial grafts had a better outcome than the 8,000 patients or so who had 2 arterial grafts and frankly they found there was no significant difference with regards to survival at 8 years and freedom from MACCE at 8 years. However, when they compare those 9 or 8,000 patients or so who had 2 arterial grafts to the rest of 40,000 or so patients who had 1 arterial graft and completions with veins they found that again there was a survival benefit. This last finding is not new and its obviously subject to indication biases as well as expertise bias as we've seen in many of the observational perspectives studies around multiple arterial grafting. But I think the concept of comparing 2 versus 3 arterial grafts is very novel in surely in this paper is being addresses with very high scientific related from the numbers and the quality of the follow up that's been brought to the exercise.

James de Lemos: I've really been struggling, I love your thoughts and Tim, your thoughts on how to reconcile the data in space. I really am having a hard time getting my head around what seems to be conflicting data about the number of arterial grafts in what an optimal CABG looks like in 2018 with the evidence that we have. What are your thoughts on that question?

Dr Tim Gardner: I think that this supports the concept that 2 arterial grafts whenever possible for some patients, younger patients perhaps 3 but I think the important point is, multiple arterial grafting should be attempted and carried out whenever possible. I leave the is 3 better than 2 to some future study or future review that can be more precise about that.

Dr Marc Ruel: This being said I think we don't view efficiently coronary surgery as being an area of expertise and many centers including very strong academic centers may not necessarily marry the concept that coronary surgery has to be something with the dedicated expertise. I think when we look at those observational perspectives series we see the effect of it may be the expertise bias, but it may be more than just 2 or 3 arterial grafts, they may be the whole wrapping of care that comes with it including optimizing beta blockers and managing diabetes etc. So, I think it may be more than purely conduits but definitely, as Tim said, 2 arterial grafts are probably better than just 1 and the jury is still out on whether 3 is better than 2.

James de Lemos: Excellent. Switching gears now Tim, an area that obviously you have tremendous experience and expertise we've got 2 innovative papers addressing surgery for individuals who have congenital heart disease. Can you update us on what we are publishing here?

Dr Tim Gardner: Sure, the one study focuses on the risks of pulmonary valve surgery in adult patients who underwent a correction of tetralogy of Fallot earlier in life. This is a growing population actually we refer to as young adult with congenital heart disease and in many centers they are more numerous in terms of the patients groups than infants because this group has been successfully treated early in life, but this particular group of patients, patients who have had tetralogy of Fallot repaired and end up with what the author calls right ventricular outflow disfunction generally regurgitation through the outflow tract pulmonary valve sometimes obstruction, these patients then face significant clinical challenges in death from heart failure, right ventricular failure or arrhythmias in their late 20's and 30's. We have been focusing now on the timing and the type of pulmonary valve replacement.

Dr Tim Gardner: Now there is catheter replacement options available, but when to do this and how to minimize risk is really the focus of this one paper that describes a four multi-center study looking at predictors of risk for these patients. Sort of a hypothesis generating paper, but it is an important study none the less, focusing on how to identify patients with right ventricular out flow tract dysfunction and who should have pulmonary valve replacement and when that should optimally be done. It a very good study. The other important study that we have is that the other age spectrum of neonates and this is a study that is based on a review of data from the pediatrics heart health information systems database, led by the group at the Children's Hospital Philadelphia.

Looking at variations in pre-operative care and management of neonates with transposition of the great arteries. This was a little controversial actually when we reviewed it among the editors because the suggestion is that earlier surgery this would be in the first week of life and more perhaps aggressive use of atrial balloon septostomy seems to improve outcomes. This is a generally low risk population, the point of the paper is that these pretty good results can be improved by paying more attention to the timing of surgery and the appropriate use of balloon septostomy. It’s sort of a quality improvement perspective based on a large database and I think it’s a very nice study and undoubtedly creates additional attention to this particular area.

James de Lemos: Marc, our last original paper is a really novel issue engineering approach to creating vascular conduits, can you tell the readers briefly what happens to her in this paper?

Dr Marc Ruel: Indeed. It’s a paper from Stanford, from Joe Woo’s lab and the first author is Daniel von Bornstädt. Essentially, as you say it’s a very innovative novel approach to try to recreate a bioengineered blood vessel. We surely know there's quite a need for such off the shelf conduits, not only in cardiac surgery but also in vascular and vascular surgery and even for things such as AV fistulas and others. It’s really interesting to see that this is what I would call transitional science at its best and surgeons have had an important role over, as you know, centuries in helping develop this and many discoveries have come from surgical labs, especially a few decades ago.

In any case, what Joe and his team have performed is to try to use clinically applicable methods to derive and create a bioengineered blood vessel and they started first with human aortic smooth muscles cells and skin fibroblasts which are literally easy to get and they used those to constructs bi-level cell sheets, they then used a 22 gauge angiocath needle so that the sheets would be wrapped around this in order to lead to a tubular vessel construct. Then the next problem has been traditionally that those bioengineered vessels would burst out with atrial pressure. What Joe's team came up with is to use a commercially available adhesive, so a glue essentially, which is dermabond which typically we use after any form of surgery to keep the incision together and they put dermabond on the surface of this sheet wrapped around an angiocath needle to act as a temporary external scaffold. They then led this into a bioreactor and implanted it in series of 20 rats as a femoral artery interposition graft. The results were excellent. Essentially, patency was perfect and there was a full vascular maturity with all 3 layers of blood vessel that you would expect including an intima that had been formed as a result of the experiment.

I think this is all very promising because none of the methods here are involving something that would have non-autologous issues, or you could easily see this being used with a patient’s own cells in order to achieve an autologous. I think this is obviously small vessels, there are 22-gauge needle is not a big conduit, you’re not going to bypass an LED with this, but I think it’s a start and it’s all done using transitional or clinically applicable methods. I guess the next step would be moving to a large animal model and certainly I think we should stay tuned to see where this leads us.

James de Lemos: I think that's exactly my thinking as well about that discussion and really leads us into some of the issues that come up in the review paper that you are a co-author on new strategies for surgical revascularization. I think this basic in translational science piece is designed to address some of the limitations of current revascularization and you all did a really beautiful job covering some new more clinically ready strategies in your papers. Can you just tell us very briefly what you all covered in that review paper?

Dr Marc Ruel: Indeed, this is a paper that was kind of aiming at being a state of the art around CABG and rapidly the focus was reshaped towards kind of new strategies around surgical myocardial revascularization. Initially we have a section on OPCAB on this and that and minimizing the inflammatory effects of the pump and quickly it became apparent that the desire of Circulation and this themed issue was to focus it more on really what are the up and coming improvements around surgical coronary revascularization. This paper focuses on essentially 4 main areas. One is hybrid coronary revascularization, the second one is less invasive coronary surgery, the third one is the use of multiple arterial grafts to which we eluded a little earlier during this podcast and fourth is the use of an aortic coronary surgery, essentially meaning bypass surgery performed without any manipulation of the aorta.

James de Lemos: As we think about innovation in terms of conduits, the procedure itself, the other aspect that's covered in our last paper is can we make the procedure safer perhaps by modifying our use of anti-platelet therapies based on meshment of the platelet phenotype and Tim do you want to bring us home by just telling us a little bit about what we learned from Paul Gurbel and his group of platelet experts?

Dr Tim Gardner: Well we learnt a lot about platelet science and appropriately so Dr Gurbel is a well-recognized expert in platelet physiology or platelet management and this is a really quite a challenging area because many of our patents come to surgery especially for coronary surgery already on platelet inhibitor agents and what Dr Gurbel and his co-authors showed in this paper is that although there is somewhat limited data there can be and should be platelet function testing and with an appropriate understanding of platelet inhibition drugs that we may be able to limit the time between removal of these or discontinuation of these platelet inhibitor drugs and the necessary surgery which will improve outcomes and reduce bleeding in patients requiring urgent CABG surgery. It’s a very useful update and it is a good example of a paper that isn't written by surgeons, but really applies very much to the cardiac surgical treatment of coronary artery disease

James de Lemos: I really like the very practical tables and figures that lay out the potential tests that surgeons or anesthesiologists may consider for assessing this and even how one might implement. I would like to bring us to conclusion now, first I want to acknowledge, Sara O'Brien at the Circulation office for her amazing work together with Marc and Tim pulling this issue together, making sure that we have a consistent high quality issue with wonderful figures and tables and it really came together beautifully and thank you both for joining me today and the podcast I think it’s obvious that we've got an issue that all of you listen to this podcast need to actually pull out the issue or download it because we have a co-host of wonderful papers to look at and cardiac surgery thriving at Circulation. As we've talked about this is the tip of the iceberg, this themed issue, we've got great content coming, issue after issue. We are already open for business next year’s issue, so please send us your best cardiac surgery research. Please pay attention to these important papers and apply them in your practice because I think many of them are already directly applicable.

Marc given your leadership role in the issue do you want to bring us home and make any concluding remarks?

Dr Marc Ruel: I think your points are very well taken James and I want to reintegrate that if I speak on behalf of the cardiovascular surgical community, we are very thankful to the leadership with Circulation. James, Joe, Tim and many others and obviously the support from the staff in clearly establishing that cardiovascular surgery is a very important therapeutic mentality and the overall scope in the broad scope of cardiovascular therapeutics.

Dr Carolyn Lam: You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation October 30, 2018 Issue

29 oktober 2018 | 25 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue provides much long awaited healthcare resource utilization and cost implications in the MOMENTUM 3 randomized controlled trial of a magnetically levitated cardiac pump in advanced heart failure. All of this coming right up after these summaries.

The first original paper this week provides important mammalian data on the acute effects of phosphodiesterase type 1 inhibition on the heart. Now phosphodiesterase type 1, or PDE1, is known to hydrolyze cyclic AMP and cyclic GMP in the heart. However, what's important to understand is that data from rodents may not be applicable to humans because rodents express mostly the cyclic GMP favoring PDE1A isoform, whereas human hearts predominantly express PDE1C isoform which has a balanced selectivity for cyclic AMP and cyclic GMP.

In today's paper, first author Dr Hashimoto, corresponding author Dr Kass from Johns Hopkins University School of Medicine and colleagues, determined the acute effects of PDE1 inhibition on PDE1C expressing mammals, dogs and rabbits, in normal and failing hearts. They found that selective inhibition of PDE1 with ITI-214 induced positive inotropic, lusitropic, chronotropic, and arterial vasodilatory effects in dogs and rabbits. These effects occurred via cyclic AMP modulation and were observed in failing hearts. ITI-214 contractile increase was insensitive to beta adrenergic blockade or heart rate increase, but inhibited in vivo by adenosine receptor inhibition. Furthermore, isolated myocytes revealed differences between PDE1 and PDE3 inhibition. Wherein PDE3 inhibition, augmented beta receptor agonism and calcium transients, whereas PDE1 inhibition enhanced function without calcium increase. These findings have important clinical implications for ITI-214 which has completed phase 1 trials and may provide a novel therapy for heart failure.

We know that macrophages are involved in foam cell formation in atherosclerotic plaques, but our next paper tells us we may now have a way to therapeutically modify this. Co-corresponding authors Dr Wei and Schober from Ludwig Maximilian's University Munich elucidated the role of microRNA generating enzyme Dicer in macrophage activation during atherosclerosis. They showed that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited, whereas lipid filled foam cell formation was exacerbated in Dicer deficient macrophages due to impaired mitochondrial fatty acid oxidative metabolism. MicroRNA biogenesis promoted the degradation of fatty acids by mitochondrial respiration in macrophages, which in turn reduced intracellular lipid storage and limited atherosclerosis. Thus, reducing foam cell formation in atherosclerotic arteries by enhancing energy metabolism through microRNA mediated fatty acid oxidation may be a promising approach for the treatment of atherosclerosis.

The next study evaluates how aortic stiffening relates to resting cerebral blood flow and cerebral vascular reactivity in older adults. First and corresponding author Dr Jefferson from Vanderbilt Memory and Alzheimer's Center and her colleagues studied participants free of clinical dementia, stroke, or heart failure, including 155 older adults with normal cognition and 115 mild cognitive impairment. They found that greater thoracic aortic stiffening quantified by cardiac magnetic resonance was associated with lower cerebral blood flow in cognitively normal older adults. Aortic stiffening was associated with reduced resting cerebral blood flow in the presence of preserved reactivity and associated vasodilatory capacity, particularly among participants without hypertension. ApoE4, a well-known genetic susceptibility risk factor for Alzheimer's disease, modified the results with stronger effects among carriers in the temporal lobes, where Alzheimer's disease pathology is known to first evolve. In summary, greater aortic stiffening related to lower regional cerebral blood flow and higher cerebral vascular reactivity in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow for earlier detection and targeted interventions to prevent or mitigate the onset of more serious cerebral vascular damage associated with greater aortic stiffening.

Aortic valve replacement for aortic stenosis is usually timed according to the development of symptoms, but could the timing be too late once irreversible myocardial scar has developed? Co-first authors Drs Musa and Treibel, corresponding author Dr Greenwood from University of Leeds and their colleagues found that in patients with severe aortic stenosis, focal myocardial fibrosis determined by cardiac magnetic resonance imaging was present in over 50% of patients and was associated with a two-fold higher late mortality. Focal scar was independently associated with all cause and cardiovascular mortality, after both surgical and transcatheter aortic valve replacement. In severe aortic stenosis, late gadolinium enhancement appears to be a useful biomarker of left ventricular remodeling, and its presence is associated with worse long-term outcomes following aortic valve intervention. Thus, in severe aortic stenosis, late gadolinium enhancement may be a useful biomarker of left ventricular remodeling, and its presence may be associated with worse long-term outcomes following aortic valve intervention.

The next study suggests that endogenous factor Xa activity may be irrelevant pharmacodynamic marker to guide Edoxaban dosing in future. First author Dr Yin, corresponding author Dr Giugliano from TIMI Study Group, Brigham and Women's Hospital in Boston, and their colleagues, describe the value of endogenous factor Xa activity as a pharmacodynamic marker, linking Edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. They showed that the extent of inhibition of endogenous factor Xa activity was influenced by Edoxaban dosing and clinical characteristics, and was associated with both antithrombotic benefit and risk of bleeding. The implications are that this approach of linking endogenous factor Xa activity to clinical outcomes may be used to guide dose selection in future clinical trials, to monitor patients in certain clinical scenarios, or to define the doses of oral factor Xa inhibitors in patients who require precise anticoagulation therapy.

The next paper describes a novel multi-protein complex that plays a critical role in regulating cardiomyocyte survival. First author Dr Zhang, corresponding author Dr Yan from University of Rochester School of Medicine and Dentistry and colleagues, showed that phosphodiesterase 1C is activated by transient receptor potential canonical channel-3 derived calcium, thereby antagonizing adenosine A2 receptor cyclic GMP signaling and promoting cardiomyocyte death or apoptosis. Targeting these molecules individually, or in combination, may represent a compelling therapeutic strategy for potentiating cardiomyocyte survival.

The final paper demonstrates a molecular link between two well-recognized biomarkers of fibrosis, Galectin-3 and Osteopontin. First author Dr Shirakawa, corresponding author Dr Sano from Keio University School of Medicine and their colleagues, showed that Osteopontin was almost exclusively produced by Galectin-3 high CD206 positive macrophages, which specifically appear in the infarct myocardium after a myocardial infarct. The interleukin-10-STAT3 Galectin-3 axis was essential for Osteopontin producing reparative macrophage polarization after myocardial infarction, and these macrophages contributed to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results therefore suggest that Galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling Osteopontin levels. And that brings us to the end of this week's summaries, now for a feature discussion.

Left ventricular assist devices have truly revolutionized our management of advanced heart failure. In fact, these devices have allowed us to keep patients not just as a bridge to transplantation, but as destination therapy. The devices get better and better but also more and more expensive, and the problem is, that places a lot of strain on our healthcare systems. A lot of us are crying out for information on the cost effectiveness of these newer devices, and guess what? We have answers this week with our featured paper.

I am delighted to have with us the first and corresponding author Dr Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as our senior editor Dr Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Hello, Mandeep and Biykem! I am so pleased to be talking about a subject really close to all our hearts. Mandeep, could you start by maybe sketching out the actual issue, and maybe reminding our audience what's the difference between the different types of left ventricular assist systems that you compared.

Dr Mandeep Mehra: The era of left ventricular assist devices took a major therapeutic shift when we recognized that we could usher in continuous flow devices. These are devices that generate no peripheral pulse, they do not have systole and diastole. And these devices are small in profile, have very few moving parts, and there are several commercially available devices, two in the United States and up to three worldwide, that bear these characteristics.

The HeartMate II device, which is a continuous flow device that flows blood in an axial format. The HeartWare, or HVAD device, which is a centrifugal flow pump, where the blood comes in and then is ejected at a 90 degree angle. The Jarvik 2000 pump that is still used in some areas, in many regions experimentally, and then the new kid on the block, the HeartMate 3 device, which is a centrifugal flow pump with some very unique technological characteristics.

Dr Carolyn Lam: Nice! And now drumroll, please tell us what you found in your brilliant study this week.

Dr Mandeep Mehra: First, I'd like to remind the audience that the MOMENTUM 3 trial which randomized patients to the HeartMate II versus the HeartMate 3 device, was called MOMENTUM 3 and was a two-year study. We presented the pivotal two year trials results in 366 randomized patients earlier this year in The New England Journal of Medicine, and this study showed that the HeartMate 3 was superior on the primary endpoint when compared to the HeartMate II. The primary endpoint was survival, free of a disabling stroke, or the need to replace the pump surgically for a pump malfunction. And much of that, Carolyn, was driven by the need for replacement of the pump because the HeartMate 3 pump has some unique features that reduce its proclivity for pump thrombosis.

The HeartMate 3 pump is a frictionless pump. It's completely, magnetically, dynamically, born in the rotor. It has wider blood flow paths, so we don't see hemolysis with this pump. And this pump also has an artificial intrinsic pulse that has been created, that pulsates the pump in a 40 beats per minute configuration. So this was the primary trial result, and one of the lucky foresights that we had when we designed the trial was to embed, prospectively, economic analysis within this trial. We recognized that the cost effectiveness related issues and cost configurations with these devices would become very, very important as we scale into today's day and age of healthcare transformation. And the paper that is being presented in Circulation this week, really speaks to the health resource utilization and cost outcomes between the two devices.

We found that the HeartMate 3 pump is actually a cost minimization device, and what that means, Carolyn, is that we have become very used to thinking of new technology as providing incremental costs. So we think that, "Oh, well, what incremental costs should society bear for the benefits as we allocate new technology?" And in this particular trial, what we found is that while the costs of the pump itself, the HeartMate II and the HeartMate 3, were kept the same, which means its operational implant costs were the same, pretty much. We found that the HeartMate 3 pump was associated with a reduction in healthcare resource utilization over two years and with a marked decrease in cost. And in fact, our estimate of cost reduction was in the range of about 65 thousand dollars less, compared to the HeartMate II, in favor of the HeartMate 3.

Dr Carolyn Lam: Wow, Mandeep, first of all, congratulations on these remarkable findings. Biykem, I really have to bring you in here. What do you think of the implications of this?

Dr Biykem Bozkurt: First, I would like to congratulate the authors for a very innovative approach. As Mandeep has stated, they prospectively collected very challenging billing data from the hospitals, and then also did a very complex analysis including the VRG, as well as looking at payer reimbursements for public versus private. And did a variety of subgroup analysis, which I thought was quite helpful in sorting out that perhaps the cost effectiveness was concurrent both from the Medicare, the public, as well as the private, or regardless of the intent for destination versus bridge to transplant.

Probably the most important concept when you look at these close analysis is incremental cost effectiveness ratio, per quality of adjusted life year gained. Now, I do realize the current analysis doesn't allow us to infer the ICER benefit or the incremental cost effectiveness, which I think the investigators are planning to do with a thousand and more patients over a course of two years, which is going to be probably the more definitive. But as it currently stands, with what is provided by Dr Mehra and his colleagues is, we're probably reaching that sweet spot of what is construed as the cost effectiveness ratio of a cost.

Let's say 100 thousand dollars over the course of a year, then I would like to ask Mandeep whether on the prediction will reach that threshold of less than 100 thousand dollars. Because the former studies, looking at the ICER ratios, or incremental cost effectiveness ratios for the DT destination therapies, usually we select somewhere around 200 thousand dollars. And I know that usually that is seen as a prohibited cost, and there was a discussion whether we would be able to reduce the cost by about half, either doing index admission and add subsequent hospitalizations. With the data Dr Mehra and his colleagues have shown, it looks like the re-hospitalization cost is about, approximately half, or reduced by 50%. Mandeep, any thoughts on that, on that sweet spot?

Dr Mandeep Mehra: Yeah. I think, Biykem, you have articulated this extraordinarily well. And for the audience, since it's worldwide, I'd like to place a few things in perspective on how to think of economic modeling. First of all, the point I would make is that this is the first prospectively collected data that we have in the field, and as you pointed out, it was very, very difficult to pull this data together and is still very complex. But let's just think about what ICER really is. It all starts with what we consider to be health utility.

For example, Carolyn, Biykem, and me less so, would have a health utility of 1.0, 1.0 means a perfect health utility number. And I know, Carolyn, you and Biykem are absolutely perfect so you would be a 1.0, I probably am not a 1.0. But a patient with advanced heart failure has a health utility of about .4, so that's only 40% of what is perfect. And when we place ventricular assist devices, whether you place the HeartMate 3 or the HeartMate II, the health utility actually jumps up to about .7. So it's not perfect yet, but it moves all the way up there.

The incremental cost effectiveness ratios of implanting a device over time are calculated based on this health utility benefit, compared to the population of advanced heart failure. And the best current estimates of the HeartMate II are that ICER is about 200 thousand dollars, per quality adjusted life years gained, and this has been done by creating what's known as Markov modeling. A lot of that, by the way, is conjecture, it's not real information. It is predicted information, so one has to take that data with a grain of salt.

Here in this health resource analysis for MOMENTUM 3, we actually looked at actual data. There are some estimates used in this analysis as well, where we did not have accurate billing forms available, but we focused on those things where we had very clear knowledge of the cost of outcomes. For example, we did not look at the costs of outpatient follow-up care. We mainly looked at the cost differences of hospitalizations. And what we essentially found here is that just looking at hospitalizations and differences between the two devices, the cost differential, whether it's Medicare which is public [inaudible 00:20:14], or whether it's commercial. It ranges somewhere between 50 to 65 thousand dollars of difference between the two devices.

Now, if you assume that the ICER for the HeartMate II is accurately at about 200 thousand, and you reduce that ICER by about 50 to 60 thousand, the ICER would naturally come into the range of what you would consider to be about 135 thousand to 150 thousand dollars per quality adjusted life years gained for the HeartMate 3, compared to an advanced heart failure population. Once we look at it from that perspective, as Biykem pointed out, we are getting closer and closer to the societal norms.

At one time-point, society used to think of a quality adjusted life years gained cost of 50 thousand dollars as something that would be acceptable to society, and this was seemingly based on the threshold for what dialysis provides in benefit. And now, we recognize that we have to really expand that to somewhere around 100 thousand more logically, or between 100 and 150 thousand for some technologies. The important thing I would say to you is that, that is society dependent. So what the United States considers to be a reasonable ICER, say 100 to 130 thousand dollars per quality adjusted life years gained, may not be the same that Great Britain would look at, or Sweden would look at, or another country would look at. And each country actually creates their own economic value propositions, and this will have to be taken into account as we think about this data as well.

Dr Carolyn Lam: How cleverly and clearly articulated, thank you so much Mandeep. Just one last question for both you and Biykem, what do you think this implies for moving to less and less advanced heart failure with these left ventricular assist device systems? Biykem?

Dr Biykem Bozkurt: It's an ever-expanding field, and as these devices are becoming smaller, lower profile with lesser complications and more affordable, probably the utilization will likely increase as we have been seeing. As you know, even the percutaneous non-durable device used, as well as our mechanical circulatory support durable devices are definitely increasing utilization. And thus, one may wonder not only the bridge to transplantation, but the destination therapy portfolio, or bridge to decision portfolio, may really increase as these devices become safer and more affordable.

Dr Carolyn Lam: Wow, that's amazing. How about you, Mandeep, what do you think?

Dr Mandeep Mehra: Carolyn, I couldn't have said it any better than what Biykem articulated. I do think that at least in the United States, as we reach the thresholds of cost effectiveness that we as a society accept, we will start to see a lot more widespread utilization, particularly for lifelong therapy or so-called destination therapy. I completely agree with that. I think that moving the needle to the less sicker population is still challenging, because there are complications with these devices that make that slightly difficult.

There was a trial called the REVIVE-IT trial that was stopped midstream largely because of concerns about pump thrombosis, and that trial was looking at taking these devices to a less sick NYHA class 3 population and was stopped midstream. Now that the HeartMate 3 has pretty much resolved the issue of pump thrombosis, and even show a halfing in stroke rates with this device over two years, I think that that portfolio of evidence needs to be reopened. I would caution though, that until we have confirmatory randomized data in those less sick populations, the use to that population should still stay restricted.

Dr Carolyn Lam: I don't think anyone could have said it better than both of you. Thank you so much for this very insightful and balanced conversation.

Thank you so much for listening today. You were listening to Circulation on the Run, and don't forget to tune again next week.

Circulation October 23, 2018 Issue

22 oktober 2018 | 18 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors.

I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. The ORBITA Trial of percutaneous coronary intervention and stable single vessel coronary artery disease has to be one of the most hotly discussed in the cardiology world. The featured paper of this week adds important knowledge that will help us understand the physiology stratified results of ORBITA.

Coming right up after these summaries.

The first original paper this week provides novel mechanistic insights that may lead to a new treatment approach for obesity and hypertriglyceridemia. Co-corresponding authors, Drs Xiang and Xia from Central South University of Xiangya in China, looked at Reticulin 3, which is an endoplasmic reticular protein that has previously shown to play a role in neurodegenerative diseases.

In the current paper, the authors show that over-expression of Reticulin 3 in mice induced obesity and a greater accumulation of triglycerides. Remarkably, increased Reticulin 3 expression was also found in patients with obesity and hypertriglyceridemia. They further showed that Reticulin 3 played critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Thus, these results suggest that inhibiting the expression of Reticulin 3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia in the future.

The next study provides insights into the genetic determinates of residual cardiovascular risk in patients already receiving statins. First author Dr Wei, corresponding Dr Denny from Vanderbilt University Medical Center and their colleagues performed a genome-wide association study and identified that a variation at the LPA Locus was associated with coronary heart disease events during statin therapy and independent of the extent of LDL cholesterol lowering. The association of the LPA Locus with coronary heart disease events persisted in individuals with an LDL cholesterol less than 70 milligrams per deciliter. These findings, therefore, provide support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce coronary heart disease events in patients already receiving statins.

The next paper provides important mechanistic results that help us understand pathways in atherosclerotic plague regression. Co first authors, Drs Mueller and Zhu, corresponding author Dr Fazio from Oregon Health and Science University and their colleagues have previously shown that mice lacking an LDL receptor with beta protein 1 in macrophages undergo accelerated atherosclerotic plague formation. However, in the current study they sought to explore the role of macrophage LDL receptor protein 1 during plague regression. They did this by placing EPO E deficient mice on a high fat diet for 12 weeks, then reconstituting their bone marrow using wall type or macrophage LDL receptor protein 1 deficient mice as donors, and finally switching them back to a chow diet for 10 weeks. The authors found that the lack of LDL receptor protein 1 expression in macrophages unexpectedly caused more atherosclerosis regression. Mice with macrophages lacking LDL receptor protein 1 showed less M1 macrophages in the plague and increased CCR7 dependent egress of macrophages from the plague. Thus, loss of macrophage LDL receptor protein 1 has a dual and opposite effect on plague biogenesis, depending on whether the plague is growing or shrinking.

The next paper highlights the intercalated disc, which is a specialized intercellular junction, coupling cardiomyocyte electrical activity in forced transmission as a mechanosensitive signaling hub for causative mutations in cardiomyopathy. First author Dr Trembley, corresponding author Dr Small from University of Rochester School of Medicine and Dentistry and their colleagues showed that myocardin related transcription factors associated with desmosome proteins of their intercalated disc in both murine and human hearts. Genetic deletion of myocardin related transcription factors in cardiomyocytes led to rapid onset of dilated cardiomyopathy in response to pressure overload hypertrophy. Furthermore, myocardin related transcription factors were required for the maintenance of sacromere and intercalated disc integrity under pathological stress. These findings, therefore, provide a unique link between the intercalated disc and mechanosensitive transcriptional regulations. Since myocardin related transcription factors redistribute from intercalated disc in human heart failure, this may represent a novel signaling complex present in cardiomyopathic characterized by desmosome dysfunction.

The next paper investigated the association of blood pressure with peripheral arterial disease events, using data from the ALLHAT Trial. Co first authors Drs Itoga and Tawfik, corresponding author Dr Chang from Stanford University School of Medicine and their colleagues found that both lower systolic blood pressure of less than 120 and higher systolic blood pressure of above 160 millimeters of mercury were both associated with higher rates of peripheral arterial disease events. Diastolic blood pressure less than 70 and a pulse pressure above 65 millimeters mercury were also associated with increased rates of lower extremity peripheral arterial disease events. Given that the recent revised blood pressure guidelines advocate lower systolic blood pressure targets for overall cardiovascular risk reduction, the authors called for future, further refinement of optimal blood pressure targets, specific for peripheral artery disease.

The final original paper this week provides the first integrated atherosclerotic disease risk calculator to incorporate risk factors including high sensitivity C reactive protein, family history, and coronary artery calcium data. First and corresponding author Dr Khera from UT Southwestern Medical Center and colleagues used 3 population-based cohorts to develop Cox Proportional Hazards Models for the outcome of atherosclerotic cardiovascular disease. The derived Astro-CHARM model incorporated factors like age, sex, systolic blood pressure, total and HDL cholesterol, smoking, diabetes, hypertension treatment, family history of myocardial infarction, high sensitivity c reactive protein, and coronary artery calcium scores. The model performance was validated externally in a 4th cohort, and shown to improve risk prediction compared with traditional risk factor equations, and showed good discrimination in calibration in the validation cohort. A mobile application and web based tool was developed to facilitate the clinical application of this tool, and is available at www.astrocharm.org.

And that brings us to the end of this week's summaries. Now for our featured discussion.

Gosh, I am learning for the first time today that it's terribly inconvenient to lose my voice when I am a podcaster. This is Carolyn Lam and our featured discussion that I am so excited about, but the cool thing is the thing we are talking about is so hot that you don't even need me to say anything. And what we are talking about is the ORBITA Trial. That was greeted with as much hype and hoopla and sensationalism since its publication in 2017. I am so proud to have the first and corresponding author Dr Rasha Al-Lamee from National Heart and Lung Institute Hammersmith Hospital in London. I also have Dr Ajay Kirtane from Columbia University Medical Center in New York Presbyterian Hospital and the Cardiovascular Foundation in New York as the editorialist for the paper. And finally, our associate editor Dr Manos Brilakis from UT Southwestern. Rasha, why don't you just take it away and just tell us, what is your paper focusing on in this week's issue?

Dr Rasha Al-Lamee: The paper that was published in this issue in circulation is basically our second analysis of the ORBITA Trial, a substudy analysis. Essentially, looking at the primary endpoint and the secondary endpoints of ORBITA, and having a look at those patients from ORBITA and seeing whether there was any association between their invasive physiological assessment using FFR and ISR at the pre-randomization stage and seeing whether the level of ischemia on ISR or FSR was associated or predicted in the way in which they performed in terms of their endpoints. To see whether there was any difference in the placebo control efficacy of angioplasty in those patients who have more or less severe ischemia on their invasive physiological assessment.

Dr Manos Brilakis: First off, that's a phenomenal paper, and I think she puts things into perspective. I know Ajay put an excellent tutorial. I think all of us were surprised about the findings. You would expect that the more ischemia, that you might see a little more response. Any thoughts as to why there wasn't such an association?

Dr Rasha Al-Lamee: I think it's so difficult because, of course, as we all know from the primary paper that was published in The Lancet, in terms of the primary endpoint, which would be change in exercise time and the difference between the two groups, the difference is actually much smaller than we expected. And when we have such a small difference in exercise time, the ability to be powered enough to be able to split that endpoint based on stratification of invasive physiology becomes very difficult, and we're perhaps underpowered to be able to do that.

Where we did see a very great effect in terms of the primary assessment in The Lancet paper was in stress echo ischemia. What we saw is those patients who had angioplasty were far more likely to have an improvement, or indeed, a normalization of their ischemia on their stress echo. Where we saw a big difference the two groups we were then clearly powered to be able to stratify those patients based on their invasive physiology, and for that secondary endpoint we saw that, in fact, tied to your stenosis or the lower your ISR or FRR, the more likely you are to have an improvement in stress echo, having had placebo controlled angioplasty.

Dr Manos Brilakis: Ajay, I know you had a lot of things insight into the vision of the tutorial for the ORBITA Trial. What are your thoughts about the findings?

Dr Ajay Kirtane: I would, first of all, congratulate Rasha and the ORBITA team, there are others, for not only doing the main trial, but for conducting these detailed analyses, which were clearly set up ahead of time, and that's been one of the critiques of the trial is why were patients with normal-ish range FFRs included. Well, part of it was to test this hypothesis, and perhaps to show that there would be a correlation between the change in the FFR, if you will, and the endpoints that were measured.

So, I think that that's the first part, that this is actually a scientific experiment, and a thoughtful one in doing so. I think exactly as Rasha said though, if there is a limited signal, with respect to the overall trial, then further subsetting is less likely to show a significant signal. I think that's exactly what the investigators found. The only other comment I would make though is, I would commend Rasha and the team for producing other analyses that are novel in this manuscript including the freedom from angina analysis, as well as responding to some of the earlier critiques of the trial and not using specific methodologies to adjust the baseline differences improves. Those are also included in this analysis.

Dr Manos Brilakis: Yeah, absolutely, I think that was very enlightening to see, the freedom of angina. And I know there was some questions whether that might change the overall findings from the studies, so there is some quality of life benefit. Rasha, what is your thoughts about this? I mean, you must understand this study better than anyone else. People who have stable angina, should they undergo PCI or not?

Dr Rasha Al-Lamee: I think the freedom from angina signal was very important, and obviously not something that we had pre-specified, so it wasn't reported in the primary analysis. We're obviously much more able now, since we've published that primary analysis to do secondary analyses and look at things that perhaps we haven't pre specified. And it's interesting to see that 20% more patients are free from angina having had angioplasty vs. placebo. Having said that, to me, it's a fantastic finding, but still a little unexpected. Much less than we might expect looking at unblinded data, or our unblinded clinical experience. I would have expected much higher levels from freedom of angina.

Dr Rasha Al-Lamee: I think what we know, and what we've seen both from this paper, very importantly, and also the primary manuscript, is that the efficacy of angioplasty is very tightly linked to the improvement in ischemia. We've actually, in fact, got more papers that are coming out from our group recently. And that you can predictably tell your patients that if I sense a lesion that's causing a reduction in ISR or FFR, and potentially symptoms, then I will improve your ischemic burden.

What I think is more tricky is how much I will relieve your symptoms, or make you feel better. That may be because symptom assessment itself is very tricky, and perhaps that actually just diagnosing cardiac angina is actually a very difficult thing. The easiest way to piece out improvement in symptoms is to find those patients who become free of angina because, of course, that's the binary end point. When we look at grades of symptoms, and whether their angina frequency improves, or whether the level of angina improves in terms of PCI, then I think it becomes much harder, especially in a blinded trial where, of course, when people come back, even with atypical chest pain, it will still be recorded as potentially angina because, of course, both the investigators and the patients have no idea what they've had done, which is quite different from real life where, of course, you are able to think more about whether this chest pain might indeed be from the heart or from other causes.

Dr Manos Brilakis: Perfect, thank you very much. And I would completely agree with you that, the study was perfect. And, as Ajay said, it is something that we needed, and more of them should be done. And I think you are right that this is the best way to piece out the symptom improvement.

Ajay, any final comments?

Dr Ajay Kirtane: I think that the toughest challenge with trials like this is to really enroll the patients that many of us as interventionists feel would really improve in terms of their symptom class. Even despite these efforts, if one looks at the baseline of anginal frequency in the trial, the means are relatively high, which suggest that the anginal burden, at least in terms of measurements through the anginal questionnaire is not that severe. One could argue that somebody has severe angina that is occurring all the time, that those are types of patients that are hard to randomize in a clinical trial.

I think, at least my overview stepping back perspective of the context of ORBITA within clinical practice, is exactly that. The trial is an important scientific advance, but this does not encompass the answer for every single patient that comes to see us in the office that have a range of symptoms, very severe to less severe. That was something Rasha has been saying all along as well. It's not something that we could over extrapolate this to every patient that we see. So, I think that when the hype dies down, these types of scientific analyses will stand out. They emphasize the need for regular clinical research, and in that way, I think has generated a lot of attention not only to the clinical field here, but also the scientific pursuit of evidence. That's a really magical thing.

Dr Rasha Al-Lamee: I think, if I can add to that Ajay, I think it's probably also sort of the assessment of symptoms is incredibly important. I think many of us, and I'll include myself in this, when we see a very tight stenosis, are happy to essentially correlate any level of symptoms to that tight stenosis. One thing I've learned from all this, I want to see reproducible angina that very much is textbook, cardiac caused chest pain, and the atypical anginas we see, perhaps some of that pain is not from that stenosis, but from somewhere else. Therefore, by fixing that stenosis, we don't necessarily make that pain go away.

Dr Manos Brilakis: Absolutely, and I think you are absolutely, if it is something simple vessel disease, if it's something a little more straightforward, then I think you are right Ajay, that this is much harder, multiple vessel disease especially in people with reduced ejection fraction.

Dr Carolyn Lam: You've been listening to Circulation on the Run! Don't forget to tune in again next week!

Circulation October 16, 2018 Issue

15 oktober 2018 | 25 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Will artificial intelligence replace the human echocardiographer? Aha, well to find out the answer, you have to wait for the incredibly exciting discussion of today's feature paper coming right up after these summaries.

The clinical benefits of the cholesterol ester transfer protein, or CETP inhibitor dalcetrapib depends on adenylate cyclase type 9, or ADCY9 genotype. However, what are the underlying mechanism responsible for the interactions between ADCY9 and CETP activity? In the first paper from today's journal first author Dr Rautureau, corresponding author Dr Tardif from Montreal Heart Institute, and colleagues used a mouse atherosclerosis model inactivated for ADCY9 and demonstrated that loss of ADCY9 protected from atherosclerosis and was associated with improved endothelial function, but only in the absence of CETP. ADCY9 in activation increased weight gain, adipose tissue volume, and feed efficiency, but only in the absence of CETP.

This mouse model reproduced the interactions between ADCY9 and CETP activity observed in patients, and offers new mechanistic insights for the importance of ADCY9 in determining the responses to CETP inhibition. For example, the dal-GenE clinical trial is currently testing prospectively whether patients with coronary disease and the favorable ADCY9 genotype will benefit from dalcetrapib.

The next study addresses the controversy around the cardioprotective effects of Omega-3 polyunsaturated fatty acids, and uncovers signaling pathways associated with eicosapentaenoic acid, or EPA supplementation that may mediate protective effects in atherosclerosis. First author Dr Laguna-Fernandez, corresponding author Dr Bäck from Karolinska Institute, and their colleagues showed that EPA supplementation significantly attenuated atherosclerotic lesion growth. They performed a systematic plasma lipidomic analysis and identified that 18 monohydroxy eicosapentaenoic acid was a central molecule formed during EPA supplementation. 18 monohydroxy eicosapentaenoic acid was a precursor for the plural resolving lipid mediator called resolvent E1.

In the present study, a resolve in E1 was shown to regulate critical atherosclerosis related functions in macrophages through its downstream signaling receptor to transfuse protective effects in atherosclerosis.

Are there racial differences and long-term outcomes among survivors of in-hospital cardiac arrest? In the next paper first and corresponding officer Dr Chen from University of Michigan and her colleagues performed a longitudinal study of patients more than 65 years of age who had an in-hospital cardiac arrest and survived until hospital discharge between 2000 and 2011 from the National Get With The Guidelines Resuscitation Registry whose data could be linked to Medicare claims data. They found that compared with white survivors of in-hospital cardiac arrest, black survivors had a more than 10% lower absolute rate of long-term survival after hospital discharge. This translated to a 28% lower relative likelihood of living to one year, and a 33% lower relative likelihood of living to five years after hospital discharge for black versus white survivors.

Nearly one-third of the racial difference in one-year survival was dependent on measured patient factors. Only a small proportion was explained by racial differences in hospital care, and approximately one-half was the result of differences in care after discharge, or unmeasured confounding. Thus, further investigation is warranted to understand to what degree unmeasured, but modifiable factors, such as post-discharge care may account for the unexplained disparities.

The next study provides insights into a novel mechanism of atherogenesis that involves protease-activated receptor 2, a major receptor of activated factor 10, which is expressed in both vascular cells and leukocytes. Co-first authors Dr Hara and Phuong, corresponding author Dr Fukuda from Tokushima University Graduate School of Biomedical Sciences, and their colleagues showed that in ApoE-Deficient deficient mice, protease-activated receptor 2 signaling activated macrophages and promoted vascular inflammation, increasing atherosclerosis.

Furthermore, they showed that in humans, plasma-activated factor 10 levels positively correlated with the severity of coronary artery disease, suggesting that the signaling pathway may also participate in atherogenesis in humans. Thus, the protease-activated receptor 2 signaling pathway may provide a novel mechanism of atherogenesis and serve as a potential therapeutic target in atherosclerosis.

The next paper tells us that biomarkers may help to predict specific causes of death in patients with atrial fibrillation. First and corresponding author Dr Sharma and colleagues from Duke Clinical Research Institute evaluated the role of biomarkers in prognosticating specific causes of death among patients with atrial fibrillation and cardiovascular risk factors in the ARISTOTLE trial.

They looked at the following biomarkers: high sensitivity troponin T, growth differentiating factor 15, N-terminal pro-B-type natriuretic peptide, and interleukin 6. They found that sudden cardiac death was the most commonly adjudicated cause of cardiovascular death, followed by heart failure and stroke or systemic embolism deaths. Biomarkers were some of the strongest predictors of cause-specific death, and may improve the ability to discriminate among patients' risks for different causes of death.

How do the complement and coagulation systems interact in cardiovascular disease? Well in the final original paper this week, first author Dr Sauter, corresponding author Dr Langer from Eberhard Karls University Tübingen, and their colleagues used several in vitro, ex vivo, and in vivo approaches as well as different genetic mouse models to identify the anaphylatoxin receptor C3AR and its corresponding ligand C3A as platelet activators that acted via intra -platelet signaling, and resulted in activated platelet fibrinogen receptor GP2B3A. This in turn mediated intravascular thrombosis, stroke, and myocardial infarction. This paper, therefore, identifies a novel point of intersection between the innate immunity and thrombosis with relevance for the thrombolic disease of stroke and myocardial infarction.

That wraps up with week's summary. Now for our featured discussion.

Can we teach a machine to read echocardiograms? Well today's feature paper is going to be all about that. I am so excited to have with us the corresponding author of an amazing, and I think, landmark paper, Dr Rahul Deo from the One Brave Idea Science Innovation Center and Brigham and Women's Hospital in Boston, as well as our associate editor Dr Victoria Delgado from Leiden University Medical Center in The Netherlands. Now let me set the scene here. We know that echocardiography is one of the most common investigations that we do in cardiology, and in fact even outside of cardiology, and it is hands down the most accessible, convenient tool to image the heart.

Now let's set this up by remembering that echocardiograms are performed with machines, but led by echocardiologists like me. Now this is really scary Rahul because I think your paper is trying to say ... Are you trying to put people like me out of business?

Dr Rahul Deo: Definitely not. I think what I'm hoping to do is actually two things. One of them is, despite the fact that it's an accessible and safe tool, because it needs people like us, it's probably not used as often as ideally it could be. So part of our hope was to democratize echocardiography by being able to take out some of the expenses from the process so that we can hopefully get more simpler studies done at an earlier stage in the disease process. Because in many ways, at least from my experiences being an attending, it feels like if we could just have gotten to these patients earlier we may have been able to start therapy that could've changed the disease course, but our system can't really afford to do huge numbers of echoes on asymptomatic patients. Really we were trying to find some way of facilitating this by at least helping out on trying to quantify some of the simple things that we do with echocardiography.

Dr Carolyn Lam: I love that phrase, democratizing echo. And you're absolutely right, if we could put it in the hands of non-experts and help them interpret them, we could really lead to detecting disease earlier, and so on and so forth. Wow. But everyone's wondering, how in the world do you go about doing that?

Dr Rahul Deo: One of the things that's really been amazing in these last five years or so is that the field of computer vision, so the field by which computers are trained to mimic humans in terms of visualizing, recognizing, identifying images, has really advanced, and incredibly rapidly. And one of the reasons for that is that the video game type of computing system, the same things that go into Playstations and such, have resulted in much, much more rapid computing. And that's allowed us to train more complex models.

So that's one of the things that's changed, and also, it's just much easier to get our hands-on training data. So machines can be trained to do things, but they need lots of examples. And the harder the task, the more examples they need. So the widespread availability of digital data has made that easier, though I would say that it wasn't that easy to get our hands on enough echocardiography data to be able to train. But in general, almost any task where there's enough data has been solved on the computer vision side. So this has really been an exciting advance in these last few years. So we thought we could very well just used these same technologies on a clinical problem.

Dr Carolyn Lam: Okay, but Rahul what are you talking about here? Like the machine's actually going to recognize different views, or make automated measurements? That's the cool thing, frankly, that you've written about because we know that the machines can already kind of do EF, ejection fraction, but you're talking about something way bigger. So tell us about that.

Dr Rahul Deo: Yeah, so there are many cute examples in the popular press about machines being able to recognize the differences between cats and dogs, or some breeds of dogs. And so if you think about things that way, it really shouldn't be that much more difficult to imagine recognizing between different views, which probably are much more dramatically different than different breeds of dogs. So you could really just take the same models, or the same approaches, give enough examples, label them, and then say figure out what the differences are.

And I think one of the challenges with these systems is they're often black boxes. They can't tell us exactly what it is that they're using, but when it comes to something like recognizing whether something is an apical four chamber view or a parasternal long axis view, we actually don't care that much as to how it is that the computer gets there. We just wanted them to do it accurately, and that's one of the places for some of these computer vision models. It's a field broadly called deep learning, and it's just great at achieving complex tasks.

So, once you recognize views, then the other thing that computers have been shown to be able to do is recognize specific objects within an image. For example, you could give an entire football field and you could find a single player within it. You could recognize where the players are, where the ball is, where the grass is. So computers can distinguish all those things too. And then once you know where something is, you can trace it and you can measure it. So in that sense it's very similar to what a human reader would do, it's just broken down into individual steps, and each one of those needs to be trained.

Dr Carolyn Lam: You put that so simply so that everyone could understand that. That's so cool. You mentioned, though, accuracy. I could imagine that a machine would likely interpret one image the same way again and again, and that addresses something that we really struggle with in echo doesn't it? Because, frankly, one reader against another, we always know. Ejection fraction has got a plus minus seven or something, and then even within the same reader you could read the same thing and say something one day, and say something the other. So this is more than just automating it, is it?

Dr Rahul Deo: Yeah, so it's certainly making it more consistent, and the other thing that we were able to do, I mean once you can teach it to identify and traces the contours of the heart in one image you can have it do it in every single image within the video, and every single video within the study. So now, I mean it's quite painful. I know this from my own experience in terms of tracing these things, so a typical reader can't trace 150, 200, 300, 500 different hearts, that's not going to happen. So instead, they'll sort of sift through manually, pick one or two, and if there's variability from one part of the study to the other, that really won't be captured.

And in this case, the computer will very happily do exactly what you ask it to do, which is to repeat the same thing again and again and again, and then be able to average over that, capture variability. So that's one of the tasks that is much more easy to imagine, setting a computer who won't talk back to you and won't resist and won't refuse to actually taking on the mundane aspect of just getting many, many, many more measurements. And that could happen not only in a single study, but also could happen more frequently. So you could imagine that, again, there's just not that resistance that's coming from having to have an individual do these things.

Dr Carolyn Lam: Oh, my goodness, and not only does he not ... well he, machine, not say no, I mean they don't need to take time off or weekends off. We could get immediate reports directly. Oh my goodness. Victoria I have to bring you in on this. We knew as editors when we found this paper that this is something we just have to publish in Circulation that's going to be groundbreaking. Could you tell us a little bit more about what you think the implications of this is?

Victoria Delgado: I think that this is a very important paper because it's a very large study and it's sets, I would say, three important questions that we deal every day in clinical practice. One is how to reduce burden in very busy echo labs by facilitating the reporting of the echoes and the interpretation of the echoes. Second: to have an accurate measurement and quantification of the images that we are acquiring, and third: this is recognition of the pattern.

And I think that this very important, particularly in primary care because, for example in Europe here, echocardiography is not really in the primary care and the patients are being referred to secondary level hospitals or third level hospitals. That means that the waiting days sometimes is too long. If we train the general practitioners, for example, to do simple echocardiograms with the handheld systems which are also the technologies that are coming and are really available in your iPhone, for example, on your phone, you can get an echocardiographic evaluation of a patient that comes to a general practitioner.

And if you don't have too much knowledge on interpretation, these tools that can have recognition of the pattern of the disease can trace a red flag and say, okay this patient may have this disease or may have this problem, you should consider sending or referring this patient to us at Leiden Hospital where he's going to have a regular check-up and a complete echocardiogram. That could lead to less burden in very busy labs and only refer the patients in a timely manner to the centers when they have to be referred, when the others can wait of can be referred much later.

I think that that's important, and next two technologies that are coming now and it will be very important, some groundbreaking technologies. One is the handheld systems, the ones that you can have in your phone, the ones that you can have in your tablet for example. And the other one is going to be the artificial intelligence to, if not diagnose completely, at least to recognize the pattern that there is a pathology where we need to focus, and we need to act earlier.

Dr Rahul Deo: I think that one place we would like to see this used is in a primary care setting where you have individuals who have risk factors that we know would be risk factors, for example, for let's say heart failure with preserved ejection fraction. But really, my experience in that phase of clinical practice is there's a lot of resistance from patients to get on the medications. So hypertension is, at that point, often, I just got worked up because I had a hard time finding parking, and so on, and so on, where there's just a natural resistance.

So if you could imagine having objective measures describing, let's say how their left atrium is doing at that point, how it looks the next year, what the change in therapy is doing, all these things, you actually can bring in that quantification at a low enough cost that makes it actually practical, then that would be one place we could imagine motivating or intensifying therapies on the basis of something like this.

And I think one area we have to admit we didn't solve is we haven't solved the ability to facilitate getting the data in the first place. We do know that there are these focused workshops around trying to get some simple views, and more and more of our internal medicine residents are able to get some of these, but we can't dismiss that this is still an important challenge in terms of being able to get the images. What we want to do is say, well you can get some images and we can help you interpret them and quantify in an effort to try to motivate therapies being initiated or intensified in a way that's sometimes difficult to do in the current system.

Dr Carolyn Lam: So, Rahul and Victoria, you both mentioned that one of the key aspects is the acquisition of the echo. Not just the machine that does it, but also who takes the images that will then be automatically analyzed. So, Rahul, do you think that sometimes you're going to invent something that will replace even the acquisition, or maybe even simplify it so that we may not need Doppler anymore?

Dr Rahul Deo: One of the things that we thought about was, we wanted to limit ourselves to views that might be easier to acquire, in part because we wanted to reduce the complexity of the study and yet still try to capture as much information as possible. And getting back to the first part of your question, you could imagine that recognizing a view is not that different from recognizing that a view is 10 degrees off from where it should be. You could imagine training a computer to do just that very same thing too. It could recognize a slightly off axis apical four chamber view and guide you into correctly positioning the probe, and you could even imagine a robotic system that does this and just takes the person out of it all together. In part because a very skilled sonographer can quickly look at something and say, oh I just need to tilt my wrist this way and move it this way. I was always humbled by that because I never could quite do that myself.

But in the same way, and in the way, that's happening is that an image is recognized, and then the reference image is held in one's brain, and then they just know from experience what needs to be done to turn one into the other. But that very well-oiled machine could very well be taught to do that exact same thing too.

Dr Carolyn Lam: Oh wow. That is just totally amazing. I know the listeners are being blown away by this just as I am. Let me just end by asking for any last words, Victoria and Rahul, of the clinical application of this. When are we going to have this primetime? What do you think?

Victoria Delgado: I think that this is coming. This is one, for example, of the first studies showing the feasibility of this technology. In terms of accuracy, probably we need improvement, but that depends very much on the quality of the echocardiographic data that we obtain. And in the future, I think that we are going to rely more and more on this technology, and we will have the expert view for those cases that are ambiguous or where the technology has limitations. But in terms of accuracy, for example, I can imagine one of the clinical scenarios that we face in everyday clinical practice is the evaluation of the effect of the treatment in heart failure patients for ejection fraction, and in patients, for example, treated with chemotherapy to see changes in ejection fraction.

That, if we do it manually as we do now, we know that we have limitations in terms of the own viability of the observer. If you leave it for artificial intelligence, maybe that viability may be reduced, and you may be better in terms of adjusting the medication if needed. Because you removed completely what would be the individual viability. So these are the fields that probably I see more and more application of this technology in order to improve the reproducibility of the measurements and accuracy. But yeah, for that we need probably very good image quality, and I see in echocardiography we always tend to say, yeah the image quality is not that good. I'm sure that echocardiography can give you much more than just using through the echocardiography. You can use contrast, you can use many other techniques in order to improve the image quality. And artificial intelligence, the better the image quality is, probably the better it's going to be as well, the accuracy of the measurements and the recognition of disease.

Dr Carolyn Lam: Wow, and Rahul?

Dr Rahul Deo: I completely agree with Victoria. I think that we're going to have to be clever about where we incorporate something like this into the current clinical workflow. You have to choose your problem carefully, you have to understand it. Any system like this is going to make some mistakes. To figure out how to minimize the impact of those mistakes, and at the same time add benefit and potentially enable things that wouldn't even be done. So I think that the fun stuff is yet to come here in terms of really incorporating this in a way that can really change clinical practice.

I want to add one thing that I really haven't mentioned. And we, at this point, really just focused on trying to mimic the stuff that we're already doing. Part of the motivation of this work is to try to potentially see things that we can't even see right now and try to potentially predict onset of disease or early latent forms of something that would really be difficult to detect by the human eye. And we've seen examples of that in some of the other fields around radiology, and I think that's going to be a place that would be augmenting beyond what we're even doing currently.

But of course, the challenge is that the system has to be interpretable enough that we understand what it is that it's seeing, because otherwise I'm sure we'll be reluctant to embrace something clinically that we don't understand.

Dr Carolyn Lam: You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation October 9, 2018 Issue

8 oktober 2018 | 21 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.

The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.

The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.

In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"

Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.

In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.

Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.

They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.

That wraps it up for our summaries, now for our feature discussion.

Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?

Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.

Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings?

Dr Richard Haynes: So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.

It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan.

Dr Carolyn Lam: Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan?

Dr Richard Haynes: That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way.

Dr Carolyn Lam: Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that?

Matthew James: Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease.

Dr Carolyn Lam: Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right?

Dr Richard Haynes: Eligibility was actually determined by the EGFR, the estimated GFR.

Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm.

Dr Carolyn Lam: Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm?

Dr Richard Haynes: I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial.

Dr Carolyn Lam: Justin, I mean you come from the heart failure world too just like me. What was your take?

Dr Justin Ezekowitz: I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.

Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well.

Matthew James: Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.

I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction.

Dr Richard Haynes: I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients.

Dr Justin Ezekowitz I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.

I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.

The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.

The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published.

Dr Carolyn Lam: You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages?

Braden Manns: Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes.

Matthew James: I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population.

Dr Justin Ezekowitz: So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely.

Dr Richard Haynes: I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has.

Dr Carolyn Lam: Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.

Thank you very much to audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation October 2, 2018 Issue

1 oktober 2018 | 18 min

FDG-PET CT was recently introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, can we improve on its diagnostic performance? Well, to learn more you have to listen to the upcoming featured discussion, right after these summaries.

Our first original paper this week describes a potential novel therapy for hypertension. In this study from first author Dr Hu, corresponding author Dr Soong, from Yong Loo Lin School of Medicine National University of Singapore, authors showed that galectin-1 is a key regulator for proteasomal degradation of CaV 1.2 channels. L-type CaV 1.2 channels are known to play crucial roles in the regulation of blood pressure. In a series of elegant in vitro and in vivo experiments, the authors showed that galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and thereby, exposing specific glycines for polyubiquitination. This mechanistic understanding provided the basis for targeting CaV 1.2 galectin-1 interaction and demonstrated the modulatory role that galectin plays in regulating blood pressure. The study, therefore, offers a potential novel approach for the therapeutic management of hypertension.

Direct oral anticoagulants or DOACs, are surpassing warfarin as the anticoagulant of choice for stroke prevention in non-valvular atrial fibrillation. However, DOACs outcomes in elective peri-procedural settings have not been well elucidated and remain a source of concern for clinicians.

The next paper in today's issue was a meta-analysis designed to evaluate the peri-procedural safety and ethicacy of DOACs versus warfarin. For author Dr Nazha, corresponding author Dr Spyropoulos, from the Feinstein Institute for Medical Research in Northwell Health at Lenox Hill Hospital in New York, reviewed the literature for data from phase three randomized controlled trials comparing DOACs with warfarin in the peri-procedural period among patients with non-valvular atrial fibrillation. Sub study from four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF. The short-term safety and ethicacy of DOACs and warfarin were not different in patients with non-valvular atrial fibrillation peri-procedurally. Under an uninterrupted anticoagulation strategy, DOACs were associated with a 38% lower risk of major bleeds compared to warfarin.

The next paper presents results from the Sarcomeric Human Cardiomyopathy Registry or SHARE, which combined longitudinal data sets curated by eight international hypertrophic cardiomyopathy specialty centers to provide a better understanding of the factors that contribute to heterogeneous outcomes in lifetime disease burden in patients with hypertrophic cardiomyopathy. First and corresponding author Dr Ho from Brigham and Women's Hospital and colleagues analyzed longitudinal clinical information on 4,591 patients with hypertrophic cardiomyopathy. By examining the data set spanning more than 24,000 patient-years, the mortality of patients with hypertrophic cardiomyopathy was shown to be 3-fold higher than the general population at similar ages. The lifetime cumulative morbidity of hypertrophic cardiomyopathy was considerable, particularly for patients diagnosed before age 40 years and patients with sarcomere mutations. Atrial fibrillation and heart failure were the dominant components of disease burden. Thus, young age of diagnosis and the presence of sarcomere mutations are powerful predictors of adverse outcomes in hypertrophic cardiomyopathy. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.

The final original paper this week provides molecular insights into atherosclerosis and it shows that defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Now, we know that atherosclerotic blocks demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine lesions. In today's paper, first author Dr Shah, corresponding author Dr Bennett from University of Cambridge and colleagues studied levels of 8-oxoguanine and its regulatory enzymes in human atherosclerosis. They found that human plaque vascular smooth muscle cells showed defective nuclear 8-oxoguanine repair, associated with reduced acetylation of the base excision repair enzyme 8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base excision repair defect in vascular smooth muscle cells alone markedly reduced plaque formation, thus indicating that endogenous levels of oxidative DNA damage in vascular smooth muscle cells promoted plaque development.

And that brings us to the end of this week's summaries. Now for our feature discussion.

Prosthetic valve endocarditis is a life-threatening complication. However, making a timely diagnosis of prosthetic valve endocarditis before the occurrence of severe complications is really difficult. Now, FDG-PET CT has recently been introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, previous studies reported only modest diagnostic accuracy and may have been hampered by confounders. But today's study, our feature study in Circulation, addresses this issue. We have none other than the corresponding author, Dr Ricardo Budde from Erasmus Medical Center in Rotterdam, the Netherlands, and our dear associate editor, Dr Victoria Delgado, who is in Leiden University Medical Center, also in the Netherlands.

So please tell us, how does your study help us address this issue of the accuracy of FDG-PET CT

Dr Ricardo Budde: What we actually did is that of course endocarditis is a relatively rare disease, so we had six hospitals in the Netherlands that collaborated on this study and in each of the hospitals we searched for PET CT scans that were performed in patients with a prosthetic heart valve, either because they were suspected of having endocarditis, or if they were meant for other purposes, for example oncological follow-up. Then we grouped all those CT scans together, interpreted the PET CTs anew by dedicated interpreters, and then compared the findings with the actual diagnosis in the patient, which of course is always difficult in endocarditis because to make the diagnosis is difficult. So, also, one year follow-up period was included in that to be absolutely certain whether the patient had endocarditis or not. By taking this whole cohort of patients, we were able to determine the diagnostic accuracy of PET CT, as well as by using a logistics model, identify confounders which influence the diagnostic accuracy of PET CT.

I think the study that we did addresses several important aspects and the way it helps physicians in actually interpreting and implementing PET CT to diagnose endocarditis is two-fold. First of all, we identified confounders that have to be taken into account when interpreting and using the PET CT. For instance, low inflammatory activity at the time of imaging and the use of surgical adhesive during a prosthetic heart valve implantation are confounders which should be taken into account when interpreting the PET CT. Furthermore, the guidelines have always insisted on not to use or use it very cautiously PET CT within the first three months after prosthetic heart valve implantation. However, we showed that actually this period after implantation does not necessarily have to be taken into account as also a good diagnostic accuracy can be obtained within the first three months after implantation.

Dr Carolyn Lam: Ricardo, that's wonderfully put. I don't do a CT, PET CT, routinely. In fact, I am echocardiologist and it used to be that infective endocarditis was diagnosed with echo. So Victoria, tell us, how does echo stand now with this information?

Dr Victoria Delgado: That's a very good question but I think the guidelines set a very clear figure of how the diagnostic workup of patients with prosthetic valve endocarditis should be performed. An echocardiography is the first imaging technique. The point is that transthoracic echocardiography in patients with suspicion of prosthetic valve endocarditis is very challenging. In terms of ideal, echocardiography is probably the best imaging technique to do first to evaluate whether it is endocarditis or not. It's difficult, we have to take into account that for a specific prosthetic valve, particularly mechanical, the shadowing can make that we don't see the [inaudible 00:10:22] and sometimes it's difficult, particularly in the early phase immediately after implantation, all the inflammation can be confounder for presence of endocarditis. In those cases, I think that this study provides additional and important data highlighting which are the confounders when you use PET CT to evaluate depressions of endocarditis. I think that, when you take into account those confounders, the accuracy of this technique is very good in order to make or help in the diagnosis of these patients. So, echocardiography, I think that will remain as our first imaging technique to rule out [inaudible 00:11:10] we can see but in those cases where the diagnosis is not confirm or rule out with transthoracic and transesophageal echocardiography this study provides additional data and important data showing that PET CT is a valuable complementary imaging diagnostic test for these patients.

Dr Carolyn Lam: Ricardo, would you agree with that because I think your study also emphasized that perhaps FDG-PET CT should be implemented early in the diagnostic workup to prevent the negative confounding effect of the low inflammatory activity? So how do we put this all together?

Dr Ricardo Budde: Well actually, I agree with Dr Delgado that echocardiography is and should be the first-line test that you do if you have a patient that has a suspicion of endocarditis. I mean, the advantages of echocardiography are many and it's non-invasive, it's bedside-available if needed, it's patient-friendly, and it provides a huge amount of information so you should always start with echocardiography. However, sometimes it can be difficult by echocardiography, for the reasons just explained by Dr Delgado, and I think then PET CT should be considered. And when you want to do a PET CT, then you should do it early within the diagnostic workup.

Actually, in the article, one of the figures is a flow chart which we provide, and it provides information on how we think PET CT can best be implemented in the workup of endocarditis. In this flow chart we also start with doing an echocardiography and also, importantly, consult the endocarditis time to make initial classification of whether it's a rejected, possible, or definite prosthetic heart valve endocarditis. After that, you can follow the flow chart and see when you can best implement PET CT, in our opinion.

Dr Carolyn Lam: Indeed Ricardo, I am so glad you brought up this figure and listeners, you have to take a look at it. I can imagine that everybody will be using this and discussing it and how to incorporate this in the workflow. And indeed you do start with either transthoracic or transesophageal echo and blood cultures, so thank you for clarifying that.

Now, for our clinicians out there, are there any situations you may be telling us to be a little more careful? Could you put it simply for us when it comes to the FDG-PET?

Dr Ricardo Budde: You mean when not to perform a PET CT?

Dr Carolyn Lam: Yeah, or when we have to be really careful about inaccuracies.

Dr Ricardo Budde: I think, of course, the confounders that we indicate in the article, especially if bioglue has been used by the surgeon during the initial surgery. We know that bioglue can be seen on a PET CT as a false positive uptake of FDG and it's also important to note that this is a phenomenon that can persist for a very long time after a valve implantation. It could be for years, so especially that I think is a very important confounder to take into account and be careful when you interpret PET CT or use the PET CT and always read the original surgical report if it is available to obtain this information.

Dr Carolyn Lam: That's wonderful advice. Victoria, do you have anything to add?

Dr Victoria Delgado: No, I think that Dr Budde explained perfectly this figure that is key in the article and also how to evaluate patients with suspected endocarditis of prosthetic valve. One thing that sometimes we forget is starting from the first step that is a good clinical history which includes also a good evaluation of previous history and, if possible, what has been done in the patient. I think that this key information to understand the findings on the echocardiography, transthoracic or transesophageal, and the subsequent investigations that you are going to perform. Either CT which is considered, for example, when you have a definitive prosthetic valve endocarditis and you want to rule out potential complications such as abscess, for example, and if you perform a PET CT or other imaging modalities that then also indicate the presence of infection like, for example, [inaudible 00:15:26] leukocytes with PET, for example.

Dr Carolyn Lam: And I just want to end up with one little point. Ricardo, how about the fact that part of your results don't corroborate the ESC guideline recommendations that they say you have to avoid FDG-PET in the recently implanted prosthetic valve. How do you feel it's going to play out for clinicians?

Dr Ricardo Budde: Well, I think the 2015 ESC guidelines on endocarditis are a very important document. One must take into account that the inclusion of PET CT in the ESC guidelines was a major step, and some might say that it was a little premature to include the use of PET CT because the number of data that was out there were still relatively limited. I think it's something that we are learning along the way. Now that we are using PET CT more often we are more aware of what we do to findings that we get and also the findings that we have within specific timeframes after the implantation of a prosthetic heart valve. One of the things that I think is desperately needed also at the moment is to have a prospective study where we would do PET CT in patients after implantation of a prosthetic heart valve that do not show any signs of endocarditis where we do PET CT just to determine these normal uptake values. I think that would be a major contribution to the whole learning experience that we're currently having with implementing PET CT within prosthetic heart valve endocarditis.

Dr Carolyn Lam: Indeed, and Ricardo your paper has added significantly to our understanding. Readers, remember, it's Figure 6 of our feature paper this week. It is a beautiful figure. Pick it up, take a look. In the meantime just thank you so much Ricardo and Victoria for joining me today.

Listeners, don't forget to tune in again next week.

Circulation September 25, 2018 Issue

24 september 2018 | 18 min

Ticagrelor has shown superior efficacy to clopidogrel in the management of acute coronary syndromes. But what about in patients undergoing PCI for stable coronary artery disease? Well, our feature paper this week gives us answers to this question but you're going to have to wait to the feature discussion to hear these answers. That's coming up right after these summaries.

Our first original paper this week shows that RBM20 mutation carriers have an increased risk of arrhythmias. You may recognize RBM20 as that splicing factor which targets multiple pivotal cardiac genes such as Titin and Calcium/Calmodulin-Dependent Kinase 2 Delta or CAMK2D. In today's paper first author Dr van den Hoogenhof and co-corresponding authors Dr Pinto and Creemers from Academic Medical Center Amsterdam, compared the clinical characteristics of RBM20 and Titin mutation carriers and used RBM20 knock out mice to investigate the downstream effects of RBM20 dependent splicing. They showed that loss of RBM20 disturbed calcium handling and led to more pro-arrhythmic calcium releases from the sarcoplasmic reticulum. Patients that carried a pathogenic RBM20 mutation had more ventricular arrhythmias despite a similarly depressed left ventricular function compared to patients with a Titin mutation.

Targets of RBM20 splicing were enriched for calcium and ion handling genes, most notably CAMK2D and type 2 Ryanodine receptor. Loss of RMB20 induced an increased L-Type Calcium current density, intracellular calcium overload, increased sarcoplasmic reticulum calcium content and increased spontaneous calcium releases which all could be attenuated with treatment with an L-type calcium channel blocker. Furthermore, these results suggest that RBM20 mutation carriers should be closely monitored for potential electrical disturbances and cardiac arrhythmias even in the early stages of disease.

Echocardiographic quantitation of degenerated mitral regurgitation is recommended in clinical guidelines but is it really scalable to routine clinical practice? First author Antoine, corresponding author Sorano from Mayo Clinic Rochester Minnesota and their colleagues looked at more than 3900 patients diagnosed with isolated mitral valve prolapse between 2003 and 2011 and to any degree of mitral regurgitation quantified by any physician or sonographer in routine clinical practice. They found that in multi-variable analysis routinely measured effective regurgitant orifice area was associated with mortality independent of left ventricular ejection fraction and systolic diameter symptoms or age and comorbidities. Furthermore, compared with general population mortality excess mortality appeared for moderate mitral regurgitation with an effective regurgitant orifice area above 20 squared millimeters and became notable with an effective regurgitant orifice area above 30 squared millimeters which then steadily increased with even higher levels of above 40. Thus, quantitation of degenerative mitral regurgitation is scalable to routine clinical practice with strong independent prognostic power when performed routinely by multiple practitioners.

The next study identifies a novel mechanism of lipid homeostasis that is linked to a pseudo gene associated with the recently discovered apolipoprotein known as APOO. Co-first authors Montasser and O'Hare, corresponding author Dr Mitchell from University of Maryland School of Medicine in Baltimore, performed an array based association analysis in more than 1100 Amish subjects and identified a variant strongly associated with LDL cholesterol levels. They identified a founder haplotype on chromosome 5 which was associated with a 15 mg/dl increase in LDL cholesterol after recombination mapping, the associated region contained eight candidate genes. Using a zebra fish model to evaluate the relevance of these genes to cholesterol metabolism they found that the expression of the transcribed pseudo gene APOOP1 increased LDL cholesterol and vascular plaque formation. Thus, based on these data the authors proposed that APOOP1 regulates levels of LDL cholesterol in humans and represents a novel mechanism of lipid homeostasis.

The Orion-1 trial demonstrated that inclisiran which is a small interfering RNA therapeutic that targets PCSK9 MRNA with [inaudible 00:05:42] produces significant LDL reduction. In today's study from Dr Ray from Imperial College London and colleagues, the authors described in detail the effect of inclisiran on prespecified secondary lipid and lipoprotein outcomes over time for up to 210 days and also described the individual variation and response in these measures. They found that a single 300 milligram dose of inclisiran lowered non-HDL cholesterol at day 180 by 35% and a second dose at day 90 resulted in a 46% reduction at day 180. Similarly a single dose of 300 milligrams of inclisiran reduced apolipoprotein B by 31% at day 180 and a second dose of 300 milligrams administered in day 90 reduced apolipoprotein B by 41%. Significant reductions in all atherogenic lipoproteins measured were sustained through today 210. Furthermore, every individual had a reduction of apolipoprotein B and non-HDL cholesterol at 180 days with the 300 milligram two-dose regimen of inclisiran. Thus, inhibiting the synthesis of PCSK9 through small interfering RNA may be a viable alternative to monoclonal antibodies with respect to effects on atherogenic lipoproteins and that brings us to the end of our summaries. Now for our feature discussion.

Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndrome but it has not really been assessed in patients undergoing PCI for stable coronary artery disease. For our feature paper today it's going to shed some light and help us with this question and these are the results of the STEEL-PC trial. I'm so pleased to have with me right now the corresponding author Dr Robert Storey from University of Sheffield in the UK as well as our associate editor who managed this none other than Dr Stefan James from Uppsala University. Thank you.

Rob, could you tell us what is the issue you tried to address and because your study is not that simple, we're not used to thinking about these pharmacodynamic and kinetic studies so could you explain a bit of what you did?

Rob Storey: Well it's quite a few concepts that we assessed in this study. We've got data from a number of studies showing that Ticagrelor both at doses of 90 mg twice daily and 60 mg twice daily is more reliable and superior P2Y12 inhibitor compared to clopidogrel. We've got this issue of very variable response to clopidogrel with some poor responders and some high responders and a range in between. That's fairly well established and part of this study was to get more data on the 60 mg dose of Ticagrelor in these stable CAD patients undergoing PCI and get some pilot data on clinical efficacy obviously this study was not part of clinical outcomes.

But, there's another issue in terms of adenosine uptake so Ticagrelor has a relatively weak effect on adenosine uptake into red cells and other cells and this may or may not explain some of its clinical effects including some adverse effects such as dyspnea. We wanted to get a better idea of the impact of Ticagrelor at both these doses on adenosine uptake.

Dr Carolyn Lam: Could I ask ... Okay this may be naïve. I'm not an interventional cardiologist but why would you expect something different in an acute coronary syndrome compared to stable coronary artery disease? Is there an underlying hypothesis there?

Rob Storey: Well there can be changes to their differences in platelet reactivity although those aren't particularly great and overwhelmed really by P2Y12 inhibitor like Ticagrelor which gives such reliable inhibition of the P2Y12 receptor. But, there have been a limited number of groups that have looked at adenosine uptake and so we wanted to get independent confirmation or not of whether Ticagrelor therapeutic concentrations impacting on adenosine uptake and get some ideas of whether it's affecting circulating adenosine levels. That's an important question in terms of understanding the mechanisms and actions of Ticagrelor.

Dr Carolyn Lam: Got it. Thanks for breaking it down so nicely. So what did you find?

Rob Storey: What we found was surprisingly that we saw no impact of Ticagrelor at either dose and at any time point within a month after PCI on adenosine uptake. That is the circulating levels of adenosine and the rate at which adenosine is taken up by cells in the blood mainly red blood cells. The explanation for that really is that the therapeutic levels of Ticagrelor that you see are not sufficient to impact on adenosine uptake because it's a very weak inhibitor of the adenosine uptake pathway known as the MT1. The therapeutic levels are just not getting up to a high enough concentration to have a significant impact on that.

Dr Carolyn Lam: Stefan, you've thought a lot about this. What did you think of the findings?

Stefan James: I think it's very interesting. Of course, the pharmacodynamic effects that you can measure by pretty simple means, the level of platelet inhibition, it should be similar in ACS and stable coronary artery disease and I think it's sort of confirming what Rob has been showing in other populations with ACS ... we have been very interested in trying to understand the additional mechanisms of action of Ticagrelor... try to understand the mortality rate without the benefit for Plato, for example. Was it only -- platelet inhibition or were there other mechanisms? And, there is a specific Ticagrelor related side effect, dyspnea, which we would have been interested in understanding... is this a mechanism of action? We can't really explain that. There are other mechanisms and other effects that we have seen can also be explained by adenosine, so I thought it was very interesting and important to understand more about these mechanisms.

Dr Carolyn Lam: Yeah.

Stefan James: But I would like to ask you, Rob. Do you think this adenosine hypothesis now, is dead, or should we still try to explore this?

Rob Storey: Well of course in this study what we didn't look at was the adenosine kinetics in the tissue level which is where we hypothesize the dyspnea may arise from stimulation of C5 is in the lung tissue so we're missing that piece of information. It's still conceivable that very weak levels of ENT-1 inhibition may impact from adenosine levels in the tissue. We're not seeing a strong ENT-1 inhibition sufficient to raise circulating levels or something that we can pick up on this in vitro assay.

I think it still remains an open question. We've got this sort of contradictory information from drugs like cangrelor and other drugs in development like Elinogrel where we don't see an impact on adenosine but they still may cause dyspnea. So I think it's a very open question still.

Stefan James: Do you think that your paper gives us additional strength to the hypothesis that the mortality benefit for ticagrelor as seen in Plato is explained by the platelet inhibition and the balance between the reduction in ...

Rob Storey: Well I think what we see really in all these studies is that Ticagrelor is a fantastically effective PTY12 inhibitor. It gives you the best level of platelet inhibition during maintenance therapy out of all the available PTY12 inhibitors. And clearly having such more reliable PTY12 inhibition than clopidogrel could still be driving a mortality benefit in high risk patients so we can't exclude the adenosine pathway contributing to some of the clinical effects but I think this sways me a little bit more to the position of thinking this is most of the benefits through platelet inhibition.

Dr Carolyn Lam: Interesting. So you're on the cutting edge of this. What's the next step then?

Rob Storey: Clearly we can see that very effective and reliable P2Y12 inhibition is important and leads to clinical benefits and I think we need to implement that wherever we're using P2Y12 inhibitors. We need to take that message and use a more consistent therapy rather among those with associated with variable response which doesn't seem to make sense. I think this stable PCI population, their risk has fallen. And we see that in this study, quite a number of patients report a response to clopidogrel but no stent thrombosis.

That really reflects, I think improvements in stent design and implantation techniques, so the implication is that maybe aspirin alone is enough to prevent stent thrombosis with modern techniques if you get a good result but in the higher risk patients particularly the ACS patients it's likely you need much more reliable platelet inhibition and that's why Ticagrelor really provides this security.

Dr Carolyn Lam: So, Rob there is one thing you tested two doses and they seemed to be equivalent at least in antiplatelet inhibition, right? So what does this mean? Should we maybe preferentially use the lower dose from now on, is there still room for the higher dose? Could you share some insights there?

Rob Storey: Well I think one has to be cautious in not jumping to adopt a dose just on the basis of pharmacodynamic data but clearly what we show is that the 60 mg dose of Ticagrelor offers a very reliable and consistent level of PTY12 inhibition and that's likely to be very effective in preventing stent thrombosis in combination with aspirin. We also show signals that were also shown in the Pegasus study that the 60 mg dose may be better tolerated such as with lower levels of dyspnea.

So, there is the option for off label use of the lower dose of Ticagrelor in those who cannot tolerate the high dose due to dyspnea because certainly they'll have better platelet inhibition down titrating from 90 to 60 and if they were to switch to Clopidogrel. So I think our study offers some comfort in terms of that aspect. The only caveat is that you have to be careful not to use strong CYP3A inducers such as some epilepsy drugs with Ticagrelor cause that can increase the metabolism and we did have one case of high platelet reactivity with strong CYP3A inducers so using a higher dose initially I think is a good idea. The label says 90 mg for 1 year following ACS and the 6 is licensed beyond one year as a down titration predominantly.

Our study certainly gives some comfort that down titrating earlier if a patient can't tolerate the 90 for whatever reason, seems to be a justifiable thing. And the other thing is the European guidelines support the use of Ticagrelor off label in elective PCI and our study certainly gives some comfort that off label use and the low risk elective PCI patients of the 60 mg dose can be justified at least from a pharmacodynamic point of view.

Dr Carolyn Lam: Well, thank you because that's exactly what our audience is loving to hear. How do these findings translate into the clinical practice - Would you have any other take home messages for the clinicians listening in?

Rob Storey: Well I think one thing we looked at also was troponin release which is very common after PCI. We didn't see an impact of PTY12 inhibition high levels on troponin release and I think that sort of caveat in terms of that's not going to be the best measure in terms of surrogate for efficacy in the PCI population. The other question really is, how much of the platelet inhibition and how much of the adenosine effects of Ticagrelor influence the clinical outcomes and clearly the studies sways towards the platelet inhibition very consistent high level of platelet inhibition explaining most of the benefits.

Carolyn Lam: You've been listening to circulation on the run, don't forget to tune in again next week.

Circulation September 18, 2018 Issue

18 september 2018 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's journal features two papers that deal with genetic testing in young athletes and for sudden arrhythmic death, and with findings that may surprise you. They really show the complexities of this era of genetic testing and cardiovascular medicine, and in fact are discussed as growing pains in cardiovascular genetics. You must listen to our feature discussion, which is coming right up after these summaries.

The first original paper this week suggests that targeting fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis. Fibronectin polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblast following cardiac injury. In today's paper, first author Dr Valiente-Alandi, corresponding author Dr Blaxall from University of Cincinnati College of Medicine and Heart Institute, and their colleagues hypothesized that interfering with fibronectin polymerization, or its genetic ablation and fibroblasts, would attenuate myocardial fibrosis and improve cardiac function following ischemia reperfusion injury. Using mouse and human cardiac myofibroblasts, authors found that the fibronectin polymerization inhibitor pUR4 attenuated the pathological phenotype exhibited by mouse and human myofibroblasts by decreasing fibronectin polymerization and collagen deposition into the extracellular matrix as well as by myofibroblast proliferation and migration.

Inhibiting fibronectin matrix deposition by pUR4 treatment or by deleting fibronectin gene expression in cardiac fibroblasts confirmed cardioprotection against ischemia reperfusion-induced injury by attenuating at first left ventricular remodeling and cardiac fibrosis, thus preserving cardiac function. In summary, interfering with fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure.

The Insulin Resistance Intervention after Stroke, or IRIS trial, demonstrated that pioglitazone reduced the risk of both cardiovascular events and diabetes in insulin-resistant patients. However, concern remains that pioglitazone may increase the risk of heart failure in susceptible individuals. To address this, Dr Young from Yale Cardiovascular Research Center and the IRIS investigators performed a secondary analysis of the IRIS trial. They found that older age, atrial fibrillation, hypertension, obesity, edema, high CRP, and smoking were risk factors for heart failure.

Pioglitazone did not increase the risk of incident heart failure, and the effect of pioglitazone did not differ across levels of baseline risk. It should however be noted that in the IRIS trial, the study drug dose could be reduced for symptoms of edema or excessive weight gain, which occurred more often in the pioglitazone arm. Overall, pioglitazone reduced the composite outcome of stroke, MI, or hospitalized heart failure in the IRIS trial.

The next study highlights the importance of genetic variation in cardiac fibrosis and suggests that while fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In this paper from co-first authors Dr Park and Ranjbarvaziri, corresponding author Dr Ardehali, from David Geffen School of Medicine, University of California, Los Angeles, the authors utilized a novel multiple-strain approach known as the Hybrid Mouse Diversity Panel to characterize the contributions of cardiac fibroblasts to the formation of isoproterenol-induced cardiac fibrosis in three strains of mice.

They found that isolated cardiac fibroblasts treated with isoproterenol exhibited strain-specific increases in the levels of activation, but showed comparable levels of proliferation. Similar results were found in vivo with fibroblast activation but not proliferation correlating with the differential levels of cardiac fibrosis after isoproterenol treatment. RNA sequencing revealed that cardiac fibroblasts from each strain exhibited unique gene expression changes in response to isoproterenol.

The authors further identified LTBP2 as a commonly upregulated gene after isoproterenol treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure, suggesting that it may be a potential therapeutic target. That brings us to the end of our summaries. Now for our feature discussion.

We all know that t-wave inversion is common in patients with cardiomyopathy, however up to a quarter of athletes of African descent, and five percent of white athletes also have t-wave inversion on ECG, but with unclear clinical significance despite comprehensive clinical evaluation. Now, what is the role in diagnostic use of genetic testing beyond clinical evaluation when we investigate these athletes with t-wave inversion? Well we're about to get some answers in today's feature paper, and I'm so pleased to have the corresponding author of the paper, Dr Sanjay Sharma from St. George's University of London, as well as our associate editor Dr Mark Link from UT Southwestern.

Sanjay, please let us know what you did and what you found.

Dr Sanjay Sharma: Well as you rightly say, that up to 25% of black athletes have t-wave inversion, as do three to five percent of white athletes. And these t-wave inversions often overlap with the sort of patterns that you see in patients with hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. For example, 80% of people with hypertrophic cardiomyopathy have t-wave inversion as do 60% of patients with ARVC. Now we know that some ECG patterns, t-wave inversions in V1 to V4 are benign in black patients, but the significance of other ECG patterns is unknown. Cascade screening in family members with cardiomyopathy have shown that t-wave inversion may be the only manifestation of gene inheritance, and there are reports to suggest that some athletes with t-wave inversion do go on to develop overt cardiomyopathy. Now when we investigate the vast majority of our patients with t-wave inversion, these are our athlete patients, we don't actually find anything. But over the past decade, also, these has been major advance in next generation sequencing that allows us to perform genetic testing in a large number of genes that can cause diseases, capable of causing sudden death.

And so, we thought we'd investigate the role of this gene testing in athletes with t-wave inversion. We looked at a hundred, 50 black athletes and 50 white athletes who had t-wave inversion, and we investigated them comprehensively with clinical tests. But we also added in a gene panel looking at 311 genes implicated in six cardiac diseases, notably hypertrophic cardiac myopathy, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, long QT syndrome, and the brugada syndrome. We found that 21% of our athletes were then diagnosed with a cardiac disorder capable of causing sudden death, and the vast majority of these people had hypertrophic cardiomyopathy. And this diagnosis was based on clinical evaluation. When we looked at gene testing, we found that gene testing only picked up a problem in 10%. So, the diagnostic yield of gene testing was half that of comprehensive clinical investigation.

When we actually looked at athletes who had nothing wrong with them in clinical investigation, and actually had a gene mutation, we found that only 2.5% of athletes who had t-wave inversion but clinically normal tests, actually had something wrong with them. And our conclusions were that gene testing picks up only half the athletes that clinical testing does, and gene testing is only responsible for identifying 2.5% of athletes with t-wave inversion, where clinical tests are negative. That was the summary of our study in short. We did find that black athletes were less likely to have a positive diagnosis of cardiac myopathy than white athletes, and black athletes are also less likely to have a genetic mutation capable of causing a cardiomyopathy than white athletes.

Dr Carolyn Lam: First and foremost, congratulations on such a beautiful paper, and so wonderfully summarized as well. It really seems to fly in the face, doesn't it? Of the way we've been discussing personalized medicine and saying that we're going to start whole genome sequencing everyone and that's going to provide all the answers for future disease risks. I mean, if I'm not wrong, what your paper is trying to tell us is that at this moment we don't have good examples where genetic testing may trump clinical diagnoses, and in fact we should be still focusing on a comprehensive clinical evaluation of patients and in the absence of a genotype we should learn to question what we're doing in genetic testing. Do you agree with that?

Dr Sanjay Sharma: You couldn't have said that more precisely. As I've said, the diagnostic yield of clinical testing was 21% versus only 10% with genetic testing. The diagnostic yield of pure genetic testing in people with otherwise completely normal findings clinically was only 2.5%. And the other thing that I forgot to tell you was that genetic testing, if we included genetic testing in addition to comprehensive assessment, cost us three times as much as clinical investigation on its own, and had we relied solely on genetics, and nothing else, it would have cost us ten times more than clinical testing. So our cost per making a diagnosis using genetics only would have amounted to $30,000 per condition.

Dr Carolyn Lam: Wow, what a great wake up call. Mark, you've thought a lot about this and in fact there was another paper in this week’s journal that has very complimentary messages. In fact you invited an editorial by Dan Roden, and I really loved his title of it, "Growing Pains in Cardiovascular Genetics." Would you maybe add your thoughts in relation to the other paper, as well as overall?

Dr Mark Link: Sure. Circulation was very interested in these papers. These are really ... Now, as Dan Roden says, "Growing pains." Twenty years ago when genetics came out it was looked upon as it was going to completely change our clinical medicine and precision medicine is really relying a lot on genetics. And while ultimately that may be the case, we are in a stage now where the honeymoon is over. And the other paper that was in this same issue was a paper by Hosseini and colleagues, and it was the Clin Gen paper looking at the Brugada Syndrome abnormalities. Now the Clin Gen is an NIH sponsored group that takes individuals from a number of different institutions and actually gene testing, and tries to provide an independent assessment of the abnormality of genes. Previously is was companies that did this. A company would gene test ... They would look for gene abnormalities, try to link it with clinical disease, and they could basically then do just on their patients. But Clin Gen now is trying to tie all those companies together to get a broad consortion and to look at genetic abnormalities and whether they're truly pathologic, where there's areas of unknown significance, or whether they're truly not pathologic.

So as an example, they took Brugada Syndrome, and they took the different gene abnormalities that have been described from basically different companies and different labs and different institutions, and they looked at the evidence behind the fact that they were truly pathologic, 'cause all 21 genes were defined as pathologic. They found in their independent assessment that only one ended up to be truly pathologic, and the others ones were disputed. And sort of another wakeup call that just because a single company calls a gene pathologic or Brugada Syndrome, does not make it pathologic necessarily. So we all thought these were two very important papers that looked at some of the limitations of genetic testing. We asked Dan Roden, who is really a very accomplished scholar in this field, to provide perspective on this. And I agree, I loved his title, "Growing Pains in Cardiovascular Genetics." And what he did is reviewed the history of genetic testing, and he actually starts before genetic testing and starts with Mendelian genetics, and [inaudible] genetics. And then 23 years ago they started linking that Mendelian genetics to gene abnormalities, especially in diseases such as long QT syndrome and hypertrophic cardiomyopathy.

We've come a tremendous way in diagnosing gene abnormalities and associating them with these underlying cardiac myopathies and hind channel abnormalities. So no one doubts we've come a tremendous way, but there's a long way to go in terms of getting better diagnostic accuracy and really defining where these genetic testing are ultimately going to play out in clinical medicine. So everyone's excited about it, but I think these two papers are two cautionary tales that we do have to remember that genetic testing in 2018 is not the end all and be all.

Dr Carolyn Lam: I love that, cautionary tales. So important. But where do we go from here? What's the take home message for clinicians listening to this today in 2018? I mean is it that perhaps when we do these things we now need to include medical geneticists and genetic counselors as vital partners as we look at this all? Perhaps we need to not forget the primacy of clinical evaluation. What do you think, Sanjay?

Dr Sanjay Shar: Well, there are guidelines from the American Medical Genetics side as to what one defines as a disease-causing mutation. But I agree that we need to be using certified laboratories that can actually interpret the genetic mutations. For example, in our study of athletes, 63% actually had variance of undetermined significance. So they had spinning mistakes in their genes which probably didn't account to anything at all, but had these mutations, or these so called variance of undetermined mutations been interpreted by someone who didn't really know much about this, these could have resulted in false positive results which could cause absolute chaos for an athletes career. So I do think this type of testing has to be governed very, very carefully and needs to be performed in very specialized and certified laboratories.

Dr Carolyn Lam: Indeed. Not just to the athlete, but to their families too, isn't it? Mark, what do you think is the take home message [inaudible 00:16:18]?

Dr Mark Link: I think one of the big take home messages that I took away from these papers is that clinical medicine is not dead. In fact, clinical medicine in this day and age is still the prime way of taking care of patients. Genetic testing is still in its infancy. It doesn't help clinically in too many situations yet. It will in the future. It helps in the diagnosis, it's not as useful in the treatment. So we have a long ways to go with genetics. I like your comment that going forward we're going to need more genetic counselors to make sense of these results. Clinicians are going to have a hard time making sense of these results. I do think that there is plenty of role once a disease causing mutation has been defined, and in that situation it's invaluable in cascade screening in identifying other family members who may be affected, but outside that I do believe and I agree completely with both of you, that clinical medicine is not dead. And clinical evaluation should be number one and should enjoy it's prime time because that's where we still are at. And genetics is still in its infancy and so is cardiology.

Dr Carolyn Lam: Perhaps in selective settings ... We're not talking here about, for example, hypercholesteremia variance, we're not talking about cancer gene variance for which screening may be a little bit more advanced, and we may understand the gene phenotype associations that are perhaps-

Dr Mark Link: I think that understanding gene phenotype associations are going to be critically important in the future. I think, as Sanjay said, the real use of genetic screening now is cascade screening for the family, and there it's invaluable. That you can tell if you've got a co-band with the disease, and with a defined pathological mutation. You can test siblings, sons and daughters, parents to see if any of them have the gene. I think that's where it should be used for sure in 2018.

Dr Carolyn Lam: Thank you so much Mark and Sanjay. So some precautions, some hope. Very, very balanced discussion. So much more we could discuss, so I really want to highly encourage our audience. Pick up this issue. You have to read these amazing papers and the editorials.

Dr Carolyn Lam: So, here's a podcast with all your colleagues, and don't forget to tune in next week.

Circulation September 11, 2018 Issue

10 september 2018 | 20 min

Dr Carolyn Lam: We start today's podcast with a few words from our Editor-in-Chief, Dr Joe Hill.

Dr Joe Hill: I speak with you today with a heavy heart as we recently lost an esteemed and beloved colleague, Professor Bongani Mayosi. Bongani was a pioneering leader, a renowned investigator, Dean of the Medical School at the University of Cape Town, and an important member of our Circulation editorial leadership team.

Bongani had an abiding passion for the under-served, especially those in his native Africa. He died tragically and suddenly at the early age of 51, just 10 days after recording the podcast you're about to hear.

We mourn the loss of this colleague and our hearts go out to his family. It is a very poignant moment, as we hear his voice once again. We grieve deeply, and are reminded of Bongani's towering achievements and contributions to the betterment of our world.

CD4-positive T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Today's paper describes the first study to detect apolipoprotein B peptide 18 specific CD4 T cells in mice and humans. First author Dr Kimura, corresponding author Dr Ley from La Jolla Institute of Allergy and Immunology and their colleagues constructed novel P18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotypes by flow cytometry. They found that these P18 specific T cells were mainly anti-inflammatory regulatory T cells in healthy donors, but co-expressed other CD4 lineage transcription factors in patients with sub-clinical cardiovascular disease.

Immunization with P18 reduced atherosclerotic burden in APOE deficient mice and induced antigen specific T regulatory cells. This study therefore, identifies APOB peptide 18 as the first T regulatory APOtope in human atherosclerosis.

The next study suggests that testing intracellular calcium handling in circulating B lymphocytes may be a novel biomarker for monitoring patients with heart failure. During [inaudible 00:02:47] intracellular calcium is released from sarcoplasmic reticulum into the cytoplasm through Type II ryanodine receptor calcium release channels. In heart failure chronically elevated, circulating catecholamine levels cause pathologic remodeling of these Type II receptors, resulting in diastolic sarcoplasmic reticulum calcium leak, thus decreasing myocardial contract [inaudible 00:03:09]. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum calcium release and this occurs through Type I ryanodine receptors. Chronically elevated catecholamine levels in heart failure cause Type I mediated sarcoplasmic reticulum calcium leak, thus contributing to skeletal myopathy and weakness.

In today's paper, first author Dr Kushner. Co-corresponding authors Dr Kitsis from Albert Einstein College of Medicine and Dr Marx from Columbia University, New York hypothesized, that since circulating B lymphocytes express Type I ryanodine receptors, they may be a potential surrogate for defects in intracellular calcium handling due to leaky ryanodine channels in heart failure. Indeed, they found that circulating B lymphocytes from humans and mice with heart failure exhibited remodeled Type I ryanodine receptors and decreased endoplasmic reticulum calcium stores, consistent with chronic intracellular calcium leak. This calcium leak correlated with circulating catecholamine levels. The intracellular calcium leak was significantly reduced in mice treated with S107, which is a drug that specifically reduces ryanodine receptor calcium leak.

Furthermore, heart failure patients treated with LVADs exhibited a heterogenous response. Thus, Type I ryanodine receptor mediated calcium leak in B lymphocytes assessed using flow cytometry may provide a surrogate measure of intracellular calcium handling and systemic sympathetic burden and therefore represent a novel biomarker strategy for monitoring the responses in heart failure therapy.

Hypouricemia and gout are known to be associated with increased risk of cardiovascular disease. And xanthine oxidize inhibitors such as allopurinol and febuxostat are the mainstay of urate lowering treatment of gout, but do they have different effects on cardiovascular risk? First author, Dr Jong, corresponding author, Dr Min from Brigham and Women's Hospital Harvard Medical School in Boston, Massachusetts, studied a cohort of almost 100,000 older Medicare patients with gout and found that there was, overall, no difference in the risk of MI, stroke, new onset heart failure, coronary revascularization are all cause mortality between patients initiating febuxostat compared to those initiating allopurinol. However, there did seem to be a trend toward an increased opiate not statistically significant risk for all-cause mortality in patients who use febuxostat for over three years compared to allopurinol use for over three years. The risk of heart failure exasperation was slightly lower in febuxostat initiators.

The final original paper this week provides important contemporary data on the clinical characteristics in hospital management and long-term outcomes of patients with acute myocarditis. Co-corresponding authors, Dr Ammirati and Kamichi, both from Milan, Italy and their colleagues screened 684 patients with suspected acute myocarditis and recent onset of symptoms within 30 days between May 2001 and February 2017 and included 443 patients with acute myocarditis diagnosed either by endomyocardial biopsy or by increased troponin and edema and late gadolinium enhancement on cardiac magnetic resonance imaging. They showed that among these 443 patients, 118 patients or 26.6% had either left ventricular ejection fraction less than 50% sustained ventricular arrhythmias or a low cardiac output syndrome. While, the 73.4% had no such complications.

Cardiac mortality and heart transplantation at five years was 4.1%, but went up to 14.7% in the patients with complicated presentation and contrast down to zero percent in the uncomplicated cases. Similarly, major acute myocarditis related cardiac events after the acute phase, such as post discharge death and transplantation, sustained ventricular arrhythmias, symptomatic heart failure needing device implantation all occurred in 2.8% at five years, but was much higher in patients with a complicated presentations at 10.8% versus zero percent in the uncomplicated presentations. Thus, the authors concluded that patients with acute myocarditis can be effectively stratified based on their initial clinical presentation. Patients with left ventricular ejection fraction less than 50% at the first echo. Those with sustained ventricular arrhythmias or those with low cardiac output syndrome are at higher risk of cardiac events compared to those without these manifestations.

And that brings us to the end of our summaries. Now, for our feature discussion.

With advances in therapy most deaths in people with HIV are now due to noncommunicable diseases, especially cardiovascular disease. What does the global burden of HIV associated cardiovascular disease really look like? Well we're going to get some answers in today's feature paper. I have with us today the first and corresponding author of the paper, Dr Anubshaw from University of Edinburgh, as well as our associate editor, Dr Bongani Mayosi from University of Cape Town in South Africa.

Dr Carolyn Lam: Welcome to you both. And Anub, what an important question to examine. Could you tell us how you looked into this question and what you found?

Dr Anubshaw: Sure. So, this is a very interesting question from our end and we had in short idea looking at the risk of cardiovascular disease in patients with HIV. And there are many studies of it, varying results. I'm looking at the risk of heart disease and stroke in patients with HIV. So, what we did was a big systematic review to extract all the data out there looking at the risk of heart disease in patients with HIV, we then developed a model that looked at what the overall risk was and then tried to calculate the actual burden of cardiovascular disease attributable to patients with HIV. In some of the work we found, well, primarily we found that the majority of the burden, as expected in Sub-Saharan Africa and that is primarily the cause, in prevalence of HIV is the highest in Sub-Saharan Africa, accounting for about two thirds of all people living with HIV.

Dr Anubshaw: The risk of cardiovascular disease with patients with HIV is twofold higher compared to patients not infected by virus. And there was not [inaudible 00:10:12] variations in the actual burden. The majority of the burden in Sub-Saharan Africa and Southeast Asia.

Dr Carolyn Lam: Wow, Sub-Saharan Africa and Asia Pacific, isn't it? Oh my goodness, Bongani, your views please on these standing results from Africa.

Dr Bongani Mayosi: Yes. I think these results are actually very important in the Sub-Saharan African region, reaching the, at the center of the HIV/AIDs epidemic in the world. And particularly important now that we are finding people and are on treatment and that they are growing older and there's a thriving proportion of people above the age of 60, they are on HIV infection and therefore the whole question of cardiovascular disease in these patients has become very important and clearly now these data suggest that HIV [inaudible 00:11:08] for cardiovascular disease, but what is more important [inaudible 00:11:14] they are important [inaudible 00:11:17] for cardiovascular disease, but also a [inaudible 00:11:22]. [inaudible 00:11:23] such as another vascular condition, which is pulmonary hypertension associated with HIV detection. [inaudible 00:11:35] with the increase of the number of people on treatment, these particular conditions are becoming [inaudible 00:11:43] in the context of how to [inaudible 00:11:48], but is an important condition in the African continent. So that the overall burden of cardiovascular disease is likely to be greater than is estimated here because the study is only estimating atherosclerotic cardiovascular disease.

Dr Anubshaw: That brings up a very intriguing question, Anub. Could you at all distinguish between atherosclerotic risk factors and the role that played versus more HIV specific risk factors, such as the medication, the degree of HIV control, level of inflammation, for example? Now, of course in a meta-analysis this may be difficult, but just your thought.

You're absolutely right from a meta-analysis point of view it's very difficult for a couple of reasons. Firstly, we do not have individual patient level data, so we couldn't really see a [inaudible 00:12:45] level which patients are on [inaudible 00:12:47] therapy and what their personalized risk factors are. Varying schools of thought estimated around the candidates that they need, which kind of portrays a risk of heart disease in the [inaudible 00:12:59] artery in patients with HIV. And what we think may be happening there, one that HIV represents a degree of sub-clinical inflammation that leads to vascular inflammation, which then leads to accelerated atherosclerosis and there's some fantastic mechanistic evidence looking at this where, workers have looked at vascular inflammation in the arteries in patient HIV can go through control and you do get much more vascular inflammation. There is some evidence about the fact that the [inaudible 00:13:31] therapy itself can cause [inaudible 00:13:34] and therefore increase the risk of atherosclerotic heart disease.

And finally, some risky behavior is probably much more, have a look at HIV for example, smoking entered the [inaudible 00:13:46] etc., etc. and there may be a degree of overlap in terms of or correlation in terms of risk factors being much more common in HIV patients, which are more conditional for atherosclerotic heart disease. I think a combination of all those three things probably explain the increase risk of atherosclerotic heart disease and strokes in these patients.

Dr Carolyn Lam: Indeed. Your paper is so important to raise awareness of that very risk. I mean, if I could please re-iterate, you show very clearly that people with HIV are the two fold increase risks of cardiovascular disease and that that global burden had tripled over the last two decades. I think that your paper really shines a bright light in this area, that we have to study further because the clinical implications are enormous aren't they? Because we're using guidelines developed in non-HIV patients to perhaps treat these cardiovascular diseases in HIV patients and there may be other pathophysiologic mechanisms like you just mentioned. What do you think are the main clinical implications of your paper?

Dr Anubshaw: The clinical implication is quite important because what the burden estimate show is that the majority of burden is in no or little information and therefore the resource of those innovations are quite limited, but there's one condition that has been treated so well in these countries. One of the main success stories of medicine, over the last two or three decades and how they've tackled HIV, who runs PEP for has made intrical virals available so widely in the Sub-Saharan African regions, while there's other highly prevalent regions. And they set up logistically clinics to deliver and scare for persons with HIV and if you and I will see that the survival in these patients [inaudible 00:15:39] just mentioned. Then, these patients are at more high risk of other among AIDs related conditions, such as strokes and heart disease. What you now have in these poor resource countries or limited resource countries, where clinics and the logistical support is only set up to deliver cardiovascular risk prevention strategies and therapy. Which is not expensive in terms of antihypertensives, in terms of [inaudible 00:16:06] and in terms of lifestyle factors.

So, I think there is [inaudible 00:16:10] here that the region has to further reduce the cardiovascular burden in this population.

Dr Carolyn Lam: Bongani, you too recognize the very important clinical implications and in fact invited the editorial by Priscilla Sue and David Waters from San Francisco General Hospital. I love the title of it. Is it time to recognize HIV as a major cardiovascular risk factor? Bongani, what are your thoughts?

Dr Bongani Mayosi: I think it is time we should be considering the HIV as a risk factor for cardiovascular disease. You know these data arriving from this [inaudible 00:16:48] are quite compelling and when you look, for example at that this is a hot study [inaudible 00:16:55] in the editorial and conferred by HIV, it is almost the same as the other [inaudible 00:17:02]. I mean if you go into it now that in fact the European Society of Cardiology it is already [inaudible 00:17:12] in HIV infected individuals with [inaudible 00:17:19]. So, if now may be entering their [inaudible 00:17:27] of practice, they consider HIV as a significant risk factor for cardiovascular disease and maybe contribute to bring a drug that will modify outcome. I do think though that because of the mechanism of cardiovascular disease it [inaudible 00:17:45] HIV it is not common on the basis of atherosclerotic disease. In Africa as an example, we know very well that the patient tend to [inaudible 00:17:55] with not a lot of traditional risk factors of cardiovascular disease, in fact, atherosclerotic diseases such as [inaudible 00:18:07] still have a relatively low level of [inaudible 00:18:10].

So, we still, I think need to discover what are the other [inaudible 00:18:14] mechanisms that are involved, I mean they do that very much more targeted drug [inaudible 00:18:21] where it needs to be tested, that don't know our traditional interventions for reducing risk and preventing cardiovascular disease. So, there is need for further research here and the mechanisms and specific intervention. That is the important in this large HIV infected populations because at the moment there at least 27 million people in the world, living with HIV who already facing a major public health issue on a global scale.

Dr Carolyn Lam: Exactly and all these new research efforts, paying attention to this, making sure that we don't underestimate cardiovascular risk and HIV based on traditional risk calculators. All of this starts with awareness and with important papers such as yours, Anub. Thank you so much for publishing that with us at Circulation.

Well, listeners you know how important this is globally, so please share this podcast with your colleagues and don't forget to tune in next week.

Circulation September 4, 2018 Issue

4 september 2018 | 22 min

Current guidelines recommend measurement of one of the cardiac specific isoforms of cardiac troponin complex. However, what's the utility of combining measurements of troponins I and T in the early diagnosis of acute myocardial infarction? Well, you have to wait for our upcoming feature discussion, but it's coming right up after these summaries.

The first original paper this week sheds light on the genetic basis and mechanisms of bicuspid aortic valve, the most common congenital heart defect in the population. We know that bicuspid aortic valve is an autosomal dominant trait with variable expression and incomplete penetrants suggestive of genetic and environmental modifiers. In the current study, first author Dr Gharibeh, corresponding author Dr Nemer from University of Ottawa, and authors of the Bicuspid Aortic Valve Consortium assessed cardiac structure and function in mice, lacking a GATA6 allele. They found that GATA6 heterozygous mice had a highly penetrant type of bicuspid aortic valve with right and left leaflet fusion, which is the most frequent type found in humans. GATA6 transcript levels were lower in human bicuspid aortic valve as compared to normal tricuspid valves. Mechanistically, GATA6 haploinsufficiency disrupted valve remodeling and extracellular matrix composition through dysregulation of the importance in the molecules including matrix metalloproteinase nine. Cell-specific inactivation of GATA6 reveal that an essential rule for GATA6 in secondary heart field myocytes. Thus, the study identifies a new cellular and molecular mechanism underlying bicuspid aortic valve.

In the field of cardiac regeneration, c-Kit positive adult progenitor cells were initially reported to produce new cardiomyocytes in the heart. However, more recent genetic evidence suggests that such events are exceedingly rare. Today's paper provides insights into this discrepancy and it is from first author Dr Maliken, corresponding author, Dr Molkentin from Howard Hughes Medical Institute Cincinnati Children's Hospital Medical Center. The authors took a novel approach of deleting the necessary cardiogenic transcription factors, GATA4 and GATA6, from c-Kit expressing cardiac progenitor cells to determine whether true de novo cardiomyocyte formation would occur. They found that deletion of the necessary cardiogenic transcription factors, GATA4 and GATA6, from these c-Kit+ cardiac progenitor cells remarkably resulted in greater apparent cardiomyocyte derivation from the c-Kit+ cells. Deletion of GATA4 from c-Kit–derived endothelial progenitors altered the integrity of the endothelial cell network in the heart, resulting in greater c-Kit+–derived leukocytes entering the heart and fusing with cardiomyocytes.

Thus, they demonstrated a new role for GATA4 in endothelial differentiation, specifically showing for the first time that GATA4 is essential for vascular development by the c-Kit lineage. The study shows that leukocyte to cardiomyocyte fusion is the primary basis for path lineage tracing results, incorrectly suggesting that c-Kit+ cardiac progenitor cells generated de novo cardiomyocytes in the heart.

Lecithin–cholesterol acyltransferase, or LCAT, is the sole enzyme that esterifies cholesterol in the plasma. Its role in the supposed protection from atherogenesis remains unclear, because mutations in LCAT can cause more or less carotid atherosclerosis. Addressing this conundrum, co-first authors Drs. Oldoni and Baldassarre, co-corresponding authors Dr Kuivenhoven from University Medical Center Groningen, Dr Holleboom from Academic Medical Center Amsterdam, and Dr Calabresi from University of Milano in Italy hypothesized that genetic mutations causing complete LCAT deficiency versus partial LCAT deficiency would be differentially associated with carotid atherosclerosis in carriers of LCAT mutations. To study this, they looked at 74 heterozygotes for LCAT mutations who are recruited from Italy and the Netherlands and who were assigned to complete versus partial LCAT deficiency. These were also compared to 280 controls. Using carotid intima-media thickness as a measure of atherosclerosis, the authors demonstrated that carriers of LCAT mutations leading to complete LCAT deficiency exhibited less carotid atherosclerosis, indicating a reduced risk of cardiovascular disease.

By contrast, however, carriers of LCAT mutations leading to partial LCAT deficiency showed marginally more atherosclerosis. The association of mutations in LCAT with subclinical atherosclerosis appeared to be related to the capacity of LCAT to esterify cholesterol on apoB-containing lipoproteins since the abnormal LCAT present in the partial deficiency was only active on this class of lipoproteins. These important findings bear relevance for pharmaceutical strategists that target LCAT.

After a bioprosthesis aortic valve replacement, what is the incidence, correlates, and outcomes of hemodynamic valve deterioration? First author Dr Salaun, corresponding author Dr Pibarot from Quebec Heart and Lung Institute and their colleagues studied 1,387 patients who underwent bioprosthetic aortic valve replacement and found that hemodynamic valve deterioration identified by Doppler echocardiography occurred in one-third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes and renal insufficiency were associated with early hemodynamic valve deterioration whereas female sex warfarin use and stented bioprosthetic valve versus the stentless ones were associated with late hemodynamic valve deterioration. These findings suggest that following bioprosthetic valve replacement, a systematic echocardiographic follow-up may be considered to ensure adequate detection and quantitation of hemodynamic valve deterioration.

That wraps up on the summaries this week. Now for our feature discussion.

We are recognizing the critical role that cardiac troponins play for the early diagnosis of acute myocardial infarction. We also know that there are different isoforms of cardiac troponins, the cardiac troponins T and I. Now, have you ever considered combining the two? How does that help the early diagnosis of acute myocardial infarction? Well, I am delighted to have with us the corresponding author of our feature paper today, Dr Christian Mueller from University Hospital Basel in Switzerland, a very familiar voice on this podcast. Welcome, Christian, and thank you so much for publishing yet another wonderful paper with us.

Dr Christian Mueller: Thank you very much for highlighting this important work and allowing me to comment on it in the podcast.

Dr Carolyn Lam: Christian, first of all, could you paint the background to help us understand what's the difference between the two isoforms, I mean, in terms of diurnal variation, the way that they may be released earlier or later, the way they may or may not be impacted by comorbidities like renal dysfunction or hemolysis? Could you help us understand why there may be rational to combine the two in looking at their impact on the diagnosis of acute myocardial infarction?

Dr Christian Mueller: The measurement of cardiac troponin as a structural protein unique to the heart clear is a central piece in our early diagnosis of acute myocardial infarction, so both for the early rule out in patients who present with chest pain and are finally found to have more benign disease as well as the early ruling. In general, I think it's important to highlight that there are two isoforms exactly as you have mentioned, so there is cardiac troponin T and cardiac troponin I. So these two proteins are cardiac specific and are used in the diagnosis of acute myocardial infarction. Now with the development of high-sensitivity methods or measurements of both cardiac troponin T and cardiac troponin I concentrations, we have been able to get a little bit of a better understanding of in fact differences in the pathophysiology as well as analytical details between cardiac troponin T and I.

Before I start highlighting the differences, I think it's important, I mean, both signals show a very strong correlation, so still very, very similar to each other. However, the small differences that have begun to emerge kind of allow to suggest that possible we could use them together as two pieces of information in the diagnosis.

So, what are the differences? First, exactly as you have highlighted, that if in fact that diurnal rhythm with cardiac troponin T, which means that cardiac troponin T concentrations are higher in the morning hours as compared to the evening, we still have no clue why that's the case, but it's a relevant difference about 25% and it has been shown in two cohorts and a group from Maastricht who was the first one highlighting this. This rhythm has not been found for cardiac troponin I. The second difference is that, again, probably understood in many, many population studies cardiac troponin T concentrations are even stronger predictors of death as compared to cardiac troponin I concentration. Then the third difference it seems that if we measure it with high-sensitivity assays, for example high sensitivity, it seems to rise or if you released from injured cardiomyocytes even slightly earlier as compared to T and possibly even less injuries necessary to release I as compared to T.

Then you mentioned renal function. Cardiac troponin T concentration shows slightly higher correlation with renal function as compared to I. Also, other pre-analytical issues, hemolysis seems to affect T and I concentration in a different way. So a lot of small tiny differences that have emerged and that underlie the hypothesis that possibly by combining the two signals we could be even more accurate in the diagnosis rather than relying on one on its own.

Dr Carolyn Lam: That's good. That really sets up the rational very well. I think in and of itself is a learning lesson, because I think most clinicians sort of take the two equivalently. So could you tell us what you found?

Dr Christian Mueller: I would like to of course thank the fantastic team that has allowed us to generate this data. It's a collaboration between the APACE investigators, the ADAPT investigators and experts in clinical chemistry from Maastricht University and Noreen Fandalin and Karen Villa of the first office. So we used two large diagnostic studies, APACE and ADAPT. We measured high-sensitivity cardiac troponin T and I and both of them and compared the diagnostic performance as compared to the final adjudicated diagnosis by two independent cardiologists who, of course, had all information, cardiac imaging and whatever you need to adjudicate.

So, what we found is that in general if you look at diagnostic accuracy, overall is quantified by the area under the curve. Combining the two signals did not consistently increase overall diagnostic accuracy as compared to the individual isoforms. However, we were able to document some improvement for the rule out for the very early rule out of acute myocardial infarction. So the concept that is extremely attractive of course from a medical as well as from an economic perspective is to rule out the presence of acute myocardial infarction with a single blood draw. So, we can do this if we assess the ECG. The ECG doesn't show relevant changes. Then if the troponin concentration measured with a high-sensitivity assay is very low, then the likelihood that the patient would have an acute myocardial infarction again is extremely low or in scientific term sort of a negative predictive value approach is 99 to 100%. By combining very low concentration for high-sensitivity T and very low concentration for I, we were able to increase the efficacy of the early rule out and that seemed to be the most likely possible clinical utility of combining the two signals.

Dr Carolyn Lam: Even that so-called neutral findings are very important. It's an important question to ask and important answer to get. Could you give us an idea for the rule-out part? How much do we gain? How much exactly do we gain by using both assays instead of just one?

Dr Christian Mueller: So, the efficacy of the early rule-out depends to some extent on the assay used and the cut off applied. So the current you see algorithm uses cut-off that has been shown to be very safe. However, they are regarding their efficacy not very high. So the current you see recommended cut-offs and approach, allows the rule-out only in about perhaps 10 or 15% of patients. That number can be significantly increased, likely doubled or perhaps even increased threefold by using the combination approach. So this has been consistently showed both in the derivation and the validation cohort.

Dr Carolyn Lam: Yeah. Do you think this is ready for prime time? I noticed a very balanced discussion actually calling for future studies, but perhaps you could state it better now.

Dr Christian Mueller: The main limitation regarding prime time is the fact that currently manufacturers either of a high-sensitivity TSA or of a high-sensitivity high method, which means that the vast majority of hospitals at this point in time do only have one method available. It would require quite substantial investment in both hardware as well as changing of the logistics in the lab to implement measurement of both assays. So I think it's likely feasible, but it would be associated with relevant investment from a hospital perspective. In addition, I mean, also the rule-out approaches that use of only one assay also there are studies ongoing in trying to further increase the efficacy of the single marker approach. So I think it's the best tool marker strategy that we were able to come up with recently, because many of the other biomarkers that we had tested really didn't work out. Still, as you mentioned, I think it's also important to be very, very honest that it will be difficult to implement tomorrow in most institutions.

Dr Carolyn Lam: Yeah, and perhaps a little bit more work needs to be done to sort first identify perhaps special situations where these may be particularly helpful. I supposed like you just said when we're thinking of the ESCs to review one-hour type algorithm, who knows maybe we should be having that extra insurance of the second test in those that test it negative in the first or something like that. Do you plan further work? I always ask you because you're always in the forefront of these things and we just love touching your work.

Dr Christian Mueller: We have several additional analyses ongoing. Again, I think the main part is for just to go ... I go back from a clinical perspective. So I think for many hospitals that are using T at the moment, it's important to have I available for certain situations. So for example if you have a patient in whom you have evidence of chronic skeletal muscle disease, most of these disorders are rare but some of them have been shown to be associated with increasingly highly troponin T that do not seemed to be related for cardiac diseases but from skeletal muscle. This is rare but if you have a patient with that kind of history, then the dual mark measurement is I think mandatory.

The same applies to iso that the other reasons to have false positive results for iso whenever you are ... If your hospital is using I, you should have the T method also available because once in a while you will identify patients in whom you have an I result that doesn't really match the clinical setting, then it's so easy and often so helpful to get the T result to decide on the most appropriate measurement of patient.

For which patients are kind of a standard that measures T and I would be justified, I think that's something to tease out in future study. I think that the rational is there and likely it will depend also on kind of which T or which I method we might use in the future. So at the moment, we have one method for high-sensitivity T, but there are several other methods in development and kind of applying for FDA approval for high-sensitivity I and possibly combination of these might be even more beneficial regarding the single measurements and I think that has to be teased out in future studies.

Dr Carolyn Lam: Exactly, but what great insights for us to consider as clinicians now for specific cases where we may consider find those if we have those in our institutions. At the end of the day, I supposed cost-effectiveness analysis will need to be done. Agree?

Dr Christian Mueller: Absolutely, absolutely. The good thing about troponin, it's extremely inexpensive. So as compared to most of the new fancy biomarkers that are usually, rather prices of troponin is a routine marker. It's inexpensive. It's there for very likely that if we are able to document some clinical value that also the cost-effectiveness study that's definitely unnecessary will show also some economic benefit.

Dr Carolyn Lam: Oh, Christian, thank you for publishing yet another impactful and clinically relevant paper with us here in Circulation. I mean, it's exactly the kinds of papers that we really treasure here, because they directly inform clinicians and open our eyes to actually things that we should be considering in our everyday practice. Clod I ask you maybe cheekily to share about your experience with publishing at Circulation? Someone like you will be the best person to tell the world what it's like.

Dr Christian Mueller: Oh, of course. I mean, for us as a research group and for me as a researcher, it's fantastic. It's perfect to have some of our work published in Circulation that has fantastic impact factor, fantastic readership and ensures that the research catch the attention that's fantastic. Also, I think for us as a research group, the recognition of being able to publish in Circulation is outstanding and it helps us continue in the research group that we do. The comments made to large extent also by the editors. Also, on this manuscript, I think we're incredibly insightful and definitely had a major contribution to the final product to make it as attractive and also as balanced and insightful I think as it is at this point in time.

Dr Carolyn Lam: Thank you so much for providing that feedback, because it is our aim, explicit aim to put a partner authors in getting the best of the manuscript and working really closely with you. So thank you once again, Christian, for your time today. Audience, I know you've heard many times from this favorite person that we have on our podcast.

Do share this podcast with all your colleagues and don't forget to tune in again next week.

Circulation August 28, 2018 Issue

27 augusti 2018 | 23 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Do we finally now have a simple, evidence-based way to make a diagnosis of heart failure with preserved ejection fraction? Well, today's feature paper certainly brings us closer to that goal and you must listen to the discussion coming right up after these summaries.

Bleeding is commonly cited as a reason for stopping oral anti-coagulants. However, what is the prognostic significance of minor bleeding events, or so called nuisance bleeding, in patients with atrial fibrillation on oral anti-coagulants?

First and corresponding author, Dr O'Brien from Duke Clinical Research Institute and her colleagues, identified 6771 patients with atrial fibrillation in the Orbit AF Prospective Outpatient Registry. They ascertained nuisance bleeding from medical records defined as minor bleeding that did not require medical attention. Overall, 20% had documented nuisance bleeding giving an incidence rate of 14.8 events per hundred person years. Nuisance bleeding was not associated with a higher risk of major bleeding, or a stroke and systemic embolism over the next six months.

These findings therefore suggest that the occurrence of nuisance bleeding or minor bleeding should not lead to changes in anti-coagulant treatment strategies in patients treated with anti-coagulants.

The next study sheds new light on mechanisms linking NLRP3 inflammasome activation to atherogenesis. Dr Westerterp from Columbia University, New York and colleagues studied mice with myeloid deficiency of ATP binding cassette transporters A1 and G1 and concomitant deficiency of the inflammasome components NLRP3 or caspase-111.

They showed that cholesterol accumulation in myeloid cells activated the NLRP3 inflammasome. NLRP3 inflammasome activation enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques thus accelerating atherogenesis.

Patients with Tangier's disease, who had ATP binding at transporter A1 loss of function, had increased myeloid cholesterol content and showed markers of inflammasome activation. Thus, inflammasome activation may underline cardiovascular disease in these patients.

The next study identifies TPX20 as a novel transcription factor regulating angiogenesis. TPX20 is a crucial transcription factor for embryonic development and its deficiency is associated with congenital heart disease. However, its role in angiogenesis has been not been previously described. At least until today's paper from co-first authors Dr Meng and Dr Gu and co-corresponding authors Dr Cooke and Dr Fang from Houston Methodist Research Institute.

These authors use loss and gain function approaches to explore the role of TPX20 in angiogenesis both in vitro and in vivo. They showed that with VEGF stimulation, the transcription factor TPX20 upregulated PROK2 with is secreted from endothelial cells and gauges its receptor PROKR1 and thereby promotes angiogenesis in autocrine manner.

This novel signaling pathway appeared to be highly conserved as it functioned in zebra fish vascular development and the angiogenic response to ischemia in a mouse model of peripheral disease. The authors furthered showed the selective role of TPX20 in endothelial migration but not proliferation. Furthermore, treatment with recombinant PROK2 the critical effector of TPX20, improved blood profusion and functional recovery in the mouse peripheral artery disease model. Thus, these data highlight the therapeutic potential of PROK2 in augmenting functional angiogenesis for diseases associated with this regulated angiogenesis.

In patients with atrial fibrillation, left atrial appendage closure with the Watchman device, is known to prevent thromboembolism from the left atrial appendage. However, thrombus may still form on the left atrial face of the device, which then may potentially embolize. This next paper provides important data on the incidents, predictors, and clinical outcomes of device-related thrombus after left atrial appendage closure.

First author, Dr Dukkipati and corresponding author Dr Reddy from Icahn School of Medicine at Mount Sinai, New York and their colleagues studied the device arms of 4 prospective FDA trials of patients undergoing the Watchman implantation. These were the PROTECT AF, PREVAIL, CAP, and CAP2 trials.

They found that following percutaneous left atrial appendage closure with the watchman device, the incidence of device-related thrombus was 3.7% and this was associated with a more threefold higher risk of stroke and systemic embolism. Predictors of device-related thrombus were a history of trans- ischemic attack or stroke, permanent atrial fibrillation, vascular disease, a larger left atrial appendage diameter, and a lower left ventricular ejection fraction.

Device-related thrombus was not associated with an increased risk of cardiovascular or all-cause mortality. Nearly 75% of patients that developed device-related thrombus did not experience a stroke. And ischemic strokes occurring in patients with device-related thrombus accounted for approximately 10% of all ischemic strokes, following left atrial appendage closure. Thus, given the ramifications of device-related thrombus, a judicious surveillance strategy using periodic transesophageal echo cardiography may be considered particularly when risk factors for device-related thrombus are present.

Well, that wraps it up for our summaries. Now for our feature discussion.

Heart failure with preserved ejection fraction or HFpEF, notoriously difficult diagnosis to make, but do we finally have a validated diagnostic algorithm for HFpEF? Oh, you have to listen to our conversation today. I am so proud and pleased and thrilled frankly to have with me today the corresponding author of the feature paper, and that's Dr Barry Borlaugug from Mayo Clinic in Rochester, Minnesota as well as editorialist Dr Walter Paulusus from VU University Medical Center in Amsterdam.

Thank you so much both of you for making it here. I want to dive straight into it. So, Walter, maybe could you please paint the background to this because you wrote I think the most highly cited diagnostic guidelines of HFpEF, but that was in 2007. Tell us how does today's paper take us forward?

Dr Walter Paulus: Thank you very much, Carolyn. It's quite an honor for me to give you comments about this paper, which I think is going to be a landmark event. Over the years we have seen multiple algorithms being proposed usually by professional societies like V and C or the American Society of Echocardiography for the diagnosis of HFpEF. The major drawback of all these algorithms is that they have never been validated in clinical practice. And the reason they have never been validated was that it was extremely difficult to establish a gold standard for HFpEF.

And Barry was so clever to already invest in an establishing a gold standard for HFpEF ten years ago, and he very vigorously subjected all his patients in whom he suspected HFpEF to an invasive stress test and could establish the diagonals of HFpEF using this as a gold standard. And then he used all these consecutive patients with subsequently used to devise some form of an algorithm that was immediately validated against a gold standard. I think this has been a giant leap forwards. And again, I want to congratulate him with this unique endeavor.

Dr Carolyn Lam: Barry, I want to echo Walter's words and congratulate you. Now, has it really been ten years in the making? Tell us about this, Barry.

Dr Barry Borlaug: It has. In fact, it was 12 years ago when we started doing this, in 2006. But, yeah, these patients were examined in our laboratory between 2006 when I joined the staff at the Mayo Clinic to 2016. And really just doing this work up, we kind of started out doing it on a few patients and then we realized how powerful the methodology was. We did the invasive exercise testing with hemodynamics and a larger number of patients and just through accumulating a large number, as Walter points out, with a gold standard assessment this allowed us to then determine which less invasive attributes could be used to identify the likelihood that heart failure was the diagnosis.

Dr Carolyn Lam: That's so great. But you know beyond just that it is such a precious data set and so on, your paper is just so beautifully written and so clinically applicable. You've got this HFpEF score now for diagnosis. Everybody's going to be talking about it. So tell us about it. What does HFpEF score? What makes you think it'll work? How do you apply it clinically?

Dr Barry Borlaug: Thinking about diagnosis a lot, you really have to go back to [00:19:19] thinking, estimating the probability of disease, and when you're able to do that then you can find people where you need to perform really more invasive testing like the exercise testing. So really, we started like we need to have a better way to define who needs that more expensive and invasive evaluation. So we have this large cohort of patients, over 500 patients, 414 in the initial cohort, and then another 100 in the validation cohort. And they had all undergone this work up, they'd all undergone very detailed clinical evaluation and pheno typing. And we hypothesized which characteristics we thought would be most relevant. And then we did logistic regression to identify all the predictors.

There were many things that are associated that you would expect with HFpEF, but there were only 6 factors in the end in a multi-variable model that were all independently associated. That provided the most parsimonious sort of model or score that we could develop. We included these six different variables. So there's two for letter H- heavy and hypertensive, and by heavy we define that as a body mass index above 30. Hypertensive is defined as two or more antihypertensive medicines. The F in the H2 HFpEF score is atrial fibrillation, either paroxysmal or persistence a. Fib. The P is for pulmonary hypertension as estimated by echo with an estimated PA systolic pressure on echocardiography of 35. We wanted all of these to be noninvasive criteria for this score. E is for elder. I specifically didn't call it elderly because that can be a pejorative term and its only 60 years which is not that old. So E is elder. And F is for filling pressures, again estimated by echo doppler cardiography as an EE prime ratio greater than 9.

All of the scores are not one point each. They were arranged based on the strength of correlation in the logistic model. So being obese, having a BMI above 30 was awarded two points because it has a strong correlation. Being in atrial fibrillation or having a history of atrial fibrillation was even stronger at three points. If you tally these up, the score can range from 0-9, and based on that score you can then estimate a probability that HFpEF is present, if you're evaluating a patient that meets the entry criteria of the study, which is basically normal ejection fraction, and exertional breathlessness.

Dr Carolyn Lam: Nice. Okay, Walter, I think I can safely say that you have been thinking about this syndrome longer than either Barry or I. So I'd love your perspectives on how do you think this will be put into practice clinically perhaps, and where is the key area that it will change practice compared to perhaps the old diagnostic algorithms were like?

Dr Walter Paulus: I think this is a very important point, Carolyn. I think this score is so easy to handle and it is so well validated that we can now go to general practitioners and cause a general awareness for the disease. What vies me is that many patients are still unreported. The reason is that general practitioners and even general internal medicine people do not realize the [00:19:19] heart failure with preserved ejection fraction. Now with this score at hand, we can convince them that there needs to be an awareness when they see people that have value higher than six on the score, that they should be suspicious of heart failure being part of the symptomatology. I think this score mainly has its usefulness for general practitioners and general internal medicine.

Apart from the score, and it's more up to Barry to comment on this, but I want to highlight also, that he did not only develop the score, but he also had these very beautiful nomograms which is more of a find than a score, where he treated the variables in a continuous way. I think this is fairly useful for cardiologists and especially for people who want to have acute patients into trials because here we now have a very refined scale that goes from 0-160 and that allows you again to see what type of population you are addressing, what type of patients you are seeing that eventually what type of patients you are recruiting. I think for me the HFpEF score is of importance for general practitioners, general internal medicine, and especially I think we should also promote the nomogram. The nomogram, I think, are so refined that it would be useful tool, I think an excellent tool, for includement into trials.

Dr Carolyn Lam: Oh wonderful. Both of the simplicity and the cleverness, if I may, of this paper are precious to generalists and cardiologists. But Barry, I do have a couple of questions for you. Both you derivation and validation were in Olmsted if I'm not wrong. Now how am I supposed to apply it to my skinny HFpEF patients in Asia or elsewhere?

Dr Barry Borlaug: That's an important point, Carolyn. And it's a limitation of the paper. The people in Olmsted County, MN are not the same as they are in other parts of the United States or other parts of the world. I think that additional evaluation and other cohorts are important. We did the best we could with what we had. We did look at the patients carefully at Mayo Clinic. People think of it as quaternary referral center, but a pretty substantial number of the patients are from the local area, I think about 2/3 of them were. And when we looked in a subset in a sensitivity analysis of the people that were more local practice rather than coming from large academic medical centers, the HFpEF score, or as Walter pointed out, the continuous HFpEF model performed equally well. When we looked at people with so-called advanced HFpEF so high hemopressures at rest versus people at so called early stage HFpEF the people that have normal hemodynamics at rest but elevation during exercise. The model also worked well in that cohort.

But, like most studies that come out of where I work in southeastern Minnesota, it is mostly Caucasian people, the mean BMI was in the low 30s. So we need to look at other populations to make sure this works elsewhere as well.

Dr Carolyn Lam: Barry, let it go on record that I am your biggest fan. So thank you so much for this. I was just thinking even in other populations where the mean BMI may be lower for example here in Asia, we still definitely see an association with a higher BMI albeit at a lower cutoff with the presence of HFpEF. So it does raise this issue of do we need to maybe calibrate the score differently in different geographies or ethnicities. But that's not by any way take away from the tremendous input that you've made.

One other question is also the strength of atrial fibrillation in impacting the score. What are your thoughts on the possibility of misdiagnosis for example atrial fibrillation as HFpEF or the similar situation since they share symptomatology?

Dr Barry Borlaug: This is a great point, Carolyn. People still sort of argue about this. Somebody has breathlessness and effort intolerance and atrial fibrillation. Some doctors say they have symptomatic atrial fibrillation, but when we put catheters when we take these patients to the so-called table of truth and put catheters in and exercise them, we see hemodynamic arrangements that are diagnostic of heart failure. This led us to believe that this isn't just symptomatic a fib. It's really HFpEF. And that's why they have a fib. We published a paper earlier this year in circulation, more of a brief report, on the association between atrial fibrillation and HFpEF where we first reported this. That if you have normal EF, and especially permanent atrial fibrillation, you can pretty much take it to the bank that the patient probably does have heart failure with preserved ejection fraction, at least in the way that we have sort of defined it and the way that [00:19:19] initially defined it as an inability of the heart to pump blood adequately at normal filling pressures.

These patients almost all have that criteria for cardiac failure. I think that it is a really strong indicator and we probably are really just like in the general clinics, under recognizing HFpEF. I think probably in other clinics where people have atrial fibrillation and effort intolerance, we're again really under recognizing HFpEF in these people.

Dr Carolyn Lam: Indeed, and it's actually very consistent with Walter, your recommendations where atrial fibrillation played a big part too. Do you have any thoughts or advice?

Dr Walter Paulus: My idea is that atrial fibrillation and HFpEF are both manifestations of the same underlying process, which is systemic inflammation because of a metabolic disturbance. We used to think of atrial fibrillation as a consequence of left atrial dilatation, which itself was caused by the high filling pressures. I think that this does not hold, there is more to it. I think the atrium is as sick as the left ventricle and it undergoes similar pathological changes. That's why the presence of a fib becomes such a strong determinant of the presence of HFpEF in Barry's H of HFpEF score. All of this makes a lot of sense to me.

I just want to add something else. You spoke about the Asian population having less BMI and already having HFpEF. I think if you look at Barry's variables in uni-variant analysis, there's one which was presence of diabetes or prediabetes which did not make it in the multi-variant analysis on 0.06. It's my belief that if you got to the Asian population, that probably the BMI could be replaced with the presence of prediabetes and diabetes. Usually the insulin tolerance or insulin resistance is presence and the BMI is still low. I think there is need for some fine tuning, maybe in Asian populations, and I think this should be a challenge to go ahead with it. In fact, I'm leaving for Japan the day after tomorrow and I'm going to show the slides of Barry's paper. I'm going to try to set something up to also validate the score in Japanese populations.

Dr Carolyn Lam: We've got our work cut out for us, Barry! Let's get on to this too in southeast Asia.

Dr Barry Borlaug: I totally agree with Walter. I think that's great. And Carolyn, you, in a lot of papers, point this out, that the metabolic, cardio-metabolic associated with excess body mass, the way we define it with BMI, is shifted way down in southeast Asian population, and south Asian population, so I would agree with Walter's hypothesis that diabetes, prediabetes maybe that's the better way to go when we look at this in other patient populations.

Dr Carolyn Lam: You both absolutely made my day with this discussion today. Thank you so much. What a thrill to be on the same podcast with the people I admire most.

Listeners, I know you enjoyed this as much as I did. Don't forget to tune in again next week.

Circulation August 21, 2018 Issue

20 augusti 2018 | 19 min

Can we get better at predicting clinical benefit of PCSK9 inhibition based on the severity and extent of coronary artery disease? Well coming right up after these summaries we have an important discussion of an analysis from the FOURIER trial, so stay tuned.

The first original paper this week suggests that targeting visceral adiposity may be the crucial step to limit age-related cardiac remodeling and to promote healthy cardiac aging. Co-first authors Drs Sawaki and Czibik, corresponding author Dr Derumeaux, from INSERM France, and their colleagues, hypothesize that since aging induces cardiac structural and functional changes, linked to increase deposition of extracellular matrix proteins including osteopontin, well osteopontin may play a role in myocardial aging.

To test this hypothesis, they studied osteopontin-deficient mice and their wild-type litter mates at two and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. They found that during aging, visceral adipose tissue represented the main source of ostepontin and altered heart structure and function via its profibrotic secretome. Furthermore, interventions targeting osteopontin, such as visceral adipose tissue removal and osteopontin deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. This work uncovers ostepontin's role in the context of myocardial aging and suggests that osteopontin may be a potential new therapeutic target for a healthy cardiac aging.

The next study shows that higher triglyceride rich lipoprotein cholesterol may be a risk factor for cardiovascular disease and potential therapeutic target. First author Dr Vallejo-Vaz, corresponding author Dr Ray from Imperial College London, and their colleagues assess the relationship between triglyceride-rich lipoprotein cholesterol and cardiovascular risk and whether this risk was modifiable among patients receiving statins in the TNT trial. They found that higher levels of triglyceride rich lipoprotein cholesterol were associated with a significantly higher rate of cardiovascular events among coronary patients treated with statins. Statin therapy reduced triglyceride-rich lipoprotein cholesterol and to a greater extent among those treated with a higher statin dose.

Based on their post hoc analysis of the TNT trial, they found that more intensive statin therapy with atorvastatin 80 milligrams, compared to atorvastatin 10 milligrams, resulted in a significantly greater cardiovascular risk reduction among patients with higher triglyceride-rich lipoprotein cholesterol. These results were consistent for higher triglycerides and directionally concordant for non-HDL cholesterol. A higher percentage reduction in triglyceride-rich lipoprotein cholesterol was associated with lower cardiovascular risk independent of LDL cholesterol reduction. Thus, these findings suggest that triglyceride-rich lipoprotein cholesterol is not only a cardiovascular risk marker, but also potentially a therapeutic target.

Late gadolinium enhancement on cardiac magnetic resonance imaging represents fibrosis and is seen in 60% of adult patients with hypertrophic cardiomyopathy. However, what about in children and adolescents with hypertrophic cardiomyopathy? First author Dr Raja from University of Copenhagen in Denmark, corresponding author Dr Ho from Brigham and Women's Hospital in Boston, and their colleagues looked at cardiac magnetic imaging data from 195 children and adolescents with hypertrophic cardiomyopathy. Late gadolinium enhancement was present in 46% of patients with overt hypertrophy as opposed to 60% typically represented in an adult population of hypertrophic cardiomyopathy. On the other hand, late gadolinium enhancement was not seen in mutation carriers without left ventricular hypertrophy.

In patients who underwent serial imaging, increases in late gadolinium enhancement, left ventricular mass, and left atrial size were detected over two and a half years. Thus these findings in children provide additional insights into the biology and natural history of hypertrophic cardiomyopathy and confirmed that fibrosis is a significant part of the disease process in both children and adults.

Whether the adult mammalian heart harbors cardiac stem cells for the regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. This week's paper adds to the growing knowledge in this area. First author Dr Li, corresponding author Dr Zhou from Chinese Academy of Sciences and their colleagues developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, they assessed if non-myocytes generated any new myocytes during embryonic development, adult homeostasis and after myocardial infarction. Skeletal muscles were also examined after injury and acted as internal controls.

By using this stem cell marker free and dual recombinases mediated cell tracking approach, the author showed that new myocytes arose from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive controls, the same lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. Thus, this study provides in vivo genetic evidence for non-myocyte to myocyte conversion in the embryonic but not the adult heart. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.

Well, that wraps it up for our summaries this week, now for our feature discussion.

Are there subsets of patients that derive greater clinical risk reduction with the PCSK9 inhibitors? Well we're gonna find out about that right now with a discussion of our feature paper entitled the “Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease.” So pleased to have with us Dr Marc Sabatine from the TIMI Study Group, who is the first and corresponding author of today's feature paper, as well as our editorialist, Dr Roger Blumenthal from Johns Hopkins University. And of course, we have a familiar voice, a very important editor of our digital strategies and that's Dr Amit Khera from UT Southwestern.

Welcome everyone, I think I'd really like to start with maybe asking Roger to paint the background of the importance of this paper. Simply because I just love the title of your editorial, which is “Realizing the Value of PCSK9 Inhibitors: Are We Closer to Finding the Sweet Spot?” I think that really encapsulates it. So Roger, your thoughts?

Dr Roger Blumenthal: As Amit Khera knows, I'm a golfer, so when you think about the sweet spot on the club, and we know that PCSK9 inhibitors are a great story of translation from bench to bedside, and we also know that the high cost of the therapy presents a challenge. So what Dr Sabatine and colleagues did was to try to identify the sweet spot for its most effective use and that was a pleasure to comment on Dr Sabatine's excellent study.

Dr Marc Sabatine: I think taking a step back I would say from pure biologic perspective, we know that lowering LDL cholesterol will reduce events and that's true and primary and secondary prevention and so if you have therapies that were safe and inexpensive, then I think you wouldn't need to really look for that sweet spot cause it would be all sweet if you will to extend the analogy. But Roger's absolutely right that when you have therapies that are then expensive, then you have to decide, okay in which patients will I get the biggest bang for my buck? And that's a very legitimate question to ask.

And so in FOURIER, overall the trial was positive but as we look for subgroups we say, "Can we find individuals who enjoy a greater absolute risk reduction?" Because therefore the benefit cost ratio is gonna be particularly favorable. And so we approach that in a couple different ways. First you can look for just predictors of baseline risk, so if someone has twice the baseline risk and the same relative risk reduction, you should get about twice the absolute risk reduction and therefore the number needed to treat would be cut in half. And so based on our experience from other TIMI trials and other datasets, we looked at three features that have identified patients with higher baseline risks.

Amongst those with a history of MI which is in and of itself a heterogeneous group. And so those features were patients with a more recent MI, those with multiple prior MIs and those with known residual multivessel coronary disease. And all three features in the FOURIER dataset, not surprisingly, were predictors of risk with patients having an average about a 50% higher baseline risk. But what was particularly nice was that the subgroups also identified patients who had greater relative risk reduction. And so when you couple the two, the higher baseline risk with the greater relative risk reduction, that translated into greater absolute risk reduction then in each of these high-risk groups, the absolute risk reductions over three years or for CV death, MI, and stroke was around 3% versus around 1% for the low-risk groups.

And so that changes the number needed to treat by a factor of three.

Dr Carolyn Lam: Wow, that's so cool. Amit, do you think you could just give us a sneak peek into the editors’ discussions when you saw this paper?

Dr Amit Khera: This was an easy one, it's clearly a very important paper and if you step back 10,000-foot view, these drugs were initially approved based on LDL lowering and people were using them without knowledge of whether or not they actually lowered events. Marc's group and others have now shown us that certainly they do lower events, but really the next most important thing is application. Who should we use them in and when should they be used and where might they be most effective and I think it was said out in the introduction of this paper, this idea of personalized medicine. And I think this really is an important step forward, not just for PCSK9 field but in general, how we should be thinking about drugs, about balancing cost and benefits and who would benefit most.

So maybe one analogy, I think PCSK9 was not prescribed as much as they had been predicted given costs and other considerations and maybe with analysis like this they've hit it out of the rough back on the fairway, I threw that in for you, Roger. And I do have one question for Marc, which is this is clearly important to better define who would benefit the most and I guess in terms of action abilities, the goal here to provide guidance for clinicians where, you know, if I'm seeing a patient this morning I would take this into account or is this something larger where we recently saw with alirocumab, they changed pricing based on sub-group analysis of a higher risk group. How do you think we should move forward with this type of information?

Dr Marc Sabatine: I’ll get back to the point I raised earlier, I do want to underscore that I think that the true biologic notion is that all these patients, sub-types of secondary prevention or primary prevention all benefit from LDL lowering. So I wouldn't want people to walk out with the notion that it's the only subset that would benefit and really from a population level, obviously Roger's in a better position to speak about this, but sort of shifting the population LDL lower in general would have a huge impact on the risk for cardiovascular disease. But to your question Amit, looking in for a patient in front of you, I think it's quite fair to say right now there's this kind of tug of war back and forth between payers and clinicians.

Clinicians saying, "I have a patient in front of me, they have known atherosclerotic cardiovascular disease, I wanna lower their risk, I wanna manage their risk factors and I wanna get their LDL cholesterol lower and I have a bunch of great tools in front of me." Statin for sure is the foundation, maybe acetamide and PCSK9 inhibitors. And then payers saying, "Well wait a minute, these are expensive drugs and so we're gonna try to restrict that and create a lot of hoops for clinicians to jump through." And so I would rather than wasting all that time back and forth, I think it is logical to say, "What are the high-risk groups?" Where we can agree there's the large enough absolute risk reduction that for a given cost, that makes sense.

Allow there to be alignment for that and have clinicians just be able to write a script and have it filled rather than wasting a lot of time with preauthorization and letters back and forth.

Dr Amit Khera: That's a great point, maybe I'll just take one follow-up, which is now trying to sift through all the high-risk groups and they end up maybe becoming a bit of a Venn diagram. I know in Roger's editorial he talked about the other FOURIER analysis with PAD and there's more groups to come or do we have enough of a starting place where we think we have enough for decision making?

Dr Marc Sabatine: I would say there are a variety of groups, there is some overlapping even in the paper then we looked at the union of those three high-risk features, which identified about two thirds of the patients who were enrolled in the trial with a history of MI. But you're right, the other slices of the data that will also identify high risk groups, PAD is a particularly good one because most of the therapy for those patients has focused on antithrombotic therapy, which always will have some downside for increased bleeding, whereas risk factor modification in this case has no downside. So that's a very high-risk group, it certainly is important to focus on. But I think within the MI subset, this is a great place to start the other analyses we're doing.

And probably after we've sort of finished the series of, if you will, these kind of univariant slices, then we'll try to put that together into a more comprehensive picture.

Dr Roger Blumenthal: We tried to say that we still need the formal cost-effective analyses in these specific high-risk groups, but it seems most reasonable to focus on engaging in shared decision making now with our patients about PCSK9 inhibitor use and those with a recent ACS and the basis of Odyssey Outcomes and we're awaiting the final publication of that. Symptomatic peripheral arterial disease, which Marc previously published in Circulation, and then looking at these high-risk features that was the subject of this article, those with a more recent MI within the past two years, multiple prior MIs and residual multivessel coronary disease.

And one of the things that we especially found interesting was among the more than 8,000 individuals without a high-risk feature, the event rates were nearly unchanged in the evolocumab versus placebo groups. So I think that's very important, but one other point that we have to keep in mind is that the focus of the last set of guidelines and probably the next cholesterol guidelines that likely will be out in November, will have a large component of the shared decision making and we need to see where the cost comes down, whether these companies that make these medications will be able to significantly lower the cost in a reproduceable manner and patients and clinicians will have to jointly decide what to do, do we add acetamide? Do we add a PCSK9 inhibitor?

But we finished our editorial saying that all clinicians and patients should currently pursue a comprehensive lifestyle and medical regimen for secondary prevention. We all have to remember that and if a person's LDL, a high-risk individual is at least 70 with high-risk features and certainly above 100 on maximum tolerated statin therapy, it's important to strongly consider a PCSK9 inhibition and it'll be very interesting to see what the final wording is when the ACC/AHA cholesterol guidelines come out in November.

Dr Carolyn Lam: Amit, would you like to add any further take-home for the clinicians listening in?

Dr Amit Khera: I just first want to congratulate both of these discussions today, I think the paper was so incredibly important and I think Roger's group really helped frame it well in the field. The one thing I'd say is this is a moving target, we have some early guidance now that I do think is actionable, so I actually have clinic in about an hour and I'm sure I'll be thinking about this as I think about how to apply PCSK9. Which groups might benefit most, so I do think this is actionable now, I think the points that were made about cost effective analysis, how do we bundle all these concepts or high risk patients into maybe an algorithm and how do the guidelines interpret this as a moving target. We'll wait to see, but I do think there's some important actionable information even now for our clinical patients.

Dr Carolyn Lam: I just love that, and you know that is just so much in line with the ethos of what Circulation is about now. We really, really love the papers that you have to pick up because they're of immediate applicability to your clinical practice.

Well audience, you heard it right here. Thank you so much for joining us this week and of course don't forget to tune in again next week.

Circulation August 14, 2018 Issue

13 augusti 2018 | 25 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. I'm the one you usually hear chatting about all the papers in your weekly issue, however I am so delighted to be handing over the mic this week to two beloved colleagues, and they are Dr Greg Hundley and Dr Vlad Zaha, who will be taking us through this week's very special issue centered around cardio-oncology. Here they are.

Dr Greg Hundley: My name is Greg Hundley. I'm a professor at VCU Health Sciences in Richmond, Virginia. We also have Vlad Zaha, who is an assistant professor at University of Texas Southwestern in Dallas.

Dr Vlad Zaha: Hello, everybody.

Dr Greg Hundley: We're going to be talking about the field of cardio-oncology today. As we all know, there have been many advances in the treatment of cancer lately, such that cancer is now becoming in some regards almost a manageable disease or a chronic disease for many individuals. But unfortunately we're seeing the emergence of cardiovascular disease in many patients, so much so that for some cancers, for example breast cancer survivors, cardiovascular events have supplanted the occurrence of cancer-related morbidity and mortality overall.

And so emerging today is this new field of cardio-oncology, which is really a bridging discipline between oncologists and cardiologists that have been focused almost on examining the relationship between chemotherapies, radiation therapies, newer targeted immunologic therapies on the development of cardiovascular events. We as cardiovascular medicine specialists often become involved and then we are consulted to see a patient that might be scheduled to receive a cardiotoxic therapy and what should we do. Maybe they've already received, they're in the middle of the therapy, and we're asked to provide guidance to help the patient move through that therapy successfully.

We're examining survivors now, those that have gone on the therapy and are experiencing increased cardiovascular risk. And then finally, a new emerging field that examines the association of risk factors that seem to be common between cancer and cardiovascular disease.

In this issue of Circulation there are theories, really a miniseries of manuscripts, that are at this interface between cardiovascular and oncologic science and medicine. Following a similar miniseries that we published in 2015, this new block of manuscripts looks on some of the risk factors and mechanisms that may be common between these disorders.

We're going to start today and look at this particular issue and examine the original manuscripts, look at the letters, and then talk a little bit about the review articles. I will walk through some of the introduction and then Vlad Zaha, who is working in cardio-oncology at University of Texas Southwestern, will help interpret for us some of the results and the meaning.

The first study, an original manuscript by Simes et. al that's a subanalysis of the lipid study, and that's the Long-Term Intervention with Pravastatin in Ischemic Disease. The study is going to examine the relationship between D-dimer and the future development of cardiovascular events, but also importantly, cancer-related events. Remember, D-dimer is the degradation product of cross-linked fibrin markers of hypercoagulation and thrombosis. We use this a lot in the emergency department as an identifier of those at risk when we're suspecting one of CVT, pulmonary emboli, etc.

This particular study focused on individuals aged 31 to 75 years that had experienced previously a myocardial infarction. The patients were randomized to receive 40 mg of pravastatin versus a placebo and as part of the study they were followed for six years to identify cardiovascular events. But at the end of the study another examination, an extended review, was enabled so that the patients or participants could be followed for another ten more years and in addition to looking at cardiovascular events, they also looked at all-cause mortality and etiologies of that mortality and specifically cancer.

Vlad, can you tell us a little bit about some of the results and what did D-dimer predict?

Dr Vlad Zaha: D-dimer has been considered a rather non-specific product that was first introduced in clinical practice in the 1970s for diagnosis of venous thromboembolisms. It is really interesting in this study that the others identified D-dimer that it is an independent predictor of not only long-term risk of arterial and venous events but all-cause mortality, cardiovascular disease mortality, cancer incidents and mortality and non-cardiovascular disease and non-cancer morality.

It raises interesting questions that are further explored in an editorial in the same issue about what is a low and what is a high D-dimer and also what drives the D-dimer generation in these patients.

Dr Greg Hundley: And so, it's interesting as well that one is identifying those at risk of cardiovascular disease but also cancer. Do the authors and the editorialists speculate on what that connection may be?

Dr Vlad Zaha: The question that is discussed is a common area of etiology that is being more and more discussed nowadays as bridging the domains of heart disease and cancer, and that is information. Information resulting then in alteration of the clotting cascade and hypercoagulability that may then influence downstream both atherosclerosis and cancer processes.

Dr Greg Hundley: Very good. It's interesting that we're bringing up this whole area of thrombosis because that really follows in the next study, which is a large population cohort assessment that is collected from a Danish registry of 6600 subjects that had experienced a lower extremity arterial, not venous, but arterial thrombosis. In that study what did they uncover, Vlad, in terms of an association with cancer and previously experiencing a lower extremity arterial thrombosis?

Dr Vlad Zaha: Another interesting study where the patients uncovered an increased risk of cancer compared to the general population, especially during the first six months before, the investigators identified an association between lower limb arterial thrombosis and increased all-cause mortality in common especially for the smoking-related cancers. This is a very interesting study that brings up the possibility of opportunistic screening, again focused on cancer-related signs and symptoms during the diagnostic workup for lower limb arterial thrombosis.

Dr Greg Hundley: And so, in these first two studies, both large in number, were identifying issues related to thromboembolic events and cardiovascular disease that also appear related or associated with the future development of cancer. The next couple of studies now switch and address issues related to mechanism. The first is a relatively large complex translational study by Meijers and associates that were examining the relationships between heart and vascular injury and the future development of colon cancer.

In this particular study there were two separate experiments, one group performed in mice and the other performed in analyses of serum and plasma that were collected from human subjects that had experienced colon cancer. In the first series of experiments in mice, the mice were induced myocardial infarction and then they were a strain that were somewhat predisposed to development of colon cancer. What the investigators did is they examined in this strain predisposed to the development of colon cancer, the impact of inducing a myocardial infarction and promoting heart failure versus those that were not and they identified what looks to be some sort of association between an increased risk of development of colon cancer.

Vlad, what were your observations and thoughts in terms of these particular findings and results?

Dr Vlad Zaha: This is an interesting paradigm of bringing basic science observations and testing them in a translational fashion. It is a combination of really elegant studies in a mouse model that identifies potential targets of clinical relevance in a model of myocardial infarction. The authors evaluate the fact that such molecules in human cell line models and test the proliferation in that environment. The question is then: How does this reflect in a cohort of patients? That, I think, is really the strength of the study to be able to show that some of the biomarkers identified which events can have an implication at the bedside.

Dr Greg Hundley: It was really interesting in that in the animals, independent of the hemodynamic compromise, so the hypotension, the reductions in EF, these circulating biomarkers that you identified seemed more associated with the development of colon cancer and then in the human study, examining similar factors were observed in patients with colon cancer and heart failure from the circulating blood of those individuals. Very interesting relationship identified in a very elegant translational study that involved both animal models and human subjects.

The second mechanistic paper is by Li and associates and it's really addressing the issue of anthracycline-related cardiovascular injury. Remember, we still utilize anthracycline chemotherapy today as a fundamental curative component of the therapeutic regimen for lymphoma, leukemia and sarcoma, also in those with triple-negative breast cancer as an important component of that regimen for adjuvant treatment. In this particular study, the investigators were examining the implication of phosphoinositide 3-kinase. That is an important enzymatic regulator of tumorigenesis, but it also when it's expressed is up-regulated during cardiac stress and really impacts adverse remodeling and promotion of heart failure.

In this particular study, the investigators in a mouse model were looking at blocking this particular enzyme and they had some really interesting results pertaining to the development of heart failure and cancer. Vlad, what did you see in this study that looked unique in that perspective?

Dr Vlad Zaha: This is an especially interesting study for the perspective of the oncologists who still have to prescribe anthracycline, given the uncertainty of early toxicity that can manifest in some studies in five to ten percent of patients. Also, related to the late toxicity of anthracycline treatment in survivors of childhood cancer. What is particularly interesting about this isoform of phosphoinositide 3-kinase, the gamma isoforms, is that at the same time blocking this enzyme in macrophages increases the anti-tumor, I think it's the anthracycline therapy, and blocking it in the cardiomyocytes, suggests a potential cardioprotective mechanism.

Having a target that can be used both to enhance the anti-cancer effect of anthracycline and to enhance the cardioprotective mechanism is really a potential ideal intervention that would help maximize the anti-cancer treatment and at the same time protect the heart.

Dr Greg Hundley: Fantastic. Again, new research helping to come up with ways for those that continue to need anthracycline therapy that we may be able to attenuate some of the untoward cardiovascular effects, all the while preserving the antagonistic features associated with the treatment for cancer.

Let's switch to the other sort of prospective original research format that we have in Circulation, and that's our letter format. Remember, our letters are addressing a specific point that can be readily appreciated in 800 words or less. The first is a letter by Anquetil et al that examines individuals recorded in the VigiBase World Health Organization database. This is basically a database organized around treatment of cancer and cancer therapeutics and it is examining those individuals that received sort of a newer class of agents called immune checkpoint inhibitors. Remember, that is modulation of our immune system to help attack cancer.

In some rare circumstances, relatively infrequent, when these agents have been administered, the immune system has been unlocked and attacks the heart, promoting a myocarditis that if not recognized can be fulminant and lead to death. This particular group identified a new phenomenon that we need to be aware of and that's just frank myositis.

Vlad, what are your thoughts on now perhaps these agents being associated with the development of myositis in the skeletal muscle?

Dr Vlad Zaha: Often when adverse events, as you mentioned Greg, are an important concern for these new powerful tools for the oncologists and it has been pretty early in the process where some of the cases have demonstrated severe cardiovascular events. Fortunately it is a very low percentage, less than 1% of cases that can manifest with fulminant myocarditis, but this raises again a question of expanding the view towards other systems when we are applying one of these early novel molecular interventions.

In this context, the recognition of myositis in another small percentage of patients is an important observation and increasing awareness of both cardiologists and oncologists towards this side effect is important as not all fatigue is equal and sometimes that can be due to manifestations of cardiomyopathy and sometimes it can be a manifestation of oxygen extraction in the peripheral tissue than muscle contractility. It is an important hypothesis-generating piece that will allow people to appreciate more of the complexity of addressing the intrinsic molecular mechanisms in cancer and heart disease.

Dr Greg Hundley: It sounds that we need to be aware of another potential etiology of fatigue to put in an armamentarium of differential diagnoses for those patients that are not getting quite back to where they were from an exercise and activity level after treatment. The second research letter focuses on individuals that are receiving a Fontan procedure. Remember, Fontan procedures are surgical corrections for those primarily with single ventricles where we're diverting caval blood to the pulmonary circulation, since in some situations there's really no functional right ventricle. These patients over time experience chronic venous hypertension and have associations with liver disease.

In this particular research letter, the authors are examining the relationship between really for the first report in an aggregate form of the relationship between undergoing a Fontan procedure and the development of hepatocellular carcinoma. Vlad, any quick comments to highlight on this particular procedure? I thought something that was interesting is that these individuals experienced these hepatocellular carcinomas in their 20s and 30s.

Dr Vlad Zaha: That's right, Greg. This study confirms observations from previous case reports and the early occurrence of hepatocellular carcinoma is raising still important hypotheses for future clinical trials. On one hand, either there is an increased risk of hepatocellular carcinoma development in patients with non-cirrhotic livers after a Fontan operation, or the current screening modalities using imaging are insufficiently sensitive to identify early signs of cirrhosis in such patients and this stratifies them effectively at an early stage in their disease post-op Fontan procedure.

Dr Greg Hundley: Lastly, let's just briefly discuss here, Vlad, some of the other editorials and review article formats that we have in Circulation. A particular one, a perspective that was written by Peter Libby and Ebert and associates that highlights this phenomenon potentially implicating inflammation and the link between cancer and atherosclerotic cardiovascular disease. The topic of this perspective is really on something called CHIP, which stands for clonal hematopoiesis of indeterminate potential.

What is this CHIP? As we age, basically what happens is we accumulate mutations of hematopoiesis stem cells in our bone marrow. Over time these little clones, they actually have within our bone marrow some survival advantages and they can spill out into the blood and actually can be associated with future leukemias. Those that have a large population of this particular clonal progeny, these CHIP-type cells, they have an increased risk of developing cancer, but also the levels of these are associated with increased overall mortality and it appears some risk of cardiovascular disease. How could that be? One characteristic of this particular cell line is they are associated with dysregulation of inflammatory genes that go on to produce, are associated with other inflammatory mediators.

Vlad, this is calling in question and helping us to examine the relationship between inflammation, cancer and cardiovascular disease. What are your thoughts here about these very important insights provided by Libby and Ebert?

Dr Vlad Zaha: This is a fascinating perspective, Greg. It really brings, again, in the offline novel molecular mechanisms that have been discovered recently and that are becoming a turning point into the molecular interventions, not only in cancer but potentially soon in cardiovascular disease prevention and treatment. Having a common root for a problem set involving such a prevalent cardiovascular problem as atherosclerosis and cancers reveals the connection between the different systems and the fact that integrating our understanding of the molecular regulation of cell proliferation results in an effective translation of leading to new targets and new approaches to treat disease.

It is striking that there are multiple areas where cancer and inflammation are interacting, one of them being at the cellular level and other ones at humoral levels, in a way reproducing other complex mechanisms that we see in regulation of inter-system interactions within the body.

Dr Greg Hundley: And so, summarizing this entire issue in Circulation, what a wonderful collection of a series of original manuscripts, both in the extended and the letter format as well as review articles, including a primer by Handy and associates that evaluates or draws attention to our screening tools that how we might examine the relationship between cardiology and the whole world or hematologic oncology related issues. And then this very unique perspective by Peter Libby and really is a continuation of the growth of this, as we called earlier, the bridging discipline of cardiovascular medicine and oncology as we work toward improving survivorship of all individuals with cardiovascular disease and cancer.

I want to thank you for the opportunity to be with you today and encourage you to follow these issues further with the journal. I'll turn this over to Vlad for any closing remarks.

Dr Vlad Zaha: Thank you, Greg. This has been a really exciting overview of important points that are emerging now at this nexus between cardiology and oncology that give us a broader view of the complex interactions that the future will materialize for us, emerging from a molecular intervention on cancer, heart disease, immunologic disease and probably metabolic endocrinology disease.

Thank you for listening.

Dr Carolyn Lam: Thank you so much, Vlad and Greg. This is a tremendous issue and I'm sure, audience, you will be reaching for it right now, I would.

Please let all your colleagues know about this podcast and tune in again next week.

Circulation August 7, 2018 Issue

7 augusti 2018 | 19 min

Can proteomic biomarkers distinguish between subtypes of aortic stenosis even years before surgery? Well, to find out more, stay tuned. That's coming right up after these summaries.

The first original paper this week adds to the evidence that smoke-free policies are associated with a lower risk of cardiovascular disease. First and corresponding author, Dr Mayne from Northwestern University Feinberg School of Medicine, and her colleagues linked smoke-free policies to participants of the Coronary Artery Risk Development in Young Adults, or CARDIA study, which has a follow-up of up to 20 years. They found that smoke-free policies in workplaces were associated with significantly lower risk of incident cardiovascular disease after controlling for a wide range of covariants. Results were weaker for bar and restaurant bans, but in the same direction.

Preventive fractions range from an impressive 24 to 46%. Thus, smoke-free policies may improve cardiovascular health through reducing population exposure to tobacco smoke. However, we should remember that much of the US population remains unprotected by smoke-free policies. Thus, taken together with prior ecological work, these results support the continued expansion of smoke-free policies in indoor public places.

Most phase-3 randomized control trials feature time-to-first event end points for their primary analysis. In chronic diseases, however, a clinical event can occur more than once and recurrent event methods have been proposed to more fully capture the disease burden, as well as to improve statistical precision and power.

However, is this really the case? This question was examined by first author, Dr Brian Claggett, corresponding author, Dr Scott Solomon, from Brigham Women's Hospital in Boston, Massachusetts, and their colleagues, who sought to better characterize factors that influence the statistical properties of recurrent events and time-to-first event methods in the evaluation of randomized therapy.

They performed repeated simulated trials with 1:1 randomization of 4000 patients to active versus control therapy. Through simulation, they varied the degree of between-patient heterogeneity of risk as well as the extent of treatment discontinuation. They then compared their findings with those from the actual randomized control trials.

The authors found that the statistical power of both recurrent events and time-t- first event methods were reduced by increasing heterogeneity of patient risk, a parameter that's not usually included in conventional power and sample size formulae. Furthermore, data from real clinical trials were consistent with the simulation studies, confirming that the greatest statistical gains from the use of recurrent events methods occurred in the presence of high patient heterogeneity and low rates of study drug discontinuation.

The next paper uncovers a novel biomarker and therapeutic target of pulmonary arterial hypertension, and that is selenoprotein P. First author Dr Kikuchi, corresponding author, Dr Shimokawa, from Takaoka University Graduate School of Medicine in Japan and their colleagues performed micro-array analyses using pulmonary arterial hypertension, pulmonary artery smooth muscle cells, and found a 32-fold up regulation of selenoprotein P compared with controls.

Selenoprotein P promotes cell proliferation and apoptosis through increased oxidative stress and mitochondrial dysfunction. Using five strains of genetically modified mice, the authors demonstrated a pathogenic role of selenoprotein P in the development of hypoxia-induced pulmonary hypertension.

Furthermore, sanguinarine, which is an orally active small molecule identified by throughput screening reduced selenoprotein P expression and pulmonary arterial smooth muscle cell proliferation and ameliorated pulmonary hypertension.

In summary, this study shows that selenoprotein P plays a crucial role in the pathogenesis of pulmonary arterial hypertension and may be a useful and novel biomarker and therapeutic target in this disorder.

Familial hypercholesterolemia is known to be associated with a high risk of ischemic heart disease, including myocardial infraction, but what about the risk of ischemic stroke? Well, first author, Dr Beheshti, corresponding author, Dr Nordestgaard, from Copenhagen University Hospital and their colleagues examined the associations of familial hypercholesterolemia and high LDL cholesterol with ischemic stroke in both causal, genetic, and observational analyses using more than 106000 individuals from the Copenhagen General Population Study, and more than 10000 individuals from the Copenhagen City Heart Study.

They used a Mendelian randomization design to test whether high LDL per se had a causal effect on ischemic stroke risk using a combination of the familial hypercholesterolemia causative mutations and common genetic variants associated with high LDL.

The authors found that there was no association between familial hypercholesterolemia mutations and ischemic stroke risk. In the Mendelian randomization analysis, also including common genetic variants, there was also no causal effect of high LDL on the risk of ischemic stroke.

These findings imply that the predominant goal of targeting LDL lowering in those with and without familiar hypercholesterolemia is likely to reduce myocardial infractions, rather than ischemic stroke. Well, that wraps it up for our summaries. Now for our feature discussion.

Circulation publishes numerous papers regarding circulating biomarkers. We talk about biomarkers in the diagnostic, prognostic sense, but what about in a pathophysiologic sense, and especially in a disease as important as aortic stenosis? Well, that's what our featured paper this week is all about and I'm so excited to have with us corresponding author, Dr Stefan Söderberg, from Umeå University in Sweden, as well as our associate editor, Dr Peipei Ping from UCLA. We will be discussing the paper entitled “Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement.” Stefan, could you tell us a bit about what made you look at this very interesting question, and perhaps the unique resources you had in Sweden to look at this?

Dr Stefan Söderberg: I'm a practicing cardiologist, and I have been working a lot with aortic stenosis over the years. It's frustrating that we can't do anything to stop the process. In many cases, the patients are old and frail, and if you could find the means to stop the process long before they need surgery, it will be of great benefit for the human and for the society.

Also, knowing that the interventions on the statins, for example, have been unsuccessful, we thought that there must be better ways or other biomarkers. Furthermore, that many of these studies, the phenotype of aortic stenosis has been very poorly described and there is probably much more behind just aortic stenosis than just, for example, calcium deposits in an X-ray, et cetera, et cetera.

Dr Carolyn Lam: You used some very unique resources in Sweden to therefore look at the proteomic signatures of aortic stenosis. Could you describe that and simplify perhaps the results so we can understand it?

Dr Stefan Söderberg: First of all, I got this idea from other studies done up in northern Sweden. If you have an absolutely unique setting, the combination of huge population-based studies in 30 years back, we have a huge biobank with examples of extraordinary good quality from each of these participants. For example, for each participant, the blood has been spun and put into freezer, deep freezer, within one hour for 30 years, and they are now, as I said, about 100000.

Furthermore, I'm working as a cardiologist at a university, and up here, you do all of the aortic surgery for the whole northern Sweden. That is, we can combine the names of the person undergoing surgery together with these population-based surveys and we can get details from all those who have participated in the surveys long before they did the surgery, and they can go and retrieve samples from cases and match controls from the freezers. It's a unique setup. Then, when we were designing the study, we got the chance to get these analyses done by our friends at the university to get the proteomic analysis via a unique data technique.

Dr Carolyn Lam: Wow. Could you describe your results?

Dr Stefan Söderberg: The results that we found in the first set of 334 patients who underwent surgery is 10 years after their first sampling, we found six proteins. Then, we got the question back from Circulation to establish a validation cohort, and we were able to do so to include all those new cases in the last 2 years, and there we could replicate five of these proteins.

The interesting thing that the pattern is completely different between those having coronary artery disease from those without. That kind of phenotyping has not been done throughout other aortic stenosis studies. Therefore, this study is unique. We have had two papers in the last year in the Journal of American Heart Association from the cohort, as well, showing the thing that happened.

For example, lipoprotein little A is only associated with future aortic stenosis valve replacement only in those with concomitant coronary artery disease. There are many unique things, the prospective design, and the phenotype differentiating those with and without coronary artery disease.

Dr Carolyn Lam: Yeah, and if I may just reiterate that the population base that you work with is just enviable and just so that the audience realizes, these are biomarkers that were collected 11 years before the aortic stenosis surgery, isn't it? You really had a long follow-up.

Also, just to let everyone know, it was a proximity extension assay that you used for the discovery, and the six proteins were growth differentiating factor 15, or GDF15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and PCSK9, so very interesting. Peipei, you have a way of putting things into context so beautifully. Could you tell us your thoughts when you saw this paper?

Dr Peipei Ping: I thought this is a very high-quality study that actually benefited from the long-term established, well-controlled cohort in northern Sweden, as Dr Söderberg just shared with us. On the other end, it married a technology platform that's very well-established and -validated, and this situation targeted proteomics platforms using multi-proximity extension assays with carefully controlled markers and screened 92 cardiovascular candidate markers.

This is the kind of approach that provides semi-quantitative as well as quantitative outputs and is capable to offer validated screens on large population clinical subsets. A study of such with a high value cohort combined with a validated and well-controlled technology platform offered results that clearly have clinical significance, as well as setting up examples for other studies to follow. The enthusiasm from the editorial boards, as well as the reviewers, have been substantially high and supportive.

Dr Stefan Söderberg: Fantastic. I'm very glad to hear this.

Dr Carolyn Lam: Stefan, you also mentioned that a very unique element was the separation of aortic stenosis with and within coronary artery disease, or at least established or visible coronary artery disease. Could you explain how that provided pathophysiologic insights?

Dr Stefan Söderberg: First, I should say we were very, very strict. Our routine is that everyone was 100% undergoing, aortic valve replacement, they undergo a coronary angiogram before. If we saw any sign of atheromatosis, it was not enough that they had the significant stenosis, but any signs, they were put into the group of coronary artery disease. Those without, we couldn't see anything there. Radiograph here reported absolutely clean coronary arteries. Of course, we cannot exclude if there were aortic changes within them all, of course.

We believe that this is a very important message that in order to further study aortic stenosis, we should be very careful in phenotyping the disease. We hope the growing cohort will be able to do this further. For example, cuspid versus tricuspid valves, women versus men, et cetera.

My answer in short is phenotype. Let me take one example which I found very, very exciting. That is the finding of PCSK9, which is closely related not only to cholesterol symptoms, but also to lipoprotein little A emphasis. As you know, the first strong finding in aortic stenosis was the LP little A. This is related to that genetic finding, and that was in the huge study from Canada. They did not have the same phenotyping, so we had information to his important findings. That's one example.

Another example is the transferring receptor, where data has shown that bleeding acutely in the valvular tissue causes damage, and this relates iron metabolism to the formation of the aortic valve. Obviously, it seems that the process in the aortic valve is very much similar to the vessel arteriosclerosis. It seems to be different. This is the indication that when we formulate new studies or new drugs on aortic stenosis, we must be very careful to use the right drug for the right type of valvular disease.

Dr Carolyn Lam: Those are great points. Peipei, do you think that's the main clinical take-home message, beyond that great comment you made earlier that this paper's just a great example of the use of tools, modern tools, that we have in proteomic characterization like the proximity extension assay to provide pathophysiologic insights when you have a really well-phenotyped cohort? What's the critical take-home message, though? Is there one now?

Dr Peipei Ping: The take-home message is marriage of amazing high value cohort's data sets with that of the well-controlled clinical study using target proteomics approaches. In this particular study, one main critical innovation is the study is capable of providing insights regarding molecular signatures that have predicted values. As stated in the manuscript, the circulating proteins that found critically important, their alterations took place years before the surgery were associated with aortic stenosis. That is of value, clinical value, to many other clinical studies to follow.

Dr Carolyn Lam: Wow. That's wonderful. Thank you so much for putting these findings in context for us. Thank you, listeners, for joining us today. Don't forget to tune in again next week.

Circulation July 31, 2018 Issue

31 juli 2018 | 19 min

Does measuring baseline BNP add prognostic information in patients undergoing revascularization for left main coronary artery disease? Well, to find out the answers, you have to stay tuned and listen up for our feature discussion coming right up, after these summaries.

The first original paper this week reports a new role for bone morphogenetic protein 9, or BMP9, as an endogenous inhibitor of cardiac fibrosis. Now, we are familiar with transforming growth factor beta-one, or TGF-β1, as a promoter of cardiac fibrosis. TGF-β1 also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. BMP9 is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1.

In the current paper from first author Dr Morine, corresponding author Dr Kapur, from Tufts Medical Center in Boston, and their colleagues. The authors examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. They utilized the thoracic aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. The authors’ results identified a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload. They further showed that treatment with either recombinant BMP9 or inhibiting a high affinity receptor for BMP9 known as endoglin promoted BMP9 activity and limited cardiac fibrosis in heart failure. Thus, this provides a potential novel therapeutic approach for patients with heart failure.

The next paper shows that endothelial C-type natriuretic peptide, or CNP, regulates microcirculatory flow and blood pressure. First author, Dr Špiranec, corresponding author Dr Kuhn, and colleagues from University of Würzburg in Germany analyzed whether vasodilating response to CNP changed along the vascular tree. In other words, whether the guanylyl cyclase–B receptor was expressed in microvascular types of cells. The authors used novel gene-modified mouse models to show that guanylyl cyclase–B cyclic GNP signaling in parasites diminished microcirculatory resistance and arterial blood pressure. In contrast, endothelial, or macrovascular smooth muscle cell guanylyl cyclase–B signaling was not involved. This indicated that CNP participated in the local cross talk between endothelial cells and parasites, thus playing an important role in the maintenance of normal microvascular resistance and blood pressure. Thus, pharmacological augmentation of endogenous CNP signaling in parasites may provide a useful therapeutic tool to combat increased vascular resistance and hypertension.

Has the rapid and exponential growth in transcatheter aortic valve replacement, or TAVR, demand overwhelmed capacity, thus translating to inadequate access and prolonged wait times? Well, the next paper provides some answers. First author, Dr Elbaz-Greener, corresponding author Dr Wijeysundera, from University of Toronto, evaluated temporal transient TAVR wait times and the associated clinical consequences in their population-based study of all TAVR referrals from April 2010 to March 2016 in Ontario, Canada. Their study cohort included 4,461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons, and 11% remained on the wait list at the conclusions of the study.

For patients who underwent a TAVR, the estimated median wait time in the post reimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability at 80 days of wait-list mortality was 2% and of heart failure hospitalization, 12%, with an increase in events with increased wait times. Thus, post reimbursement wait time has remained unchanged for patients undergoing a TAVR procedure, suggesting that the increase in capacity has kept pace with the increase in demand. The current wait time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access.

The final paper shows that patients with type 2 diabetes and a history of heart failure are particularly likely to benefit from treatment with the SGLT2 inhibitor canagliflozin. First author, Dr Rådholm, corresponding author Dr Figtree, from Royal North Shore Hospital in Australia, and colleagues, studied more than 10,000 participants with type 2 diabetes and high cardiovascular risk in the CANVAS Program who were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. Participants with a history of heart failure at baseline constituted 14.4% of the study population and were more frequently women, white, and hypertensive, with a history of prior cardiovascular disease. The benefit of canagliflozin on cardiovascular death and hospitalized heart failure was greater in patients with a prior history of heart failure compared to those without heart failure at baseline with a p for interaction of 0.02. The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in patients with and without heart failure at baseline. Effects were apparent across a broad range of participant subgroups, including those using established treatments for the prevention of heart failure, such as renin-angiotensin-aldosterone system inhibitors, diuretics, and beta-blockers. Thus, patients with type 2 diabetes and a history of heart failure may be particularly likely to benefit from treatment with canagliflozin. The beneficial effects of canagliflozin on heart failure outcomes unlikely to be accrued on top of other therapies for heart failure management.

And that brings us to the end of this week's summaries, now for our feature discussion.

In patients with left main coronary artery disease who are undergoing revascularization, could BNP assessment be that precision medicine tool to aid us in our clinical decision making? Well, I am just so excited to discuss this very topic with the corresponding author for this feature paper, Dr Gregg Stone from Columbia University Medical Center, as well as our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo.

Gregg, it was a super smart idea to look at circulating BNP and how this may associate with outcomes, as well as therapies in the EXCEL trial. Please tell us what inspired you to do this and please tell us what you found.

Dr Gregg Stone: As everybody knows, BNP has been identified as an important prognostic factor in patients with heart failure and ischemic heart disease. It correlates with both cardiovascular and noncardiovascular mortality. Patients with left main disease are among the highest-risk patients that either interventional cardiologists or cardiac surgeons treat because of the amount of myocardium at risk, they often present in heart failure, and even if they're not in overt heart failure, they can be prone to large severe left ventricular dysfunction. So first we wanted to establish the prognostic utility of BNP in this patient population and then we were interested to see if it might have a role in helping differentiate which patients might have a better prognosis with either PCI or coronary artery bypass graft surgery.

EXCEL is the largest trial to date of left main PCI versus CABG in a randomized format with 1905 enrolled patients. And overall, we found that PCI and CABG had similar rates of deaths, large myocardial infarction, or stroke in 3 years. But of course, there are high risk-patients and low-risk patients buried within those overall aggregate outcomes, and BNP was an important prognostic predictor of overall mortality in the trial. Both cardiovascular and noncardiovascular, but not of any other ischemic end points interestingly. Not myocardial infarction, stent thrombosis, graft occlusion, bleeding, revascularization. But definitely, mortality. Even independent of left ventricular ejection fraction and heart failure status.

Now, when we looked at the outcomes of PCI versus bypass surgery, we actually found a very powerful interaction, such that at relatively lower BNP levels, patients who underwent PCI had a better prognosis and tended to have lower mortality. Where patients with high baseline BNP levels tended to have a better prognosis after surgery.

Dr Carolyn Lam: You know, Torbjørn, I love your editorial where you contextualize these findings so nicely. Could you do that for us now?

Dr Torbjørn Omland: First, I would like to congratulate Gregg and his team with this very interesting and very well-done study, and I think Circulation is very fortunate to be able to publish papers like this. We have known for quite a long time that BNP is a strong prognostic indicator across the spectrum of cardiovascular diseases and it seems to be particularly strongly associated with risk of heart failure events, cardiac arrhythmias, and risk of death. And, as shown in the EXCEL trial, the association with left ventricular ejection fraction is actually quite weak, and also the association with ischemic events. So, these findings fit very well with previous observations. The really novel and intriguing finding of this study is the very strong interaction between procedural BNP levels and the effect of the randomized therapies and, as you alluded to, all the investigators have tried to look at this in other more low-risk populations like in the LIPID trial but actually failed to find any significant interaction. It's really a novel and important finding.

Dr Carolyn Lam: That's true. Does it bring up the question are the natriuretic peptides just a better EF measurement? You mentioned that there was a correlation, what do you think, Gregg?

Dr Torbjørn Stone: Well, you know, there was a weak correlation between BNP and ejection fraction and history of heart failure but the prognostic utility of BNP in this study and its ability to differentiate between the outcomes of PCI versus CABG in patients with low versus high BNP was actually strongly independent of both congestive heart failure history and acute left ventricular ejection fraction. So, I think the BNP is giving a useful independent information. It's a strong reflector of both atrial and ventricular pressures and volume status, but it also reflects myocardial hypoxia, it may be involved in glycolysis and lipid peroxidation, and other mechanisms that we don't fully understand. There may be elements of diastolic dysfunction that we have not measured in this study and other mechanisms related to prognosis in these patients. So, while EXCEL was not set up to truly differentiate and delve deeply into the mechanisms of our observations, statistically these were strong associations that may prove clinically useful.

Dr Carolyn Lam: Right, I thought that was so intriguing as well, just the points that you brought up. First, let's just clarify for the audience that when you say low and high you were using a cutoff of 100.

Dr Gregg Stone: We did use a cutoff of 100 pg per mL as is common, but we also modeled BNP as a continuous measure. And actually the relationships were even stronger when modeled as a log hazard ratio continuous measure, both for mortality and for the primary end point.

Dr Carolyn Lam: Yeah, that's so cool. And Torbjørn, you talked about this in your editorial as well and I thought your point about the distributions of the ejection fraction versus the distribution of natriuretic peptide, that was very revealing, too. Would you like to explain your thoughts there?

Dr Torbjørn Omland: I found it very interesting that all of this is clearly a high-risk operation overall. More than 90% actually had what we regard a normal, or at least not a reduced ejection fraction. Whereas the distribution of BNP values were more widely distributed so that actually about 40% of participants had BNP levels above this ratio of 100 pg per mL. And that probably shows that in this population, BNP provides additional and independent information about the status of the myocardium that is not revealed by angiography or ejection fraction measurements.

Dr Carolyn Lam: That's true, and that's an important point because it added above the SYNTAX score, too, right Gregg?

Dr Gregg Stone: That's right, it was an independent predictor, and in fact the SYNTAX score and the severity of left main coronary disease did not vary, according to BNP levels, that is. High versus low BNP were equally distributed, not related to the anatomic extent and complexity of coronary artery disease. So, BNP is clearly reflecting a different state of the myocardium in a way that we can't measure with any other available test and that makes it quite a useful biomarker.

Dr Carolyn Lam: Exactly, so I think I'd like to wrap up with asking you both, you can already see what the potential clinical implications are, right? Which means that perhaps in a similar type of patient where there's equipoise of the revascularization method and has left main disease, maybe we should be using natriuretic peptides to guide our clinical decision making. What do you think are next steps before this is prime time?

Dr Gregg Stone: Well I can mention that when one makes a decision of the best revascularization modality for patients with extensive multi-vessel or left main coronary artery disease, there are many factors that go into that determination, both clinical, anatomic, is the patient a good candidate for one versus the other revascularization modality, what are the patient's preferences, what's the surgeon's or interventionalist's likelihood of being able to safely get the patient through the procedure and achieve complete revascularization.

The SYNTAX score makes a difference, as does gender and age and kidney disease and COPD and ejection fraction and many other factors. So I think we can now add to that list BNP, although I will say this was a post-hoc study, we only had BNP available in approximately 60% of the patients, and while the outcomes were similar in the patients who we did not versus who we did have BNP, this has to be looked at as hypothesis-generating analysis, and we would love to also see this type of finding replicated in other large datasets. That being said, there are no other large left main or new multi-vessel disease trials that are planned right now to my knowledge, and I think given the breadth of this dataset and its size and scope, I do think that these findings are robust enough to use BNP as one of the clinical factors to consider in revascularization decisions.

Dr Torbjørn Omland: I actually agree with that and I think ideally, we would, of course, like to see external validation in another dataset and even retrospective randomized study comparing conventional versus BNP-guided strategy but that may not be realistically undertaken. So, I think these are clearly the best data we have and as clinicians need to integrate this in our overall evaluation in making this important decision.

Dr Carolyn Lam: Yeah, I mean Gregg, could I ask you, do you apply this clinically already?

Dr Gregg Stone: We have not been before this, although I believe we will now. I believe BNP should be a biomarker that we more routinely measure in patients with ischemic heart disease as well as those with overt congestive heart failure. And again, use as one of the factors of many when making revascularization decisions. And I think it's important to note also that the PCI patients tended to preferentially benefit, in fact with even lower mortality when BNP was lower. Where the surgical patients tended to benefit when BNP was higher. So, it's one factor, not the only factor, but I think it's one additional piece of the puzzle.

Dr Carolyn Lam: Yeah, I have to say too I mean, after reading this, after reading this awesome editorial, it's hard not to think I should be applying this clinically because it's going to be really hard and take a long time to prove this with more prospective data, for example. Although, external validation and other datasets may be better, this is the largest trial already to show this and show it so clearly with a significant interaction. I think that is striking to me.

Torbjørn maybe I've put you on the spot with the last word, does this change your clinical practice?

Dr Torbjørn Omland: I agree with Gregg. This will be one of maybe several other factors but I think it's ready for being taken into account when making this sometimes very difficult decision.

Dr Carolyn Lam: Thank you so much Gregg and Torbjørn for joining me today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation July 24, 2018

24 juli 2018 | 22 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Did you know that despite being one of the wealthiest nations in the world, the United States population has a shorter life expectancy compared to almost all other high-income countries in the world? Well, stay tuned to learn what Americans could do to narrow the life expectancy gap between the United States and other industrialized nations. Coming right up after these summaries.

Are microRNAs involved in nitrate tolerance? Well, the first original paper this week provides some answers. This is from co-corresponding authors Dr Bai and Zhang from Central South University in Changsha, China. Nitrate tolerance develops when there's dysfunction of the prostaglandin I2 synthase and prostaglandin I2 deficiency. These authors hypothesize that prostaglandin I2 synthase gene expression may be regulated by a microRNA-dependent mechanism in endothelial cells. They induce nitrovasodilator resistance by nitroglycerin infusion in Apoe deficient mice and studied endothelial function in both the mouse models as well as human umbilical vein endothelial cells. They found that nitric oxide donors induced atopic expression of microRNA 199a/b in endothelial cells, which was required for the nitrovasodilator resistance via repression of prostaglandin I2 synthase gene expression. Targeting this axis effectively improved nitrate tolerance. Thus, the atopic expression of microRNA 199 in endothelial cells induced by nitric oxide may explain prostaglandin I2 synthase deficiency in the progression of nitric tolerance. Thus, microRNA 199a/b may be a novel target for the treatment of nitric tolerance.

What are the long-term outcomes of childhood left ventricular noncompaction cardiomyopathy? Well, the next paper presents results from the National Population-Based Study in Australia. First author, Dr Shi, corresponding author, Dr Weintraub, from Royal Children's Hospital in Melbourne, looked at the National Australian Childhood Cardiomyopathy Study, which includes all children in Australia with primary cardiomyopathy diagnosed at less than 10 years of age between 1987 and 1996. Outcomes for left ventricular noncompaction patients with a dilated phenotype will compare to those with a dilated cardiomyopathy.

There were 29 patients with left ventricular noncompaction with a mean annual incidence of newly diagnosed cases of 0.11 per hundredth thousand at risks persons.

Congestive heart failure was initial symptom in 83%, and 93% had a dilated phenotype. The median age at diagnosis was 0.3 years of age. Freedom from death or transplantation was 48% at 10 years after diagnosis, and 45% at 15 years. Using propensity score inverse probability of treatment-weighted Cox regression, the authors found evidence that left ventricular noncompaction with a dilated phenotype was associated with a more than two-fold greater risk of death or transplantation.

The next paper reports the first application of multiomics and network medicine to calcific aortic valve disease. Co-first authors Dr Schlotter and Halu, corresponding author Dr Aikawa from Brigham and Woman's Hospital and Harvard Medical School in Boston, and their colleagues examined 25 human stenotic aortic valves obtained from valve replacement surgeries. They used multiple modalities, including transcriptomics and global unlabeled and label-based tandem-mass-tagged proteomics.

Segmentation of valves into disease stage–specific samples was guided by near-infrared molecular imaging. Anatomic-layer specificity was facilitated by laser capture microdissection. Side-specific cell cultures was subjected to multiple calcifying stimuli, and the calcification potential and basil or stimulated proteomics were evaluated. Furthermore, molecular interaction networks were built, and their central proteins and disease associations were identified.

The authors found that global transcriptional and protein expression signatures differed between the nondiseased, fibrotic, and calcific stages of calcific aortic valve disease. Anatomical aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression and identified glial fibrillary acidic protein as a specific marker of valvula interstitial cells from the spongiosa layer. In vitro, fibrosa-derived valvular interstitial cells demonstrated greater calcification potential than those from the ventricularis. Analysis of protein-protein interaction networks further found a significant closeness to multiple inflammatory and fibrotic diseases. This study is significant because it is the first application of spatially and temporarily resolved multiomics and network systems biology strategy to identify molecular regulatory networks in calcific aortic valve disease. It provides network medicine–based rational for putative utility of antifibrotic and anti-inflammatory therapies in the treatment of calcific aortic valve disease. It also sets a roadmap for the multiomic study of complex cardiovascular diseases.

The final paper tackles the controversy of antibiotic prophylaxis for the prevention of infective endocarditis during invasive dental procedures. This is from a population-based study in Taiwan. First author, Dr Chen, corresponding author, Dr Tu from Institute of Epidemiology and Preventive Medicine College of Public Health in National Taiwan University aimed to estimate the association between invasive dental treatments and infective endocarditis using the health insurance database in Taiwan.

They chose 2 case-only study designs. First a case-crossover, and second, self-controlled case series. Both designs used within-subject comparisons such that confounding factors were implicitly adjusted for. They found that invasive dental treatments did not appear to be associated with a larger risk of infective endocarditis in the short period following invasive dental treatment. Results were consistent from both study designs. The authors also did not find any association between invasive dental treatments and infective endocarditis even among the high-risk patients, such as those with a history of rheumatic disease or valve replacement.

In summary, these authors found no evidence to support antibiotic prophylaxis for the prevention of infective endocarditis before invasive dental treatments in the Taiwanese population. Whether antibiotic prophylaxis is necessary in other populations requires further study.

Alright, so that wraps it up for our summaries, now for our feature discussion.

The United States is one of the wealthiest nations worldwide, but Americans have a shorter life expectancy compared with almost all other high-income countries. In fact, the US ranks only 31st in the world for life expectancy at birth in 2015. What are the factors that contribute to premature mortality and life expectancy in the US? Well, today's feature paper gives us some answers. And I'm just delighted to have with us the corresponding author, Dr Frank Hu from Harvard T.H. Chan School of Public Health, as well as our dear associate editor, Dr Jarett Berry, from UT Southwestern.

Frank, could you begin by telling us a bit more about the inspiration for looking at this, what you did, and what you found?

Dr Frank Hu: So, we look at the impact of healthy lifestyle habits, life expectancy in the US as a nation. As you just mentioned, Americans have a shorter life expectancy compared with almost all other high-income countries, so in this study we wanted to estimate what kind of impact of lifestyle factors have, premeasured that and life expectancy in the US population.

What we did is to combine three datasets. One is our large cohort, Nurses’ Health Study, and Health Professionals Follow-Up Study. We use this large cohort to estimate the relationships between lifestyle habits and mortality. And the second data set we use is to get age and sex to specific mortality rates in the US as a nation. This is the CDC WONDER dataset. And the third dataset we used is the NHANES dataset, this is the National Health and Nutrition Examination Survey. We used this dataset to get the prevalence of healthy lifestyle factors in the general US as a nation. So, we used the three datasets to create age-specific, sex-specific life tables and estimated life expectancies.

At age 50, according to the number of healthy lifestyle habits that people would follow, what we found is that following several lifestyle factors can make a huge difference in life expectancies.

Here we talk about five basic lifestyle factors: not smoking, maintaining a healthy weight, exercise regularly—at least a half hour per day—and eating a healthy diet, and not drinking too much alcohol. No more than one drink per day for a woman, no more than two drinks per day for men. What we found is that, compared with people who did not adapt any of those low-risk habits, we estimated that the life expectancy at age 50 was 29 years for woman and about 26 years for men. But for people who adapted all five healthy lifestyle habits, life expectancy at age 50 was 43 years for women and 38 years for men. So, in other words, a woman who maintains all 5 healthy habits gained, on average, 14 years of life, and the men who did so gained 12 years life compared with those who didn't maintain healthy lifestyle habits. So I think this is a very important public health message. It means that following several bases of healthy factors can add substantial amount of life expectancy to the US population, and this could help to reduce the gap in life expectancy between the US population and other developed countries.

Dr Carolyn Lam: Thank you, Frank. You know that is such an important public health message that I am going to repeat it. Adhering to five lifestyle risk factors mainly, don't smoke, maintain a healthy weight, have regular physical activity, maintain a healthy diet, and have moderate alcohol consumption, AND a woman could increase her life expectancy at age 50 by 14 years and a man could do that by 12 years more. That is absolutely amazing.

Okay so Frank, actually, I do have a question though. These are remarkable datasets obviously, but they also go back to the 1980s. So did you see any chief risk factor that may have played more predominant apart with time?

Dr Frank Hu: We didn't specifically look at the changes in risk factors life expectancy, but among the five risk factors, not smoking is certainly the most important factor in terms of improving life expectancy. The good news is that prevalent smoking in the US has decreased substantially in the past several decades. However, the prevalence of other risk factors has actually increased. For example, the prevalence of obesity has increased two- or three-fold and the prevalence of regular exercise remained at a very low level, and also the diet quality in the US population is relatively poor. So, the combination of those risk factors have contributed to relatively low life expectancies in the US population.

Dr Carolyn Lam: Right. Obesity, not smoking, I hear you. I just wanted to point out to all the listeners too, you have to take a look at Figure 1 of this beautiful paper, it’s just so beautifully illustrated in it.

Jarett, you helped to manage and bring this paper through. What are your thoughts?

Dr Jarett Berry: Yeah, I just want to echo your comments, Carolyn, and Dr Hu. This is a fabulous paper, and a very important contribution characterizing these important associations in the US population. And I think, and the discussion thus far has been really helpful in putting all of this into context.

I do want to ask you, just a couple of, I guess more, philosophical questions about some of the observations in the paper. And one of them is the prevalence of the low-risk factor, those with a large number of low-risk factors, for example, in both the Nurses Health and in the Health Professional Follow-Up Study, you observed that the presence of five lifestyle factors was less than 2%. And it's interesting you see this in a large number of datasets and I think important, maybe for our readers to realize that there's two sides to the coin here.

One, the benefit of these low risk factors, but also, unfortunately, the low prevalence of these collections of healthy lifestyle factors that you've outlined.

Could you comment a little bit on that, and what that means, both maybe from a scientific point of view of perhaps, more importantly, from a public health stand point?

Dr Frank Hu: Yeah and this is very important observation and the number of people or the percentage of people who maintained all the five low-risk lifestyle habits is quite low in our cohort, even the nurses and health professionals, they are more health conscience in the general population. They have much better access to health care and also better access to healthy foods and have physical activity facilities. Despite all this potential advantages, and these more percentage of people who are able to maintain all five lifestyle risk factors.

On the other hand, about 10 to 15% of our participants did not adopt any of the five low-risk lifestyle habits. So it means that we still have a lot of work to do in terms of improving the lifestyle habits that we discussed earlier. The five risk lifestyle factors and in the general population, I think the percentage of people who adapt all the five lifestyle factors, probably even lower than 2%. And so that means that we have a huge public health challenge in front of us and have to improving the five lifestyle risk factors. One of the most important public health challenges as mentioned earlier is obesity because currently we have two-third of the US population is overweight or obese. So that's something I think is major public health challenges for us.

Dr Jarett Berry: Right, and it’s interesting looking at your Table 1, and those individuals who have all five low risk factors. It's interesting that the prevalence of physical activity was incredibly high. I have a great interest of impact of exercise on these types of outcomes and it's interesting that in both cohorts, six or seven hours a week of exercise was the mean physical activity level in those with five risk factors. So, it's interesting and in some ways, these lifestyle factors, they do tend to congregate or covary with one another such that those individuals who do spend that kind of time, albeit unfortunately more rare than we would like to see it, the increase in physical activity does tend to have a positive impact, not only on the weight, but also on healthy lifestyle or healthy diet choices.

Dr Frank Hu: Right, yeah this is a very good observation that what I do want to point out that our definition of regular exercise is pretty cerebral to put it in terms of the definition. So we define moderate to vigorous physical activity in our cohorts. We included not just running, playing sports, but it was also walking in a moderate intensity. So it means that people can incorporate physical activity into their daily life. For example, by walking from a train station and with climbing stairs in their workplace and so on and so forth. So here physical activity means both recreational activity and also moderate intensity activities such as graceful walking.

Dr Carolyn Lam: Frank, I think both of us listening are breathing a sigh of relief there and just for the listeners to understand too. These factors were dichotomized, right, and so you were describing the type of exercise and actually you used a three and a half hour per week limit to define healthy or not.

Similarly, just for reference the alcohol intake was 5 to 15g a day for women, or 5 to 30g a day for men. And normal weight was defined as a BMI of 18.5 to 24.9. I'm just thinking that if I were listening I'd want to know those cutoffs.

Now, can I ask a follow-up question, therefore to this dichotomy. As far as I understand you counted each of these risk factors equally, but did you try to do a weighted analysis by any chance? Did any one of them play a bigger role than others?

Dr Frank Hu: That's an interesting mathematical question because it’s very difficult to assign different weights to different risk factors because we look at, not just total mortality but also cardiovascular mortality and cancer mortality. So, you would have to use different weights for different causes of mortality. That would make the analysis much more complicated. But we did calculate a different type of score using five categories of each risk factor and then using that score, we were able to rank people in more categories so for that score the range is from five to 25, and we categorized people into quintiles or even more categories and the contrast in life expectancy between the lowest and the highest group is even greater. So, it means that, the higher number of healthy lifestyle factors, the greater life expectancy. Also, with each category, each lifestyle factors a high degree of adherence to that factor, the greater health benefit people will get. So, I think it's really accumulative fact of multiple risk factors and also the degree of adherence to each of the factors.

Dr Carolyn Lam: Again, such an important public health message.

Jarett, how do you think this is going to be received by the public at large?

Dr Jarett Berry: Very well received. I mean this is a very important observation demonstrating some of these disconcerting observations about life expectancy in the United States and as we think about strategies for improving the public health, I think Dr Hu's group has really helped us outline, very clearly, what other bodies such as the American Heart Association have been saying for years now, that lifestyle factors are so important in influencing cardiovascular risk, and in this case, life expectancy. It really does put, once again, the right amount of emphasis on the role these lifestyle factors of improving the public health. I think it’s going to be very well received and really helpful and important observation that all of us need to hear.

Dr Carolyn Lam: Listeners, don't forget this important message and tell your friends about it, please.

Thanks for joining us today, don't forget to join us again next week.

Circulation July 17, 2018 Issue

17 juli 2018 | 23 min

In this day and age of endovascular treatment for acute ischemic stroke, does time to treatment really matter? Well, we will be discussing results of the MR CLEAN Registry from real-world clinical practice, coming right up after these summaries.

The first original paper this week describes the first mouse model of progerin-induced atherosclerosis acceleration. Progerin is an aberrant protein that accumulates with age, causes a rare genetic disease known as Hutchinson-Gilford Progeria Syndrome. Patients with Progeria Syndrome have ubiquitous progerin expression and exhibit accelerated aging and atherosclerosis, dying in their early teens mainly from myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part due to the lack of appropriate animal models. First author Dr Hamczyk, corresponding author Dr Andrews, and colleagues from CNIC in Madrid performed an elegant series of experiments and generated not only the first mouse model of progerin-induced acceleration of atherosclerosis, but also provided the first direct evidence that progerin expression restricted to vascular smooth muscle cells but not to macrophages was sufficient to induce premature atherosclerosis and death. Progerin-induced loss of vascular smooth muscle cells caused atherosclerotic plaque destabilization that led to myocardial infarction. Ubiquitous and vascular smooth muscle cell specific progerin expression increased LDL retention in aortic media, likely accelerating atherosclerosis.

The next original paper implicates dysregulation of mitochondrial dynamics as a therapeutic target in human and experimental pulmonary arterial hypertension. Now, mitotic fission is increased in pulmonary arterial hypertension. The fission mediator, dynamin-related protein 1, or Drp1, must complex with adaptor proteins to cause fission. In the current paper from co-first authors Dr Chen and Dasgupta, corresponding author Dr Archer from Queens University in Ontario Canada, and colleagues, the authors examined the role of two recently discovered but poorly understood Drp1 adaptor proteins known as mitochondrial dynamics protein of 49 and 51 kilodalton. They found pathological elevation of these mitochondrial dynamic proteins in pulmonary artery smooth muscle cells and endothelial cells in both human and experimental pulmonary arterial hypertension that accelerated mitotic fission and supported rapid cell proliferation. Mitochondrial dynamics protein's expression was epigenetically upregulated by a decreased expression of microRNA-34a-3p. Circulatory microRNA-34a-3p expression was decreased in both patients with pulmonary arterial hypertension and preclinical models, silencing the mitochondrial dynamics proteins or augmenting microRNA-34a-3p regressed experimental pulmonary arterial hypertension, thus, proving to be potential new therapeutic targets for pulmonary arterial hypertension.

Dyslipidemia guidelines currently recommend that non-HDL cholesterol and apolipoprotein B, or apoB, are secondary targets to the primary target of LDL cholesterol. However, how frequently does non-HDL cholesterol guideline targets change management, and what is the utility of apoB targets after meeting LDL and non-HDL targets?

Well, answers are provided in the next paper from first author Dr Sathiyakumar, corresponding author Dr Martin, and colleagues from Johns Hopkins University School of Medicine. These authors analyzed more than 2,500 adults in the US National Health and Nutrition Examination Survey, as well as more than 126,000 patients from the Very Large Database of Lipids Study with apoB. They identified all individuals as well as those with high-risk clinical features, including coronary disease, diabetes, and metabolic syndrome who met the very high and high-risk guidelines targets of LDL cholesterol of less than 70 and less than 100 mg/dL, respectively, and this was measured using either the Friedewald estimation or a novel, more accurate method. They found that after using the more accurate method of estimating LDL cholesterol, guidelines suggested non-HDL targets could alter management in only 1 to 2% of individuals, including those with coronary disease and other high risk clinical features.

However, using the Friedewald estimated LDL cholesterol gave a much higher percentage. Among all individuals with both LDL cholesterol less than 100 and non-HDL cholesterol less than 130 mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus, the utility of current non-HDL targets appears to be contingent on the accuracy of LDL cholesterol estimation. When using a novel, more accurate estimation method to assess LDL cholesterol, the non-HDL cholesterol is infrequently above current guidelines' suggested targets after the LDL target is met. Current guidelines suggest that apoB targets also provide only modest utility after cholesterol targets are met. These findings were robust to high-risk clinical features, sex, fasting status, and presence of lipid-lowering therapies.

The final paper tells us that HIV infection increases the risk of developing peripheral artery disease. Dr Beckman from Vanderbilt University Medical Center and colleagues studied almost 92,000 participants in the Veterans Aging Cohort Study from 2003-2014 over a median follow-up of nine years. They excluded participants with known prior peripheral artery disease or prevalent cardiovascular disease. They found that infection with HIV was associated with a 19% increased risk of incident peripheral artery disease beyond that explained by traditional atherosclerotic risk factors. Once peripheral artery disease had developed, HIV infection increased the risk of mortality compared to uninfected patients. Whereas for those with sustained CD4 cell counts above 500, there was no excess risk of incident peripheral artery disease events compared to uninfected people. Furthermore, worsening HIV infection as measured by CD4 cell count and HIV viral load was associated with increased incident peripheral artery disease and mortality. In summary, HIV infection increased the risk of developing peripheral artery disease and mortality. The findings also suggest that aggressive antiretroviral therapy to reduce viral load and increase CD4 cell counts may reduce the risk of developing peripheral artery disease. Furthermore, clinicians should solicit clinical complaints and physical signs consistent with peripheral artery disease to facilitate the diagnosis of peripheral artery disease in patients with HIV and ensure the addition of guideline-based anti-atherosclerotic therapies in these patients.

Well, that wraps it up for our summaries. Now for our feature discussion.

When it comes to acute ischemic stroke treatment, we've learned from trials of intravenous thrombolytics that time is brain. But what about the situation with endovascular treatment of strokes? Also, what's the situation like in the real world? Well, today's featured paper really provides precious data telling us about time-to-endovascular treatment and outcomes in acute ischemic stroke. I am so delighted to have with us the first and corresponding author of the MR CLEAN Registry, Dr Maxim Mulder from Erasmus University Medical Center, as well as our editorialist, Dr Micheal Hill, from University of Calgary, and our associate editor, Dr Graeme Hankey, from University of Western Australia, all here to discuss this hugely important topic.

Maxim, could we start with you? So, MR CLEAN Registry means there was a MR CLEAN trial. Could you tell us a little bit more about your paper?

Dr Maxim Mulder: Sure, well to start with, I think it's important to make sure all the people know the difference between the MR CLEAN trial and the registry since of course the trial was to show whether the intra-arterial treatment is effective when it comes to acute ischemic stroke treatments and then, of course, for people treated within six hours. When the MR CLEAN trial finished we continued in the Netherlands with all the participating centers from the trial to gather all the data from everybody who is treating in the whole country with the intra-arterial treatment, but they're not anymore in the light of the trial but in the clinical practice. We've had a lot of trials, but we don't have a lot of clinical practice date yet of the intra-arterial treatment, so that's where it all started.

So, what we found is we consider our data, so with the least possible selections or the only selection was basically to treat within six and a half hours and have patients that had a proven large vessel occlusion that were treated in the Netherlands and of course as we also know from when intravenous therapy was introduced that what happens in clinical trials doesn't necessarily happen when a new treatment is introduced into clinical practice. There are less strict criteria for patients to get treated, and you know everybody, of course, there is a lot of debate about which patients should be treated. In clinical trials it is very strictly coordinated, but in clinical practice there's a lot more room to have an interpretation and also treat a different population. So, we also see that our population is somewhat older and has more comorbidities than in all the trials. Also what we found, of course, our most important finding was that when compared to all the trials or the large trials combined together in the Emberson analysis about time that when we look at the influence or the association of time with functional outcome of intra-arterial treatment that this association is clearly stronger than we found in the previous, the trial data.

So, I think that's a very important finding. Also, for everybody who's now treating this patient in clinical practice.

Dr Carolyn Lam: Exactly. I mean this is really stunning results. If I could paraphrase from your paper, every hour delay in time from stroke onset to the start of endovascular treatment resulted in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality. This is stunning. Thank you, thank you for publishing these results with us in Circulation. I would like to ask Michael, I love the point you made in the editorial that time of stroke onset is really quite a difficult thing to determine. Could you tell us your thoughts about that, Michael?

Dr Micheal Hill: I mean, it's something like 15-20% of the time stroke is unwitnessed, either because stroke occurs in sleep and the patient is discovered with their stroke symptoms on awakening. Or the patient is simply alone and has their stroke unwitnessed by any bystander. Even in so-called witness stroke, there are probably significant errors in determining the exact time of stroke onset because it's an emergency, and everybody's flustered and time anchors are not necessarily well known. And, so, I think it's an important point that the actual measurement of time is challenging, yet it's still an easier clinical tool for us to use in gauging the extent or evolution of stroke. That's the most important thing to point out here is that this population effect that Max has observed in the MR CLEAN registry is certainly concordant with clinical trial data.

I certainly think it's correct, and, as you pointed out in your comments, dramatic, but a really important issue is that for the individual patient, there's quite a lot of variance in the evolution of stroke. So, whereas, on a population basis, it's absolutely true that the average time from estimated time of stroke onset to treatment initiation is absolutely critical; in some patients, the individual might be still a good candidate for treatment even in late time windows, and some patients, even after a couple hours, the damage is already extensive, and they may not be good candidates for treatment. It still requires individual decision making, and it still leaves a lot of room for clinical judgment largely based on imaging.

Dr Carolyn Lam: True, and I think you've really succinctly put that solid take-home message in the title really, which is acute ischemic stroke biology really demands fast treatment. I think that's the one thing that we'd really like clinicians to come away with. You agree?

Dr Micheal Hill: Absolutely. Especially, I think, the advantage of looking at whole populations and large, I mean this is a large registry, the MR CLEAN registry, and the group should be congratulated because it's clearly the biggest registry in the world right now of available data, and it's only getting larger week by week as they carry on with their work. You know the whole Netherlands group, the MR CLEAN group, are a fantastic group, but absolutely right, on a population basis, we absolutely have to get our systems in place so that on average we're treating patients incredibly fast. On an individual basis, the clinicians and the teams treating an individual patient still need to make judgments about that patient's eligibility for treatment. It's easy when the times are fast, so if you're an hour and a half from onset, nearly everybody's gonna be a good candidate for treatment, but as time elapses you need to make judgements on the basis of imaging.

Dr Carolyn Lam: Well put. You know, Graeme, you're over there in Australia. What are your take-home messages about how generalizable these findings are to places outside perhaps of the Netherlands?

Dr Graeme Hankey: I think you're asking about the external validity. I think the internal validity is certainly there. As Michael said, this is the largest registry that we have that's been published data on this before. It's certainly novel, and we're very confident that the results are valid, although this is an observational study and not a randomized trial. The association between time and outcome seems to be independent of the major patient factors that may influence time to endovascular therapy. For example, younger people who are less frail and they're alert and they're mobile can get to treatment earlier. So, you might say, well of course they're gonna have a better outcome. But these factors were adjusted for. And, of course, there are procedural factors that could influence the association between time and outcome, but we're very confident in the results and the novelty of them in supporting and building on the randomized trial data.

We're also very confident in the registry and the nature of the population. The results are likely to be generalizable beyond the Netherlands population where this was conducted in routine clinical practice, certainly across Caucasian populations that are similar and with similar stroke interventional and assessment protocols, and I would hope to see this sort of study validated externally in other populations. But, also, as Michael said, I think this study not just highlights the importance of time as a factor and its implications for systems of care and recognizing people with disabling stroke and ensuring they’re assisted urgently to the appropriate imaging but also to acknowledge that time isn't the only factor. And as Michael has alluded to, our brain tissue has different collateral circulations and different probable genetic factors and metabolic factors. So, someone with a stroke at one hour, it might be all over for them. Whereas, another person with a stroke at 24 hours ago, they might have salvageable tissue.

So, although, generally time is an important prognosticator as we've learned here, there are probably other factors that need to be considered and accounted for. But this certainly takes us a step forward, and, in answer to your question, I think we have confidence in its generalizability.

Dr Carolyn Lam: Thank you Graeme. Maxim, in line with that, are there any next steps you plan?

Dr Maxim Mulder: In light of the most recent trials, the DAWN and DEFUSE 3 trial about 6 to 25-hour, 24-hour window, I think that both of the trials are very exciting, and they shine a new light into a new set of patients that are still able to offer a great benefit intra-arterial treatment. In my opinion, the most important thing, especially in those two trials, those are highly selective patients, especially selected on all the extra imaging parameters, and I guess that there's a whole larger population that could still benefit in this time window and that's also one of the things we're currently studying in one of our new trials in the Netherlands in the MR CLEAN-LATE trial, and that is randomizing patients who are having a large vascular occlusion 6 to 24 hours, and the only extra criteria they should meet is they should have at least a little bit of collateral circulation on the ischemic brain side.

Dr Carolyn Lam: Michael and Graeme, what do you think are the priorities for next steps in research.

Dr Micheal Hill: I guess overall in the field, I don't think there's any doubt that faster treatment is better. What we need to do across the world is make sure that everybody's receiving it on a system-wide basis. Right? I think there needs to be a lot of more careful work done on getting systems of care in place to make sure that patients are getting the treatment they can get. We have very many weaknesses. Some are related to lack of accreditation. Some are related to the resources required to get people treated quickly. Some are related to continuing resistance in some specialties to even giving intravenous thrombolytic drugs. So, I think faster treatment in general for acute stroke is a theme; it's not just limited to endovascular treatment. It's treatment for patients for intravenous thrombolysis. It's also actually true for TIA and minor stroke. We've had recent data on fast antiplatelet therapy, so, it's not an emergency in the same way in terms of minutes, but it's still a general theme of acute stroke care.

We need to be like the Ferraris and the Formula One, right? And get ourselves moving. That's a big challenge for people. Right? It's a big stress on systems. But, I think there are other examples in medicine. We've seen this evolution in acute coronary care, and we've seen the evolution in acute trauma care. In many ways, the next things that need to really continue to happen are publications like this and getting the message out that people need to start changing their mind. The biggest thing that I find when I talk to people or talk at meetings or talk to administrators is that they say, "Well, we can't do this many CTs that fast. We can't respond that fast." And the answer is actually that you can't change the biology of the disease, so if you decide you wanna treat stroke patients, you better figure out how to change your systems. It's a question of will here rather than trying to bend the disease to the system.

Dr Carolyn Lam: Wonderfully put. Can't change the biology so we better change the systems. How about you, Graeme? Any last words?

Dr Graeme Hankey: Just to concur with Michael’s comments there and Max's underlying theme that time is very important. And as Michael alludes to, it's not just acute ischemic stroke due to large vascular disease, it's also acute intracerebral hemorrhage. We're learning now really if we're gonna have an effect in the bleeding brain probably we have to do that within the first three hours and maybe not be waiting so late. And as Michael alludes to, someone with a minor ischemic stroke who's had a hot volcano gone off in their neck, as you know, ruptured atherosclerotic plaque, it's like those volcanoes in Hawaii, they're gonna keep going off again. And the risk is 5% in the next two days and 10% in the next week. So, a TIA and a mild ischemic stroke, it is a medical emergency to find the cause and to get it treated, and that's why the synopsis of this message from Max's study is that people, if they do avail themselves of acute assessment early, even if they don't have a large vessel occlusion causing an ischemic stroke, they may actually have their intracerebral hemorrhage treated quickly or, more evidence based at the moment, their TIA or mild ischemic stroke have the cause ascertained and treated emergently and reduce that early risk of recurrence should they survive.

Dr Carolyn Lam: Excellent points. Thank you so much, gentlemen. This has been an amazing podcast.

Thank you so much for joining us today. Don't forget to tune in again next week, listeners.

Circulation July 10, 2018 Issue

10 juli 2018 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor for the National Heart Center, and Duke National University of Singapore.

How do resuscitation teams at top-performing hospitals for in-hospital cardiac arrest actually succeed? Well, to learn how, you have to keep listening to the podcast, because we will be discussing this right after these summaries.

The first original paper this week tells us that recent developments in RNA amplification strategies may provide a unique opportunity to use small amounts of input RNA for genome wide-sequencing of single cells. Co-first authors, Dr Gladka and Molenaar, corresponding author, Dr van Rooij, and colleagues from Hubrecht Institute in Utrecht, the Netherlands, present a method to obtain high-quality RNA from digested cardiac tissue, from adult mice, for automated single-cell sequencing of both healthy and diseased hearts.

Based on differential gene expression, the authors were also able to identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cells subpopulations.

For example, they identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlated with known myofibroblast markers, in both mouse and human cardiac tissue. This paper raises the exciting possibility for new biology discovery using single-cell sequencing that can ultimately lead to the development of novel therapeutic strategies.

Myeloid-derived suppressor cells are a heterogeneous population of cells that expand in cancer, inflammation, and infection, and negatively regulate inflammation. However, their role in heart failure was unclear, at least until today's paper in this week's journal. Co-first authors Dr Zhou, Miao, and Yin, and co-corresponding authors, Dr Wang and Li, from Huazhong University of Science and Technology, measured the myeloid-derived suppressor cells by flow cytometry in heart failure patients and in mice with pressure overload–induced heart failure, using isoproterenol infusion or transverse aortic constriction.

They found that the proportion of myeloid-derived suppressor cells was linked to heart failure severity. Cardiac hypertrophy, dysfunction, and inflammation were exacerbated by depletion of myeloid-derived suppressor cells but alleviated by cell transfer. Monocytic myeloid-derived suppressor cells exerted an antihypertrophic effect on cardiomyocyte nitric oxide, but monocytic and granulocytic myeloid-derived suppressor cells displayed antihypertrophic and anti-inflammatory properties through interleukin 10.

Rapamycin increased accumulation of myeloid-derived suppressor cells by suppressing their differentiation, which in part mediated its cardioprotective mechanisms. Thus, these findings revealed a cardioprotective role from myeloid-derived suppressor cells in heart failure by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin 10 and nitric oxide. Pharmacological targeting of myeloid-derived suppressor cells by rapamycin constitutes a promising therapeutic strategy for heart failure.

In the FOURIER trial, the PCSK9 inhibitor evolocumab reduced LDL cholesterol and cardiovascular risk in patients with stable atherosclerotic disease. However, was the efficacy of evolocumab modified by baseline inflammatory risk?

While Dr Bohula from the TIMI Study Group and colleagues explored this question by examining the efficacy of evolocumab stratified by baseline high sensitivity CRP. They also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL concentrations. They found that the relative benefit of evolocumab for the prevention of adverse cardiovascular events was consistent, irrespective of baseline high sensitivity CRP. However, because patients with higher high sensitivity CRP levels had higher rates of adverse cardiovascular events, they also tended to experience greater absolute benefit with evolocumab.

In an analysis of baseline high sensitivity CRP in achieved LDL cholesterol, the authors found that at first cardiovascular event rates were independently associated with both LDL cholesterol and high sensitive CRP. Event rates were lowest in patients with the lowest hsCRP and LDL cholesterol, supporting the relevance of both inflammatory and residual cholesterol risk.

The next paper provides further evidence that residual inflammatory risk, as measured by on-treatment high sensitivity CRP, remains an important clinical issue in patients on combination statin and PCSK9 inhibitor therapy. Dr Pradhan, from Brigham and Women's Hospital and colleagues, evaluated the residual inflammatory risk among patients participating in the SPIRE-1 and -2 cardiovascular outcome trials, who are receiving both statin therapy and the PCSK9 inhibitor bococizumab, according to on-treatment levels of high sensitivity CRP and LDL cholesterol measured 14 weeks after drug initiation.

They found that among high-risk stable outpatients treated with moderate or high-intensity statins and PCSK9 inhibition, roughly one in two had residual inflammatory risk defined by an on-treatment high sensitivity CRP level of 2 or more mg per liters, and roughly one in three had values above 3 mg per liter.

PCSK9 inhibition was associated with a 60% mean reduction in LDL cholesterol but little change in high sensitivity CRP. Levels of high sensitivity CRP above 3 mg per liter were associated with a 60% greater risk of future cardiovascular events, corresponding to a 3.6% annual event rate, even after accounting for on-treatment LDL cholesterol.

Thus, PCSK9 inhibition, added to statin therapy in stable outpatients, does not lower high sensitivity CRP. Persistent elevations of CRP is associated with future cardiovascular risk in these patients, even after low levels of LDL cholesterol are achieved. If corroborated, these data suggests that inflammation modulation may yet have a role in the primary and secondary prevention of cardiovascular disease when LDL cholesterol is already controlled. Well, that wraps it up for our summaries. Now, for our future discussion.

In-hospital cardiac arrests are common worldwide and they're so important because they represent opportunities for us to improve survival. Now, yet, overall rates of hospital survival after in-hospital cardiac arrests remain poor and there is substantial variation across facilities. This may be surprising because we all seem to follow or should follow the same ACLS algorithms across the world and yet, there are different outcomes.

How do resuscitation teams, at top performing hospitals, for in-hospital cardiac arrest, how do they succeed? Pleased to be discussing this with a real star team in today's podcast. We have first and corresponding author of our feature paper, Dr Brahmajee Nallamothu. We also have Dr Steven Kronick, who is the chair of the CPR committee and both are from University of Michigan Medical School. We also have Dr Sana Al-Khatib, who is a senior associate editor of Circ, from Duke University. So, welcome everyone! Let’s go straight into it. Maybe starting with you Brahmajee, could you tell us what inspired you to perform this study?

Dr Brahmajee Nallamothu Thank you, Carolyn, for giving us the opportunity to talk about this study. I'm an interventional cardiologist here at the University of Michigan and typically, this isn't an area that interventional cardiologists are really greatly involved with. I became interested because I also, at times, I round in the cardiac intensive care unit, and that's a place where a lot of patients often times end up after they've had an in-hospital cardiac arrest at our institution and what I've noticed over the years, is the variability in care that would be occurring out there, and then also lots of gaps in the literature.

Over a decade or so ago, I started partnering with a close friend and colleague, Paul Chan, from the Mid America Heart Institute and we started to do a series of studies on how in-hospital cardiac arrest care varies across institutions in the United States and we published a number of articles that have been in really high-profile journals over the last 10 years, but the problem has always been that even though we could describe really well what was happening, we had very little understanding of why it was happening or how certain hospitals were seeming to outperform others in this really challenging situation.

We wanted to dive a bit deeper into the questions and reasons behind top performers doing so well and that's what brought us on to doing this study.

Dr Carolyn Lam: Great. You want to tell us a little bit about it? It's really very different from the other CPR studies I've seen. Could you tell us about it and what you've found?

Dr Brahmajee Nallamothu: Sure, so in the broader framework, it's a qualitative study and what I mean by qualitative is, we didn't really collect data either through surveys or through outcome assessments. What we did was, we actually went out and talked to people.

The study though was really focused on what people call a mixed methods approach. We didn't just randomly talk to different hospitals, we actually focused on hospitals that were at the top-performing levels. We also focused on some hospitals that were non-top-performing as well, to get some contrast between the two and when I said we talked, we did this in a very systematic and pretty rigid way.

We always had four interviewers go out to nine hospitals. We split them up, so we had two content experts and then two methodologic experts in qualitive studies, and we started to interview a bunch of people. In fact, we interviewed almost 160 people across these nine hospitals.

We interviewed everyone from CEOs and hospital leadership, down to boots on the ground, including both clinical providers and even non-clinical providers, such as spiritual care, security. We tried to get this comprehensive view of what was actually happening during an in-hospital cardiac arrest across these nine hospitals, and really the results were quite fascinating to us.

For someone, like myself, that's been in this space for ten years, I tell people I learn more talking to these nine hospitals than I have in the last ten years of looking at numbers on a spreadsheet. I really started to understand, for the first time, what was really going on, how these hospitals were dealing with these challenging situations because there's no bigger emergency in a hospital, and Steve, who we're going to hear from, we talk about this, but Steve has a great line about how when an in-hospital cardiac arrest occurs, that patient automatically becomes the sickest person in an institution and yet, we haven't set up systems that really build on how to handle that in the most consistent and positive way.

Dr Carolyn Lam: Oh, my goodness, I just love that line! Now, you have to tell us, so what's the secret? What's the secret of the succeeding hospitals?

Dr Brahmajee Nallamothu: What we found in general was, that resuscitation teams at top-performing hospitals really demonstrated the following features. They had dedicated or designated resuscitation teams. They really included the participation of diverse disciplines as team members during the in-hospital cardiac arrest. There were really clear roles and responsibilities of the team members that were set up right from the front.

There was better communication and leadership, actually, during these events and finally, in the training aspect, one of the unique things we found was, the top-performing hospitals seem to have a high rate of in-depth mock codes, that they used as strategies for getting their clinicians ready for these events.

Dr Carolyn Lam: As you were speaking I was just thinking through the experiences of in-hospital cardiac arrests that I've encountered, and you're right. These elements, though we don't talk about them much, make a huge difference. Steve, I am so curious about your outlook. I mean you must have attended a kajillion CPRs as chair of the CPR committee. Tell us, what do you think is the take home message for clinicians and hospitals?

Dr Steven Kronick: My field is in emergency medicine and as chair of the CPR committee, I have responsibility of overseeing how we respond to cardiac arrests in our hospitals. I think that many institutions spend a lot of time and effort looking at in-hospital cardiac arrests are managed, and how to improve on it. We're able to use data to help compare ourselves to similar institutions, but beyond the bottom line of either ROSC or survival to discharge, we've most relied on process measures to figure out what we're doing.

We're essentially flying blind, or at least not flying in any sort of formation when we do that. I think that this study validates some of the operational aspects of the arrest response, for those centers who use those and can help other decide where they want to direct their efforts. I think a good example that Brahmajee brought up, is this distinction we found between the use of dedicated teams, designated teams, or not having any organized team, and the impact that has on survival.

The use of these teams can mean significant use of resources but showing that it's associated with better outcomes help provide support for that concept and for those centers who might already use one of those models, it helps them to steer their efforts to improving the delivery or the efficiency of that model.

Dr Carolyn Lam: Yeah, and indeed. Congratulations to both of you, Steve and Brahmajee. I do think that these are novel contemporary data, at least the first that I know of. Sana, you handle the paper and recognize this. Could you tell us a little about what you think are the novel and important aspects?

Dr Sana Al-Khatib: I really have been a fan of this paper from the get go and yes, it doesn't have the quantitative analysis that the statistical modeling, most of us are used to. It is a qualitative study, but I think that gives it strength. It makes it unique. This type of research, it can really only be effectively done through a qualitative study that really has all the important aspects of a good qualitative study, so I do want to congratulate them. Clearly, a lot of work went into this, and I appreciate all their efforts.

In terms of the main findings, some of us might look at this data and say, well it's not surprising that those are the characteristics, or the features, of the top performing hospitals, but I felt like it was great, in terms of how the data were presented. Encouraging hospitals to adopt this. Giving them almost like a checklist of what they need to be doing to improve the outcomes of their in-hospital cardiac arrests, in terms of ensuring that they have designated resuscitation teams.

The whole idea about diversity of participants in these arrests, and making sure everyone has a clear role and responsibility. The whole idea of making sure that somebody takes leadership and you have clear and very good communication among the different people who are doing this and great training. In fact, these people were doing in-depth mock codes. I think that spells it out very nicely and gives a lot of the hospitals, hopefully, action items that they can implement to improve the outcomes these patients. I love this paper.

Dr Carolyn Lam: Sana, I love the way you put that. Checklist, and you know what I was thinking as Brahmajee and Steve were talking earlier? I was thinking blueprint, almost, of the things that we should have. So Steve, could I ask your thoughts. I mean, are you going to put some of these things into practice in your own committee and how?

Dr Steven Kronick: There are a variety of things we can do. Some of these things are a pretty high-functioning place, but still looking at recommendations that have been laid out and how we help modify those things. Though the example is the roles that people play at an arrest. We can certainly improve on assigning those roles, how people work together as a team, and then also, getting to work more as a team, so that when they are called upon to perform those duties, they can do it in a more coordinated way.

Dr Carolyn Lam: How beautifully put. I'm going to steal a couple of minutes at the end of this podcast. I really have to because it's so rare to have Brahmajee on the line today and he's the Editor-in-Chief of Circ: Cardiovascular Quality and Outcomes. Brahmajee, could I ask you to say a few words to our worldwide audience about your journal?

Dr Brahmajee Nallamothu: We are a kind of daughter journal to Circulation. We are a bit more unique than the others, in the sense that we aren't disease or subspecialty focused. We deal with, broadly, the issues around outcomes research, health services research, quality of care research, and really health policy. We publish an issue once a month. We have a broad interest in things that are really relevant to the community around outcomes research and health services research.

I will say that I really appreciate this because of the worldwide audience and reach, one of the big issues we've been very interested in is expanding our reach, from the United States to other parts of the world, and in fact, last fall, we had a global health issue, which was well received, and we received papers from across the world.

In fact, every paper in that issue was a non-US-based paper, and it touched on a number of things from issues around healthcare utilization in Asia to demographics and disease registries in Africa, and it was a wonderful experience, so I think it's a journal that we're excited about.

It was first launched by Harlan Krumholz, who has set a high bar and standard for us, and I think that my editorial team, which has been fantastic, has continued with that work. We would love to see papers from your readers and your listeners from across the world and excited about what that journal is going to be doing in the next five years.

Dr Carolyn Lam: Oh wow! That's so cool! Well listeners, you heard it right here, first time on Circulation on the Run. Thank you so much for joining us today. Don't forget to tune in again next week.

Circulation July 3, 2018 Issue

2 juli 2018 | 17 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week features Circulation Global Rounds, a brand-new series of papers from all across the world that you are going to want to hear about, coming right up after these summaries. The first original paper this week tells us that community trends and acute decompensated heart failure may differ by race and sex. Dr Patricia Chang from University of North Carolina in Chapel Hill and colleagues examine the 10-year rates and trends of hospitalized acute decompensated heart failure in the Atherosclerosis Risk in Communities or ARIC study, which sampled heart failure–related hospitalizations in four US communities from 2005 to 2014, using ICD-9 codes. They found that acute heart failure with reduced ejection fraction was more common in black men and white men, whereas acute heart failure with preserved ejection fraction was most common in white women. Rates of hospitalized acute decompensated heart failure increased over time, with higher rates in blacks, and rising cases of preserved ejection fraction heart failure. Mortality rates were 30% at one year with a more pronounced decrease over time in blacks but generally did not differ by heart failure types. Whether racial differences may be related to age of onset comorbidities, or other community level and social economic factors, deserve further study. The next paper is a population-based study identifying long-term outcomes and risk factors and children with hypertrophic cardiomyopathy. Dr Alexander from Boston Children's Hospital and colleagues examine the National Australian Childhood Cardiomyopathy Study, a long-term national cohort study with a median follow-up duration of 15 years. They found that the greatest risk of death or transplantation for children with hypertrophic cardiomyopathy was in the first year after diagnosis, with 14% of patients achieving this combined end point compared to 0.4% per year thereafter. Risk factors for death or transplantation included symmetric left ventricular hypertrophy at diagnosis, Noonan syndrome, increasing left ventricular free wall thickness, and lower fractional shortening during follow up. The majority of surviving patients had no symptoms. Thus, children with hypertrophic cardiomyopathy who are alive one year after diagnosis have a low long-term rate of death or transplantation. Deaths from heart failure usually occur soon after diagnosis, whereas the risk of sudden cardiac death is ongoing. The next paper is the first demonstration of a peripheral clock in the perivascular adipose tissue that could contribute to the homeostatic regulation of circadian blood pressure variation. Co-corresponding authors Dr Chang and Chen from University of Michigan and their colleagues used a novel brown adipose specific aryl hydrocarbon receptor, nuclear translocator-like protein 1 or Bmal1 and angiotensinogen knockout mouse model to demonstrate that local Bmal1 in perivascular adipose tissue regulated angiotensinogen expression and the ensuing increase in angiotensin II, which acted on smooth muscle cells in the vessel walls to regulate basal activity and blood pressure in a circadian fashion during the resting phase. In fact, deletion of Bmal1 or angiotensinogen in the perivascular adipose tissue resulted in a superdipper phenotype with exacerbated hypotension during the resting phase. These findings imply that it is possible that obesity could alter the perivascular adipose tissue peripheral clock, thus promoting abnormal dipper phenotypes and increasing cardiovascular risk. The results therefore inform the design of novel therapeutic approaches for hypertension by targeting the perivascular adipose tissue peripheral clock. What is the net clinical benefit of oral anticoagulation for very elderly patients with atrial fibrillation? Well, the next paper by first author Dr Chao, cocorresponding authors, Dr Chen from Taipei Veterans General Hospital and Dr Lip from University of Birmingham, addresses this question. These authors use a nationwide cohorts study in Taiwan to compare the risks of ischemic stroke and intercerebral hemorrhage between patients with and without atrial fibrillation, all aged 90 years and above, from 1996 to 2011, and they also compared patients treated with warfarin and non-vitamin K antagonists oral anticoagulants, or NOX from 2012 to 2015 when NOX were available in Taiwan. They found that even among these very elderly patients aged 90 years and above, atrial fibrillation was associated with an increased risk of ischemic stroke compared to patients without atrial fibrillation. Warfarin use was associated with a lower risk of ischemic stroke, with no difference in intercerebral hemorrhage risk compared to nonwarfarin treatment. The use of warfarin was associated with a positive net clinical benefit compared to being untreated or to antiplatelet therapy. Compared to warfarin, NOX were associated with a lower risk of intracerebral hemorrhage, with no difference in the risk of ischemic stroke. Thus, oral anticoagulation may still be considered for thromboprophylaxis in very elderly patients with atrial fibrillation, with NOX being a favorable choice The final paper provides insights into the mechanisms linking obesity and cardiovascular diseases. Co-corresponding authors, Dr Kong and Wang from Peking University Health Science Center and colleagues use a combination of animal models and human adipose biopsies to characterize a new adipokine named family with sequence similarity 19, member A5 or FAM19A5. This novel adipokine was capable of inhibiting post injury neointoma information via sphingosine-1-phosphate receptor 2 and downstream G12/13-RhoA signaling. Thus, down regulation of FAM19A5 during obesity and loss of its vascular protective function may trigger cardiometabolic diseases. Well, that wraps it up for our summaries. Now for our feature discussion. I'm just so excited about today's feature discussion, because we're talking about Circulation going global. And I am just absolutely delighted to have with us, our Editor-in-Chief himself, Dr Joe Hill from UT Southwestern, as well as our Senior Advisory Editor, Dr Paul Armstrong from University of Alberta. So Joe, could you start by telling us a little bit more about your vision for the global outreach of Circulation? Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global journal with a global footprint. We have editors distributed around the world in 16 countries and 10 time zones. And importantly, those editors all have an equivalent role at the leadership table. Part of the reason for this is because cardiovascular disease is now, as we are all aware, a global scourge. There are no more final frontiers for cardiovascular disease. That said, the manifestations of cardiovascular disease differ in different parts of the world. In the developed world, and the developing world, for example, the way cardiovascular disease manifests itself can be very different. And at the same time, the way in which the disorders are tackled are different. The way we tackle heart disease in the West can be different than it is in the East, for example. And there are important initiatives that have emerged in different pockets of the world, best practices that we need to understand better. What can we all learn from the way in which cardiovascular disease manifests itself around the world and it's being addressed around the world? Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in - Chief and I heard you say this, I was just floored, because coming from Singapore and all our listeners out there in Japan and China, we just really appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit more about this new initiative then for the journal. Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from Canada, who is a household name in the cardiovascular world, he and I cooked up a scheme that Paul will describe, where we will reach out on a regular basis for insights from various different countries, ultimately, circling the globe progressively over time. And I will defer to Paul to tell us more about the specifics. Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but still believing that you can teach an old dog new tricks, I would point out that Circulation is almost 70 years old, and it has staying power. And one of the reasons that it has staying power is because it is capable of reinventing itself, and so I was attracted to help out again, from the editorial process, given Joe's vision and leadership and the excitement around the reinvention that you've described, to get involved with this initiative. And I was inspired, of course, by the fact that those of us who do clinical trials appreciate that a lot of different ideas, a lot of different cultures and perspectives are brought to a collaborative table. And I'm thinking back now, Carolyn to three years ago, when you and I first met enjoying courses as part of a trial in heart failure, which involves 43 countries, 800 sites, it will be 5000 patients centers, we've traveled separately and together around the world, convincing people that there are unmet needs in heart failure and other parts of cardiovascular disease, we learned that the approach to standard of care, the rigor which is applied, the exquisite sensitivities around differences that are meaningful, and the tricks that some investigators and countries use that we can all I think, learn from has been very revealing. So I think in this initiative, we want to have thought leaders. And we've already I think, commenced and have two outstanding leaders from Japan and India to come forward in the first two quarters of this initiative. Tell us about the regional epidemiologic features, cardiovascular disease in their regions, what the most important challenges are, what their best practices are, that you're alluded to, who provides cardiovascular care and what the impediments are to progressing because we think if we listen and learn as essentially knowledge brokers, because welcome to Circulation, we can facilitate raising the level of all of the boats in the water and potentially make new partnerships and do a better job. So I'm excited about this. I'm delighted that Joe was receptive and really look forward to working with him and some of these terrific people around the world, you included who brings such a unique and important perspective from which we can all learn. Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International knowledge brokers, that's what we hope to be. Isn't that fabulous, just an opportunity to learn from each other, everybody having stuff to bring to the table? Tell us a bit more though, what are you looking for in these papers? Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic. We're going to allow diversity of approaches. We're going to invite a thought leader and hope that that thought leader might invite one or two others, we want to limit it to three co-authors. We want obviously some insights into how cardiovascular health professionals are being trained, what research infrastructure exists, and how they access the literature, how do they read Circulation, how do they read other journals, and are there collaborative ideas that they've developed to their neighbors to the East and West that may be could be broadened? Are there unmet needs that they've indicated similar or different from those in Western Europe, South America? We've got about seven or eight points of light that we hope to illuminate in the course of this exercise. And the prospectus that's laid out in an editorial that Joe and I collaborated on that I believe, Joe, is going to come out in early July. Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just the opposite of a formulaic, cookie cutter approach. We want to leverage the beautiful diversity of our world. The different approaches that people take to attack this scourge that is keeping a humble approach to tackle instead of the visas that is humbling bar none. There is nothing that is more globally important than the continued growth and expansion of cardiovascular disease. And importantly, we can all learn from each other. There are exciting initiatives that I've learned about in South America and in pockets of Europe and in Asia, and in the Middle East that we can all benefit from, and we want to shine a bright light on that. These pieces will be relatively short. They will be in our Frame of Reference section, so 1200 words or so, so that they are accessible so that people, you know, feel that they can carve out, you know, four minutes in their busy day to read what cardiovascular disease looks like, as Paul said, our first ones will be from Japan and India, and we plan to reach out to South America and to the Middle East, and just continue on around until over the course of the next number of years, we've touched virtually every country in the world. Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that you might be looking to focus on? Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is that in the West, in the developed world, cardiovascular disease increasingly has become a chronic disorder where more and more people, over the course of the last six years are surviving their acute coronary syndrome, their tachyarrhythmia events, and they are developing chronic disorders like heart failure, whereas in the East, it is the atherothrombotic manifestations that have both MI and stroke that are expanding rapidly. So given that the face of cardiovascular disease is different in different parts of the world, different strategies have to be leveraged to address that, and we want to learn about that. Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these papers and just reflect on the things that we're learning. Paul, did you have anything else that you wanted to add? Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes and obesity and the expanding epidemic that seems to effect some regions such as India, in the Middle East, even more than other areas, but I think this is going to be great. We're gonna have some fun and learn and exciting and hopefully it will catalyze better care and better thinking around this enemy that we all face. Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited as I am about this. You have to read the editorial. It's a fantastic read. Thanks for joining us today. And don't forget to tune in again next week.

Circulation Fellows-in-Training June 2018

26 juni 2018 | 24 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. And I am joined today by our Editor of Digital Strategies, Dr. Amit Khera from UT Southwestern, as well as three wonderful fellows in training. Yes, you've guessed it, it's our FIT Podcast and I'm just so thrilled to be here again.

Dr Carolyn Lam: Amit, any words of introduction before we start?

Dr Amit Khera: Thank you Carolyn. I think, for both of us, this is our favorite podcast, or two podcasts, that we do, a year. It reminds us of how bright the future is, with superb cardiology fellows in training around the country, and it really is a testament to how important we find fellows in training, to Circulation, to our mission, and how much we learn from them.

So we're really excited about this group, today, and thank them for participating.

Dr Carolyn Lam: Absolutely. So, why don't we start, now, with ladies first? Let's hear from Dr. Elizabeth Hill.

Dr Elizabeth Hill: Thanks for having me today. My name is Beth Hill, and I'm a first year cardiology fellow at Scripps Clinic, in La Jolla, California. I've a particular interest in sports and exercise cardiology, which brings me to the article I picked today about sudden cardiac death and hypertrophic cardiomyopathy, hot topics in the field and in general.

And so, today, I'm excited to be discussing the EVIDENCE HCM study, looking at the hypertrophic cardiomyopathy of risk, sudden cardiac death model.

Dr Carolyn Lam: Nice. So tell us a little bit about what really struck you about the paper and, perhaps, how that may apply to where you practice?

Dr Elizabeth Hill: What I really liked about the paper is that, when I see patients in clinic with hypertrophic cardiomyopathy, prior to having this risk stratification tool, we didn't really have a way to objectively risk stratify our patients with hypertrophic cardiomyopathy and really guide the discussion about who may benefit from an implantable cardiac defibrillator or ICD. And so, I've been using this a little bit with my patients. While it hasn't made it fully into the AHA or ACC guidelines yet, I'm using it as a tool.

Dr Carolyn Lam: Great. You know, these are seven risk factors, isn't it? I'm always struck by that survival curve that really shows that those with a predicted 6% risk stand out. Is that what you use, as well, to guide your decisions?

Dr Elizabeth Hill: Yeah. I think, as the authors noted, they picked this somewhat arbitrarily so that they could study their risk model. But I think what they found is that it seemed to fit well with the observed high risk of sudden cardiac death cohort, such that those that were seen and observed, about 9% risk of sudden cardiac death in five years, were in that greater than 6% cohort. So I think that population should receive ICDs, and that is one factor that I used to guide my decision making as well.

Dr Amit Khera: Beth, this sort of interest that you've had for a long time, in sports cardiology, I've noted you've done some prior work in EKG screening and other screenings. In terms of this article specifically, as you pointed out, this is a really helpful tool because I still remember back when I was a fellow in training, there was, sort of, this thought that everyone was high risk with hypertrophic cardiomyopathy, and I think we realized that's not true at all. The overall incidence of sudden death was only 2.4% in this cohort.

The question I have for you, in terms of application, is, as Carolyn pointed out, these are reasonably simple variables, but as we sometimes are now using cardiac MRI and genetics and other more advanced tools, where do you think they fit in, in the current paradigm, since this is a bit of a more simplistic score?

Dr Elizabeth Hill: The seven risk factors they put into this tool were noted to be independently associated with an increased risk of sudden cardiac death, and those are well known factors, entricular tachycardia, maximum wall thickness. But I really do think that other factors will come into play soon and are part of my discussion, and colleagues' discussions, including the late gadolinium enhancement on MRI, genetic factors, and I really think this may be a place for tools like machine learning. These authors, O'Mahoney and colleagues, they really did, kind of a tour-de-force, going back to the 1970s, but there is still a decent amount of data missing. So maybe we can partner with the machines and help them go back into these records, a little bit more effortlessly, and look at genetics, maybe some wearable device data, and really refine our risk stratification tool moving forward. But that's definitely something I use in risk stratification in some of my intermediate risk patients.

Dr Amit Khera: Those are great points. I think your point about machine learning and novel algorithms will definitely take foot in the future.

Maybe a follow-up, again, given your background interest, I think it's a trade-off where we're trying to, of course, avoid sudden death, but you also don't want to overtreat. Especially, when you think about athletes getting ICDs and how that changes, or anyone, for that matter, about maybe telling someone they're at high risk, or giving them an ICD when perhaps they don't need it. I guess that comes to, what's the threshold? Here they use 6%, but that ends up being a bit arbitrary, in terms of what threshold we use. And how do we decide, when we talk to our patients, about what threshold's a right threshold to apply an ICD?

Dr Elizabeth Hill: Yeah. That's a great question. Like you mentioned, these devices come with inherent risks, such as unnecessary shocks, increased risks for infection, and sometimes there's restrictions with athletic sport, although that's been changing recently.

But, I think that's where the shared decision-making process comes into play, where you put current data on the table with the patients and, perhaps, their families as well, and have a risk-benefit discussion. Perhaps gather a little bit more data about the patient, maybe follow them over time, but I guess I wouldn't jump to put an ICD in, in every patient and, especially, the lower-risk cohort. And what number that is, I'm not quite sure. Here they say maybe less than 4%, but, again, somewhat arbitrary, I think.

Dr Carolyn Lam: Thanks Beth. I mean, as Amit said, it's just so inspiring to see how the papers are being used in practice. Really loved those perspectives.

Now, from sunny San Diego all the way to snowy New Zealand. We have Dr. Mesfer Alfadhel. And Mesfer, tell us a little bit about yourself, and the paper that you've chosen?

Dr Mesfer Alfadhel: Thank you very much. I'm thrilled to be part of this podcast. I'm a second-year cardiology fellow-in-training at the Needham Hospital, in Needham City, New Zealand, where it's snowing at the moment. I'm also a clinical lecturer at the University of Otago School of Medicine. I do have great interest in general cardiology, as the rest of my colleagues, but also am passionate about interventional cardiology and structural heart disease.

The paper I've chosen is really quite relevant to everyone in cardiology, and perhaps extends to other colleagues in other health professions impacted by automated external defibrillator use on survival and functional outcomes in shockable observed public cardiac arrest. The aim of the study was to determine the association of bystander automated external defibrillator use, the survival and function of outcomes in shockable observed out of hospital cardiac arrests. The study was from 2011 to 2015 and the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at nine regional centers, six in the United States and three in Canada.

They also found that among nearly 50,000 out of hospital cardiac arrests, 8% were observed public out of hospital cardiac arrest, of which 61% were shockable. Overall, a remarkable one in five of shockable observed public out of hospital cardiac arrest were bystander shocked. Now the bystander automated external defibrillator observed, shockable observed public out of hospital arrests were associated with increased odds of survival and full or near full functional recovery almost 2.6 and 2.7 odds ratio than when compared to emergency medical service defibrillation. What's also interesting is that the longer the wait for the emergency services, the higher the benefits from a bystander observed shock.

Dr Carolyn Lam: You know, Mesfer, I appreciate that you chose this one as well. What struck out to me immediately was that more than 60% of out of hospital cardiac arrests were shockable. And when we think about the number of lives that could potentially be saved, therefore, that's quite astounding, isn't it? But can I ask you something? So these are in the US and Canada, how applicable do you think this is to New Zealand?

Dr Mesfer Alfadhel: We do have a small population, just over four million. The number of cardiac arrests here is around 2,000 out of hospital cardiac arrests. And I think probably half of them in the latest reports were shockable. The emergency response time in the urban areas is around six minutes, which I think is acceptable, but we have about 20% of population living in rural areas. And the emergency response time exceeds 10 minutes almost all the time. I think that probably a group that we need to direct intervention to in New Zealand.

Dr Amit Khera: It's really an important article. I should say that June for the American Heart Association is AED and CPR month so great choice to remind us of the value of these and especially, the one thing that was amazing, obviously this is an observational study, but the absolute change, not relative, was about 14% meaningful recovery and so that's quite impressive in terms of the number needed to treat if you will. Maybe an adjunct to Carolyn's question is, when we think about strategies to enhance bystander AED use for strategies, essentially get the AED there faster. As you know if the EMT time was not delayed it wasn't necessarily better for the bystander.

We had a paper in Circ sometime last year looking at drones and then also geocoding and other people in some countries have looked at apps where you essentially can train a group of people and then they can be texted for a sudden cardiac arrest in their area. I'm curious about any creative things, there's always training and AEDs, I think in this place it was public areas in industry, but what do you think are some creative things or things that we need to be doing to help enhance the ability for bystander or early AED use.

Dr Mesfer Alfadhel: I think this is one area in medicine in general that where technology is really going to advance how we deal with this problem. There's an app that's available, it was launched in the UK a few years ago and it’s become available in New Zealand in the last two weeks called, the Good SAM. SAM stands for smartphone activated medics. And it's become available in New Zealand two weeks ago and I downloaded it and still yet wait for it to be activated. And the way it works is you can activate a medical emergency using the app and it dials the emergency response but what it also does is it activates the nearest three people with CPR training nearest to you and it tells you how far they are from the emergency. Now if you don't have the app and you call 911 or the equivalent, the operator can activate it to the nearby personnel who have that experience. And I think it's going to reduce the time markedly.

Now the other end of the question where some of what strategies could be used I think we had a good report from Denmark where they made changes in 2007 in Denmark and then followed by the rest of the country in 2010 where they made CPR or resuscitation education as compulsory at school but also when getting a driving license they made courses available for free that increased the number of defibrillators available in public places and they shared that information with public. They’ve redone, audited their work, and compared to prior to intervention prior to 2007 and after that and they found an increase number of using the AEDs increased from somewhere around 2% to 15%, which is really encouraging. I think we are following Denmark in that regard probably at slower rate.

Dr Amit Khera: Thank you those are excellent insights.

Dr Carolyn Lam: Amit, don't you see that I just love learning from these fellows during these podcasts. We should do more of these. This is awesome.

Dr Amit Khera: I completely agree.

Dr Carolyn Lam: Thank you Mesfer, enjoy the skiing. But now from snowy New Zealand we're going all the way to Nashville Tennessee. Welcome Dr. Vineet Agrawal. So tell us a bit about yourself and your paper.

Dr Mesfer Alfadhel: So my name is Vineet Agrawal. I'm a second-year cardiology fellow at the Vanderbilt University Medical Center. My background is as a physician scientist and as a general cardiologist. My long-term goals are in understanding mechanisms underlying heart failure with preserved ejection fraction.

With that in mind I was really taken by an article that was recently by Margaret Redfield's group from the Mayo Clinic in Circulation, titled “Global Pulmonary Vascular Remodeling and Pulmonary Hypertension Associated with Heart Failure and Preserved or Reduced Ejection Fraction.” I found this article to be a very interesting, hypothesis-generating article.

In a nutshell what they did was they took an autopsy cohort of patients in the Mayo Registry and those who had heart failure with both preserved and reduced ejection fraction, normal controls, and those who had a primary pulmonary venous occlusive disease, and looked at the lung specimens of these patients. And interestingly what they found was there was a significant amount of pulmonary venous remodeling that had occurred in patients who had both preserved and reduced ejection fraction. This correlated not only with their right heart cath findings, so those who had elevated pulmonary pressures and elevated transpulmonary gradients, but also differed from the primary pulmonary venous occlusive disease in the sense that the histologic appearance of these vessels was quite different.

And while as an autopsy study this is not necessarily an article that would immediately change practice, what I think it does do though is it forces us to think about these conditions in a different context and particularly with an eye towards future therapeutics. Heart failure with preserved EF as a disease, as I'm sure we all know, is sorely missing therapies that could alter the disease progression and potentially even alter mortality in these patients. And this article in my opinion really sheds light on at least anatomically a new location for us to think about as a therapeutic target when we try to better understand this disease and find therapies for these patients.

Dr Carolyn Lam: Vineet, can I just say you're singing to the choir here. I'm such a fan of this work as well for obvious reasons. But hey, could I ask you, in your clinical practice, do you see a lot of these patients with HFpEF and pulmonary hypertension and wonder how to treat them? And along those lines, how has this paper helped you think about these patients more?

Dr Mesfer Alfadhel: I would say when I first started residency as a medical student this was not necessarily a condition that was really something that I had learned much about or felt like I had been exposed to; however, as a resident I felt like most of the patients, or at least half of the patients, I was seeing with heart failure had a component of diastolic heart failure or they had a preserved EF but very symptomatic from the standpoint of heart failure. And I struggled to treat them, particularly in some part due to the fact that many of the risk factors that contribute to HFpEF, diabetes, uncontrolled hypertension, obesity, are chronic problems that are difficult to manage as a clinician regardless.

And second because I feel that there just weren't any data to support any treatments that we were pursuing at the time and so we would try and apply what we had learned in other types of heart failure to these patients with limited results. If I could talk about what I think this article may change in terms of my practice today, one thing that we've always thought about in terms of pulmonary vascular remodeling in heart failure is that it's just a passive process that as fluid builds up you back up into the lungs and as the fluid builds up and backs up into the lungs you get remodeling.

I think one thing that this article shows is that it may actually be a bidirectional process, which would suggest that perhaps we may need to reconsider looking at pulmonary-specific therapies in this population. But more importantly I think it does confirm that chronic elevating filling pressures do have an effect and a deleterious effect on the pulmonary vasculature. Particularly when you look at other trials such as the CardioMEMS trial, the CHAMPION trial in which the data pretty convincingly showed that as clinicians we don't do the best job of reducing left-sided filling pressures in our patients with heart failure as much as we think we do. This article really drives home the point to me that I really need to make sure that when I see these patients that I'm doing everything I can to reduce their left-sided filling pressures because the consequences of not doing so can affect the lungs, which can then in turn affect the heart as well.

Dr Carolyn Lam: Vineet, that's really words of wisdom. Couldn't agree more. And these are the first sort of autopsy, histological evidence that we have, which is so important. I think if I could just add a couple of perspectives too, it makes me think about making sure that I rule out PVOD in these patients sometimes. We now keep thinking about HFpEF we forget that we need to also rule out PVOD and the other thing much as we now think about not just the filling pressures but the remodeling it's good to note that they found it more in the venous than the arterial system, which also comes therefore with a warning message that we can't just extrapolate I suppose all the PAH therapies that we know about. What do you think about that?

Dr Mesfer Alfadhel: I absolutely agree with that. It's really interesting that all of our therapies from heart failure standpoint and from a PAH standpoint have focused on the myocardium, the neural hormonal cascade, and then the arterials. The pulmonary main artery and arterials. I don't think anyone really understands the biology of pulmonary veins and yet they're actually a pretty significant part of our everyday practice in cardiology. Pulmonary veins are thought to be the source of atrial fibrillation. We look at pulmonary vein inflow when we evaluate patients with echoes. And yet we understand so little about the biology and the mechanisms by which pulmonary veins are affected in both diseased and healthy patients.

I think this article for that reason raises a number of very interesting questions and may potentially change the way we think about these patients.

Dr Carolyn Lam: I keep learning, Amit, this is awesome. I could go on forever so you better stop me.

Dr Amit Khera: I should probably just be a fly on the wall. You must know Carolyn is a HFpEF, HFrEF aficionado and you guys should have a side call for another hour after this. But I do have one, maybe orthogonal question which is, it's interesting because if you look at how insights were made, they're made off areas I would argue at least that we don't, modern environment uses much which is the autopsy and probably to a large degree hemodynamics as much as probably in the old days although that's changing. I'm curious in a fellowship training program your exposure to autopsy and kind of current in-depth hemodynamic-type training, what's your experience?

Dr Mesfer Alfadhel: Our experience with looking at pathological slides, getting under the microscope, seeing tissue first hand, is somewhat limited in our fellowship training program. I would say in certain subspecialties like our heart failure, advanced heart failure subspecialties we do get a chance to see more myocardial biopsy specimens, but I think increasingly the focus has been on noninvasive methods by which we can assess some of these same things that we used to do, use the microscope for. Invasive hemodynamics I think similarly we get a lot of experience in terms of spending time in the cath lab but I do kind of wonder if we don't have the same in-depth training that we used to have in understanding all the nuances of hemodynamics that used to exist in the past.

Certainly, I think that while that's partially a reflection of the way and the direction in which medicine is heading, there is a little bit that's potentially lost there. That said, while we have the benefit of manuscripts like this that does do in-depth hemodynamics and looks at autopsy samples from a clinical standpoint, if we were to ever try and understand this in a larger population I think we would be required to try and find a way to noninvasively or maybe through potentially invasive hemodynamics better study this in live patients.

Dr Amit Khera: Appreciate that answer and I'm just for all of you, this has been outstanding. You all have served as incredible expert discussants. I know Carolyn already said it multiple times but we've learned a ton about each of these articles and great to see how they come alive and are used in practice and how they're applied in your own thinking and specifically as fellows in training with these have meant to you. We thank you all for joining us and it's really been a fantastic experience.

Dr Carolyn Lam: Amit, I can only echo your thanks and thank you listeners for joining us today. Fellows out there you are so important to us. Please, please apply to join us on the next FIT podcast as you can see it's really fun.

Don't forget to join us again next week.

Circulation June 19, 2018 Issue 24

19 juni 2018 | 17 min

Dr Carolyn Lam: Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue is so special. It is an autopsy issue. I think it's actually the first of its kind in the history of Circulation. I am so pleased to have with me today Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center, who's the content editor for Pathology for Circulation and the guest editor for this entire autopsy issue. Welcome, Jeff.

Dr Jeffrey Saffitz: Thank you.

Dr Carolyn Lam: We also have Dr Lee Goldman from Columbia University Medical Center who wrote a beautiful perspective piece on autopsy. Thank you and welcome, Lee.

Dr Lee Goldman: Morning.

Dr Carolyn Lam: Jeff, could you start us off? I mean, an autopsy issue. How in the world did this come about?

Dr Jeffrey Saffitz: I think it really began by coincidence. The journal received submissions from several authors, each involving studies of autopsies, and the editors approached me and asked if we might consider grouping them together in a special issue focused on the role of the autopsy and cardiovascular medicine. I thought that would be a very interesting idea and this evolved into actually something much greater. Two additional papers came in focusing on the autopsy and I think looking at these papers in the aggregate, they represent what we can now consider to be the contemporary utility of the autopsy in understanding the way cardiovascular disease works. So I was particularly pleased that the editors agreed to group these papers into a single issue focused on the autopsy. We were really delighted that Lee Goldman agreed to write a perspective. He has had a longstanding history of studying the role of the autopsy and I hope the readers will find this to be a really interesting and useful issue which will, I hope, chart the course for future discovery.

Dr Carolyn Lam: Just listening to you, I love the way you say it's a contemporary look at autopsy. I mean, we covered things like molecular genetic, proteomic, autopsies, even like electronic autopsies using device. That's really cool. Lee, thank you again for sharing your time and incredible perspectives with us. The long history of autopsy. Do you think it's still necessary now?

Dr Lee Goldman: Maybe give some perspective. I first got involved in this a number of decades ago, when as a junior faculty member, I was assigned to be on the medical audit committee of the hospital where I saw patients as a cardiologist. And two of the senior people in the committee got into a debate about whether autopsies were still important given the advent of CT scans and other modern diagnostic technology. And to listen to them debate for 15 or 20 minutes, I finally had the temerity to pipe in and say we can actually study this, and so we did. We looked at autopsies in three different decades: 1960, 1970, 1980, and much to everyone's surprise, I think found, A. that the rate of which autopsies found diagnoses that doctors had missed and for which treatment would almost certainly have prolonged life was about 10 percent, and it was 10 percent, 1960, 10 percent, 1970, 10 percent, 1980.

But the difference was that doctors were missing different diagnoses. The things that got missed in 1960, and where autopsies showed there were being missed led to better diagnostic approaches and those things were rarely missed in 1980. But since people stayed alive longer, they got new things that we didn't really know much about in 1960. A big difference, fewer people missed heart attacks, pulmonary emboli, and things of that sort, but far more people had missed infections, especially fungal infections that were complication of multiple antibiotics or immunosuppressive therapies.

And so, as I followed this in 1980, if you will, to now, 2018, we find this gets recapitulated over and over again. Medicine moves forward, things we used to miss, we no longer miss, but people still die, and they still die from things that we don't always diagnose. We've done statistical analyses to show that probably the rate of misdiagnosis is going down a little bit, but it's still substantial and we still estimate that thousands of people each year die in the U.S. from things that are not what the doctors thought they had, and if that diagnosis had been made, the patient would have lived longer.

Dr Carolyn Lam: Lee, I just love that perspective. I have to say, it's really humbling. I mean, 1960s and so on would predate me as well, so I'm really humbled, and I love that reminder. Jeff, in fact, quite a number of our papers illustrate exactly what Lee said. We have four papers just dealing with sudden cardiac death, and that is still what diagnosis was struggled with. Could you tell us a little bit more about those?

Dr Jeffrey Saffitz: Yes, of course. I think we all recognize that sudden death remains a huge public health issue. We also realize that most people who die suddenly and unexpectedly don't do so in the hospital when they're being followed and monitored; rather, they die out in the community, and in many cases, these are individuals in whom major risk for coronary disease or other potentially lethal cardiovascular conditions was really not known. So I think it remains a major public health issue, and we still have a great deal to learn. So perhaps it's not surprising that four of the five papers involved autopsy studies of sudden death victims of individuals who died out in the community. A couple of them focused on sudden death in young people.

We know that these individuals often will have familial diseases, and the autopsy has been one mechanism for studying these individuals, so one of the papers from Michael Ackerman at Mayo Clinic, advanced the concept that they started many years ago, the so-called molecular autopsy in which they apply a whole exome sequencing in cases of sudden unexpected death in young people defined here as age under 40, and they identified some rare variants which were likely to be of potential pathogenic significance in sudden death. A related paper from Junttila et al in Finland looks at the finding of myocardial fibrosis in young victims of sudden death. They identified several cases in which that was the only structural change in the myocardium, and when they applied next gen sequencing, the identified variance that we typically associate with the familial non-ischemic cardiomyopathies, arrhythmogenic, dilated, and hypertrophic cardiomyopathy. But the key insight here is that we traditionally think of these diseases as having rather characteristic structural changes which we can recognize at autopsy. What they showed is that those structural changes might be limited to nothing more than some fibrosis. And so the key here is that this expands our potential opportunity to recognize these familial cardiomyopathies, and the overarching idea is we use the autopsy to serve the living. This is a way to gain information at autopsy that we can then use to help family members and other individuals by virtue of the insights gained at autopsy.

Dr Lee Goldman: When we did the estimates in my editorial, and I estimated that roughly 28,000 people die each year in America with diagnoses that doctors missed and for which treatment would have been different if they hadn't missed it, that's really based on, I'll call traditional autopsy methods, which are anatomical, include microscopic evaluation, include culture, but it's not historically included genetic testing. I believe, as these articles show, that the advent of genetic testing, which you could argue could have been done while the patient was alive, but we're not quite there yet in terms of testing everyone's genome, now help you autopsies find even more things that might've been missed. And as you just heard, also can have important information for the family. So, one of the issues you often get into in autopsies is what's in it for the family, and one of the problems here is that the pathologists don't get paid. For the family members, it's mostly an aggravation. The doctors are worried they're going to get sued if something that gets found. And so, to make this work you need to bring in some incentives. Doctors not getting sued if they find things because they should get credit for trying to learn more, some way to reimburse reasonably pathologists and hospitals who do the autopsies, and the understanding of family members that they not only will perhaps be more reassured about what happens to the loved one, but also may learn things that will affect their future, because certainly, these cardiomyopathies, instead of them being diagnosed, are familial and oftentimes will lead to testing and hopefully interventions in family members that'll be to their benefit.

Dr Carolyn Lam: Lee, what great comments about bringing this into the clinical perspective and I just love what you said, Jeff, about autopsy for the living. That is just a quotable quote. That's so cool. I noticed that you did ask Dr Judge to write an editorial specifically about bringing autopsies into the molecular genetic era. So I just want to encourage all our listeners to make sure you read that as well. But Jeff, back to you about the other two papers.

Dr Jeffrey Saffitz: Well, I think one that I found particularly significant is this idea that nowadays, patients come to autopsy with implantable cardiac electronic devices, and the point of this paper is that interrogation of these devices postmortem can provide really important information about the cause and timing of those deaths. I think the reality is that most pathologists who do these autopsies are entirely unprepared or ill equipped to do such interrogations, and so I think the point of this paper is simply to encourage pathologists who do these autopsies to develop partnerships and relationships with cardiologists who are able to get this type of information from these devices. And again, it not only provides information about what happened to that one individual and what the death was all about, but it provides important information to the family and potentially information that allows the family to recognize particular risks that might impact the living members. So I thought this was just another really interesting example of how information that is potentially available at autopsy may not be fully utilized, and I hope that this paper will have an impact in that regard.

Dr Carolyn Lam: That's great. Lee, did you have any perspectives on devices and its role in autopsy now?

Dr Lee Goldman: I guess that the point that I would just reinforce would be that diagnostic technologies, including the ability to monitor someone's heart rate, have helped us diagnose things that were missed in previous eras, but medicine is always pushing the frontier forward, and as long as we develop new therapies, develop new devices, there'll be new things to learn. I want to make one other point about what I'll call overconfidence in diagnoses. The published statistics for the accuracy of most diagnostic tests are based on what doctors think the diagnosis ends up being, not the autopsy, which is the ultimate gold standard. So, if you actually go through some not-so-complicated arithmetic, you'll find that many of the tests that we think are almost perfect at finding things really aren't because the people who die with those things found that autopsies that the test missed. There's something called a virtuous circle, there's also a vicious cycle. There's a bit of a vicious cycle here that if you don't do autopsies to be sure you aren't missing things, you become overconfident in the tests that you think are finding them, and therefore think you already know everything and don't need to do an autopsy. To me, in some ways, that's the most perverse result of the plummeting autopsy rate, which, by the way, can be linked directly to changes in how hospitals get accredited, that in prior years there was a minimal autopsy rate required for accreditation. When that was removed, not surprisingly, autopsy rates plummeted, and now, most autopsies done in the US are not done in hospitals because doctors aren't sure what's going on. They've done by medical examiners as part of the laws for autopsies least being considered and people who die without having had a medical attention to some degree.

Dr Jeffrey Saffitz: You are exactly right on all of these points. I'll just say this is the point of one of the other papers from Tseng et al. This was a prospective autopsy study of sudden death in the city and county of San Francisco, and what they showed here is that only about half of the deaths that were considered to be sudden cardiac deaths as defined by the conventional criteria actually turned out to be deaths due to a rhythmic disorder. So Lee's point is exactly right. Doctors think they know a lot of things, but they're not always right about that, and the autopsy is probably one of the best ways to bring some quality control to this, and to really provide, I think, objective data that often is the case flies in the face of what the previous thinking was, and I think this paper in this issue of Circulation really brings that point home very clearly.

Dr Carolyn Lam: Yikes. OK, so here I am, I practice in Asia, and I think the autopsy rates are even lower, so this is a great wake up call for me just listening. Let's switch gears a little bit. How about the paper by Dr Herrington? Now this goes to a proteomic bisection almost of maybe preclinical disease and atherosclerosis. Would you like to comment on that on, Jeff?

Dr Jeffrey Saffitz: In the perspective that I wrote with Gaetano Thiene, in addition to looking at the history of the autopsy, we looked to the future and just considered briefly what role will the autopsy play going forward, and I think the paper by Herrington is a great example of how we can use the autopsy to learn so much more about the way human disease works. The basic idea here is that something like coronary artery disease or atherosclerosis, we think of as being a disease that only involves the blood vessels, and we tend not to recognize it until it is rather advanced and clinically manifest, but we recognize that these diseases begin decades before they become clinically manifest. We really don't know how to identify the earliest antecedents, and without knowing that we really, I think, very much limit our ability to identify the disease way early before it becomes clinically manifest, and then be able to practice preventive measures and intervene to prevent the disease from occurring.

So, what this paper showed is that it's an application of high-throughput proteomics looking at coronary artery and aortic samples obtained at autopsy, and these authors identified particular changes in proteins that they then were able to show in a prospective independent clinical cohort were able to predict the development of coronary artery disease. So I think going forward, we are going to redefine our understanding of human disease by learning about its earliest expressions and its full systemic distribution, and in doing so, we'll be much better prepared to diagnose earlier and intervene and prevent disease. So I think this was a great example of how the autopsy can help in that effort.

Dr Carolyn Lam: I feel like we are going full circle in history and going back to learn about how to go forward. I don't know if I expressed that well, but I am just in awe of what I've learned from both of you. Thank you so much, Jeff, for putting together this amazing issue, and thank you so much, Lee, for sharing your perspectives. Thank you, audience, for joining us this week. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

Circulation June 12, 2018 Issue

11 juni 2018 | 23 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today's feature discussion revolves around important hemodynamic and echo data from the reprise three trial, comparing the lotus and core valve transcatheter aortic valves in patients with high surgical risk. Can't wait? Well it's coming right up after these summaries.

The first original paper this week provide experimental data showing that the endothelium controls cardiomyocyte metabolism and function via notch signaling. Corresponding author, Dr. Fischer, from German Cancer Research Center in Heidelberg, Germany, and colleagues, studied fatty acid transport in cultured endothelial cells and transgenic mice with endothelial specific notch inhibition, or wild type mice treated with neutralizing antibodies against the Notch ligand. They showed that notch signaling in the endothelium controlled blood vessel formation and fatty acid transport in the adult mouse heart. Inhibition of Notch signaling in the vasculature led to expansion of the cardiac vasculature and impairment of fatty acid transport to cardiomyocytes. This resulted in metabolic reprogramming and heart failure.

Together, these data provide compelling evidence for a central role of Notch signaling at the coordination of nutrient transport processes in the heart. These findings help to explain how pharmacological inhibition of Notch signaling, for example, in oncology could lead to heart failure. The findings also help to identify the signals and molecules involved in endothelial transport capacity and show how these could offer new targets for the treatment of heart failure.

The next paper raises the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure. Ischemic injury to the myocardium is known to trigger a robust, inflammatory response, which is an integral part of the healing process, although much effort has been directed at tempering the inflammatory response in hopes of achieving clinical gain. Major efforts have focused on individual cytokines, the complement cascade, and antibodies to adhesion molecules preventing leukocyte invasion.

In contrast, relatively little effort has focused on macrophages. Although macrophage transformation is known to be crucial to myocardial repair, the events governing this transformation are poorly understood. In today's paper, co-corresponding authors of the trial in Hill, from UT Southwestern Medical Center, performed an elegant series of experiments and showed that release of DNA from necrotic tissue during myocardial infarction, triggered in macrophages a recently described innate immune response known as the GMP-AMP synthase-stimulator of interferon genes pathway or cGAS-STING pathway.

This response in turn promoted an inflammatory macrophage phenotype. Suppression of the pathway promoted emergence of reparative macrophages, thereby mitigating pathological ventricular remodeling. These results therefore reveal for the first time, that the cytosolic DNA receptor, GMP-AMP synthase, functions during cardio ischemia as a pattern recognition receptor in the sterile immune response.

Furthermore, this pathway governs macrophage transformation, thereby regulating post injury cardiac repair. As modulators of this pathway are currently in clinical use, these findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.

Cigarette smoking is a well-known risk factor for atherosclerotic cardiovascular disease. However, less is known about the risk for heart failure. First author, Dr. Kamimura, corresponding author, Dr. Hall, from University of Mississippi Medical Center, and their colleagues investigated 4129 black participants without a history of heart failure or coronary heart disease at baseline in the Jackson Heart Study.

They examined the relationship between cigarette smoking and left ventricular strength and function by using cardiac magnetic resonance imaging. They found that current cigarette smoking status, smoking intensity in terms of cigarettes per day, and smoking burden in pack-years, were independently associated with higher left ventricular mass, lower left ventricular strain, higher brain natriuretic peptides, higher BNP levels and higher risk of incident heart failure hospitalization in blacks.

These relationships were significant after adjustment for coronary heart disease, suggesting mechanisms beyond atherosclerosis may contribute myocardial dysfunction and increased risk of heart failure in smokers. In summary, these findings suggest that smoking is associated with structural and functional left ventricular abnormalities that lead to heart failure in blacks and that smoking cessation should be encouraged in those with risk factors for heart failure.

What happens to the risk modifying effects of exercise in individuals with increased genetic risk of cardiovascular disease. Drs. Tikkanen, Gustafsson, and Ingelsson from Stanford University School of Medicine performed the study in about 500,000 individuals from the UK Biobank and reported and compared the association's objective and subjective measures of fitness and physical activity with prospective cardiovascular disease events and all-cause death.

They found consistent and robust inverse association, particularly between objective measures of fitness and physical activity and six cardiovascular outcomes and total mortality. Using genetic risk scores for coronary heart disease and atrial fibrillation, they showed that these inverse associations were present in each genetic risk category, suggesting that elevated genetic risk for these diseases can be compensated for by exercise.

The knowledge that lifestyle choices have substantial effects on disease risk could encourage individuals to initiate a healthier lifestyle to reduce their overall risk. In the longer term, identifying subgroup space on genetic risk that benefit most from lifestyle interventions, could help personalize preventive strategies for chronic diseases.

Well, that wraps it up for our summaries, now for our feature discussion.

Today's featured paper deals with transcatheter aortic valve replacement, which we are all going to recognize has rapidly emerged as a treatment of choice in inoperable patients and, it's a reasonable alternative to surgical aortic valve replacement in high- and intermediate-surgical-risk patients. However, the success of this technology is in large part due to the rigor with which quantitative echocardiography by core laboratories has been used to assess the native and prosthetic aortic valve function.

Today's feature paper gives us such important data from the REPRISE III trial, which compares the Lotus and the CoreValve transcatheter aortic valve in patients with high and extreme surgical risk. I'm so pleased to have the corresponding author, Dr. Federico Asch, from MedStar Washington Hospital Center, as well as our associate editor, Dr. Dharam Kumbhani from UT Southwestern. All right Federico, please help me here, so as a noninterventionist and a person who doesn't deal with all these different types of valves every day, please tell us what was the motivation of looking so closely at the echocardiographic data from REPRISE, because the REPRISE III trial results were already published?

Dr Federico Asch: The most interesting aspect of this analysis is really that there is a very methodic, blinded comparison of two different valves. The valve that is being tested and that the reason why Boston Scientific has sponsored the study, is the Lotus valve, the Lotus System is, if you want, a new valve that is not clinically approved in the United States yet, that basically, it's a completely repositionable bovine pericardial valve that comes in different sizes.

The three sizes that were tested in here are what we would call the small, or 23 millimeters, the medium, 25 millimeters, and the large, 27 millimeters. Each patient, at the moment of randomization, or at the moment of inclusion, were randomized to the small, medium, or large Lotus valve vs the clinically approved CoreValve, which is a Medtronic product. Obviously, this is taken as the control group because this is one of the valves that is widely clinically available nowadays in the United States and worldwide.

This is exactly the motivation here. On one side, to prove whether this valve was as good as CoreValve or not and whether it was as safe as the CoreValve as well, and that, the study was about. Every three patients that were randomized, two were randomized to the new valve, the Lotus, and one was randomized to the CoreValve.

An important note to make here is because the control arm included clinically available valves at the beginning of the study, the previous generation of CoreValve was used and then about halfway through the trial, the Evolut valve was the one being used, so there's two different valves on the CoreValve system that were tested in this trial while Lotus was a single earlier generation valve.

We focus here on the hemodynamic implications, that meaning, the gradients and the degree, if you want, of obstruction that these valves could have over time, and the amount of regurgitation that these two valves and how they compare to each other.

Dr Carolyn Lam: That's great. Could I ask if you had any hypothesis going in, because as I recall, the Lotus valve actually met the non-inferiority comparison, but it did have significantly higher rates of new pacemaker implantation and valve thrombosis, right? So, was that perhaps a hypothesis going in and what did you find?

Dr Federico Asch: So, the initial hypothesis of the trial overall was that this new valve was one that was designed to have less paravalvular regurgitation, which is something as you probably know, has been of significant concern in the cardiology world ever since the initial clinical trials for Tyler with Partner and CoreValves.

Patients with more significant paravalvular leak did have worse outcome over time, so, one of the main goals of this valve itself, was to prevent that paravalvular regurgitation. So, that was the initial idea behind this product I would say, not just the clinical trial and obviously, this clinical trial tried to prove that, indeed, as I mentioned before, the primary effectiveness end point was mortality, disabling stroke, and paravalvular leak, the main driver on the difference between the two valves there was indeed a much lower paravalvular regurgitation on the Lotus valve compared to CoreValve.

There was also lower stroke rate, but the most important difference was on the paravalvular aortic regurgitation. Of course, when you think of any of these devices, for them to be able to prevent paravalvular leak, they have to have some kind of skirt or cushioning around the valve, an adaptive seal, which in the case of the Lotus valve, that would prevent any flow around the stent, but one of the risks of that of course is that by trying to seal the valve, you're actually, you may be decreasing a little bit the effective orifice area, so it was actually very important to understand whether gradients with this valve were higher and whether the potential differences in the gradients did turn into any difference in clinical outcomes.

Dr Carolyn Lam: That is super clear now. What did you find?

Dr Federico Asch: I would say, the findings from a hemodynamic standpoint, we can briefly summarize them in two aspects of it. No surprise, the paravalvular leak was significantly lower for Lotus compared to CoreValve, and that was true for any of the three sizes, for the small, medium, and large size in all of them, the rate was significantly lower for Lotus. It was actually under 1% of the patients with moderate or higher paravalvular leak, as opposed to an average of 6.7% on the CoreValve, but on the other side of the spectrum, the gradients and the effective orifice area, and the dimensional index were all significantly better on the CoreValve compared to the Lotus.

The bottom line is, we have two valves that each of them has a specific strength. On one side, Lotus has less paravalvular leak. On the other hand, CoreValve has a better gradient profile than Lotus. I would say in two lines, that's the findings of this study. We did take these findings further and compared among different valve sizes and we saw that these differences were consistent at each of the valve size, so if we would compare the small Lotus with the small CoreValve or the large Lotus with CoreValve, the findings were very similar.

They were always significant, and what is important is that while there was a difference, both for paravalvular leak and for gradients and other hemodynamic parameters, the reality is that when it came to clinical outcomes, there was no significant difference among the two.

Dr Carolyn Lam: Dharam, you have to weigh in now as an interventional cardiologist, what does this mean to you.

Dr Dharam Kumbhani: First of all, Federico, congrats to you and Ted and the rest of the group. I think this is obviously a very important trial and I think this hemodynamics paper, I think definitely moves, helps understand the differences a little bit better, so I think this is a very valuable contribution. I think you said it exactly right. I think what is really interesting is that you have a significant introduction into the paravalvular leak, but yet you have, because of difference in valve design, one being annular vs the other being super annular, you have higher gradients with the Lotus valve compared with the CoreValve, so you wonder if the two differences can cancel themselves out in some way, because you don't see any difference in clinical end points at one year, and also, I guess, what we've learned from the Partner data and other CoreValve data is it would be really helpful to see how this evolves over time, whether there will be any late separation of the curves or just a long-term follow-up, whether that will still be important.

I think that is the really interesting insight that we glean from this analysis. I want to make two other points. I think the other interesting thing about the design of the Lotus valve, and probably having such a great seal for the paravalvular leak reduction and having higher radial strength, I would think, at the annulus, I suspect that that's probably also the reason why the pacemaker rate is higher with this, compared with CoreValve, so it's almost 30% in this trial. About 20%, 18% already had an existing pacemaker, so particularly I guess, as we move to lower-risk population, I think that will certainly, balancing the two and deciding probably one valve doesn't fit everybody and we may have to have strategies to figure out which may be the best valve for a given patient based on this.

The other point I'd like to make is the question about stents or valve thrombosis and I know that your group has been heavily invested in that research, because I know in the JAMA paper, there was a report of few valve thrombosis events and you also bring that home here in this hemodynamics paper. Is there anything you want to elaborate on that or any insights that you feel would be helpful for the next set of trials and next generation of the Lotus valve?

Dr Federico Asch: Yeah, you're bringing two very, very important points. Let me address the thrombosis one first. As you very well described, we have been working a lot on multiple different valves and understanding why this is happening. It's clearly something of concern. In this study in particular, we did not have data collected to detect subclinical thrombosis, which is what most of us have been talking mostly about over the last few years. The diagnosis of thrombosis here was not so clinical. These were patients that mostly, because gradients were going up, were detected. They were image ... there was one or two cases with TE and the other ones with CTs and then they were given anticoagulation and those results, and based on that is that the diagnosis of thrombosis was made. All those cases, nine cases, indeed, happen on the Lotus group. The CoreValve is one in that overall has shown to have lower rates of thrombosis in general and I'm not just talking about our own report. Our report was consistent with that.

That may be something related to the fact that it's a super annular valve and the flow through the valve may be better, if you want, but we don't know that. The rate of thrombosis, again, clinical thrombosis, in this case, for the Lotus valve was 1.5%, which is still low, but it's impossible to compare to all those new reports that are coming out because those are mostly subclinical, which is not the case here.

One could argue that if would have done CTs on every patient here at 30, 45 days, we would have found much higher rates in both valves, but we don't know that. We don't have the data to address that.

Dr Dharam Kumbhani: As I remember, almost all of them, I think seven out of eight of those reported, were in the 23 valve, right? They were not ... I think the larger valves ...

Dr Federico Asch: Exactly. There were nine cases overall, eight of them were on the small valve, on the 23 millimeters, and one was in the middle size, on the 25 millimeters. You are completely right.

Dr Dharam Kumbhani: I don't know what to make of that, but that was an interesting observation as well.

Dr Federico Asch: Yeah. It's interesting because when you look at reports of subclinical thrombosis, actually some of the reports suggest that this is more common in bigger valves than in smaller valves. Registries, I'm talking about, but that didn't seem to be the case here, but again, we need to understand the limitations. This was not a study geared towards detecting sub clinical thrombosis or thrombosis overall. These are just clinically reported cases that were analyzed thoroughly but they were triggered by some kind of clinical event, what's mostly an increase in the gradient.

That's all that I would make out of the thrombosis. I think there is definitely more that we need to learn about it. We know that both CoreValve and Lotus have been reported to have cases of thrombosis, but in general, CoreValve seems to be of all the type of devices, the one with the lowest incidents.

Dr Dharam Kumbhani: Maybe your studies will help in understanding the influence of hemodynamic profile, patient-prosthesis mismatch, to the risk of thrombosis. I think the interactions are not well understood. I think that will be very interesting going forward.

Dr Federico Asch: Exactly. And the other comment that I wanted to make, Dharam, regarding your first impression about the pacemakers and the gradients, a couple of observations that I want to make out of that, one is that the difference in gradients between Lotus and CoreValve seem to be the highest early and then over months, that difference seemed to get smaller and smaller, still significant though, even at one year, but one could argue that if, as we continue following up these patients, maybe the difference starts getting smaller and smaller to the point that to become irrelevant, but we don't know that. That is just the impression that we get at looking at the curves over time.

The pacemaker, obviously, as you can imagine, this is something that is of concern for everybody. It's a high rate, the newer Lotus generations are geared towards having lower paravalvular leak, like the head Lotus Edge and so we would expect that in the future that would be the case, but we don't know. The same way that it is important to mention that CoreValve has been addressing their initial concern, which was paravalvular leak.

I mentioned before that the control arm in this clinical trial included CoreValve classic, earlier generations from roughly half of the patients, and the paravalvular leak in that group was a little bit over 10%, while the second group, which was the Evolut R had already a much lower rate of paravalvular leak, but was still significantly higher than Lotus, but was definitely better.

I think what this points out to, is that all these devices are so early in their life, in their history, that all the efforts that each of these companies are making into fixing the specific problems that each of them have, really turn into a next generation that addresses more aggressively all these things. In the case of CoreValve, definitely the paravalvular leak is one and they are making very good progress in the care of Lotus, the permanent pacemaker is one and we expect in subsequent generations to improve as well.

Dr Carolyn Lam: It's been very enlightening for me and I'm sure for all our listeners. Thank you for joining us today listeners. Don't forget to tune in again next week.

Circulation June 5, 2018 Issue

4 juni 2018 | 20 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associated editor from the National Heart Center and Duke National University of Singapore. This week's feature paper reports results of the SWAP-4 study, which is the first study to evaluate the pharmacodynamic impact of the timing and dosing of clopidogrel administration when de-escalating from ticagrelor therapy. Extremely important take-home messages for clinicians looking after patients with coronary artery disease and a must listen to. Coming up right after these summaries.

In the first original paper this week, chondroitin sulfate, well known in the context of the monogenic disease mucopolysaccharidosis type 6 may actually represent a novel therapeutic approach for the treatment of general heart failure. First author Dr Zhao, corresponding author Dr Foo, from Genome Institute of Singapore studied changes in myocardial chondroitin sulfate in non-mucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. They found that failing human hearts display an abundant accumulation of chondroitin sulfate proteoglycans in the extracellular matrix largely localized to fibrotic regions.

The main component of chondroitin sulfate glycosaminoglycan chains in human hearts was chondroitin 4 sulfate. TNF alpha was a direct binding partner of glycosaminoglycan chains rich in chondroitin 4 sulfate. Modification of the chondroitin sulfate chain with the recombinant human arylsulfatase B, which is an FDA-approved treatment for mucopolysaccharidosis type 6 that targets chondroitin 4 sulfate, actually ended up reducing myocardial inflammation and overall fibrosis in vivo. In two independent rodent models of pathological cardiac remodeling, this recombinant human arylsulfatase B treatment prevented cardiac deterioration and improved functional recovery. Thus, targeting extracellular matrix chondroitin sulfate represents a novel therapeutic approach for the treatment of heart failure.

The next paper focuses on the subcutaneous ICD, which is an entirely subcutaneous system that does not require intra-procedural vascular access or endovascular defibrillator leads or coils. Now the subcutaneous ICD has a novel mechanism of defibrillation and is associated with an increased energy requirement for defibrillation when compared to traditional transvenous ICDs. Thus, ventricular fibrillation or VF conversion testing at the time of subcutaneous ICD implantation is a class 1 recommendation.

Yet, what is the current adherence to this recommendation? Well, today's paper addresses this question from first and corresponding author Dr. Friedman from Duke Clinical Research Institute. He and his co-authors studied first time subcutaneous ICD recipients between 2012 and 2016 in the National Cardiovascular Database Registry ICD Registry to determine the predictors of use of conversion testing, predictors of an insufficient safety margin during testing and in-hospital outcomes associated with the use of conversion testing.

Results show that use versus non-use of VF conversion testing after subcutaneous ICD implantation in the US was more related to physician preference than patient characteristics. The study also identified several patient characteristics associated with an insufficient defibrillation safety margin. That included increased body mass index, severely decreased ejection fraction, white race, and ventricular pacing on the pre-implantation ECG. Use of VF conversion testing after subcutaneous ICD implantation was not associated with a composite of in hospital complications or death. These data may inform ICD system selection and a targeted approach to conversion testing.

We know that elderly patients are at elevated risk of both ischemic and bleeding complications after an acute coronary syndrome and display higher on clopidogrel platelet reactivity as compared to younger patients. Does prasugrel at five milligrams compared to clopidogrel reduce ischemic events without increasing bleeding in the elderly? Today's paper addresses this question from corresponding from corresponding author Dr Savonitto from Manzoni Hospital Italy and his colleagues.

These authors performed a multicenter randomized open label blinded end point trial comparing a once daily maintenance dose of prasugrel five milligrams with the standard clopidogrel 75 milligrams in patients more than 74 years old with acute coronary syndrome undergoing percutaneous coronary intervention. The primary end point was a composite of mortality, myocardial infarction, disabling stroke and re-hospitalization for cardiovascular causes or bleeding within one year. Enrollment was interrupted due to futility for efficacy according to pre-specified criteria after a planned interim analysis when 1,443 patients had been enrolled with a median follow-up of 12 months.

At this point of interruption, there was no difference in the primary end point between reduced dose prasugrel and standard dose clopidogrel. The results of this Elderly ACS 2 study therefore could not show overall clinical benefit of prasugrel five milligrams versus clopidogrel in elderly ACS patients undergoing early PCI.

The final study is the first to define the cellular and molecular mechanisms of cardiac valve inflammation and fibrosis occurring in the setting of systemic inflammatory disease. First author Dr. Meier, corresponding author Dr Binstadt from University of Minnesota used T-cell receptor transgenic mice which spontaneously developed systemic auto antibody associated autoimmunity leading to fibro inflammatory mitral valve disease and arthritis.

They identified a critical population of CD301b/MGL2 expressing mononuclear phagocytes that orchestrated mitral valve inflammation and fibrosis in this mouse model. They further demonstrated an analogous cell population was present in human inflammatory cardiac valve disease. Finally, they defined key inflammation molecules that drove mitral valve disease in this model, thus providing multiple potential therapeutic targets that are required for mitral valve inflammation and fibrosis.

Dr Carolyn Lam: That wraps it up for your summaries. Now for our feature discussion.

Searching between different classes of P2Y12 inhibitors including de-escalation from ticagrelor to clopidogrel commonly occurs in clinical practice. However, what are the pharmacodynamic profiles of this strategy? Well, today's feature paper is going to provide a lot of insights. I am so pleased to have the corresponding author of the SWAP-4 study, Dr. Dominick Angiolillo from University of Florida College of Medicine Jacksonville, as well as our associate editor Dr. Gabriel Steg from Hôpital Bichat in Paris, France. Dominick, now this is SWAP-4. That means there was a SWAP 1, 2, 3. Could you just paint the background and rationale for SWAP-4 and tell us what you found?

Dr Dominick Angiolillo: We performed this study on the background of a line of research that we've been conducting over the past number of years of switching antiplatelet therapies. There's so many different types of switches that can occur and one of them is that which is defined as a de-escalation which is that from a more potent P2Y12 inhibitor to a less potent and one of those that occur frequently in clinical practice is the switching from a ticagrelor to clopidogrel and this was essentially the rationale for conducting the SWAP-4 study.

Now I want to start off with saying that the reason for doing this study is not to advocate switching because we always recommend that individuals follow guideline recommendations but we performed this study because we wanted to provide clinicians with some additional insights that if you're going to switch particularly from ticagrelor to clopidogrel, which would be the modality which is associated with, put it this way, with the smoothest transition one drug to another.

This is the rationale. What we did was do a pharmacodynamic, conduct a pharmacodynamic study taking patients who were on standard treatment with dual antiplatelet therapy aspirin and clopidogrel and they had a run-in phase with ticagrelor. And the reason why we took patients on the back part of aspirin and clopidogrel is because we then wanted to look at the effects after switching to compare it with a baseline. There have been some discussions about drug-drug interactions. And patients were randomized to either continue with treatment with ticagrelor to switch with a loading dose of clopidogrel, 600 milligrams 12 hours after last dose of ticagrelor. 24 hours after last dose of ticagrelor or directly switch with a maintenance dose. So, the randomization was into four groups.

Essentially to keep a long story short, what we observed was that when de-escalating from ticagrelor to clopidogrel we did see an increase in platelet activity obviously as expected. But the use of a loading was not able to mitigate this increase but there were no differences according to timing of administration of the loading dose clopidogrel 12 or 24 hours. We had anticipated in our study design that with the administration of the loading dose 24 hours after last maintenance dose we could have achieved a smoother transition, but this was not the case.

Nevertheless, the overall conclusions of our study are supported by the pharmacodynamic data in terms of you still achieve a better transition when you give a loading dose than without a loading dose. I was also want a little bit cautious and I think during the review process of the journal and feedback from the editors we kind of phrased in a very cautious way the suggestion for a drug-drug interaction, in fact we suggested because there are other ways to look into this phenomenon in more detailed manner. For example, doing some specific pharmacodynamic analysis which was not done in this study. Nevertheless, the take-home message from a clinical perspective remains unchanged.

Dr Carolyn Lam: Thanks so much, Dominick. That was a very important framing of the paper that you gave us at the start that this trial was not designed to try to say who should be de-escalated or not and that should be in line with the guideline recommendations and yet such an important just take-home message that if there is a need that the 600-milligram loading dose of clopidogrel should be used. You know, Gabriel, you've thought a lot about this and especially the drug-drug interaction question. What are your thoughts there?

Dr Gabriel Steg: Yeah, well first of I think this is an extraordinary, important study even though it's a pharmacodynamic study, which many clinicians might look at and then quickly read the abstract and turn the page I think this is actually one of the most interesting papers we've published in recent months. The reason for this is this is tackling a very common clinical scenario, which is having or desiring or wanting to de-escalate the intensity of platelet therapy after a PCI or ACS from a potent agent such as ticagrelor to a less potent agent such a clopidogrel. And as nicely explained in the paper, there are multiple reasons why this can occur.

A common clinical scenario is that cost is a major issue. Because of the cost patients or physicians may want to switch to clopidogrel, a generic drug as opposed to a branded drug. Another scenario which is fairly common is side effects. Either nuisance bleeding or maybe dyspnea with ticagrelor may prompt some physicians and patients to want to deescalate to clopidogrel. To a less intensive therapy which may not have dyspnea or may not cause as much nuisance bleeding. And finally, sometimes it's done on purpose because some believe that within a few weeks or months following PCI or ACS the benefits of more intensive patient therapy is less, the risk remains the same and therefore maybe we could proposedly de-escalate therapy to clopidogrel and get away with it and there have been a number of randomized studies and observational studies that suggested that this might be feasible although these studies have weaknesses. They're often open label. They're often fairly small and somewhat underpowered.

So, we don't have a definitive answer. Nevertheless, this happens on an everyday basis in most large clinical centers and we don't know exactly how to do it and what the best way to do it and I really want to credit Dominick's team for doing a rigorous series of investigations, including this one, which is the latest one but not the only one in trying to really map out how exactly we should as clinicians manipulate these agents to achieve the best safety and efficacy for our patients. And I think the message here is very clear. Yes, you can de-escalate but you have to be careful on how you do it. And I think you really need to use a loading dose, a 600-milligram loading dose of clopidogrel if you're going to deescalate from ticagrelor to clopidogrel to avoid a gap in protection that might be deleterious to patients.

That does not address all of the questions that are raised by de-escalation and as I pointed out I think outcome trial data are really of paramount importance here, but I think this really important because it has major practical implications for clinicians worldwide on how to do this. So, I think this is a great study. I really want to congratulate Dominick.

Dr Dominick Angiolillo: Thank you.

Dr Carolyn Lam: You looked at the genetic status as well. Could you tell us about your findings there?

Dr Dominick Angiolillo: We in the spirit of trying to perform the most comprehensive possible assessment we have also looked at the genetic background of our patients and in particular looking whether the presence of a loss of function allele for CYP2C19, which is involved with clopidogrel metabolism, could have affected the outcomes. And the reason why we did this there've been a lot of studies clearly showing that if you have a loss of function allele for CYP2C19 you do have higher levels of platelet reactivity. Therefore, we want to see if those carriers would have had even a greater increase in platelet reactivity. And again, we did all this in the spirit of really trying to define again this from a pharmacodynamic standpoint, if there could be any potential safety hazards with such an increase in platelet reactivity with the de-escalation.

When we did our analysis, we did not find any impact of a CYP2C19 on our data. However, I think it's important to underscore that we did not have too many patients with a loss of function allele so clearly the study was not designed or nearly closely powered to look into this assessment. So, I think that aspect does need to be interpreted with caution.

Dr Carolyn Lam: Thanks so much, Dominick. Were there perhaps caveats that clinicians listening in should pay attention to? For example, this study was conducted in stable patients with coronary artery disease. What about patients with recent acute coronary syndrome?

Dr Dominick Angiolillo: That's a great point. The reason why we conducted this study in a more stable setting was largely driven by two aspects. Well first of all, we wanted to have a run-in phase of patients switching from clopidogrel to ticagrelor to have some sort of baseline to reference to after the switch. And this would have been mostly ACS patients that would be less likely to be on clopidogrel. The second is purely a safety issue. We know that patients with acute coronary syndromes are associated with higher levels of platelet reactivity and in the context of a study where we do not know the pharmacodynamic profiles associated with de-escalation or better off we don't know the details.

And so, there was a safety consideration there which is why we did it in stable patients. But what we can say is tied with Gabriel's comment before in all the studies out there are not powered or do not have the rigor of a mega trial. Although we give our suggestions and recommendations, practical recommendations on how to switch, there is an increase in platelet reactivity and we stress in our manuscript that if you are going to switch, please try to delay this as much as possible because those increases in platelet reactivity for example, in a patient with an ACS for example, immediately after PCI, something that we probably would not want for our patients. I'm very happy actually that we conducted the study in the more stable cohort because we had less confounders. This is kind of the reason behind all this.

Dr Gabriel Steg: The last question maybe I would ask Dominick is whether he believe that results would be different if we had the patients on a maintenance therapy for longer with clopidogrel, do you believe that the risk of rebound or drug-drug interaction are the same early on after institution of therapy or later on? Is there any reason to expect a difference?

Dr Dominick Angiolillo: That's a great question. My personal opinion would be that with longer duration the platelet reactivity would have gone back down to baseline. We actually continue to study out up to around 10 days following the switch which we thought would have been sufficient time to get back to baseline and it was not the case particularly in the patients whose switch was a 75 milligram. The answer's probably yes. Probably yes. To redesign the trial again maybe having that 30-day time point as well would have been obviously of added value.

Dr Carolyn Lam: Thank you so much, Gabriel and Dominick. This has been extremely insightful. Fun as always.

You've been to Circulation on the Run. Don't forget to tune in again next week.

Circulation May 29, 2018 Issue

29 maj 2018 | 22 min

What do salty, Chinese meals, neurotransmitters, cancer, and pulmonary arterial hypertension have in common? Well, you are not going to want to miss this week's feature discussion. It's going to reveal a new therapeutic approach to pulmonary arterial hypertension that may just surprise you, coming up right after these summaries.

Do congenital heart defects signal a familial predisposition to cardiovascular disease? Well, this question was addressed in this week's first original paper from first and corresponding author, Dr. Auger, from University of Montreal Hospital Research Center in Quebec, Canada. Dr. Auger and colleagues aimed to determine whether the risk of cardiovascular disorders later in life was higher in women who had newborns with congenital heart defects. To answer the question, they studied a cohort of more than one million women who had delivered infants between 1989 and 2013 in Quebec. They showed for the first time that congenital heart defects in offspring were associated with increased risk of maternal cardiovascular morbidity later in life, including atherosclerotic disease, cardiac hospitalization, and cardiac transplantation. The association with subsequent cardiovascular morbidity risk was present for both critical and noncritical congenital heart defects. Thus, women who have given birth to offspring with congenital heart defects may benefit from early attention to traditional cardiovascular risk factors and more aggressive primary prevention strategies.

Acute myocardial infarction, or AMI, is a major cardiovascular complication of non-cardiac surgery, but what are the outcomes following perioperative AMI? This question was answered in the next paper from co-corresponding authors, Dr. Smilowitz and Berger, from New York University School of Medicine. The authors identified more than 8,000 patients who were diagnosed with AMI during hospitalization for major non-cardiac surgery using the 2014 US Nationwide Readmission Database. They found that perioperative AMI after non-cardiac surgery was associated with a high in-hospital mortality and a 19% risk of 30-day hospital readmission among survivors. The majority of hospitalizations after perioperative AMI were because of infectious, cardiovascular, or bleeding complications. Recurrent AMI occurred in 11% of patients re-hospitalized after perioperative AMI. At six months after perioperative AMI, more than 36% of patients were re-hospitalized, and the overall risk of in-hospital deaths was almost 18%. Thus, hospital readmissions and mortality among patients with perioperative AMI pose a significant burden to the healthcare system. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted.

What is the recent status of hypertension in China? Co-corresponding authors, Dr. Wang and Gao, from Fuwai Hospital, Peking Union Medical College, and Chinese Academy of Medical Sciences in China used a stratified, multistage, random sampling method to obtain a nationally representative sample of more than 450,000 residents from 31 provinces in mainland China from 2012 to 2015. The authors found that more than 23% of Chinese aged 18 years or old had hypertension, and that's equivalent to an estimated 284.5 million individuals. The prevalence of hypertension was similar in rural and urban settings, whereas three municipalities, mainly Beijing, Tianjin, and Shanghai had the highest prevalence of hypertension. Almost half the hypertensive population was aware of their hypertension. About 41% were treated, and only 15% achieved a blood pressure control. Among treated patients, barely 32% were prescribed two or more antihypertensive medications. Thus, this study revealed a considerable prevalence of hypertension in Chinese adults, as well as low awareness and control rates, representing an urgent public health message in China.

Patients with systemic sclerosis-associated pulmonary arterial hypertension have a far worse prognosis than those with idiopathic pulmonary arterial hypertension. But why is this the case? In the next paper, from co-corresponding authors, Dr. Hsu and Dr. Kass, from Johns Hopkins University School of Medicine, these authors tested whether the disparity involved underlying differences in myofilament function. They studied cardiac myocytes isolated from the right ventricular septal endomyocardial biopsies from patients with systemic sclerosis-associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, or systemic sclerosis with exertional dyspnea but without pulmonary arterial hypertension. They also looked at control right ventricular septal tissue obtained from non-diseased donor hearts.

They found that right ventricular myofilaments isolated from humans with systemic sclerosis-associated pulmonary arterial hypertension exhibited diminished contractile force and abnormal calcium sensitivity versus control myofilaments. This is in sharp contrast to the hypercontractile compensation in idiopathic pulmonary arterial hypertension. Systemic sclerosis patients with dyspnea and only exercise-induced pulmonary hypertension exhibited an intermediate right ventricular myocardial filament phenotype. These myofilament contractile abnormalities correlated strongly with in vivo right ventricular function at rest and right ventricular contractile reserve during exercise, suggesting a central role of right ventricular myofilament dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.

In summary, these findings uncover key deficiencies in the right ventricles of systemic sclerosis-associated pulmonary arterial hypertension, and these findings suggest that therapies targeted at right ventricular myofilament contractile dysfunction may prove particularly useful for this vulnerable subpopulation. That wraps it up for our summaries. Now, for our feature discussion.

Today's feature paper promises a new therapeutic approach in pulmonary arterial hypertension. We know that pulmonary arterial hypertension is a rare disease, but nonetheless it casts a large shadow because it most commonly afflicts young women and remains a disabling disease. Despite treatment advanced in the last 20 years, high-risk patients still succumb at a rate of 15% annually. Moreover, our most effective therapy is a continuous infusion of parenteral prostacyclin, which is both cumbersome and expensive. Thus, there remains an urgent need for better therapies to improve survival and quality of life. Today's feature paper introduces a novel approach to this.

I'm so pleased to have the corresponding author, Dr. Sylvia Cohen-Kaminsky, from Inserm, Paris, France, as well as associate editor Dr. Charlie Lowenstein, from University of Rochester, to discuss today's special paper. You know, I'm gonna start with Charlie, because you have a way of explaining things and just putting the background to mechanistic papers so well. Could you do that for us, please?

Dr Charlie Lowenstein: Sure. When I started in research, I worked in a neuroscience laboratory. One of the things we studied was glutamate and its class of receptors. Glutamate, as you know, is one of the major neurotransmitters in the brain. The brain releases small amounts of glutamate, which acts as a messenger, neurons talking to other neurons. But when there's a stroke, the brain releases huge amounts of glutamate, and it's actually toxic and can cause damage, and mediate neuronal damage and cell death. Glutamate is a hot topic in the world of neuroscience. But in the cardiovascular field, people don't know much about glutamate. They don't appreciate glutamate as being important at all. So, I have a question for you, Sylvia. How did you start to get interested in glutamate and its family of receptors?

Dr Sylvia Cohen-Kaminsky: It started around 2000, and since 2000 we are having some clues about peripheral glutamate receptor in different cells in different organ. But basically, for vascular cells and for the topic of PAH, there was two things that make me thought about it. First of all, it was shown that the NMDA receptor contributes to the proliferation of different cancer cell types. Human tumor cells express the NMDA receptor, then an NMDA-receptor antagonist may inhibit cancer cell growth and migration. We know that pulmonary vascular cells from PAH patients have cancer-like properties. They are also proliferative and resistant to apoptosis, and they have several properties of cancer cells, such as metabolic shift and so on.

In addition, not only neurons in the brain express the NMDA receptor, but also brain microvascular endothelial cells that respond to an NMDA receptor activation by gross production, disruption of endothelial cell barrier, and monocyte transmigration. All these three processes are relevant to PAH development. That's why I thought that perhaps an NMDA receptor is expressed on microvascular cells from the lung, and perhaps we could have a process involving an NMDA receptor in this vascular remodeling.

Dr Charlie Lowenstein: As you know, there are three flavors of glutamate receptors. How did you discover that there was one particular kind, the NMDA receptor, that was really important for smooth muscle cells?

Dr Sylvia Cohen-Kaminsky: You are right. We did analysis of mRNA expression, and most of the known receptor in the brain, either metabotropic or ... ionotropic, sorry, indeed expressed in vascular cells and they may cooperate to activate this NMDA receptor exactly as it happens in the brain. We didn't work that on these other receptor, but we are pretty sure they are at work in cooperation with the NMDA receptor. Why though an NMDA receptor? Because it's an ion channel permeable to calcium, and the calcium is an event which can be important in cell proliferation. In addition, the first thing we have shown in these remodeled vessels when we did mass spectrometry imaging was increased level of glutamate and glutamine, its precursor. That was also an additional element that makes us think about this NMDA receptor.

Dr Charlie Lowenstein: I want to go from the receptor to glutamate. There are three or four amazing things about your paper. One of them is that you suggest that cells in the vascular are releasing glutamate, which is a neurotransmitter. Do you think those are the smooth muscle cells that are talking to other smooth muscle cells by releasing these messenger molecules?

Dr Sylvia Cohen-Kaminsky: Yes. Smooth muscle cells are talking to other smooth muscle cells. But we also did some work on endothelial cells, and they are also able to release this glutamate. So we think that vascular cells in the vascular wall are discussing together through glutamate, although we don't know yet the normal function of this NMDA receptor in the vascular system. However, in the pathology it's very clear that there is this release. What is very interesting is that this release can be triggered by pathways which are already down-regulated in PAH, such as the endothelin-1 pathway.

Dr Charlie Lowenstein: Another remarkable part of your observation is that the signaling with glutamate and glutamate receptors is hyperactivated in the setting of a major human disease, pulmonary artery hypertension. How did you figure out that glutamate is so important in this special disease?

Dr Sylvia Cohen-Kaminsky: Because we showed, as I already told you, this glutamate accumulation in the remodeled vessel. We used this mass spectrometry imaging which allows analysis of metabolites directly in the remodeled vessels from sections performed from extended lengths. We saw this glutamate accumulation together with glutamine accumulation, so the ligand was overexpressed. In addition, when doing western blots from these remodeled tissue dissected from ongoing arteries, we have shown that we have a particular phosphorylation of this receptor which is very well-known in the CNS. This phosphorylation is involved in sending the receptor to the membrane and stabilizing the receptor to the membrane. Having this phosphorylation means that NMDA receptor is engaged, activated in the remodeled vessels in situ.

Dr Charlie Lowenstein: In an experimental model, you explored the role of glutamate in two very nice, complementary ways. One is with a genetic approach, the NMDA receptor deficiency. The other is using drugs. What were the drugs, what were the pharmacology that you used to block glutamate's transmission, and how did that affect the mice?

Dr Sylvia Cohen-Kaminsky: We used drugs that are very well known in the CNS. We used two drugs. One is memantine, which is already commercialized for the treatment of Alzheimer's disease. The other one is MK-801, which has been produced initially as a potential pharmacological drug but it was too potent to be used in the CNS. Therefore, this drug is only used in research at the moment. But these two drugs were able to act on this vascular remodeling and a number of PAH parameters. We have explored at least 12 parameters involved in this animal model of PAH, and hemodynamic stable parameters of hemodynamics including intra-arterial pressure, vascular remodeling, right ventricular remodeling with different parameters that shows a certain index. The cardiomyocyte hypertrophy, the fibrosis, the inflammation inside the right heart and around remodeled vessels, all these parameters were modified by the drug.

In addition, in vivo we have shown the destruction of the NMDA receptor glutamate axis with decreased engagement of the NMDA receptor in pulmonary arteries by following this phosphorylation I mentioned, decrease of apoptosis resistance and also proliferation. This was shown also after the treatment with the drugs, and also decrease of endothelial cell dysfunction that could be followed in the blood through selecting those H.

Dr Charlie Lowenstein: Your results with this drug were really impressive. I love that part of your study. You showed when you block glutamate signaling, first of all, the blood vessels looked much better in a model of pulmonary artery hypertension. In an experimental model, blocking glutamate transmission really improved the way the vessels look. But secondly, what was really amazing was, normally in humans one of the big problems with pulmonary artery hypertension, as you said, is the right ventricle gets inflamed and fibrotic, and a lot of patients die from complications of right ventricular dysfunction. In your model, when you treat with MK-801, blocking glutamate receptor, the right ventricle looks a lot better. It was really an impressive part of your study.

Dr Sylvia Cohen-Kaminsky: I think that this is view on the effect of the vessels themselves, then the right heart can recover. But we may have a direct effect in the heart. If you remember this Chinese restaurant syndrome, when you eat too much Chinese food, which is full of glutamate, you have some cardiac involvement, arrhythmia, and so on. Initially, toxicologists thought that it passed through the central nervous system. But then they realized that maybe the NMDA receptor is expressed in cardiac cells, and indeed it is expressed and is colocalized with the ryanodine receptor, meaning that it could have a function in the heart as well. But this has, of course, to be explored precisely. We know from the transplantation that, when we transplant on with the lung, the heart can recover very well. We may have these two effects. One due to the relief on vascular remodeling, and the other perhaps a direct effect on the heart.

Dr Carolyn Lam: You know, I have to chime in now. That cuts too close to home with the Chinese food and glutamate. First and foremost, I just really have to say, Charlie and Sylvia, it's people like you who make basic science come alive and simply extraordinarily exciting. Taking glutamate, something that we've talked about in the context of Chinese food and neurotransmitters, and therefore showing the potential to even repurpose perhaps some drugs for pulmonary arterial hypertension. So let me just round up by asking you, what do you think our next steps, how far are these findings away from clinical application? Perhaps, Charlie, your thoughts?

Dr Charlie Lowenstein: While I think that the use of MK-801 to treat excess monosodium glutamate during a Chinese meal, maybe that's a little bit premature. I'm much more excited about the idea of using glutamate-receptor antagonists to treat or prevent or even reverse pulmonary artery hypertension, both its vascular and cardiac complications. I'd love to ask Sylvia, do you think these medications in this class, do you think NMDA-receptor antagonists are ready for clinical trials?

Dr Sylvia Cohen-Kaminsky: In fact, they are not ready as they are. We have a program in which we have designed hypothesized new NMDA-receptor antagonist that do not go to the brain, because we want that treating PAH has to be safe, and we don't want to interfere with brain system. So we created this new NMDA-receptor antagonist that do not go to the brain. At the moment, we are in the process of the documentation. We have two patents for two series of molecules, and we expect the drug conjugate by the end of this year. To reconjugate means that we have a number of properties on this drug, the pharmacokinetics, metabolism, selectivity profile, toxicity, and so on. We are doing all this physical chemical properties, and of course validation of these new molecules in the animal models as therapy alone and also as add-on therapy with existing therapies, such as these vasodilators. We hope that we can have an additive effect between an NMDA-receptor antagonist and current PAH drugs.

Dr Charlie Lowenstein: Sylvia, as you know, drug companies about 10 or 20 years ago invented all these amazing glutamate-receptor antagonists to treat central nervous disease like stroke. One of the amazing things about your discovery is you're suggesting that glutamate receptors in the periphery are great targets as well. The exciting thing about your observation is you're really opening up new therapeutic approaches for targeting neurotransmitters in the periphery. I think your discoveries are tremendously exciting and could open up new avenues in treatment of a disease, pulmonary artery hypertension, for which there really aren't effective therapies right now.

Dr Carolyn Lam: I couldn't have said it better. Thank you so much, Charlie. Thank you so much, Sylvia.

See, listeners? Aren't you glad you heard it here right on Circulation on the Run? Don't forget to tune in again next week.

Circulation May 22, 2018 Issue

22 maj 2018 | 21 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on the challenges of cardiovascular disease risk evaluation in people living with HIV infection, an important discussion coming right up after these summaries.

The first original paper this week provides experimental evidence that nicotinamide riboside could be a useful metabolic therapy for heart failure. First author Dr. Diguet, corresponding author Dr. Mericskay, from University Paris-Sud investigated the nicotinamide adenine dinucleotide or NAD homeostasis pathways in the failing heart. They found that an expression shift occurs in both murine and human failing hearts in which the nicotinamide riboside kinase two enzyme, which uses the nucleoside nicotinamide riboside was strongly up-regulated for NAD synthesis.

Nicotinamide riboside supplemented diet administered to murine models of dilated cardiomyopathy or pressure overloaded induced heart failure restored the myocardial NAD levels and preserved cardiac function. Nicotinamide riboside increased glycolysis as well as citrate and Acetyl-CoA's metabolism in these cardiomyocytes. Thus, nicotinamide riboside supplemented diet may be helpful in patients suffering from heart failure and may help them to cope with the limited myocardial ATP supply by restoring NAD coenzyme levels and its associated signaling.

In the single ventricle reconstruction trial, one year transplant-free survival was better for the Norwood procedure with the right ventricle to pulmonary artery shunt compared with the modified Blalock‒Taussig shunt in patients with hypoplastic left heart and related syndromes. In the paper in this week's journal, authors compare transplant-free survival and other outcomes between these groups at six years. First and corresponding author Dr. Newburger from Children's Hospital Boston and her group showed that the right ventricular pulmonary artery shunt group had similar transplant-free survival at six years, but required more catheter interventions before the Fontan procedure.

Right ventricular ejection fraction, New York Heart Association class and complications did not differ by shunt time. Cumulative incidences of morbidities by six years included 20% with a thrombotic event, 15% with a seizure, and 7.5% with a stroke. These data therefore emphasize the importance of continued follow-up of the cohort, and the need to find new strategies to improve the long-term outlook for those with single ventricle anomalies.

The next paper presents results of the CREATIVE trial, which stands for Clopidogrel Response Evaluation and Anti-Platelet Intervention in High Thrombotic Risk PCI Patients). First and corresponding author Dr. Tang from Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College conducted a head-to-head comparison of the safety and effectiveness of intensified anti-platelet therapies either a double dose clopidogrel or adjunctive cilostazol and conventional strategy in 1078 post-PCI patients at high thrombotic risk as identified thromboelastography, which is a platelet function test.

The primary outcome was the incidence of major adverse cardiac and cerebral vascular events at 18 months post-PCI they find as a composite of all cause death, myocardial infarction, target vessel revascularization, or stroke. The authors found that the primary end point occurred in 14.4% of those in the conventional strategy. 10.6% in those given double dose clopidogrel alone. And 8.5% in those also given adjunctive cilostazol. Now, although both intensified anti-platelet strategies achieved increased platelet inhibition, only the triple strategy with adjunctive use of cilostazol significantly reduced adverse events in the long-term follow-up.

No increased rates of major bleeding was found with the intensified anti-platelet therapy regimes. Thus, in patients with low responsiveness to clopidogrel as measured by thromboelastography, the intensified anti-platelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding.

The final original paper sheds light on the prevalence and predictors of cholesterol screening awareness and statin treatment among American adults with familial hypercholesterolemia or other forms of severe dyslipidemia. First and corresponding author Dr. Bucholz from Boston's Children's Hospital and their colleagues used data from the National Health and Nutritional Examination Survey, and showed a high prevalence of screening and awareness above 80%. However, there were relatively low rates of statin use among individuals with familial hypercholesterolemia at 52.3%.

And even lower rates among those with severe dyslipidemia at 37.6%. The discrepancy between the prevalence of cholesterol screening and treatment was most pronounced in younger patients, uninsured patients, and patients without a usual source of healthcare. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.

And that brings us to the end of our summaries. Now for our feature discussion. The natural history of infection with HIV has completely changed with the use of potent antiretroviral therapies. We now know that people living with HIV actually have morbidity and mortality patterns that really resemble the general population, especially with regards to cardiovascular disease, which is very prominent in this population. And I suppose it's this that has led to the assumption perhaps that risk prediction tools and intervention strategies that we apply in the general population may be used in patients living with HIV.

Is this the case however? Well, this week's feature discussion is going to be so enlightening. And it's so important we are talking across the world here, from South Africa to the United States, and of course with me here in Singapore. I am so pleased to have the authors of this week's feature paper and they are none other than Dr. Virginia Triant from Massachusetts General Hospital, Dr. Ralph D’Agostino from Boston University. And our associate editor, Dr. Bongani Mayosi from University of Cape Town. Thank you so much for joining me for today's exciting discussion. Virginia, could I ask you to first describe your study?

Dr Virginia Triant: As you mentioned in the introduction, we have found that patients infected with HIV have an increased risk of cardiovascular disease. That includes both myocardial infarction and stroke compared to age-matched controls in the general population. And extensive data has suggested that the etiology of this increased risk is related both to traditional cardiovascular risk factors, as well as novel risk factors that are specific to HIV infection. And these include chronic inflammation in the immune activation. So consequently, it remains relatively unknown whether established cardiovascular risk prediction functions are accurate for patients with HIV because they include only risk factors that are traditional factors and they don't reflect the complete mechanism that we know is at play in cardiovascular disease associated with HIV.

So in our study, we assess the performance of three established cardiovascular risk prediction functions, two Framingham functions, and then the ACC/AHA pooled cohort's equations and we applied this to a longitudinal HIV infected cohort that was comprised of men. And we investigated the performance of the risk scores in terms of comparing regression coefficients, discrimination and calibration, which are standard metrics in cardiovascular risk prediction. So I'll briefly summarize our overall results as a start. We found that overall, the risk prediction functions underestimated risk in our group of HIV-infected men.

We found that discrimination was modest to poor, and this was indicated by low c-statistics for all of the equations. And we also found that the calibration or the agreement between observed or predicted risk was also poor across the board for all three risk prediction functions. So our results suggests that simply taking the risk prediction functions and transporting them to an HIV infected group may actually result in mis-classification in terms of patient risk. And in underestimation of cardiovascular risk.

Dr Carolyn Lam: Well, Virginia, beautifully summarized of a beautiful paper. But perhaps at this point, we should take a step back and ask ourselves how exactly were these risk prediction scores originally developed. And I can't imagine asking a better person than Ralph. Ralph, could you take us on a jaunt along history and tell us how were those Framingham risk scores developed in the first place? Who are they supposed to be applied to? And did these results surprise you?

Dr Ralph D’Agostino: After the second World War, what was becoming quite clear is things like cardiovascular disease were becoming very prominent. Things like infections and what have you, we were developing all sorts of ways of handling them with medicines and so forth. But with cardiovascular disease, it's a thing that progresses slowly over the years and it starts wiping out people. And back in those days, one out of three men between the ages of 30 and 60 had some kind of cardiovascular event. Women weren't that bad off, but they were pretty bad off also. And so what happened is the American government and the American Heart Institute set up this study in Framingham, where they took a third of the individuals between the ages of 30 and 60 and actually followed them. They took values of variables like blood pressure, cholesterol, things they thought might be useful.

And took values on them. And they had to come back every two years and after as time went on, they took the data after six years, after 10 years they took the data, and started to look at how each individual's blood pressure related to cardiovascular disease. Does cholesterol, and the answer was yes. And then I started getting involved and we were developing these cardiovascular functions where you could actually take an individual, take their measurements now, and make a prediction that had a lot of validity, good discrimination, high predictability over what was going to happen in ten incidents and then the government, the US Government, started having guidelines and what we did is we ran a study where we took a number of different studies in the US, different cardiac studies, the ARIC studies, number of 'em, and we thought applying our functions how well would they do. And it turned out that for whites in the country, the Framingham functions did very well.

But Japanese-Americans in the country, it over-predicted. Then we found out that you could make a calibration adjustment and what we've gone to, like in China, we have a big study where we had a function and Framingham function it over-predicted but calibration adjustment would make enough corrections and so now with Jeanne and the HIV, our hope was that you could take these functions and see how they work on the HIV population. When we did it we were quite well aware, because people have been looking at different things, there's something beyond the original cardiovascular risk. And what the paper shows, quite nicely, these cardiovascular risks do have some relationship but they don't explain enough. The HIV population have a much bigger burden and a simple calibration adjustment just isn't going to work. We need new variables, we need new insights on what to add to these functions.

Dr Carolyn Lam: Thank you so much for that. That's just such important part of history because I have to thank you for those equations. We apply those definitely in our Asian cohorts with that calibration factor. But I was just reflecting as you were telling that story of how we've come full circle now to actually talk about an infection again. It's the midst of an infection, like HIV infection, that we're now testing these equations once again. What better than to ask than Bongani, you're in the epicenter, if I may, of HIV infection. What do you think of the applicability of these findings to the patients you see?

Dr Bongani Mayosi: Yes. These findings are clearly of great interest to us here in the Sub-Saharan African region because it is really the epicenter HIV pandemic. We found population, in terms of risk factors for arteriosclerosis disease still remains low although there clearly derives, for example, in the incidence of myocardial infarction that's being detected in a number of the leading centers now. And with HIV we have observed cases of myocardial infarction while they tend to be younger men who almost always smoke and who get a lot more of a thrombotic episodes.

When you catch them on a thrombotic load, you do not find arteriosclerosis disease. It's going to be important, I think, as we move forward to make sure that as we develop risk functions that will predict cardiovascular disease in patient HIV that the African epidemiological context is completed teaching that HIV affects younger people, affects large numbers of women, but that, quite clearly, is associated with decreased cardiovascular event and stroke and stroke is well demonstrated. But in terms of actually looking at the risk factor this population was still in the early day and certainly in future studies would have to have a major contribution of the African cohort.

Dr Carolyn Lam: That's true, Bongani, but may I ask how would you, perhaps, advise your African colleagues now to look at these data? Then I'd also like to turn that same question over to you, Virginia. What do we do? What's the clinical take home message of these findings?

Dr Bongani Mayosi: I think the message is true that HIV infection is associated with the increased risk of cardiovascular event, there's no doubt about that. That there are some risk factors that can carry through, such as the smoking population but it's important for all clinicians to be aware of that. The ordinary risk you find in using Framingham and other established risk functions is not going to give us all the information that we need. So that recommendation should come through we need to know that risk factors are unknown, that they're important and we need to learn more about these patients in order to give us a perfect prediction of what will happen in the future.

Dr Virginia Triant: I think the findings have a lot of clinical relevance. This suggests, I think, that there are a lot of clinical implications for any patient who has novel cardiovascular risk factors that may not be accounted for in heart functions. And what our findings suggest is that if functions don't reflect the actual composition of risk factors in the population, that can result in misclassification and thus we underestimate risk, we might miss high-risk individuals, high-risk patients who would benefit from aggressive risk reduction but are not currently receiving it. This is a real clinical challenge as sit in clinic and we pull up the scores and calculate them for our patients, whether that is a trustworthy number or whether we should, perhaps, thinking that it's higher, thinking that it's different than what we're seeing for predicted 10-year risk. I think what this suggests is that the functions may need to be further tailored to different populations and sub-populations to reflect the actual composition of risk factors in that population. Even within HIV patients and populations, the risk factors in South Africa might be different than those in Boston, with different relative contributions.

One of the next stepped planned for our team is to actually look at developing, new risk functions which are tailored to HIV and incorporating both HIV itself as a risk factor, as well as HIV specific variables and to attempt to see if we can improve the performance of these functions for HIV populations. Perhaps HIV or HIV related factors might become sort of a new cardiovascular risk equivalent and we can serve patients in this population as higher cardiovascular risk baseline. I also just wanted to mention, briefly, that I think that there are important clinical implications beyond HIV that extend to other chronic inflammatory conditions. Inflammation is increasingly recognized as important in cardiovascular risk and this way HIV can serve as a prototype population. But these results are likely to extend to a lot of different populations who have chronic inflammation for different reasons.

Dr Carolyn Lam: That's a great point, Virginia. As I'm listening, I'm wondering is there no end to this because now we say HIV and then we put other inflammatory diseases, then we say, "Well, women may be different from men," and then different ethnicities may be different. I think gonna be going closer and closer to precision risk prediction, if I might say. Could I just pick your brain here? What do you think the future is? Where's the room for machine learning approaches for risk prediction, individual almost down to that level? What do you think?

Dr Ralph D’Agostino: I think you're right on target. In some sense, the functions we have there's a sort of massiveness about it, when you come to view this population, back in the 50s and 60s and so forth, cardiovascular disease was such a major ... it still is a major problem ... such a major problem you identify some of the real items like the blood pressure and cholesterol, and you attack and develop functions on that and you'd find that you're affecting positively a huge number of individuals, but now as, like Jeanne was saying, and others have been saying, you start focusing, you've got this massive group of individuals who should have their blood pressure controlled and what have you, but if you go into HIV, you go into a number of other populations and so forth, there are other things that are driving these disease and driving the manifestations of the disease. It isn't that blood pressure isn't important, it's that there's other things that are important. And so it's machine learning and so forth and deep learning that you're gonna have to be dealing with manifestations on very high levels and maybe even get into genetics.

Look in the cancer field ... I do a lot of work with the FDA ... look at the cancer field now; how it's so genetically driven in terms of a lot of the drugs the so-called biomarkers, which are basically driven by uniqueness in populations. I think that's definitely going to be, or is the future of these cardiovascular functions.

Dr Carolyn Lam: Okay audience. You heard it, right here. These are exciting times. In the meantime, thank you so much for this precious, valuable piece of work. Virginia, Bongani, Ralph, it was great having you on the show.

Circulation May 15, 2018 Issue

14 maj 2018 | 21 min

Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.

Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.

They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.

The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.

From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.

The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.

The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.

The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.

RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.

Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.

The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.

They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.

That brings us to the end of our summaries. Now, for our featured discussion.

Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.

I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.

Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find?

Dr Robin Mathews: The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?

We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.

ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.

What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.

We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.

What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.

When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.

We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant.

Dr Carolyn Lam: What a detailed summary. Thanks so much.

Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful?

Dr Jeptha Curtis: It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.

I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.

What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.

As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.

All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.

What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals.

Dr Carolyn Lam: Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that?

Dr Sandeep Das: Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.

One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."

I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems.

Dr Carolyn Lam: Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US?

Dr Robin Mathews: Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."

Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.

In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.

At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts.

Dr Sandeep Das: One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?

The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive.

Dr Robin Mathews: Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.

I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.

At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them.

Dr Carolyn Lam: Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.

Thank you so much for listening today, and don't forget to tune in again next week.

Circulation May 8, 2018 Issue

7 maj 2018 | 8 min

Dr Joseph Hill: My name is Joe Hill. I'm the Editor-in-Chief of Circulation and I'm very pleased today to be here today with Professor Daida from Juntendo University in Tokyo, Japan, as well as one of our associate editors, Professor Shinya Goto from Tokai University in Kanagawa, Japan. Dr. Daida is one of the senior authors on a very exciting clinical trial that we're publishing in Circulation. The first and largest trial comparing high-dose versus low-dose statins in Asia. Dr. Daida, would you please tell us more about the study?

Dr Hiroyuki Daida: Yes. Thank you. The trial, called REAL-CAD, is a randomized trial. We compare high-dose statins with low-dose statins in Japanese patients with stable coronary artery disease. The number of the patients is 13,000. It's the largest trial ever comparing high-dose and low-dose statins. We found that with that reduction of the primary end point, which is a composite end point, including cardiovascular death, non-fatal MI, non-fatal stroke, and unstable angina requiring hospitalization.

That is very exciting result because it is the largest trial ever and also the very first trial in Asia.

Professor Shinya Goto: Congratulations, Professor Daida, for that great achievement, in the REAL-CAD trial. Could you explain a little bit about the background and that the dose of statins in Japan is generally low, and what was the reason why we kept using low-dose statins, and is care to try change the standard of care in Japan and also East Asia? Could you give a comment on those two topics?

Dr Hiroyuki Daida: Our trial is quite similar to that of PNP trial of comparing Western extensive statin treatment and the Asia statin treatment. However, that extensive statin treatment, intensive statin treatment, is not popular in Asia, so we did that maximum clinical dose of statin, we use this dose in Japan. It is the maximum dose of statin approved in Japan.

Dr Joseph Hill: So as I understand it, the rationale was the thinking that Asians, East Asians, are unable to tolerate high-dose statin therapy. In this case you used pitavastatin. And, in fact, what you found was there were no increase in serious adversive events in high dose patients. And, just like Caucasians, they derived considerable benefit at multiple points in atherosclerotic cardiovascular disease metrics.

Dr Hiroyuki Daida: Actually, they didn't experience a really high-dose of statin in Japan so government approval is up to 4 mg of pitavastatin, a dose of that about 20.

Dr Joseph Hill: So, this is not what we would call high-intensity statin therapy but nonetheless, there was a dramatic benefit including an all-cause mortality, irrespective of the starting LDL level at the beginning of the trial?

Dr Hiroyuki Daida: That is right. We found that the effect is similar that the patient, the LDL is greater than 95 or less than 95. So, the effect is independent of the basal based on LDL level.

Professor Shinya Goto: The one thing, very exciting just like Joe mentioned, all cause of mortality, especially known cardiovascular caused mortality reduced with the use of high-intensive care of the statin. If any kind of speculation, what is the cause, reduce the inflammation or maybe reduce cancer, something like that. They have any kind of advance to an analysis?

Dr Hiroyuki Daida: We didn’t have further analysis but we are not so keen to emphasis the total mortality because maybe that is a chance of the effect but this is the largest trial, so the result is really exciting in this kind of aspect.

Dr Joseph Hill: So, I would reiterate Shinya’s congratulations. This is a monumental piece of work. The largest clinical trial comparing high dose versus low dose statin. The largest ever. The first in Asia. You found a benefit that makes total sense across what we know from other trials and this will change practice. Your work, I believe, will change the way patients with atherosclerotic cardiovascular disease is handled in Japan.

Dr Hiroyuki Daida: Yes, actually the current guideline in Japan for the secondary condition. The condition is LDL less than 100 and for the really high-risk secondary condition listed seventh. We didn't recommend high-dose statin initially, so, this trial result is kind of like this, changing.

Dr Joseph Hill: I can't resist asking, what comes next? What's your next project?

Dr Hiroyuki Daida: Maybe we need to have a further reduction of LDL. We have another drug, other potent drug recently. We need to investigate all of the new drug such as PCSK9 inhibitor in secondary prevention.

Professor Shinya Goto: That's wonderful. Do you have any time to extend observation of the trial? I think the trial is relatively still superior as compared to the global long-standing trial. Really, that's fine, that effect of statin on the cholesterol and even it's different from Japan and other regions of the world. There ought to be intriguing thing, I would like to know, what are you waiting to extend that observation now?

Dr Hiroyuki Daida: Fortunately, we do not intend to extend the follow-up. The whole thing is about four years but we do not plan to extend. We will further analyze the data for some group and our kind of CRP and effect of the baseline.

Dr Joseph Hill: Lots of secondary analysis underway, undoubtedly. Let me thank both of you for being here, Professor Daida and Professor Goto, I congratulate you again. It's not often that you make a practice-changing intervention in modern-day medicine. I salute you and we are honored and thrilled to publish your outstanding work in Circulation. Thank you both.

Dr Hiroyuki Daida: Thank you very much.

Professor Shinya Goto: Thank you very much.

Circulation May 1, 2018 Issue

30 april 2018 | 21 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center of Singapore and Duke National University of Singapore. Our featured discussion today is a wake-up call because despite substantial efforts to promote cardiac rehabilitation in guidelines and performance measures only a small percentage of patients are receiving this and there is a remarkable regional variation. Lots of lessons to be learned here coming right up after these summaries.

More children with congenital heart disease are surviving into adulthood, and congenital heart disease is associated with risk factors for dementia. But what is the actual risk of dementia in congenital heart disease adults? Well, in this first paper from first and corresponding author Dr. Bagge from Aarhus University Hospital in Denmark, the authors used medical registries and a medical record review of all Danish hospitals to identify more than 10,600 adults with congenital heart disease diagnosed between 1963 and 2012 and followed up until the hospital diagnosis of dementia or death, emigration, or the end of the study in the end of December 2012.

For each individual with congenital heart disease the authors identified 10 members of the Danish general population matched on sex and birth year. They found that the risk of all-cause dementia was increased by about 60% in congenital heart disease adults compared with the matched general population. The risk was higher for early onset dementia, that is dementia at less than 65 years of age, in which the risk was more than double. The risk was also elevated for all levels of congenital heart disease complexity, including those with cyanotic potential. The relative risk remained increased for those without extra cardiac defect or acquired cardiovascular diseases.

These results really underscore the importance of understanding the risk of adverse long-term neurologic outcomes in the growing and aging population with congenital heart diseases.

The next paper suggests that patient outcomes after lower limb revascularization have improved in England over recent times. This paper from first and corresponding author Dr. Heikkila from London School of Hygiene and Tropical Medicine used individual patient records from hospital episode statistics to identify almost 104,000 patients who underwent endovascular or surgical lower limb revascularization for infrainguinal peripheral artery disease in England between 2006 and 2015. During this 10-year period the estimated one-year risks of major amputation and death reduced after both endovascular and surgical lower limb revascularization in England. These trends were observed for all categories of peripheral artery disease severity, with the largest reductions seen among patients with the most severe underlying disease.

These encouraging trends coincided with a period of centralization and specialization of vascular services in England, although the current findings cannot be interpreted as resulting directly from this reconfiguration of services.

The next paper presents experimental data showing that targeting the Janus kinase and signal transducer and activator of transcription or JAK-STAT pathway may represent a disease-modifying strategy in inflammatory vasculopathy. First author Dr. Zhang, corresponding author Dr. Weyand from Stanford University School of Medicine examined whether persistent vessel wall inflammation in giant-cell arthritis is maintained by lesional T cells and whether such T cells are sensitive to the cytokine signaling inhibitor tofacitinib, which is a JAK inhibitor that targets JAK3 and JAK1.

To do this, vascular inflammation was induced in human arteries and grafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant-cell arthritis. Mice carrying inflamed human arteries were then treated with tofacitinib or vehicle. They found that tofacitinib suppressed T cell invasion into the artery, inhibited proliferation and cytokine production of vasculitogenic T cells and curbed survival of artery resident T cells. Tofacitinib treatment prevented neoangiogenesis and intimal hyperplasia in these inflamed arteries. Thus, inhibition of JAK-STAT signaling with tofacitinib effectively targeted multiple disease-relevant processes in inflammatory vasculopathy and thus represents a potential disease-modifying agent.

The next paper provides important insights into how coronary artery calcification burden and cardiorespiratory fitness, which are actually two independent predictors of cardiovascular disease but may interact with each other to impact cardiovascular risk. First author Dr. Radford, corresponding author Dr. Levine from the Institute of Exercise and Environmental Medicine Texas Health Presbyterian Hospital and UT Southwestern Medical Center studied 8,425 men without clinical cardiovascular disease who underwent preventive medical examinations that included an objective measurement of coronary artery calcification and cardiorespiratory fitness between 1998 and 2007.

They found that cardiovascular disease events increased with increasing coronary artery calcification and decreased with increasing cardiorespiratory fitness. Adjusting for coronary artery calcification levels for each additional MET of fitness there was an 11% lower risk of cardiovascular disease events. When both coronary artery calcification and cardiorespiratory fitness were considered together there was a strong association between continuous cardiorespiratory fitness and cardiovascular disease incident rates in all coronary artery calcium groups. Thus, the take-home message is for any baseline age and level of coronary artery calcification greater fitness is associated in a continuous fashion with lower risks of cardiovascular disease events.

And that wraps up our summaries. Now for our feature discussion.

We all know how cardiac rehabilitation is. It's strongly advocated in guidelines, it's very well highlighted in performance measures. But how well are we actually doing? Well, today's feature paper really gives us some very valuable information and really kind of holds a mirror in our face, doesn't it? I'm so pleased to have with us the first and corresponding author of the paper Dr. Alexis Beatty from VA Puget Sound Health Care System and University of Washington as well as Jarett Berry, our associate editor from UT Southwestern. Alexis, could you tell us what did you see when you looked at cardiac rehabilitation among the Medicare and VA populations?

Dr Alexis Beatty: Overall participation in cardiac rehab after an MI or a PCI or a bypass surgery is pretty low, only about 16% of people in Medicare and about 10% of people on the VA actually participate in cardiac rehab. But the interesting thing is that we saw pretty wide variations from state to state in participation. So some states had pretty high participation, upwards of 40% of patients, and some states had only 1, 2, 3% of people participating.

Dr Carolyn Lam: Were there any patterns to this, any factors that you teased apart?

Dr Alexis Beatty: We did observe that some regions of the country appeared to be doing better than others. So for instance, the West North Central region of the United States, Nebraska, South Dakota area has high participation in both populations and other regions like the Pacific, California, Oregon, Washington, Hawaii, Alaska, have lower participation in both populations.

Dr Carolyn Lam: And any postulations on why this may be the case?

Dr Alexis Beatty: Yeah, I have some theories. We did try to look at whether it was due to patient characteristics, hospital characteristics, socioeconomic status, and it doesn't really seem to be any of those things that are driving the differences, which leads me to believe that it's actual practice variations. So I think that literally the systems are set up better in some areas of the country than others to get patients into cardiac rehab.

Dr Carolyn Lam: And as you beautifully wrote in your paper, that means that there may be an opportunity here to identify best practices here, isn't it? Jarett, you've been thinking about this a lot. What do you think?

Dr Jarett Berry: Yeah, I was curious, Alexis, it is interesting that the hospital variation that you saw, the on-site cardiac rehab was fairly consistent across cardiac rehab participation rates in Medicare but there was quite a bit of variability in the access to an on-site cardiac rehab site in the VA patients. I thought that was an interesting observation because it does suggest perhaps that what's driving regional variability looks to be fairly complex as you point out in your paper. But I just wanted to have you speculate a little bit or think a little bit about strategies for how we might think about improving cardiac rehab participation given the fact that there doesn't seem to be one particular answer to this problem. And so as you think about this longstanding challenge, how would you think about the future, about how we could actually really move the needle in increasing cardiac rehab participation?

Dr Alexis Beatty: There's a lot of different ways that I think that we can work to start moving the needle. And as you point out, not every VA location has a cardiac rehab center on-site and sites that do have cardiac rehab on-site do tend to do better at getting their patients into cardiac rehab. And I think it may just be that there are people there who are interested in cardiac rehab and are promoting it to patients. And then there probably are some access issues as well. But I think it's not just kind of an "if you build it they will come" sort of proposition. Having cardiac rehab centers is important but then having systems in place to get people into cardiac rehab and get people going to cardiac rehab are just as important.

And so I've talked to a lot of the VAs that have centers, don't have centers, do a good job of getting people in, don't do a good job of getting people in. And even in these places that don't have cardiac rehab on-site, if they have a system in place that helps get patients into cardiac rehab they're still able to achieve pretty high rates. And so a lot of that is just doing kind of setting it up as an automatic order and having a nurse or exercise physiologist or somebody be a navigator for the patients through the process.

And then the other thing I really want to stress is the importance of providers recommending it to patients. I think that's the strength with which the providers sell cardiac rehab can really make a big difference.

Dr Jarett Berry: It's interesting, I just took over cardiac rehab as a medical director here at Southwestern about a year and a half ago and I've been struggling with this. And one of the interesting things that I just would love to get your thoughts on that I noted, which doesn't seem to get a lot of attention in the literature to me, is the role of co-payments. I don't know if most physicians who aren't involved in this space appreciate that for most insurance and for Medicare, it may not be the case for VA, I can't speak to that, but the co-payment amount for each time you come, for each visit is between $30 and $50 per visit. That seems to me in some ways ... I know you didn't address it at all in your paper, but just keeping this conversational ... What do you think the role of some of these other less discussed factors are such as just co-payment amounts that might actually be having a bigger effect on participation? Because I know if I had to pay a 1,000 bucks to go to cardiac rehab I might think twice about it.

Dr Alexis Beatty: Yeah, and I think the co-payment issue is a very real issue too and there's a lot of policy level things that makes cardiac rehab difficult. So one is this co-pay issue, there also then other changes to the way it's administered like where the location of the cardiac rehab can be and how hospitals get reimbursed for that. It has to be prescribed by a physician, it can't be prescribed by a nurse practitioner or a PA, it has to be supervised by a physician. There's a lot of restrictions on cardiac rehab that can just, practically speaking, make it difficult to deliver both from the patient and the provider and health system level.

And what I tell my patients when I am trying to get them to go to cardiac rehab, and we do have co-payers in the VA too that are kind of on a sliding scale depending on patients’ means. And so I tell them that it's an investment. You are making this upfront investment of your time and money and effort to get yourself healthy and learn how to be healthy in the long term. So we know that people who attend cardiac rehab are less likely to be hospitalized and are less likely to die from their heart disease, and so it's an important investment to make and that's sometimes the hard message to sell and I wish it were easier to sell.

Dr Jarett Berry: I totally agree with you. My own patients and also the patients that I helped manage through cardiac rehab have received such benefit in many different areas from the participation. But yeah, it is an investment.

I wanted to ask another question, if I may Carolyn, about the future. And you alluded to this in your paper, I know your work with Mary Whooley, you guys have done great work thinking about rolling out home-based cardiac rehab. And I think personally that the future of cardiac rehab for most patients, that we're really going to move the needle—I mean some of the policy issues are really important—but can you comment on just telling us what home-based cardiac rehab is and to what extent you think that is a potential solution to deal with these persistently low participation rates?

Dr Carolyn Lam: Actually Jarett, if I may just butt in before Alexis answers, I was about to ask that because I was just placing myself in the patient's point of view. And I mean even me, I hate going to gyms now and much rather work with a home app instructing me what to do and I can just do it here, you know what I mean? So I think that's a great question. Alexis?

Dr Alexis Beatty: I agree, the future is home cardiac rehab and using all the tools that we have at our disposal to make it easy to deliver home cardiac rehab. The evidence isn't quite as strong for home cardiac rehab but the existing evidence does suggest that it's equally effective to center-based cardiac rehab, it's just not reimbursed in the United States. So functionally it only exists in sort of integrated health systems like the VA.

The VA, for instance, has started delivering home-based cardiac rehab programs. I think it's now at over 30 centers in the US. And this has basically started in the last five years. And the programs are pretty similar to a center-based cardiac rehab program in that patients come in and they get an in-depth assessment from cardiac rehab professionals. But then the difference is that they go and exercise on their own at home and they check in with the cardiac rehab professionals usually on a weekly basis over the telephone. And so it ends up being more of like a coaching relationship between the cardiac rehab professionals and the patients who are exercising on their own at home. And a lot of patients really like it because, as you pointed out, it's much more convenient for them, they don't like going to a gym, they'd rather be walking around in their neighborhood or going to their local community pool to swim. So it just sort of addressed a lot of these patient issues and they don't have to pay a co-payment. So it can take some of these other barriers that are there.

Dr Jarett Berry: Like a Peloton bike for cardiac rehab, right?

Dr Alexis Beatty: Yeah. I mean you could even do that. For instance, in HF-ACTION they actually gave people exercise equipment for a HF-ACTION study for the home segment of the HF-ACTION study. So there certainly are models whereby we could just be giving exercise equipment. And in the VA I can mail people these little exercise paddlers that they can put on their floor or their table and you can use them with your legs or your arms. So certainly being able to send some of this exercise equipment to your patients may help them get them into doing things. But I think home cardiac rehab is the future.

And then also I do work on using technology to help deliver home cardiac rehab and I view technology for this space not as the solution but as a tool to help you deliver home cardiac rehab. And now that technology is so ubiquitous, I think that we need to now learn how to use the technology to help us better deliver cardiac rehab in a way that meets the patients' needs.

Dr Carolyn Lam: Wow. Jarett, I've actually got a question for you. You were just saying that you run the rehab unit there, so what messages did you take home from this paper?

Dr Jarett Berry: What I took home from this was exactly what we've been discussing, this issue of low uptake of cardiac rehab even in the scenario where you have a model where you're delivering this through Medicare or the VA we still see very low participation, albeit there is some variability. And so my interpretation after doing cardiac rehab here at Southwestern for the last year and half is exactly what Alexis is saying, is that we need to be really thinking more creatively about how we can deliver cardiac rehab where the patients are and not requiring them to participate in centers of cardiac rehab that are maybe 30, 40 miles from their home and in the middle of the workday, all of which just really makes such a model inefficient.

So I just think what this paper does really solidify is that we really need to be thinking broadly and creatively about how to bring cardiac rehab to more patients because the way we're doing this now I think unfortunately is just ineffective.

Dr Carolyn Lam: Anything to add, Alexis? This is great.

Dr Alexis Beatty: So one other point that I would like to mention. I think about 10 years ago there was another paper that used a very similar method, and we based a lot of our methods off of that paper by Suaya about 10 years ago. And they found that the rate of participation in cardiac rehab was somewhere very close to ours, I think it was 18% and we observed 16%. And since that paper was published cardiac rehab got included in guidelines, included as a performance measure, and there has been a big push and a lot of attention to try to get people into cardiac rehab and we have moved the needle zero since that time. So I think clearly something new is needed to move the needle for cardiac rehab just as Jarett was pointing out. So we got to do something because what we're doing isn't working.

Dr Carolyn Lam: That's a great call and thank you for showing that to us so clearly in your paper.

Dr Jarett Berry: Yeah, thanks Alexis and thanks for being so responsive in the revision process, it was a real pleasure to work with you all on this really important paper.

Dr Alexis Beatty: Thank you so much for publishing this paper. I feel I've been working on this for like five years.

Dr Carolyn Lam: Well you heard it here, listeners. Thank you for joining us today. Don't forget to tune in again next week.

Circulation April 24, 2018 Issue

24 april 2018 | 21 min

Dr Carolyn Lam: Welcome to "Circulation On The Run," your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center, and Duke National University of Singapore. Our featured paper today is so important for cardiac surgeons and their patients. It answers a question of whether targeting a higher versus a lower blood pressure during cardiopulmonary bypass helps to prevent cerebral injury. Curious? Well, more soon right after these summaries.

In the first original paper this week, MicroRNA-22 is shown to be a novel mediator of vascular smooth muscle cell, phenotypic modulation, and neointima formation. Co-first authors, Drs. Yang and Chen, co-corresponding authors, Dr. Zhang from Zhejiang University and Dr. Xiao from Queen Mary University of London and their colleagues used wire injury mouse models to show that MicroRNA-22 controls vascular smooth muscle cell phenotype and injury-induced arterial remodeling by modulating multiple target genes, including methyl-CpG-binding protein 2, histone deacetylase 4, and ecotropic virus integration site 1 protein homolog.

The authors observed that MicroRNA-22 expression was suppressed in human femoral arteries with atherosclerotic plaques, and that there was an inverse relationship between MicroRNA-22 and its target genes in healthy and diseased arteries. Furthermore, local delivery of MicroRNA-2 in the injured arteries prevented adverse arterial remodeling, thus suggesting that site-specific delivery of MicroRNA-22 mimics may be a potential therapy for in-stent restenosis.

The next paper adds to our understanding of the pathobiology of pulmonary hypertension related to left-sided heart failure and importantly adds histomorphometric evidence from human lung specimens at autopsy or surgery.

First author Dr. Fayyaz, corresponding author Dr. Redfield, and colleagues from the Mayo Clinic studied patients with heart failure with preserved or reduced ejection fraction and pulmonary hypertension and compared these to normal controls, as well as patients with primary pulmonary veno-occlusive disease.

They found that patients with heart failure and pulmonary hypertension had global pulmonary vascular remodeling with thickening of the media and intima in arteries and thickening of the intima in veins and small pulmonary vessels compared to normal control subjects.

This venous and small-vessel intimal thickening was more severe than the arterial intimal thickening in heart failure with a pattern that was similar to patients with pulmonary veno-occlusive disease. In fact, the severity of pulmonary hypertension correlated most strongly with venous and small vessel remodeling rather than arterial remodeling.

These findings expand our understanding of the pathobiology of pulmonary hypertension in heart failure. It also suggests that pulmonary venous remodeling in heart failure may predispose to worsening alveolar edema with pulmonary vasodilators as in primary pulmonary veno-occlusive diseases.

Are there sex and race differences in the lifetime risk of HFpEF versus HFrEF? First author Dr. Pandey, corresponding author Dr. Berry from UT Southwestern Medical Center, and their colleagues used participant level data from two large respective cohort studies, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis to determine remaining lifetime risk estimates for heart failure with preserved and reduced ejection fraction at different index ages.

They found that compared to women, men have a higher lifetime risk of HFrEF, heart failure reduced ejection fraction with a similar lifetime risk of HFpEF, or heart failure preserved ejection fraction. Compared with blacks, non-blacks have a similar lifetime risk of developing HFrEF but a higher risk of HFpEF.

Lifetime risks of HFpEF and HFrEF were similar and substantially higher in those with versus without antecedent myocardial infarction.

In summary, these findings provide novel insights on sex and race differences in the lifetime risks of HFpEF and HFrEF, and may help health policymakers in appropriate resource allocation for targeting HFpEF and HFrEF specific preventive therapies at the at-risk population.

What are evidence-based blood pressure targets during pediatric cardiopulmonary resuscitation? Well, first and corresponding author Dr. Berg from Children's Hospital of Philadelphia and his colleagues studied a multi-center population of children with invasive arterial blood pressure monitoring during in-hospital ICU cardiac arrest, and the Collaborative Pediatric Critical Care Research Network Intensive Care Units, between 2013 and 2016.

They found that a mean diastolic blood pressure greater or equal to 25 millimeters of mercury during cardiopulmonary resuscitation in infants, and greater or equal to 30 millimeters of mercury in children 1 year old or greater, was associated with a 70% greater likelihood of survival to hospital discharge, and a 60% higher likelihood of survival with a favorable neurologic outcome.

On the other hand, survival rates were markedly lower with mean diastolic pressures less than 20 in infants and less than 25 in children 1 year or older. Thus, clinicians should consider targeting diastolic blood pressure of 25 or greater in infants, and 30 or greater in children 1 year old or older during cardiopulmonary resuscitation when invasive arterial blood pressure is monitored.

That wraps up our summaries for this week. Now for our featured discussion.

Does a higher versus a lower blood pressure target during cardiopulmonary bypass surgery reduce the risk of cerebral injury? Well, the feature paper today provides some answers, and we have the first and corresponding author, Dr. Anne Vedel from University of Copenhagen with us today, as well as our associate editor, Dr. Timothy Gardner, who's a cardiac surgeon from University of Pennsylvania.

Thank you so much for being with us today and this was a terrific trial, a very difficult trial to carry out. Could you please tell us a bit more about it?

Dr Anne Vedel: Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. Up to half of our patients suffer these perioperative silent strokes. Therefore, in Copenhagen we conducted a trial investigating the importance of two distinct blood pressure levels during cardiopulmonary bypass. Now, on this subject of optimal perfusion strategy during bypass, there are many opinions, but also a stunning lack of convincing evidence, for instance, when it comes to blood pressure management.

Now, the question is whether normal physiological principles, such as cerebral autoregulation therapy, whether they apply during bypass, or if perfusion pressure indeed does play a less important role when blood flow is mechanically provided in an uncomplicated and sufficient way by the heart and lung machine.

So, in a patient on the assessor-blinded randomized trial, we allocated patients to a higher or a lower MAP target, 70 to 80, or 40 to 50 millimeters of mercury, respectively, by titrating intravenous norepinephrine during bypass.

Pump flow levels were set at 2.4 liters per minute per square meter of body surface, and our primary outcome was the total volume of new ischemic cerebral lesions, expressed as a baseline MRI, and opposed to the difference between the baseline MRI and the postop MRI on day three to six. Secondary outcomes were a number of new ischemic lesions and newer psychological test evaluations.

Now among the 197 patients enrolled who were scheduled for coronary artery bypass, or heart valve repair surgery, or a combination of both, we found that 53% of patients in the low target group as opposed to 56 in the high target group had new cerebral lesions on their postop cerebral MRI.

The primary outcome of volume of new cerebral lesions was comparable between groups, and so was the total number of newer lesions. No significant difference was observed in stroke rates in frequencies of postoperative cognitive dysfunction, or in severe adverse event rate.

Therefore, we concluded that among patients undergoing on-pump cardiac surgery, targeting higher versus a lower mean arterial pressure did not seem to affect the volume or number of new infarcts.

Dr Carolyn Lam: Wow, thank you so much, Anne. Tim, you think about these issues a lot more than I do as a non-surgeon. Could you tell me what your insights were?

Dr Tim Gardner: You know, it's a very difficult study to do a randomized control trial in this environment, and they're really to be congratulated for doing it. As Anne acknowledges, this is not an area where randomized trials are very frequent.

The first thing about the trial, I think, is a growing awareness among all of us that there seems to be a lot of imaging evidence of what we call injury or changes based on diffusion-weighted imaging in patients after cardiopulmonary bypass. This is not the first study that shows that.

But the question is are these incidental, trivial lesions? I'd have to, again, ask Anne to clarify how many of the patients in either group, what percentage had what we would consider evidence of overt strokes?

Dr Anne Vedel: Well, overt strokes, as opposed to silent strokes, 1 patient in the lower target group had stroke and 6 patients in the high target group, which corresponds to 1 as opposed to 7%.

Dr Tim Gardner: That was not quite statistically significant difference but headed in that direction with the assumption that if you have a larger sample size there might be, in fact, some association with overt stroke using the high target vasopressor approach, is that right?

Dr Anne Vedel: We can only speculate. But as you do, yes, I agree.

Dr Tim Gardner: To go back to the original question, the significance of these, well, you were referring to as silent strokes. Can you comment on the clinical significance there? We hear of silent heart attack. What is a silent stroke and what are the implications of that long term for patients?

Dr Anne Vedel: In other fields of research on the silent strokes, it's been shown that they correlate to both frequency of postoperative cognitive dysfunction and also later development of mild cognitive impairment and dementia. But these kinds of results, there isn't enough research in the field of cardiac study for us to say the same. But those are the implications from other research fields.

Dr Tim Gardner: But you can understand from the perspective of a cardiac surgeon, and this concern has been expressed and talked about in the literature for 20 years or more, the possibility that even what seems to be, with no injury apparent and no overt stroke, there may be some neurological consequence to cardiopulmonary bypass.

So just to move on from that because I agree that we just don't have any reliable information that these silent strokes result in late or permanent injury, I think again the finding that manipulating the blood pressure, which seems to be intuitively beneficial in patients, especially elder patients, did not, in fact, show any benefit and, in fact, may have been associated with a slight increase in overt stroke. Is that a fair conclusion from your study? A summary of your study?

Dr Anne Vedel: I would say it is a fair conclusion, and surprisingly so. The question is whether it is the blood pressure or the means that we apply to have this increase in blood pressure that is the point of interest here.

Dr Tim Gardner: You mean whether, in fact, using the norepinephrine, the vasoconstrictor, to increase the blood pressure whether that itself, it certainly didn't benefit, it may have been a problem.

Dr Anne Vedel: Exactly. That's what I speculate might be the case. But I also think it's fair to say at this point that this is somewhat artificial physiological scenario, the cardiopulmonary bypass.

Dr Tim Gardner: I agree with that, that you're controlling blood flow and the patient is exposed to a lower hemoglobin and oxygen-carrying capacity and so on. But I think what struck me about your findings, or strikes me about your findings, is what appears to be in many of the patients, the low target patients, pretty effective autoregulation of the cerebral circulation, despite the artificiality of cardiopulmonary bypass.

I think that's, again, something that has been not well known or well accepted by many people, thinking that if you lower body temperature, you lower hemoglobin, autoregulation may not be enough to maintain good cerebral perfusion. It looks like this study shows that in these patients, autoregulation worked fine. Is that fair?

Dr Anne Vedel: Yes. Or sufficient blood flow was delivered. All in all, what's new in our study, I think, is that hypertension per se shouldn't necessarily be considered a proxy for hyperperfusion during bypass.

Dr Tim Gardner: Yeah, that's a very good qualification. So none of your patients, despite being in their mid to late 60s had evidence of carotid artery disease or whatever? Those patients were excluded from the trial, is that right?

Dr Anne Vedel: No, that's not correct. We didn't screen for carotid artery disease because we don't routinely do that in our institution. As we describe in our discussion, we included quite a heterogeneous study sample by enrolling the patients that came to us. We didn't screen and we didn't exclude these patients that you mention.

Dr Tim Gardner: Do you know how does your group handle a patient that is known to have carotid artery disease, comes in with a known either prior endarterectomy or established disease? Do those patients, are they treated any differently either as a result of the study or just in general?

Because that is a targeted group of patients, at least in my own experience, that we would be more concerned about allowing autoregulation to be the determinant, feeling that if there is a fixed stenosis in the carotid artery that we might need to increase the mean arterial pressure.

Dr Anne Vedel: I can certainly understand your point and, of course, it is a concern in our center, as well. But having said that, there were no patients in the PPCI trial that came to us with a history of carotid artery disease, so it wasn't a concern for us in this study.

Dr Tim Gardner: That would be one point that I would make that we probably should pay attention to patients who do come for surgery and have known significant obstructive extracranial disease, but I understand that you didn't specifically have those patients or were aware of those patients.

I think that this is a very useful study for us concerned about the possibility of inducing cerebral injury with cardiopulmonary bypass. To some people it's sort of counterintuitive that increasing perfusion pressure didn't improve the tolerance of patients to cardiopulmonary bypass but that's why you did the study. I think it's a very notable and important report that's going to be in circulation.

The significance of these "silent infarcts" is merely something that we have to sort of sort out. I know you said that silent infarcts, as I agree, are associated with or presumed to be predictive of later cognitive dysfunction, dementia and so on. It really is a concerning message if that's the main message that comes out of these imaging studies. Because these are patients that, obviously, didn't have heart surgery for no reason, there was obviously a compelling indication for patients to have it.

You would hate to re-ignite this concern as we had in and around year 2000 when the group at Duke was talking about writing about patients who had cognitive decline after cardiac surgery, were going to end up being demented five or 10 years down the line, so, that's from the perspective of a cardiac surgeon. Let's stick with the evidence but let's follow-up and see how predictive these silent infarcts are and what the consequences are long term. Do you think that's fair, Anne? Am I making a fair statement?

Dr Anne Vedel: I absolutely do think it's fair. And for a cardiac surgeon as yourself, I would find it very interesting to see that these kind of studies are also conducted in TAVR patients where you have sometimes a 200% incidence of these silent strokes.

I mean you have a good taste as a cardiac surgeon if you only see them in 50% of your patients, understand me correctly, but I don't necessarily think that this high incidence, it's high, yes, but compared to other patient groups, such as TAVR patients, it's not necessarily that bad.

Dr Tim Gardner: Right. Anne, I don't know whether you've seen the editorial that's going to accompany your paper, but it's very good. It's very supportive of your study and has some good comments. You'll be pleased with the editorial, I believe, if you haven't seen it.

Dr Anne Vedel: Thank you very much. I'm happy to hear that. I know we do things a bit controversially over here in Copenhagen, compared to many centers in the U.S.

Dr Tim Gardner: That is not what the editorialists think. An anesthesiologist from Stanford and a neurologist from Penn, they have a very good commentary on your study and the whole field, so you'll be pleased.

Anne Vedel: I'm very happy to hear that. Thank you.

Carolyn Lam: Well, listeners, I'm sure you learned a lot. Thank you for joining us today, and don't forget to tune in again next week.

Circulation April 17, 2018 Issue

17 april 2018 | 22 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Does NT-proBNP-guided therapy improve outcomes in acute decompensated heart failure? Well the Prima II trial results are coming right up after these summaries.

Is hospital volume a good structural metric assessing the quality of care in heart failure? Well, in the first original paper this week from Dr. Kumbhani and colleagues at UT Southwestern Medical Center, authors determined the relationship between admission volume, process of care metrics, and short and long-term outcomes admitted with acute heart failure in the Get With the Guidelines-Heart Failure registry, which has linked Medicare in patient data at 342 hospitals.

They found that lower volume hospitals had worse adherence to important heart failure process measures, than higher volume hospitals. There was no association between risk adjusted in-hospital mortality and hospital heart failure admission volume among older adults.

After adjusting for adherence with process measures at discharge, annual heart failure admission volume had a minimal association with mortality, and readmissions up to six months post-discharge. Thus, rather than focusing solely on hospital volume, hospital profiling efforts should perhaps focus more on participation in quality improvement initiatives, adherence to process metrics, and risk standardized outcomes.

The next study describes the association between air pollution and heart disease mortality in the United States, with a focus on whether the association differs by race and ethnicity. First and corresponding author Dr. Jennifer Parker from the National Center of Health Statistics Centers of Disease Control and Prevention and her colleagues use data from the 1997 to 2009 National Health Interview Survey linked to mortality records through December 2011 and the Annual Estimates of Fine Particulate Matter or PM2.5 as an index of air pollution.

They found that the association between air pollution and heart disease mortality in this national sample was elevated and similar to estimates found in prior studies. After controlling for social demographic and geographic factors, the associations between air pollution and heart disease mortality for non-Hispanic black and Hispanic adults were not statistically significantly different from that of non-Hispanic white adults.

Thus, this study supports the application of findings from prior studies of air pollution and mortality, albeit largely from non-Hispanic white adults, but to other races and ethnicities in the United States.

The next study suggests that large cardiac muscle patches engineered from human induced pluripotent stem cells may be a reality. First author Dr. Gao, corresponding author Dr. Zhang from University of Alabama at Birmingham generated human cardiac muscle patches of clinically relevant dimensions of 4 x 2 centimeters and they did that by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human-induced pluripotent stem cells in a fibrin matrix and culturing this construct on a dynamic platform.

The results from in vitro assessments of calcium transience, action potential propagation, and forced generation, as well as the presence of intercalated disc-like structures, suggested that cardiomyocytes matured in these human cardiac muscle patches. During the 7-day dynamic culture period. When transplanted onto infarcted swine heart, measurements of cardiac function, infarct size, wall stress all improved with no increase in arrhythmias.

Changes in the expression profile of myocardial proteins indicated that the human cardiac muscle patch transplantation partially reversed abnormalities in sarcomeric protein phosphorylation. Collectively, these observations indicate that human cardiac muscle patches can be successfully generated and may improve recovery from ischemic myocardial injury.

Does a second arterial conduit improve outcomes after multivessel coronary artery bypass grafting? Well, in the next study from first author Dr. Goldstone, corresponding author Dr. Woo, from Stanford University and their colleagues used a clinical registry including all 126 non-federal hospitals in California to compare all-cause mortality, and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score matched cohorts, who underwent primary isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit or a venous conduit between 2006 and 2011.

The authors found that receipt of a second arterial conduit was associated with lower mortality, and at first cardiovascular events, compared with receipt of a venous conduit. The survival benefit associated with the use of a second arterial conduit extended to patients up to 78 years old. As a second arterial conduit, the right internal thoracic artery offered no benefit, compared with the radial artery, but it was associated with an increased risk of sternal wound infection.

These findings therefore suggest that surgeons should perhaps consider lowering their threshold for using arterial grafts and that the radial artery may be the preferred second conduit.

That wraps it up for our summaries. Now for our future discussion.

NT-proBNP and natriuretic peptides in general, have really become mainstay in management of heart failure, in the diagnosis, in the prognostication, but questions still remain regarding NT-proBNP-guided therapy. We heard about the guided trial in chronic heart failure just reported last year, and this year, in fact this week, in this week's journal, we're about to hear about PRIMA II trial in acute heart failure.

And how NT-proBNP was tested as a potentially guiding strategy for the management of acute heart failure. I'm so pleased to have the corresponding author with us, Dr. Wouter Kok, from University of Amsterdam, as well as our Senior Editor Dr. Biykem Bozkurt from Baylor College of Medicine. So welcome both of you, and Wouter may I just jump straight in it?

PRIMA II means that there was a PRIMA I trial, so could you just briefly tell us a bit about PRIMA I and the rationale for PRIMA II?

Dr Wouter Kok: Well the PRIMA II was an in-hospital guiding therapy that was preceded by the PRIMA II, it was a chronic heart failure patient population and one of things that we noticed in PRIMA I was the lack of effect of trying to reach a percentage drop in chronic heart failure patients. Why is that? Is that because there is a long time before you can achieve a therapy adjustment? Or is it something else? And shouldn't we start before patients are discharged from hospitals?

So the idea was born to do an in-hospital guiding study instead of chronic heart failure patients study.

Dr Carolyn Lam: Interesting. And could you tell us briefly, the design of PRIMA II and your findings?

Dr Wouter Kok: So the PRIMA II was designed based on the previous publication of several authors indicating that a 30% reduction in NT-proBNP would be a good target for heart failure therapy. Now, we first asked ourselves the questions, whether we should put this target in front of the hospital admission, so in the first 2 days or perhaps at the end of the hospital admission? And the 30% reduction was validated only for discharge purposes, so but we also tried to establish whether we could precede this date a little bit before discharge, but it appears that you cannot precede it too much.

So you cannot do it at day 3 or day 4, when patients are not stable. Because then you may expect a rise in proBNP again before discharge, and then you already ran the rise patients to discharge. So we decided to do it at discharge. At least 1 or 2 days before discharge, when patients would be clinically stable. And this definition of clinical stability was important because there should be one guideline for doctors to say, OK this patient has been treated well, or not.

Dr Carolyn Lam: Interesting. And so patients were randomized only after clinical stabilization, though in hospital after an acute decompensation, right? And then maybe the randomization arms, and the results please?

Dr Wouter Kok: Yeah, so the patients were randomized about day 7 or 8 after clinical stabilization, and day 3, but also patients at day 9, but when they were stable, they were randomized. And then the proBNP was measured, and when it was not reduced more than 30% they were guided. And when they were reduced more than 30% they were not guided but they were made ready for discharge.

So this was the randomization group. And the conventional group, the NT-proBNPs were measured at the randomization, and also at discharge, but nothing was revealed to the doctors. So it was only as a comparison for example, in the number of days necessary to wait before discharge, if this would influence the results.

The main finding is that the end point was negative for total mortality after 6 months, in combination with heart failure readmissions. So there were about 36% end point in both groups.

Dr Carolyn Lam: Yeah Wouter, you know, we've just come from the guided trial that was so soon neutral and infect, ended early and that was in the chronic heart failure setting so very different from what you tested in PRIMA II. Congratulations first of all for a beautifully done study.

But may I just ask, because in guided it was mentioned repeatedly that perhaps even the control arm was treated so well because these were such specialized centers. So what kind of centers took part in PRIMA II?

Dr Wouter Kok: We started at centers in Amsterdam, they were all very well educated in heart failure treatments, and all were using proBNP before the study started, so they were experienced in interpreting proBNPs. Because we had too little centers, and the inclusion rate was not so fast, then we asked other centers to participate, and we asked 2 for instance in Barcelona and Porto in Portugal, which helped us to complete the trial.

Dr Carolyn Lam: Oh that's really nice. And the design is really quite special, and I'm so appreciative that you took the time to explain that they were randomized only when stabilized.

Biykem, what do you think of that?

Dr Biykem Bozkurt: It's a fascinating trial, I have to congratulate Wouter and his colleagues. The number one very important finding I think is, about two-thirds of the patients before randomization are able to achieve reduction of NT-proBNP more than 30%. So subsequent to that in the guided therapy we're able to achieve maybe an incremental additional 15% adding to about, I think 80% of the patients initially randomized to the NT-proBNP arm. Achieving a reduction more than 30%. So overall, if the patient's naturally before randomization, achieve a reduction NT-proBNP, two-thirds of the time, pushing it further, trying to achieve a further dry state, by randomization does not appear to make any changes in readmission rates, or mortality at six months.

So this very important finding is the majority of the patients on conventional strategies are able to be decongested and achieve clinical stability. Now the other important finding is, I think about 17-20% of the patients regardless of what we do, do not demonstrate this significant drop in their NT-proBNP levels. Which I call as a non-responder team, which is a fascinating group of individuals. So we have the yin-yang, individuals may actually demonstrate that they're responsive. And when they're responsive, then the majority of the patients do demonstrate a reduction by more than 30%, and even if we push it further by targeted therapies, don't make a difference in outcomes.

About 17-20% regardless of what we do, do not respond, and from former studies we know that those patients are associated with worse outcomes. The other important finding I think, is what changed in the study? What medications, what therapies were changed? It was fascinating from Wouter's group to recognize that there was a little, significant, but a little increase in the ACE admission prescription. But there was also an interesting finding in the guided therapy, that the beta blocker used was slightly lower.

That raises a question of if we were to just chase the numbers, meaning try to just target therapies according to the NT-proBNP levels, whether we would see some unintended consequences such as reduction in medications, just because the numbers may be going in one way or the other. This is acknowledged in Lynne Warner Stevenson's editorial that will be accompanying the paper. And the editorial is very nicely titled "Getting to Dry". So I found that fascinating to recognize that the therapies, when especially the conventional arm is treated well, did not differ.

As was the case in the guided trials. When you treat the patients very well, as was seen in this trial, there was not much of a difference. But again trying to treat a number by targeted therapies may not result in all the optimization that as we envisioned to see. And the third concept is the length of stay, of course in the U.S. is a major issue, and I do realize when we're trying to treat a number, sometimes the length of stay may end up being longer. And I do realize that perhaps in the targeted therapy group, the length of stay was a little bit longer, maybe Wouter can comment on that.

But overall it didn't result in any change in outcomes, or was not associated with any of the outcomes. So that was also an interesting finding. Because we tend to focus a lot on length of stay, but interestingly I guess by secondary analysis, there was no association with the clinical outcome.

Dr Carolyn Lam: Wouter, would you want to comment the length of stay concept?

Dr Wouter Kok: Well it's indeed in the guided group, and the randomized group who were trying to attain the 30% NT-proBNP reduction, the length of stay was longer. Something about 11 days, compared to those who did not need guiding was about 8 days. Still long compared to U.S. standards, but it was the same in the conventional group, so about 9 days is respective of whether they reached a 30% reduction or not.

So here is the clinical experience. So the patient cannot tell whether he is reduced more than 30%, and the doctor isn't able to tell either. Because then the admission would have been longer probably. But trying to lower the 30% more, has some effect. There's little effect, but it has some effect. And then they have to do a sort of economic analysis, is 3 days longer in hospital, is it worthwhile to do that compared to for example reduction in admissions that you receive? This is a small population, only one-third of the patients who need guiding, and more than half of them you will reach somewhat more reduction than if you don't try at all.

So for us, that is the main result of the trial, if there is a signal, then it is still possible to do something, and the other remark about whether you increase or decrease medication, that's something that was discussed in the guided study too. So what is the best for the patient, is that the maximum medication or not, and we see for example, that if we reduce beta blockers, in some patients then some will improve in their functioning and also in the BNP.

So it's not always necessary to increase and increase medication. So that was also some signal that we tried to do some more research in. What is the target? Is the target a guideline, saying that more medication is better? Or is the target itself for proBNP a possibly better target than that?

Dr Biykem Bozkurt: And the other interesting finding for that, there were no differences in chemo concentration levels in the guided versus non-guided groups. And last point that I wanted to make is the larger BNP reduction was amongst the individuals who did not require any guidance in successfully guided versus unsuccessfully guided, compared to those who did not need the guidance.

Those who were able to achieve the more than 30%, when you look at the magnitude, meaning amongst the individuals who are going to naturally respond to therapy, the natural responders, the decrement, or the decrease in the BNP levels are larger, than those ones we're trying to push. So that was another interesting, fascinating ... I was almost thinking whether that in the future we should look at responsiveness of patients, if we see they're responders then try to target their therapy or not.

So in a sense the non-responders, they now respond regardless of what we do. Responders may be gaugeable or titratable, or maybe with the precision respond to targeted therapies that almost have a dichotomous approach. What do you think about that Wouter?

Dr Wouter Kok: I say yeah we made a big mistake in thinking that more than 30% for patients who still needed guiding would be the same as rating the more than 30% without guiding. But the difficulty you have in reaching the 30% is already indicative somewhat less increase in prognosis than you will reach it spontaneously.

So we have to adapt our numbers for the trial, so it is recalculation that how many patients we would need to be successful in our trial, and that would be 600 patients in every arm, and then even then, you have to recalculate some of the effects that you will have to reach them. Perhaps the mid-range risk group is a better risk group to target than the highest risk group. That's something that we have to think about too.

Dr Biykem Bozkurt: I think we will probably need to focus on individualization, I almost feel as though we will need to learn from the cancer trials, and see whether we could try to target rather than you know the population based clinical trials, trying to do the targeted therapies. Maybe fine tune the ability to precisely target, and of course that requires a little bit more layering of the markers and or a signal that we're going to be profiling in the individual.

So I don't think it's the end of targeted therapies, perhaps requiring a little bit of a more precision, and maybe individualization. But I am fascinated by first realizing it's a responder, and then maybe trying to accelerate and or optimize therapy, perhaps especially when we are forced or driven by administrative concepts such as length of stay or others. So making sure that maybe these variables, these biomarkers may help us recognize that maybe we haven't achieved that appropriately dry state yet.

But those all need to be determined, of course, by future trials, so far targeted therapies both in the acute and in the chronic does not seem to result in implementing outcomes.

Dr Wouter Kok: Well and the next step for us is to try and think how can reduce proBNP in all patients, we tried it with medication, but didn't do that much of catheterizations for those who were ... there were 50% of patients who were ischemic so why don't we do much of these catheterizations now days. So that's something we're thinking about how can we improve these patients? What are we missing?

Dr Carolyn Lam: Yeah, if I could add my two cents. So Wouter mentioned finding the right therapies that can effectively reduce NT-proBNP safely, and well you mentioned choosing the right patients to use this in. And if I may, you know, just adding perhaps the right settings as well. Because it's well known that not all of us take care of heart failure patients the same way. And maybe there are settings where having a number to guide us may be more useful than others. But what do you do? You know, we wait for more data, but in the meantime, just congratulations. Heartfelt, heartfelt congratulations Wouter for a beautiful study, thank you so much for the privilege of publishing it in Circulation.

Thank you for being on this podcast, and listeners don't forget to tune in again next week.

Circulation April 10, 2018 Issue

9 april 2018 | 25 min

Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I am Dr. Caroline Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Can we reverse the cardiac effects of sedentary aging? Well if you're curious, you have to read the feature paper in this week's journal, as well as listen to the upcoming discussion of a trial that addresses this issue. All coming right up, after these summaries.

Desmond mutations are known to cause skeletal and cardiac muscle disease, and also recently has been described in patients with inherited arrhythmogenic right ventricular cardiomyopathy or dysplasia. In today's first original paper, however, authors identified a novel Desmond mutation in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy or dysplasia, and a high incidence of, at first, cardiac events.

First in corresponding author, Dr. Bermudez Jimenez from Granada, Spain, describe for the first time the largest family to date with a single Desmond mutation with a phenotype of left dominant arrhythmogenic dysplasia in the absence of skeletal myopathy symptoms and atrioventricular conduction disorders and supported by strong clinical and functional data. In a series of elegant experiments using explanted cardiac tissues and mesenchymal stem cell derived cardio myocyte from the family members, the author showed that the pathogenic mechanism probably corresponds to alteration in Desmond dimer and oligomer assembly and its connection with membrane proteins within the intercalated discs, thus Desmond mutations should be suspected in patients presenting with a cardiomyopathy characterized by mild left ventricular systolic dysfunction and/or dilatation, fibrosis, ventricular arrhythmias and a family history of sudden death.

The next study is the first large scale report examining the incremental risk of surgical aortic root enlargement in patients undergoing aortic valve replacement.

First author Dr. Rocha, corresponding author Ouzounian from University of Toronto and their colleagues sought to evaluate the early outcomes of patients undergoing aortic valve replacement with or without surgical aortic root enlargement.

Now aortic root enlargement allows for larger prosthesis implantation and maybe an important adjunct to surgical aortic valve replacement in the transcatheter valve in valve era.

Among more than 7,000 patients undergoing aortic valve replacement at a single institution from 1990 to 2014, the authors observed no incremental risk in post-operative mortality or adverse events following surgical enlargement of the aortic root as compared to aortic valve replacement alone. They therefore concluded that surgical aortic root enlargement appears to be a safe adjunct to surgical aortic valve replacement in the modern era.

The next study suggests that in patients with acute coronary syndrome and an LDL cholesterol above 50 milligrams per deciliters, health care providers should consider adding ezetimibe to statins, particularly in two patient subgroups.

First in corresponding author Dr. Giugliano from the TIMI study group at Harvard Medical School in Boston, Massachusetts and his colleague explored outcomes stratified by diabetes in the "improve it" trial where patients with a recent acute coronary syndrome were randomized to ezetimibe versus placebo on top of backgrounds in the statin.

They found that patients with diabetes derived significantly greater relative and absolute benefit with the addition of ezetimibe relative to patients without diabetes. This enhanced benefit was driven by reductions in acute ischemic events including myocardial infarction and ischemic stroke in diabetics, while non-diabetic patients who were more than 75 years of age or who had a high risk score also significantly benefited from the addition of Ezetimibe to Simvastatin.

These benefits of Ezetimibe were achieved without an increase in safety events compared to placebo. Thus, the two patient subgroups of acute coronary system who are likely to achieve greater benefits with the addition of ezitimibe include: one, patients with diabetes, and two, patients without diabetes who have a high risk score.

The final study provides insight into sudden cardiac arrests in the young and the potential contribution of standard cardiovascular risk factors to this risk, even in the young.

First author, Dr. Reshmy Jayaraman, corresponding author Dr. Chugh from Cedars-Sinai Medical Center in California and their colleagues, prospectively ascertained 3,775 individuals who suffered sudden cardiac arrest between the ages of 5 and 34 years in the Portland, Oregon Metropolitan area and who were also followed up for 13 years. They found that 5% of cases occurred in young residents between the age of 5 and 34 years.

Among the young, there was an unexpectedly high prevalence of classical cardiovascular risk factors, such as obesity, diabetes, hypertension, hyperlipidemia and smoking. In fact, one or more risk factor was observed in 58% of cases, with obesity being the most common.

Less than a third had warning symptoms prior to their lethal event and sports activity was a trigger in only 14% of young cases. Thus, standard cardiovascular risk factors, especially obesity, may play a larger role in sudden cardiac arrests in the young than previously recognized. This suggests the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.

And that wraps it up for our summaries, now for our feature discussion.

Oh boy, today's featured discussion is gonna make everyone listening fall in love with exercise and seriously get off your chair right now as you listen to this discussion.

It's about how exercising may reverse cardiac aging and I am so delighted to have with me none other than the corresponding author, Dr. Ben Levine from the institute of exercise and environmental medicine at Texas Health Presbyterian and UT Southwestern, as well as Dr. Jarett Berry, and he's our dear associate editor from UT Southwestern.

Ben, I have been dying to have you on this show, so welcome and please, tell us what you did.

Dr. Ben Levine: Thank you very much, it's a pleasure to be here Carolyn, thanks for inviting me to talk about it. As you know, our lab has been particularly interested in the components of aging that are related to senescent versus those that are related to senescence activity.

Perhaps the most dramatic reason that we're interested in this, I'm just gonna give you a little bit of background, if you don't mind, comes from one of the most important studies ever done in our field, that was done in Dallas in the mid-1960s. It's called the Dallas Bedrest and Training Study.

At that time, my mentors, G Blomqvist, Jerry Mitchell, Bengt Saltin, took five young men, put them to bed for three weeks and then trained them for two months and virtually everything we know about the adaptive capacity of the circulation to exercise starts without study.

I was only ten years old, so I really had nothing to do with it, but 1996, 30 years later, we found those same five guys and brought them back to Dallas to study them again.

Now, these are the most intensively studied humans probably in the history of the world. 78 pages of circulation in 1968. What we found was quite amazing. We found that not a single one of those five guys was in worse shape 30 years later, than they were after three weeks of bed rest when they were in their 20s.

So, three weeks of bed rest was worse for the body's ability to physically work than 30 years of aging. And so, we sort of launched off that in a series of experiments, trying to figure out when in the aging process does the shrinking and stiffening of the heart develop, that is the sine qua non. if you will, of the cardiac aging. So, when does it start? How much exercise do you have to do to prevent that?

We did one interesting study where we compared a group of very highly selected seniors, all aged around 70, who were healthy, but did no exercise, compared to a group of elite Masters Athletes. Amazingly, the healthy seniors, their hearts got smaller and it shrunk and they got stiffer and the athletes had hearts that were indistinguishable from healthy 30 year olds.

So, a lifelong training at the level of being an elite athlete completely prevented that aging response, which is really interesting scientifically, but not a very good public health measure.

So, we then asked how much exercise do you need to do over a lifetime to preserve the compliance, the youthfulness, if you will, of the circulation, and at times, they act like you need to do about 4 or 5 days a week over a lifetime. 2 to 3 days a week didn't do anything. 4 to 5 days a week did almost as much as being an elite competitive athlete. So, now we've got the dose. 4 to 5 days a week.

We said, "okay, if we do that, can we reverse cardiac aging once it's occurred?" So, we took our healthy sedentary people and we also looked at a group of HFpEF patients and we trained them for a year, at the right dose, using high intensity exercises. We made them fitter, but we couldn't touch their cardiac or vascular stiffness. Quite disappointing actually.

Last thing then, we said "okay, this leads up in to our current study maybe, just maybe, if we pick the right sweet spot in time, when the heart is just beginning to stiffen in that late middle age period and deal the right dose at the right time for a long enough period, we could reverse the effects. And, that's what we did. We took 60 people, healthy, middle aged, 45-64, mean age around 50. We randomly assigned them to two years of exercise training or two years of yoga, balance, flexibility, and we did 2 light heart caths. We measured their cardiac compliance directly invasively and we showed that our 2 year training program, which included high intensity intervals, reversed the effects of decades of sedentary aging.

Dr. Carolyn Lam: Wow, Ben, you know, no one tells the story like you and I have to tell you, I've been a fan of your work, citing it since I was 10. Thank you so much for this amazing contribution to the Journal this week. I just know everybody's asking questions like "So, you've given us when to start, you given us the dose, but we want to understand a bit better, what do you mean high intensity, how many minutes and what exactly." Could you give us an idea?

Dr. Ben Levine: Sure. There are multiple different ways to go about doing HIIT or High Intensity Interval Training. And there's no magic to intervals. Intervals just allow you to do something for a shorter period of time and harder than you could do for a longer period of time. That is the strategy that athletes use to go faster and stronger and higher, because the body adapts to the load that's placed on it.

Interval training, what I like, is based on an old Norwegian ski team workout. It's called the "4x4". What that means is 4 minutes at 95% of your maximum followed by 3 minutes of recovery, active recovery, repeated 4 times. So, basically, you go as hard as you can go for 4 minutes and at the end of those 4 minutes, you should be ready to stop. Typically, your heart rate will drift up towards 95% of maximum or so. Then, at the end of the 3 minutes of recovery, you should be ready to do the next interval.

As it turns out, that's extremely effective training stimulus. Not just for healthy people or athletes, for the patients with hypertension and with heart failure.

Dr. Carolyn Lam: I noticed that you have to screen over 260 individuals to finally get your 60, so how doable is this and what was the compliance?

Dr. Ben Levine: Right. You have to remember that out of those 260 individuals that we screened, the majority of them were excluded up front because they had hypertension or if they were obese or they already had heart disease. So, the first round of screening was making sure we're getting people of the right age and were healthy. And, then another fraction, say 40 of them or so, didn't wanna undergo two light heart catheterizations. And, I get that. We were pretty pleased that somebody volunteered to do it, but you know, it's an intense commitment. People have to be willing to be randomized. So, they couldn't say "Well, I wanna do your study, but only if I get randomized to exercise", that was not acceptable.

So, everybody had to be prepared to be randomized to either yoga or the fitness training and the yoga, it makes people feel better, it's relaxing. I think it provided that clinical equipoise and it ensured that even the controlled patients had close contact with our research team.

Then, what we had was, on average 88% of the prescribed sessions were followed by our exercisers and a fraction of them, 15 or 20%, actually did 100% of their prescribed sessions over two years, didn't miss a single one.

Dr. Carolyn Lam: So, Jarett, have you started doing that yourself now?

Dr. J Berry: I tell you, I pried my kids out of bed last summer, to go do 4x4s and get them ready for cross country. I talked all about Ben Levine and told my kids that we were doing what Dr. Levine recommended. That didn't help too much, they found it rather challenging. It was interesting that the VO2 plateaus a little bit at that 10 month mark, when you guys backed off on that additional interval training. Do you think that the plateau is just a limitation of the training effect or do you think that something that has to do with the lower level of interval training at that time?

Dr. Ben Levine: You know Jarett, I think that's a fascinating question and it's one of the things that really surprised me. So, Jarett pointing to the fact that at that 10 month mark, we measured VO2 max, we didn't cath them, but we did an Echo, and it showed that from 10 months to 2 years VO2 max didn't increase very much.

There was a dramatic increase from baseline to 10 months. It took 3 months at that peak dose. But then, when we dropped one interval and did the same thing every week for 2 years, there wasn't an influence of time. The heart didn't continue to get bigger, the stroke volume didn't continue to enlarge.

I think it highlights a critical part, an essential element, to that exercise training and that is, doing the same thing, over and over again doesn't get you fitter. If you wanna get fitter than you are, you have to change things around, you have to increase the load. So, I think that if we had wanted to make them even fitter than they were at 10 months, we'd have had to either kept that second interval or added another one or increase the duration of some of the base training sessions.

It's really interesting to me, that they didn't continue to improve simply on the basis of time. That surprised me.

Dr. Jarett Berry: Yeah, cause you wonder. You think about, the guidelines suggest moderate intensity exercise, which is obviously much lower intensity than what you're talking about with this interval training, but very little guidance with regard to interval training.

Your data here obviously suggests that it's not just getting off the couch and doing something, and not just doing a decent amount, it seems to suggest that the interval training component may be a secret ingredient that might be most helpful, at least for those patients who can tolerate that level of training.

Dr. Ben Levine: Yeah, I think that maybe it's the secret sauce, Jarett, but I think, you do have to ask yourself, what is the goal of training and what is your objective outcome? What you want is to reduce cardiovascular mortality. I think we would all agree that you get the biggest bang for your buck by going from sedentary to active. And, the mechanism of that is uncertain, but could relate to autonomic function or clotting or improving stabilization of endothelium or other risk factors, inflammation, who knows, there's a lot of different candidates. So, I think that particularly for people who are at the highest risk for heart failure, either from their family history or other risk factors, like hypertension and diabetes, those are the ones who were likely to get in a special benefit on altering cardiac structure.

That's why I think our data is still an important poll. We didn't really know why do you get the biggest bank for your buck with a little training, but if you really wanna prevent heart failure, you gotta do more.

In our data that we did partnered with the Cooper Clinic and looked at people who had done the same number of exercise sessions over 25 years. None, 2-3, 4-5 or 6-7, over 25 years, we saw virtually no effect of 2-3 days a week of what we call casual training on anything we could measure, related to cardiac structure. Their vascular stiffness was the same as people who were sedentary, their cardiac stiffness was the same as people who were sedentary. They were a little fitter and perhaps there were other important differences that are related to just improving immortality, but you have to get past that low to moderate dose to have the structural effects on the circulation.

Dr. Jarett Berry: These are really great points here, Ben. I want for our listeners to hear you comment a little bit more on the primary outcome and how you guys measured stiffness, because I think in addition to the level of training, it's also the approach and the phenotype that you collected to measure this and I think it would be helpful for you to walk us through that a little bit and how you guys measured stiffness.

Dr. Ben Levine: We used an old physiological technique called "Lower Body Negative Pressure". We first let the subject settle down, we measure a variety of cardiovascular variables, cardiac output, and we do an advanced ECHO imaging and some arterial stiffness measures and after about 40-45 minutes or so, we'll measure the pulmonary capillary wedge pressure, that's what we use as an index, and plus ventricular and diastolic pressure. We'll do 3D ECHO volumes and then we unload the heart by doing Lower Body Negative Pressure. We basically seal the subject in a box at the iliac crest and turn on a vacuum cleaner and suck blood into their venous capacitance. It's a very simple way to unload the heart.

In contrast to people who do put in conductants or reflectant catheters and occlude the IVC and do pressure volume rudes, we have taken a little bit of a different approach. I do steady state and diastolic pressure volume curves. So that means, we look at the pressure and volume in the heart at baseline at two different unloading levels. So, let's say the baseline ledge is 10. The first level of LBNT of minus 15 will get it down to 6 or 7. The next level of minus 30 gets it down to 2 or 3. And, so we get a nice unloading of the heart and we're able to establish a steady state, which is probably more afunctional than a release of an IVC occlusion.

Then, we let go of the suction, everything returns to normal. We repeat our baseline measures and then we give the rapid saline infusion. When I say rapid saline, I mean 15 and 30 mls per kilogram, that's at 200 mls a minute. That's a big volume infusion, but we'll give those doses and we'll raise the ceiling pressure from 10 at baseline to 15 and then 19, 18, 19. So, we get a large physiologic range of the diastolic pressure volume curve, and then we'll fit that to an extremely widely accepted exponential equation, which allows us to calculate the overall stiffness of the heart, the diastolic component, and then we'll do a few other things, we'll measure distensibility , which is the volume at any given pressure and DPDV, the change in pressure for a given volume, which is the hansen float to the exponential curve fitting.

Dr. Jarett Berry: Can you comment a little bit about what this means for how this is distinguished perhaps from maybe more conventional non invasive measurements of cardiac stiffness?

Dr. Ben Levine: I think the most important thing to realize is that, cardiac compliance is dynamic. It depends on the volume at which you're making that measurement. So, as you unload the heart, any heart, even the stiff heart, it gets more compliant, and as you load the heart, even a compliant heart, it gets stiffer. Part of that is a function of pericardial constraint, as well as myocardial stiffness.

The whole idea that there is a measure of diastolic function that you can measure by ECHO that is load independent is frankly an oxymoron, because, diastole is load dependent. I think the ECHO measurements are interesting and useful, depending on what you're trying to find out, because there are many different aspects of feeling and diastolic suction and diastolic stiffness. All of which influence how well the heart feels at rest and during exercise.

Dr. Carolyn Lam: I have to ask you one last question. I am so pleased that you included at least 52% women. Were there any differences by sex?

Dr. Ben Levine: Of course, Carolyn, it's critical to include women, since they're 50% of the population. We've been very interested in their training responses in men and women at different age groups in many of our other studies. What's interesting is that in premenopausal women, there's a quite clear distinction in how women respond to training. They don't hypertrophy as much, even for the same stimulus, heart beats a heart beat, over a year, there's a much less hypertrophic response to premenopausal women than young men.

We didn't see anywhere near that difference in our mostly postmenopausal middle aged men and women. We didn't have enough power to clearly be confident that there was no difference, but when we tried to test that hypothesis, whether there was a different response in men or women, we could not detect a difference.

Dr. Carolyn Lam: That is a good thing. So, women out there, you heard it from Dr. Levine. We got to exercise too. High intensity. All the time.

Thank you audience, for listening today. Don't forget to tune in again next week.

Circulation April 3, 2018 Issue

2 april 2018 | 22 min

Today's feature paper is about statins, and it's the first population-based study to show a dose-dependent benefit on amputation and survival in peripheral artery disease. Very important data and a very important discussion coming right up after these summaries.

The first original paper this week indicates for the first time that the natural history of coronary stenosis is better predicted by physiologic information by FFR, or fractional flow reserve, than by anatomic information from angiography. First author, Dr. Ciccarelli, corresponding author, Dr. DeBruyne, from OLV Hospital in Belgium compared the values of angiographic diameter stenosis and of fractional flow reserve in predicting the natural history among 607 patients from the FAME 2 trial who had documented stable coronary disease and in whom no revascularization was performed. The primary end point was defined as vessel oriented clinical end point at two years, and this was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent and non-urgent revascularization.

The overall results showed that FFR predicted the natural history better than diameter stenosis. In addition, among the stenosis with mismatch between diameter stenosis and FFR, more than half had a low FFR in the presence of an angiographically mild stenosis and the rate of primary outcome was higher in those with reduced FFR regardless of whether diameter stenosis was significant or not. The take-home message is, therefore, that measurements of FFR should be considered not only an angiographically intermediate stenosis but also perhaps a mild or severe stenosis by visual evaluation.

The next study provides population-based data on cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter-2 inhibitor, or SGLT2 inhibitor. First and corresponding author, Dr. Udell, from University of Toronto, and his colleagues, performed population-based cohort study among type 2 diabetes patient with established cardiovascular disease and newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between 2013 and 2016. After propensity matching, more than 25,250 patients were followed for a median of 1.6 years. Initiation of SGLT2 inhibitors was associated with a lower all-cause mortality, lower hospitalization for heart failure events, lower major adverse cardiovascular events, but higher below-knee amputation risk. Findings underscore the potential benefits and risks to be aware of when initiating SGLT2 inhibitors. Importantly, it remains unclear whether the risk of below-knee amputation extends across a class of medications as the study was not powered to make comparisons among individual treatments.

The next paper reports results of the redefined trial, which is the first trial to study the effects of renin-angiotensin-aldosterone system inhibitors in adults with tetrology of Fallot and mild right ventricular dysfunction in the absence of severe valvular lesions. First author, Dr. Bokma, and corresponding author, Dr. Bouma from Academic Medical Center Amsterdam, and their colleagues, studied 95 patients in the redefined trial and found that 150 mg of losartan daily did not significantly improve the primary outcome of right ventricular ejection fraction change compared to placebo. There were no significant treatment effects on secondary outcomes of left ventricular ejection fraction, peak aerobic exercise capacity or NT-proBNP. However, in a post hoc analysis, losartan was associated with improved right ventricular ejection fraction in a subgroup of 30 patients with nonrestrictive right ventricles and incomplete remodeling. The conclusion is, therefore, that losartan had no significant effect on right ventricular dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups.

The final study reinforces that vesicle trafficking plays an essential role in the signal regulation of pathologic hypertrophy and identifies a novel potential target in this process. This novel target is the transmembrane BAX inhibitor motif containing 1, or TMBIM1. First author, Dr. Deng, corresponding author, Dr. Li, from Wuhan University in China, and their colleagues, found that TMBIM1 expression levels were substantially decreased in both clinical and experimental hypertrophic hearts. Mechanistically, TMBIM1 interacted directly with tumor susceptibility gene 101 and accelerated the formation of multivesicular bodies to degrade activated toll-like receptor 4. Toll-like receptor 4 degradation in turn was essentially for the progression of cardiac hypertrophy. Importantly, expressing TMBIM1 in monkeys via lentivirus protected their hearts from aortic banding induced cardiac hypertrophy. In summary, these findings shed light on the role of vesicle trafficking in signal regulation during cardiac hypertrophy and provide a novel therapeutic target for treating hypertrophy.

That wraps it up for our summaries. Now for our feature discussion.

Peripheral artery disease, a disease that affects more than 200 million individuals worldwide and associated with a high risk of cardiovascular events and death and, of course, the much feared amputations. Yes, statin guidelines for peripheral artery disease are largely based on coronary artery disease or stroke data. Well, today's feature paper really addresses an important knowledge gap between statins, doses, amputation survival in peripheral artery disease. I'm delighted to have the first and corresponding author, Dr. Shipra Arya from Stanford University School of Medicine and, of course, our favorite, Dr. Josh Beckman, Associated Editor from Vanderbilt University.

Now, Josh. I understand there's a bit of a back story of how this paper came to circulation. Want to share?

Dr Josh Beckman: Oh, absolutely. First of all, I have to say that one of the jobs of an associated editor is someone who kind of goes antiquing in every single store. Every place I am where people are presenting really good science, I'm kind of scoping it out. I'm interested. I want to see what's going on. I like to talk to the people who are doing the work to see how they're thinking about it, and I was lucky enough to see Dr. Arya's presentation. I think it was at an ATVB meeting, wasn't it?

Dr Shipra Arya: That's right.

Dr Josh Beckman: I thought that this is an incredibly cool piece of work, and I basically hoped, I prayed, I asked. I said, "You know, maybe you should send this to us because we would really like to see the full manuscript," because inside I hoped that it would be just as impressive when it was written out as a full manuscript as it was when she was discussing it at the meeting. And, lo and behold, we were lucky enough that she submitted it to us and you can see the results online right now.

Dr Carolyn Lam: Indeed! Well put. Shipra, with that kind of lineup, please, tell us about your study and what you found.

Dr Shipra Arya: Thank you for that invitation to submit to Circulation because initially I wasn't sure if Circulation would be interested in my work, so it was really great to hear when Josh said that this is something that it would certainly consider. The basic premise was to try and find out whether high-intensity statins as defined by the 2013 lipid guidelines, they would also have limb protective effects for PAD along with reduction mortality. As you said in the introduction, most of the data comes from either coronary data or comes from small groups of PAD patients, but never from such a large population.

We identified about 150,000 veterans in the National VA database from 2003 to 2014 and excluded people who didn't have a diagnosis of PAD before 2003, and why this was such a labor of love was also to figure out how to identify the certainty that people had PAD and then getting into their pharmacy files and trying to parse out whether they were on high-intensity, low, moderate, or no statin. Initially, I had done the analysis of no statin, but then after review and discussion, it became clear that we needed a control group, which was people who were also on some guideline-directed therapy and not just no statin because they could be patients who were the noncompliant patients and who don't show up to the doctor's visits, and that's why they do poorly.

That's why we chose a control group which were on antiplatelet therapy, at least aspirin or Plavix, any other antiplatelet agent. Even in that comparison, we find that after risk adjustment, patients who are on high-intensity statin had a more than 30% risk reduction of amputation as well as about a 24, 25% risk reduction of mortality compared to people who did not take a statin but at least took an aspirin. Low to moderate intensity statins were also effective, about 20%. Risk reduction in both amputation and mortality, but high-intensity statins when directly compared to the low to moderate intensity statins outperformed them.

Just to be sure of our findings, we did it so many different ways. We did the Cox modeling. Then we did propensity matching that which person is more likely to receive the statin versus the other. Then we did subgroup analyses where we put people in different subgroups that people who had coronary artery disease as an indication, maybe that's why they were on these statins. But, people without coronary artery disease also same association [stack 00:11:12]. We were pretty confident in our findings, and that's why we sent it to Circulation.

Dr Carolyn Lam: Wow. You know, Josh, you are the best at putting papers like this into context and really expounding on the significant. Tell us, why did this catch your attention so much?

Dr Josh Beckman: Every time I think that statins have become just a standard part of therapy for patients with atherosclerosis, the first thing I noticed in this paper was that there were so many people who were still not on any statins or people who were on homeopathic doses of statins, and I can't understand how that happens. I think the mortality data was nice and consistent, but the amputation data is what really made a big difference. I'll ask Dr. Arya, but in my impression, the literature has been sort of back and forth as to whether or not statins really reduced limb outcomes. Your paper, I think, was clearly the largest sample that had taken a look at that question. Can you sort of separate out your papers from some of the previous work in that area?

Dr Shipra Arya: Sure. I would add that a lot of work about amputations has been coming out from vascular surgery data, and a lot of that work just focuses on short term outcome for limb loss. They look at 30 days. Maybe they'll go look up to six months to a year, but actually patency of bypasses, patency of vessels is a long-term phenomenon. Much like mortality that can happen years later, your amputation risk can happen years later, too. I think what separates us is the lifetime followup for these patients, and we are looking in a cohort of patients who are in this veterans' healthcare system so the data is automatically getting captured even if they get their care outside. Records do make it back and diagnoses do make it back. It's the VA [inaudible 00:13:03], and we did some sensitivity analysis to show that, yes, most of the veterans we have in [inaudible 00:13:09] actually get their care and have data being added continuously into the corporate data warehouse.

That was something I think that lent to the power of making the [sure 00:13:20] conclusion and that's where previous studies have not been able to show a significant association with amputation. The studies, if they are single center or they are focused from electronic medical records or perspective followup, either the patients get lost to followup or go see other doctors or other healthcare systems, and that information doesn't get back to the researchers, while mortality data you can get from Social Security Death Index or other sources. I think that's what makes the study different than other studies in this similar field in terms of followup.

Dr Josh Beckman: I don't think you're giving yourself enough credit. There's a whole bunch of things that make the study unique. One of the things that I was most taken with right upfront was the way that you defined peripheral artery disease for this population. There has been, as far as I know, at least seven or eight different definitions that people have used with administrative data to try and ferret out who has PAD, and in contrast to coronary disease and stroke, it's a much more complicated endeavor to do that. So, when I saw the way that you did it ... I'm going to say this in a way that I know is going to sound funny, but you made the complicated look really simple. Your definition is not something that required 3,000 lines of ICD-9 codes within inclusion and exclusion criteria and speaks, in my opinion, to the power of the large sample because, basically, they needed one ICD-9 code and either two ABIs, a visit to a vascular surgeon or procedural code. Now, I know that this definition comes from some of your work, so can you tell us how you derive this and then let's talk about what that means.

Dr Shipra Arya: Absolutely. We looked at practice patterns for patients with vascular disease across the VA, and most patients who undergo procedures for PAD, we can confidently say that they do have PAD. When we look at the specificity of just that occurrence, it's pretty high, like [90% 00:15:23]. Then what we did was we did some random sampling in the VA data, about 300 patients, and used different codes to see if patients came back to the vascular surgeon within ... We used 14 months because it's usually one year followup that most people prescribe, so whether they went two months before or after because the appointment hours. We found that that was again a high specificity of about 80%. Then, when you look at patients who come back with ABI followup. So, we looked at CPT codes for ABI. We found out it's like a 99% specificity. If you have ABI followup within a year, and we relaxed it to 14 months, you could be 99% confident that this patient does have PAD.

We just combined all those three together, and this is ... If Circulation is interested, I can send you this, too. We are working on this manuscript where we are giving researchers different algorithms that they could use to identify PAD because I wanted a more specific sample because I was looking at PAD outcomes. I wanted the PAD definition to be tight. Our specificity is greater than 80% combining all these three together, about 84%. We are fairly confident in this that, yes, these patients truly have PAD, so when we follow them up for outcomes, we can be confident in our results. If researchers wanted a more relaxed definition of PAD, they could use other algorithms that we are putting in that paper where they could say, "We will only use one ABI measurement, or we would use a combination of these."

Dr Josh Beckman: That brings up two points. You talk about this brings up the power of large data and the ability to tone down on people who really, truly, absolutely have PAD without any question. So, number one, are you worried that you're missing people that probably do have PAD and would benefit from therapy, and number two, do you worry that you're basically concentrating on the sickest right end of the curve of the group of PAD patients?

Dr Shipra Arya: Right. That's a great point, and I discussed that with my coauthors and mentors and we wanted to be sure about our outcomes and not want to include people who did not have PAD, and then we are kind of including the effect size of what we may find, but yes, these are truly what we are calling a symptomatic PAD, and I think I mentioned that in the manuscript somewhere, that we probably would be missing people who are asymptomatic and not really being followed up. If we extended this analysis to people who are not regularly being followed or being under surveillance for their PAD, the results could be different. So, yes, it does not generalize the whole of that population. If we had gone that route and relaxed our inclusion, my worry was that we would get ... Because of large data setting up, as you say, if we include a bunch of people who are truly not PAD, we would be a [threading 00:18:17] risk in non-PAD patients.

Dr Carolyn Lam: Josh and Shipra, I loved the paper, but after this discussion I'm even more in love with the paper and impressed, so I think I just have a question for both of you. Is there any excuse not to give statins now? Do we actually think a trial is going to come on this topic? Is this the best data that we have? Is it going to enter guidelines? What do you think?

Dr Josh Beckman: I can give you my opinion first, if you want, because you're the person who actually has control of all the data. I would say this. I think it's been well known that statins should be used in all the patients with PAD for their cardiac outcome. My guess is that there are two things that are going to happen that are going to make people consider statins for limb outcomes.

One, data like this and there's never going to be a trial, a prospective randomized trial at this point, I mean unless you disagree, but there's no way people will randomize to not statin. I think the second reason is the recent data on the PCSK9 inhibitor, evolocumab, which showed that on top of statins in PAD patients, there was a further reduction in limb events. I think we're heading towards getting the LDL to zero. It may take a couple more steps, but that's basically what's going to happen.

Dr Shipra Arya: I agree. I think there has been time and time again data that shows, especially those already data supporting the mortality benefit for larger cohorts of patients with cardiovascular disease including PAD. I think this study really nails down the limb protector effects of statins, and doing a trial of this magnitude would be very difficult to do because to get that would be effect size that you have. You would need a huge cohort of patients, and you probably won't find statin-naïve patients because you have already half the patients with PAD have coronary artery disease, as well. So, not every study needs a trial. Not every question needs a trial, in my opinion. I think that's the power of large data sets. I think the evidence is overwhelming, and I would agree with Josh.

Dr Josh Beckman: I have always had a hard time explaining to people who came to see me for legs problems that they have to take a drug for their heart. It's sort of a weird two-step that people have a hard time accommodating. Do you think by telling them that this drug will also save their leg that they're going to be more likely to take the medicine by the end of the year?

Dr Shipra Arya: Yes, absolutely. That's what I tell my patients who come and see me, that this medication works on arterial plaques, and it stabilizes them. It's not just the same plaque that you have in your heart is the one you have in your leg. Maybe a little different, but to oversimplify, yes. This is not just a heart medication, and this is not just a cholesterol medication. This is a medication for your plaques, for your blockages. That's how I explain it to them, and I think the uptake would be more if we explain to them that, yes, this will help you keep your leg, stay ambulatory and stay at home and not end up in assisted living or nursing home.

Dr Josh Beckman: Carolyn, this is so much fun, especially when we get to talk to the people that do so much hard work to put stuff in circulation, so I just want to say thanks again to Shipra and her coauthors.

Dr Shipra Arya: Thank you so much, and thank you for giving us the opportunity. I think the comments from Circulation really made our paper better, so thank you for doing that.

Dr Carolyn Lam: I wish that we could just keep going on and on because I just know that Josh has even more great questions up his sleeve. See, Shipra, I told you, he's amazing. But, there you go. You're amazing, too. Your paper is amazing. Thank you so much for joining us today.

Circulation March 27, 2018 Issue

26 mars 2018 | 26 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore. Our featured paper this week is an in-depth paper on the cardiovascular and metabolic heterogeneity of obesity, and we will have a discussion with the authors on the clinical challenges, implications for management, and much more coming right up after these summaries.

How does MRI quantification compare with standard Doppler echo approach to identify organic mitral regurgitation and predict adverse outcomes? Well, our first paper this week addresses this question, led by first and corresponding author, Dr. Penicka from the Cardiovascular Center OLV Clinic in Belgium. These authors studied 258 asymptomatic patients with preserved left ventricular ejection fraction and chronic moderate and severe organic mitral regurgitation by echo. All patients underwent MRI to quantify regurgitant volume of this organic mitral regurgitation by subtracting aortic flow volume from the total left ventricular stroke volume. Severe organic mitral regurgitation was defined as a regurgitant volume of greater or equal to 60 milliliters.

The authors found that mean echo-derived regurgitant volume was an average 17 milliliters larger than the MRI-derived regurgitant volume. Concordant grading of organic mitral regurgitation severity with both techniques was observed in 76% of individuals. In the remaining 24% of individuals with discordant findings between the two techniques, this was mainly observed in patients with late systolic, eccentric, or multiple jets.

The MRI-derived regurgitant volume showed the highest discriminative power among all the imaging parameters to predict all cause mortality or its combination with development of indication for mitral valve surgery. Thus, this study demonstrates that MRI-derived assessments of organic mitral regurgitation are clinically accurate to identify asymptomatic patients with severe organic mitral regurgitation and at first outcomes. This may be particularly so when the mitral regurgitation is late systolic, eccentric, or multiple in jets where misclassification may occur with echo-derived approach.

The next study is the first large population-based study to analyze the association between low-dose ionizing radiation from cardiac procedures and incident cancer in adults with congenital heart disease. First author Dr. Cohen, corresponding author Dr. Marelli from McGill University, studied the population from the Quebec Congenital Heart Disease Database and performed a nested case control study comparing cancer cases with controls matched on sex, congenital heart disease severity, birth year, and age. They found that the cumulative incidence of cancer in adults with congenital heart disease between the ages of 18 and 64 years was 15%. The cumulative low-dose ionizing radiation exposure from cardiac procedures was independently associated with incident cancer after adjusting for age, sex, year of birth, congenital heart disease severity and comorbidities.

Results were similar using either the number of procedures or estimates of the effective doses with a possible dose-related response relationship between the low-dose ionizing radiation exposure level and cancer risk. Thus, increasing exposure to low-dose ionizing radiation from cardiac imaging in adults with congenital heart disease raises concerns about life-long risk of malignancy. Confirmation of these findings by prospective studies is needed to reinforce policy recommendations for radiation surveillance in patients with congenital heart disease.

The next study characterizes the long-term dynamics of potassium in heart failure and its associated risk of mortality. First and corresponding author, Dr. Nunez from Hospital Clinic University of Valencia in Spain, evaluated the prognostic implications of long-term longitudinal monitoring and dynamics of serum potassium in a prospective and consecutive cohort of patients following a hospitalization for acute heart failure. In these patients, serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings.

The authors found that on a continuous scale, the followup trajectory of serum potassium levels independently predicted mortality through a U-shaped association with higher risk at both ends of the distribution, and the same was true using potassium categories. Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Persistence of normal potassium levels was linked to a higher risk of death compared to patients who maintained or returned to normal values. Conversely, potassium normalization was independently associated with a lower mortality risk.

These findings support the need for close monitoring of serum potassium after an episode of acute decompensated heart failure and suggest that maintaining serum potassium levels within normal range may be considered a therapeutic target.

The next study gives us an example of how functional metabolomics can translate into metabolomics derived biomarkers of disease mechanisms. Co-first authors, Dr. Zhang, Wei, and Li; co-corresponding authors, Dr. Zhu, Li, and Qi from Nanjing, China, studied a cohort of 2324 patients who underwent coronary angiography from four independent centers. They used a combination of ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode for untargeted analysis of metabolites in the plasma.

The authors identified a total of 36 differential metabolites related to coronary artery disease progression. In particular, N-Acetyl-neuraminic acid, a metabolic marker highly elevated during coronary artery disease progression, acted as a signaling molecule to trigger RhoA and Cdc42 dependent myocardial injury via activation of the Rho-RACK signaling pathway.

Silencing neuraminidase-1, which is the enzyme that regulates N-Acetyl-neuraminic acid generation, ameliorated myocardial injury in vitro and in vivo. Pharmacologic inhibition of neuraminidase by anti-influenza drugs protected cardiomyocytes and the heart from myocardial injury.

Thus, in summary, functional metabolomics identified a key role for N-Acetyl-neuraminic acid in acute myocardial injury, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for coronary artery disease.

The final study addresses the controversy of whether high density lipoprotein, or HDL cholesterol, plays a causal role in cardioprotection. First and corresponding author, Dr. Jensen from Harvard T.H. Chan School of Public Health and colleagues, hypothesized that subspecies of HDL defined by apolipoprotein C3, a key regulator of lipoprotein metabolism, may contribute new information to prediction of cardiovascular risk.

They used immunoaffinity chromatography to measure the apo A1 concentrations of HDL that contained or lacked apolipoprotein C3, or apo C3, in two prospective studies of adults free of coronary heart disease, the Multiethnic Study of Atherosclerosis and the Danish Diet, Cancer and Health Study. They then conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins.

The authors identified a subspecies of HDL that contained apo C3. HDL that contained apo C3 comprised 5 to 6% of apo A1 or 10 to 15% of HDL cholesterol. In the four prospective studies, HDL containing apo C3 was associated with a greater risk of coronary heart disease, whereas HDL that lacked apo C3 was inversely associated with risk more strongly than the total HDL.

These findings support the hypothesis that apo C3 may mark a subfraction of HDL cholesterol that is associated with higher risk of coronary heart disease. These findings therefore provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations. And that brings us to a close for the summaries. Now for our feature discussion.

For today's featured discussion, we are talking about obesity, a universal issue, or is it? And when we talk about obesity, are we talking about one thing or many things? Today's in-depth review is just such a great paper. I highly recommend it to everyone. So pleased to be discussing it with Dr. Ian Neeland today from UT Southwestern Medical Center.

Ian, first of all, congratulations. A beautiful paper. I learned so much reading it, and I've got so many questions. You started off pointing out that we talk about obesity. We've always defined it by body mass index, but that may not be the ideal biomarker. I love the way you said that. So, tell us a bit more about the reason for this review.

Dr Ian Neeland: Obesity, like you said, we define it by body mass index, but body mass index is such a crude marker. It's great to use for the clinic. It's easy to implement, but it doesn't really tell us a lot of information about the person. And so you can just look at a third of the population in the US right now is thought to be obese. And if you take a third of the population, clearly not everyone has diabetes and heart disease.

So, obesity in and of itself, defined by the body mass index really is very heterogeneous, and it's not possible to use that alone to tell an individual if they're really at risk for disease. And so this review is really about getting deeper under the skin, no pun intended, to really get a sense of what it means to be obese, how the body fat plays a role in disease, and really getting to the different aspects of obesity and how we can understand it a little bit better.

Dr Carolyn Lam: Yeah. You know, Ian, you had me at hello if I could say when I read your paper because I'm from Asia, and here, the World Health Organization actually even suggests that we use lower body mass index cutoffs to define obesity, simply because there's a different relationship as well with cardiometabolic disease. So, so true, but before we get there, to maybe ethnic differences, I want to ask you something. I heard the term, obesity paradox, thrown around a lot, and sometimes I think we don't really know what we're talking about when we say obesity paradox.

I love the way, in your paper, you broke it down into four types. There are four paradoxes. Do you want to just clarify this for the audience? I think it's important.

Dr Ian Neeland: So, the obesity paradox, what we mean by that is we think that obesity causes disease and gives someone an increased risk for disease and mortality and death, but the obesity paradox means that some people who are obese we see actually have better outcomes than those who are not obese. And how to describe that paradox and why that exists is really the subject of lots and lots of research and discussion.

And so when we talk about the obesity paradox, really it's important to understand that most of the time we're talking about people who already have established disease. Let's say, for example, heart disease. So people with heart disease who are obese tend to have better outcomes than those who are not, and there are a few ways to understand that.

So people who have obesity with established disease who may have better outcomes; that's the classic obesity paradox. Then there's a paradox really about fitness and being fat and fit, and that concept that you can be fat, but if you're fit, if you're able to do exercise and you have good cardiorespiratory fitness, that you actually may be protected from disease as well. And then there's also the obesity paradox of basically the pre-obesity paradox, so that overweight, right, where you haven't yet met the threshold for obesity can also be protective in people who don't have disease. And so being a little bit plump may be protective for different diseases down the road. And then the final one is that the metabolically health obesity. When we say that, it means that the person who is obese by body mass index but doesn't really have any hypertension or diabetes or lipid abnormalities. So, that's the metabolically healthy obese person.

Those are the four types of individuals we see who may be obese but actually have better outcomes long term, and the question is why that exists. So there's a lot of thinking about it. Maybe it has to do with the fact that being normal weight nowadays, often we have older folks that are normal weight. Well, they tend to be more deconditioned. They may be frail. They may have undiagnosed disease like cancer. And that might be why those people are the worst. And there are the naysayers out there who think that it's all just about what we call confounding, so things we can't account for when we look at that. People who smoke tend to be lower weight, and obviously they have worse outcomes, and then also people who are older. So it's kind of a conundrum, this obesity paradox, but there's lots and lots of data out there coming out all the time that we keep seeing it again and again and again.

One of the areas in the paper that I wanted to address was this concept of obesity heterogeneity in the obesity paradox, meaning to say is it potentially where the body fat is that may be playing a role in which obese person gets disease, and which obese person may be protected from disease. So it could be that it's not how much fat you have but where that fat is that is really telling about what someone's risk is, and that might help to describe the obesity paradox and get us a little bit more understanding.

Dr Carolyn Lam: Yeah, now, I thought that bit was just so key and important. Not how much fat, not weight per se, but where that fat is. Do you want to elaborate on that a bit?

Dr Ian Neeland: Sure. For, I don't know, 50, 60 years we've had this concept of the apple and the pear. Right? Fat in the belly being the apple shape and fat in the pear being fat in the hips and buttocks and that being two different body types of body fat. So we have a lot of technology nowadays, and we can actually directly image body fat and where it is in the body. So we can do MRI, we can do CT, and we can actually see where the body fat is distributed and how much body fat in one area may be related to disease compared with another area.

So we've gone away from the apple and pear and really getting down to what we call body fat depots or adipose tissue depots where we deposit fat. And the area that we deposit fat that has the most risk for cardiometabolic diseases is this visceral adipose tissue or VAT. VAT is fat that's around the intra-abdominal organs, also near the kidneys, and you can't actually tell how much visceral fat someone has just by BMI or waist circumference or just looking at them. You really have to do this dedicated imaging to find out. And the reason for that is that in the belly there's two types of fat. There's the visceral fat, and there's the subcutaneous, which is the fat under the skin. Both those fat areas make up the belly fat, but they're very different. And part of the review is really going into depth about why these are different and how they're different.

They have completely different metabolic profiles, so if you would take blood, lipids, inflammatory markers, they would look completely different even in a single individual. And then if you look at the genetics of where the fat is, they're different. If you look at what these fat areas secrete, they're completely different. So it's really important to know where the fat is, and that's why I think this concept of sick fat versus healthy fat comes into play.

So, sick fat is fat that's usually in this visceral fat depot, and that is really the three central tenets we talk about are visceral fat or ectopic fat. Ectopic means fat where it doesn't belong. Then inflammation and cytokines, so secretion of abnormal factors in the blood from this fat, and then insulin resistance. So those are the three kind of tenets of this sick fat. So that's why we think that the sick fat plays a role in disease, and then there's a concept of less sick fat or healthy fat, which is maybe a sink. It actually buffers some of these cytokines and inflammation from causing disease in the body.

Dr Carolyn Lam: Yeah. I found that concept so fascinating, and just to bring it back to the obesity paradox. So, some larger people may enjoy better outcomes because they actually have a predisposition to put the fat subcutaneously perhaps, rather than viscerally. Would that be correct? You worded it so eloquently in your paper. There are some ethnicities or some genetic predispositions that could make one lose that inability to put it peripherally, and therefore it all goes viscerally, is what I got from it. And that's the stuff that puts people at risk.

Dr Ian Neeland: Yeah. We find that fat in the lower body, the hips and the buttocks, is actually in epidemiology, protective against heart disease, protective against cancer. And the problem is we don't know why some people put fat in the belly and some people put it in the hips and buttocks. There's very interesting twin-twin studies that show if someone has a predisposition for obesity, so twins may be both obese, but there is some difference in where they actually put the fat. So I think genetics certainly plays a role, but environment also plays a role. And environments, things like appropriate nutrition and physical activity can really alter genetics and help someone to put fat where it should be and prevent disease.

So this obesity paradox, this concept of putting fat where it should be, is really the next frontier for this type of research. How can we modulate it? How can we fix it?

Dr Carolyn Lam: Exactly, and I love the way you ended your review when you said, "Therefore, maybe in all our complaints and so on, saying that we want weight loss, we should actually be focusing on waist loss. You could redistribute the fat to healthy areas, not change your weight, and still become healthier." That was the concept, right?

Dr Ian Neeland: That's right. Yeah. It really is amazing, and it's been shown again and again that people can stay the same weight, but their body fat really is very plastic. It can change, and it's modifiable. And that really makes a difference with health outcomes. So whether we can do that with lifestyle changes, so there's some data to support that. There's also some data to support pharmacology, so medications may be able to move fat from one area to another. And then certainly surgery, which is now getting a lot of popularity for people who are really high risk for cardiometabolic disease. Bariatric surgery has been shown to decrease visceral fat significantly, and that may be one of the reasons why it works so well.

Dr Carolyn Lam: Exactly, Ian. Fascinating, fascinating. I tell you what. Could I just ask you to give us some take-home messages?

Dr Ian Neeland: Sure. So one take-home message I think is that we can move beyond the BMI, beyond the body mass index. Obesity is no longer just a number. It's really about the entire individual, biologic systems, what's going on, and there's just remarkable heterogeneity in the structure of obesity, where body fat is, the activity of body fat, the physiology of it, and also how it relates to diseases, either causing disease and potentially being protective for harmful outcomes.

I think it's also a key message to understand that there's sick fat and there is healthy fat and they're very different. And we can get to the bottom of those using specialized tools like imaging and special testing, but they're really very different, and not all body fat is created equal.

And then lastly, I think it's important to consider, like you mentioned earlier, that really public health and lifestyle going forward is going to be so important, and focusing on those areas that will have the biggest impact for people such as trying to promote waist loss, like you said, as opposed to weight loss. Really focusing and using our knowledge of body fat and obesity and how it's so different across individuals and populations, that it's really important to use that knowledge for our future goals and to have that mind when we recommend weight-modifying therapies for our patients.

It's really going to be a new frontier in weight. We're really moving beyond this concept of just check your weight and your height, and we can tell you what your risk is. No, it's really much more complex and complicated and much more interesting than that.

Dr Carolyn Lam: Oh, Ian, that's just so wonderful. I cannot help this last question. Who knows whether we'll put it in, but I just have to ask you. So how do you monitor your own status or your patients' status? Do you really get them DEXAs, all of them? Or PETs, FDGs? Or do you take your own weight?

Dr Ian Neeland: Yeah. I do. One thing I have noticed, I actually started an exercise and diet program for myself to improve my health about a year and a half ago. I took the research, and I said, "Okay, I'm really going to use this and apply this to my life." So, what's interesting is what I found and actually what other colleagues of mine in research are finding is that you can actually melt away visceral fat just with exercise alone, even if you don't actually go on a diet. And they've done studies like this where they do DEXA scans, and they give people high-intensity interval training. They don't give them a special diet. They just say maintain your current diet, and the visceral fat goes away.

It's really remarkable how lifestyle can be so important and make such a change. And you can see people who have diabetes who can cure their diabetes with a lifestyle program by really decreasing the visceral fat. Even if their weight doesn't change or only changes by a small amount, but their weight may change by, I don't know, five, 10 pounds, but their visceral fat may go away by 50%. And that really makes the difference.

It's obviously hard to monitor. We don't really have these tools clinically every day. Not everyone can do a DEXA and has the software to measure the visceral fat. Certainly could be coming in the future, but right now we should use the tools we do have and use the biomarkers we have and the clinical use, the waist circumference, triglycerides. These things are all surrogates for visceral fat but can be very useful to monitor for change. And it's not just about the scale. It's really about more than that with a person's metabolic status.

Dr Carolyn Lam: That is so helpful. Thank you so much, and I'm so glad you said that it was exercise, and you don't jump into a ice pool or something to try and convert the fat to brown fat or something. That's really, really encouraging to me. Thank you, Ian. This was so enjoyable. I'm sure all our listeners are thanking you as well.

Listeners, you've been listening to Circulation on the Run. Please tune in again next week.

Circulation March 20, 2018 Issue

20 mars 2018 | 22 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. How common is perioperative myocardial injury after non-cardiac surgery, and what is its significance? A very important question and a very important feature discussion coming right up after these summaries.

Our first original paper this week tells us that risk assessment using only non-laboratory based risk factors may be a useful alternative in the absence of informational lipids, in predicting adolescents at risk of developing pre-clinical atherosclerosis.

First and corresponding author, Dr. Koskinen from University of Turku Finland and colleagues, studied almost 2,900 participants, age 12-18 years, from four longitudinal cohort studies from the United States, Australia, and Finland, and followed these adolescents into adulthood. When carotid intima media thickness was measured, a mean followup of 23 years later. Non-laboratory based risk factors such as age, blood pressure, body mass index, and lipids measured in adolescence, independently predicted high carotid intima media thickness in young adulthood. The addition of lipid measurements to these traditional clinic based risk factor assessments provided a statistically significant but clinically modest improvement on adolescent prediction of high carotid intima media thickness in adulthood.

The next study demonstrates the feasibility of large scale aptamer multiplexing at a level that has not previously been reported and with sample proof that greatly exceeds other existing proteomic methods.

Now, like antibodies, DNA aptamers can be generated as affinity reagents for proteins. Emerging data suggests that they can be used to measure blood protein levels in clinical cohorts. However, the technology has, to date, remained in its infancy. In today's study, co-first authors, Dr. Jacob and Dr. Ngo, co-corresponding authors, Dr. Jennings and Gerszten, from Beth Israel Deaconess Medical Center in Boston, tested the scalability of a highly multiplexed expended proteomic technique that uses single stranded DNA aptamers to assay human proteins with a markedly expended platform containing approximately 5,000 aptamers targeting a far broader range of analytes than previously examined using this technology. They applied the platform to a cohort of individuals undergoing septal alcohol ablation for hypertrophic cardiomyopathy, using this as a human model of planned myocardial injury.

Now, in addition to confirming findings from prior studies, they identified nearly 150 additional putative markers of myocardial injury. Thus, these findings suggest that the expanded aptamer based proteomic platform may provide a unique opportunity for biomarker and pathway discovery following myocardial injury.

The next study addresses the potential long-term effects of low LDL cholesterol on neurocognitive impairment and decline. This has been a concern with pharmacologic PCSK9 inhibition. The first author, Dr. Mefford, corresponding author, Dr. Levitan from University of Alabama at Birmingham, investigated the association between PCSK9 loss of function variants and neurocognitive impairment and decline in the regards study.

In this general population sample of African American adults, they found no association between PCSK9 loss of function variants and neurocognitive impairment or longitudinal neurocognitive decline. There was also no association between lower LDL cholesterol levels and neurocognitive impairment or decline during follow-up.

The study, therefore, provides evidence in a contemporary population that PCSK9 loss of function variants and resulting lifelong exposure to low LDL cholesterol levels are not associated neurocognitive impairment or decline.

The final study explores long-term outcomes in patients with Type 2 myocardial infarction and injury. First and corresponding author, Dr. Chapman from University of Edinburgh and his colleagues identified more than 2,000 consecutive patients with elevated cardiac troponin I concentrations at a tertiary cardiac center. All diagnoses were adjudicated as per the universal definition of myocardial infarction. They found that at five years, all cause death rates were higher in those with type 2 myocardial infarction or injury compared with type 1.

Although the majority of excess deaths with type 2 myocardial infarction or injury were due to non-cardiovascular causes, the observed crude major at-risk cardiovascular events are MACE rates were similar between groups. Coronary heart disease wan an independent predictor of MACE in those with type 2 myocardial infarction or injury. Thus, despite an excess in non-cardiovascular death, patients with type 2 myocardial infarction or injury have a similar crude rate of major at-risk cardiovascular events to those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risks.

That wraps it up for our summaries. Now, for our feature discussion.

So, I'm gonna go back to my first question on this podcast. How common is perioperative myocardial injury after non-cardiac surgery and what is its significance? Well, to give us an answer, I am delighted to have the first and corresponding author of today's feature paper, Dr. Christian Mueller from University of Basel in Switzerland, and we also have Dr. Torbjorn Omland, and he is associate editor form University of Oslo in Norway. Now, in case you're having deja vu, you are right. I have had these gentlemen on this podcast before and they were so successful, I had to call them back. So, welcome, welcome Torbjorn and Christian. Thank you for coming back again. Christian, congratulations on another beautiful paper. Could you tell us the highlights of what you did and what you found, but this time in particular tell us the novel aspects in view of the previously published vision study that was just published last year. Maybe you could just point out some of the differences.

Dr Christian Mueller: The topic is about an interdisciplinary topic and something, I think that is so important for us as cardiologists to get involved in with much more detail in the future. So, we are aware of acute myocardial infarction, sustained myocardial infarction event that we have studied extensively for decades and for which I think we have a fuller understanding of its cardiophysiology and we have excellent treatments. Completely novel entity is perioperative myocardial injury, so cardiomyocytes that die in the context of non-cardiac surgery. It's something that we as cardiologists should be really focused on because its likely the most important contributor to death in the perioperative period. So, the death rate among non-cardiac surgery is despite improvements in anesthesia and surgery remains remarkably high, between 1 and 4% within 30 days, depending on patient characteristics and surgical directives. And, it seems from our current understanding that the heart really plays a major role, rather high percentage of these deaths.

So, what is new in our study? Overall, our study took advantage of insight gained in the first phase of the vision study in that its has been documented that this perioperative myocardial injury fairly commonly occur without the patient or we as physicians getting aware of it. Either because the patient is still having anesthesia or because he may have symptoms that are atypical. So, we can only reliably detect this event if we screen an appropriate population, and that's what we have done. So, I think the criteria where a patient that's at higher risk of cardiovascular complication is defined at an age of 65 or higher or having pre-existing cardiovascular disease. So, this is the first major difference in which also much younger patients were enrolled. That's the most important differentiate as we had an open label screening. So, the screening was part of clinical routine and it was fine tuned to patients of whom we thought may have a reasonable high risk of developing this complication.

Dr Carolyn Lam: And, your main findings, because they were striking.

Dr Christian Mueller: As our most important finding, we were able to report the incidence of how many patients actually have a relevant amount of cardiomyocytes dying during the operation, and it was one out of seven patients entering our study. So, an incredible high incidence of this complication and that this complication not only is a very good end point that you shouldn't care too much was highlighted again and in full agreement, the suspicious is that if patients develop this complication of perioperative myocardial injury, their risk factor of whether they have any symptoms or atypical ischemic symptoms, and again, only a small minority had the risk of dying both within 30 days as well as in one year, was substantially increased.

Dr Carolyn Lam: Christian, before you go on, could you just please clarify, how did you define perioperative myocardial injury in this case, and was it the same as the definition used in Vision?

Dr Christian Mueller: The perioperative myocardial injury concept initially in Vision it was defined as detecting an elevated troponin just after a non-cardiac surgery, and why this was a perhaps an appropriate definition at the time when we were still using very poorly sensitive troponin assays inevitably is no longer appropriate nowadays because its obvious that particularly elderly patients may have chronic elevations and high sensitive troponin usually. Mild elevations due to a variety of disorders and [inaudible 00:11:51] important studies for us to understand that it is mild elevations troponin is quite common in patients with heart failure, with coronary artery disease or hypertensive heart disease, whatever. So, if we could detect or start detecting likely elevated troponin only after operation, we would never know whether this is something related to the operation itself or whether it's perhaps had already been around for months and weeks and represents the chronic condition. So, the novel concept is that we have to identify an acute rise in troponin, a dynamic genetics or just like that requested for the universal definition of myocardial infarction also of course [inaudible 00:12:32] So, we requested in this study, an increase from the concentration prior to surgery of at least 14 ng/l of high sensitivity cardiac troponin.

Dr Carolyn Lam: Right. Wow. What a great study. So systematic. So, all patients, basically had readings before and after surgery. You know, I've got so many questions, but I really, since you mentioned Torbjorn, I would really like to ask his perspective on what you think was the most striking parts of it and any questions you may have on Christian.

Dr Torbjorn Omland: First, I would like to say that this is a very impressive study with some very important results in a neglected area of medicine, really. So, there are several very strong points with this study, and I think that if we're able to, in such a large population, both have pre-operative and post-operative and was able to calculate the delta, and the importance of that was a very strong part of the study, because it showed that, as Christian alluded to, the baseline level did carry some information but there was also important additional information from the serial measurements. So, that's maybe one of the most important findings, I think.

Then, we addressed the question, how should we use these data? So, my question to Christian is actually, how will screening for exceptional myocardial injury affect clinical practice? Will it lead to clinical deficiency interventions that will improve outcome or will it just result in unnecessary testing?

Dr Christian Mueller: Very good important point, Torbjorn. I think you are absolutely right in indicating that I think we are just beginning to understand all of the part of physiology behind the event that we can now capture, detect really, rather simple and precisely with troponin screening. So, I think it's important that we highlight that the part of physiology behind this event differs from patient to patient. So, there are some patients who clearly have a type 1 myocardial infarction as the cause of myocardial injury. Very likely, they are the minority in this setting. Likely, the majority to have a kind of a type 2 myocardial infarction have a physiology with imbalance between supply and demand, and again, in these patients, of course, the management needs to be to identify the trigger and to correct the trigger as rapidly as possible. And it can be that detecting myocardial injury by the rise in troponin, is the first indication that there is a problem ongoing. Now the patient can have a physiological rearrangement might have already been aware to the physicians if it's a type 1 myocardial infarction, then obviously very likely the same therapy will be beneficial to this patient as we would apply in spontaneous myocardial infarction.

A very important, and I'm glad you alluded to that the different ways of, a rather wide variety of patient settings that are summarized of the term perioperative myocardial injury. And the consequences, likely will have to be individualized to really ensure that we do something good for the patient.

And if I may, I would like to ask you and Carolyn for your thoughts about the most appropriate wording. So, the current wording that we used, of course, has to be in any scientific precaution, a very conservative one, perioperative myocardial injury. And it's important that, in fact, there are some entities where likely injury is derived from the patients who have the injury related to serious sepsis or related to a stroke, or pulmonary embolism. However, it's very likely that the vast majority of patients, the term perioperative myocardial infarction would be appropriate. And, I think it's so important to be aware of the implication that this, perhaps, on first slight small difference might have. As long as we keep using the term "injury", cardiologists will not really feel the same need to be involved, the same need to really take care of this patient as compared to the use of "myocardial infarction". So, I think it's a balance between scientific accuracy, but also the need to create awareness.

So, I feel that if cautiously applied, we'll do more good if would more liberally use "myocardial infarction" within this context. So, would you agree with this perchance?

Dr Carolyn Lam: I think "injury" is at least better than what we used to say, "a leak'. You know, we used to say, "Oh, it's just a troponin leak". So, at least we're saying injury, recognizing that there is damage done. I just wanna highlight that in your paper, something that really struck me was that these patients with perioperative myocardial injury or infarction, indeed did as badly as those who did or did not fulfill myocardial infarction criteria. So, that kind of supports what you are suggesting. I did get that right, right? In your paper?

Dr Christian Mueller: Absolutely. I think for spontaneous myocardial infarctions, so clearly that the criteria defined in the universal definition are mandatory. There's nothing to discuss about, but we cannot criticize a patient who is undergoing general anesthesia that he doesn't feel chest pain, and therefore, we deny him the appropriate word of the events. I think is just important that we clearly highlight that it really can be the same event in the chest without symptoms. But, not due to anything else but because he is undergoing anesthesia.

Dr Carolyn Lam: Very good point. You know, I would really like, though, to go back to Torbjorn’s point, because I think that skeptics are gonna say we've created a problem that we don't know how to solve, or that we don't know how to treat. Do you know what I mean? So we're detecting all these things, because now we have all these assays. Patients are asymptomatic, and then we really don't know whether it's modifiable. We don't know what to do to improve outcome. So, could I ask both your expert thoughts on what the future should hold? What is next step? Because, I see a gap.

Dr Torbjorn Omland: Yes, that's of course, a key question. So, I think we need to be innovative and patient, because what we really need is clinical trials, perhaps and more clinical trials looking into different strategies. But, of course, that's also challenging because as Christian told us, the path of physiology among this group of patients with perioperative myocardial injury differs. So, what's going to be appropriate for one patient, may not be the appropriate therapy for the next patient. So, I think his suggestion of an individualized approach is the best thing we can say at this moment, while we are awaiting data from future clinical trials.

Dr Christian Mueller: I fully agree with Torbjorn [inaudible 00:19:53] what you said, you will criticize some people will argue to that it's irrelevant. Why do you measure this and you don't want to hear it? You don't want to see it. But, I think it's important to remember the starting point for us as cardiologists is to get involved is death. If death is within 30 days after non-cardiac surgery in a patient who was fit, relatively fit otherwise, who underwent a surgery that was not a very high risk surgery from which he would expect a certain percentage of patients to die. So, that's the starting point. Again, of course perioperative myocardial infarction is not the only contributor to perioperative death. But, it seems, in addition to severe sepsis, to be the second commonest and most important. So, I think it's really, really important to first, as a really as a first important thing to increase the awareness of this problem and to encourage our colleagues to start bringing their research efforts, so that we get smarter in identifying the underlying part of physiology in these infarcts or injuries.

Because, only once we understand, or have a reasonable understanding what is the mechanism, we will be smart enough to select the most important priority for any intervention study.

Dr Carolyn Lam: Wow. What a wonderful note to end this podcast on. Words of wisdom, as always from both of you, Christian and Torjorn.

See, listeners. Didn't I tell you this was gonna be a great podcast? Don't forget to tune in again next week.

Circulation March 13, 2018 Issue

12 mars 2018 | 17 min

Have you ever wondered, which is better for heart health, low calorie vegetarian or a Mediterranean diet? Well, this week's feature paper provides some answers with a very intriguing discussion coming right up after these summaries.

The first original paper this week suggests that human fat pools are not the same and in fact are highly diverse in their response to lifestyle interventions during weight reduction first author Dr. Gepner, co-corresponding authors Dr. Shai from Israel and Dr. Stampfer from Boston aim to assess whether distinct lifestyle strategies could differentially affect specific body adipose depos. They performed at 18-month randomized control trial among 278 sedentary adults with abdominal obesity or dyslipidemia in an isolated work place with a monitored, provided lunch.

Participants were randomized to an isocaloric low fat or a Mediterranean low carbohydrate diet with or without added moderate physical activity. The overall primary outcome was body fat redistribution and the main specific endpoint was visceral adipose tissue. The authors further followed the dynamics of different fat depos by magnetic resonance imaging. They found that Mediterranean diet was superior to the low fat diet in mobilizing specific ectopic fat depos such as visceral, hepatic, cardiac and pancreatic fats. Exercise had an additional independent contribution to visceral fat loss. Long term persistent moderate weight loss inadequately reflected the significant beneficial effects of diet and exercise on the fat depos. Independent of weight loss, visceral and hepatic fat reduction was mainly associated with improved lipids profile whereas deep subcutaneous fat loss was associated with improved insulin resistance and superficial fat loss was neutral.

In other words, two distinct patterns were identified, a differentially responsive depo that was sensitive to the type of intervention, and those recites mostly directly related cardiometabolic health and a uniformly responsive depo, which corresponded only to weight loss per se irrespective of the intervention. Overall, these results suggest that more specific strategies for weight loss may be considered to treat distinct organ specific fat depos in the management of cardiometabolic risk.

Current guidelines recommend nonvitamin K antagonist oral anticoagulants or NOACs in patients with nonvalvular atrial fibrillation as these drugs have several benefits over the vitamin K antagonists but do these benefits remain when NOACs have to be combined with aspirin therapy? Well co-first authors Dr. Bennaghmouch and de Veer, corresponding author Dr. ten Berg and colleagues from the Netherlands provided a meta analysis comparing NOACs and Vitamin K antagonists in more than 21700 patients with atrial fibrillation who are treated with concomitant aspirin therapy. NOACs were found to be more effective in terms of stroke or systemic embolism reduction as well as vascular death reduction and as safe as vitamin K antagonist with respect to major bleeding. NOACs were in fact safer with respect to the reduction of intracranial hemorrhage. Thus, these authors found that NOACs were an effective and safe alternative as compared to vitamin K antagonists in atrial fibrillation patients treated with concomitant aspirin therapy.

The next study shows that an integrative approach using genomics and proteomics has the potential to identifying new biological pathways for biomarker discovery and pharmacologic targeting in early cardiovascular disease. Co-first authors Dr. Benson and Yang, co-corresponding authors Dr. Wang and Gerszten from Beth Israel Deaconess Medical Center in Boston had recently identified 156 proteins in the human plasma that were each associated with a net Framingham cardiovascular disease risk score using an aptamer-based proteomic platform in the Framingham Heart Study Offspring participants.

Now, in the current student these authors hypothesized that performing a genome-wide association study and exome array analyses on the levels of each these 156 proteins may identify genetic determinants of risk associated circulating factors and provide insights into early cardiovascular pathophysiology. Indeed, they discovered dozens of novel genetic variants that were each strongly associated with circulating levels of the Framingham Risk Score associated proteins. They highlighted numerous examples of how these novel gene locus protein associations provided new insights into cardiovascular disease risk pathophysiology including a novel pathway by which the gene phosphatase 1G modulated circulating levels of apolipoprotein E, a key regulator of cholesterol handling.

The final study suggests that bariatric surgery represents an effective strategy for reducing antihypertensive drugs in patients with obesity and hypertension. First and corresponding author Dr. Schiavon from Heart Hospital in Sao Paulo, studied 100 patients with obesity and hypertension who were randomized to gastric bypass or medical therapy alone. The patients randomized the gastric bypass were six times more likely to reduce by 30% or more the total number of antihypertensive medications while maintaining controlled blood pressure levels. In addition, 51% of the patients undergoing gastric bypass showed remission of hypertension. Now, the authors are quick to alert that given the morbidity of surgery these results do not imply that all patients with obesity and hypertension should be submitted for bariatric surgery. Rather, these results suggest that gastric bypass surgery represents one extra option to consider in achieving blood pressure control in these patients.

That wraps it up for our summaries now for our feature discussion.

So, which is better for heart health the vegetarian or the Mediterranean diet? Oh, what an awesome topic and to be able to discuss it from Asia to the United States to Italy, I'm so please to have the first and corresponding author of our feature paper this week Dr. Francesco Sofi from University of Florence in Italy and our dear associate editor Dr. Wendy Post from Johns Hopkins. Francesco, could you please start by telling us what inspired you to do this trial?

Dr Francesco Sofi: The aim of the study was to compare two of the most beneficial diets we know from the literature in relation to the occurrence of many chronic degenerative diseases so the Mediterranean diet we have a lot of studies showing that Mediterranean diet is beneficial for many different diseases as well as we have some studies for the beneficial effect of a lacto-ovo vegetarian diet but no studies are available comparing these two diets' dietary profiles. Our hypothesis was to compare in the same population different times the two diets, which were the similar calories, the same isocaloric but just different in terms of composition especially for meat and fish.

Dr Carolyn Lam: Tell us the bottom line. I'm holding my breath because I think I've said it before, I'm vegetarian. Half my household is Mediterranean diet so what did you find?

Dr Francesco Sofi: We found that in the same group of patients, which were a low risk population because a low risk population here in Italy they were already following a Mediterranean diet but if you control their calories and their composition in terms of the Mediterranean, which included all the different food groups and the lacto-ovo vegetarian diet so all the different groups except for meat and meat-based and fish we noticed that after three months, the lacto-ovo vegetarian diet already determined a reduction of total cholesterol and LDL cholesterol and Mediterranean diet already determined reduction of triglycerides and both were effective for reduction of body weight and fat mass.

We noticed with great interest that after three months, all the study population were quite good in [inaudible 00:09:45] with this diet. I mean they didn't have any kind of problems. This is the one of the most important thing and most of the population or many of the patients after the end of the study they started or continued to follow a vegetarian diet. It means that they accepted very well. There was no problem at all. Also, in feasibility and acceptability of this diet and in relation to this also they have a beneficial effect in some parameters such as also oxidative stress parameters and the inflammatory parameters.

Dr Carolyn Lam: Right, so if I could summarize maybe crudely so the vegetarian diet, very effective for LDL, the Mediterranean very effective for triglycerides. I know that's a simplification but Wendy, I'd like to know do you think this is the dawn of maybe a more, "Oh, here we go again individualized diet planning"?

Dr Wendy Post: I think that this study is really important because there really have been few randomized trials about the vegetarian diet and we've learned a lot of the potential beneficial effects of a Mediterranean diet. I think what was really interesting about this study is seeing that they were both equally effective as a low calorie Mediterranean diet or vegetarian diet at reducing body weight, which is most often the biggest challenge for our patients who are either at risk for cardiovascular disease like these patients potentially were or who have cardiovascular disease.

I think the vegetarian diet is potentially an excellent option for some of our patients but it really is an individual choice and I have trouble getting some patients to just give up the red meat let alone any kind of animal meat. I think it really is potentially an individual choice and those who are interested in becoming vegetarian for either health reasons or other reasons these are additional data to suggest potential beneficial effects more to the Mediterranean diet.

Dr Francesco Sofi: I think one of the most important things to know from this study is that we have now two options. We need to individualize the diets to patients but if a person wants to follow a vegetarian diet for different reasons including also healthy reasons, we can say that it's beneficial. He or she can follow this diet without no problems so without having any health problems as well as if a person wants to follow also a Mediterranean diet, which included meat and fish with a regular and moderate consumption during the week.

Dr Wendy Post: Right but this is just a three month trial with intermediate outcomes so I'm not sure we can necessarily make definitive statements that this is potentially not leading to any adverse effects or some of the other statements that you made. I think we could just make the statements better relative to the outcomes that were seen here related to weight loss and traditional cardiovascular risk factors. Whereas, we have had long term clinical trials of the Mediterranean diet suggesting reduction in risk for events so I think this is definitely supportive of the vegetarian diet but I think we can't say that more studies aren't needed to potentially look at longer term outcomes and more definitive events as opposed to intermediate outcomes that this is a great first start and is really helpful in trying to understand some of the potential differences between the vegetarian diet and the Mediterranean diet.

Dr Francesco Sofi: Of course, I completely agree on that. We need more studies and larger studies and longer duration to establish some things but it was just a pilot study but the good thing is the first comparing two beneficial diets. In the literatures now, most of the studies were investigated either already a vegetarian person or vegetarian diet versus a westernized diet so probably there were some biases.

Dr Carolyn Lam: Indeed, I want to just echo in these words. Congratulations, Francesco. Beautifully done, very elegant, controlled in terms of caloric intact and I like that message that it's not saying that one is bad and the other is good. It's saying, "They're different but they both resulted in weight loss". I love that comment about getting a bigger study. I want to do it right here in Asia because the diets are just so different here and I'm just wondering how about in the US? Wendy, your perspective? How adoptable are these results?

Dr Wendy Post: Well, again I think it's a personal choice and if somebody is willing to become vegetarian then that's potentially wonderful especially if they have high LDL cholesterol and are trying to lose weight but we have to be careful about with the vegetarian diet is the carbohydrate intake, which might affect triglycerides. It might be an individualized approach based on the patient's individual risk factor profile and they're preferences but this is really impressive data suggesting that the vegetarian diet is very similar to the Mediterranean diet in many aspects especially as it relates to weight loss, which is really important.

Dr Carolyn Lam: You've hit the nail on the head. Let's remember that this is a low calorie vegetarian diet. I think that's the issue. Sometimes when I say vegetarian diet to some communities here in Asia that is actually a lot of calories and a lot of starch, which is not what we're talking about here.

Dr Wendy Post: Right, a low calorie diet so that's the key. That's the hard part isn't it?

Dr Carolyn Lam: Yeah, sadly.

Francesco?

Dr Francesco Sofi: We should say that most diets are similar background I mean in the backbone is similar so a dietary profile full of fruit and vegetables, complex carbohydrates, fiber, so the different things are meat and fish but with you can see in a regular consumption also Mediterranean diet of course, especially Mediterranean diet is beneficial for cardiovascular profile.

Dr. Wendy Post: Yeah, if we could get our patients in the United States to follow either the vegetarian or the Mediterranean diet that would be fabulous because they are obviously eating too much in the way of sugar sweetened beverages and deserts and fast food so just trying to follow either of these diets would be especially beneficial if it was a low fat vegetarian or Mediterranean diet. I think we need to get all our patients to be eating more fruits and vegetables, which is a key component of both of these diets and what they share in common, which often can lead to beneficial effects with weight loss due to the increased fiber and satiety and the healthful benefits of high fruit and vegetable diet.

Dr Carolyn Lam: Thank you so much.

Audience, thanks also for joining us. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation March 6, 2018 Issue

5 mars 2018 | 21 min

Dr Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week's journal features an international external validation study of the 2014 ESE Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy. A very exciting discussion coming right up after these summaries.

The first original paper this week suggests that proteomics, a tool of precision medicine may prove useful in improving the safety and efficiency of drug development. First author, Doctor Williams, Corresponding Author, Doctor Ganz, from the Zuckerberg San Francisco General Hospital retrospectively applied large scale proteomics to blood samples from Illuminate, the trial of Torcetrapib, a cholesterol estrotransfer protein inhibitor, which raised HDL and lowered LDL cholesterol. Recall that this trial was terminated due to increases in cardiovascular events and mortality.

In the current study, the authors found that plasma concentrations of 200 proteins changed significantly with Torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in aldosterone function and glycemic control. A previously validated nine protein risk score was similar in the two treatment arms at baseline, but higher in participants with subsequent events. At three months, the absolute nine protein derived risk increased in the Torcetrapib plus Atorvastatin arm compared to the Atorvastatin only arm. Thus, this protein-based risk score predicted harm from Torcetrapib within just three months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. This is discussed in an accompanying editorial entitled "Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials" by Doctor Maggie Lam and Ying Ge.

The next study suggests that personalized monitoring of heart transplant outcomes may be achieved by profiling the genetic and phenotypic markers of the CD16-dependent natural killer cell activation pathway. First and corresponding author Dr. Paul from Vascular Research center in Marseilles in France and his colleagues collected blood samples from 103 patients undergoing routine coronary angiography for cardiac allograph vasculopathy diagnosis, a median of five years since their heart transplantation. They used a non-invasive natural killer cellular-humoral activation test to evaluate the association between genetic and phenotypic markers of the CD16 dependent natural killer cell activation pathway. They showed that the Fc-gamma receptor IIIAVV polymorphic variant, which encodes the highly responsive CD16-Fc receptor, was an independent baseline predictor of cardiac allograph vasculopathy, and may be useful for stratifying patients at higher risk of rejection. The implications of these findings also include the fact that individualized natural killer cell targeted therapies may limit vascular damage in responsive patients.

The next study suggests that estimation of polygenic atrial fibrillation risk is feasible, and together with clinical risk factor burden, can explain lifetime risk of atrial fibrillation. Co-first authors Dr. Weng and Preis, corresponding author Dr. Lubitz from Massachusetts General Hospital, and colleagues estimated the lifetime risk of atrial fibrillation in individuals from the community-based Framingham Heart Study. Polygenic risk for atrial fibrillation was derived using a score of approximately 1000 atrial fibrillation-associated SNPs. Clinical risk factor burden was calculated for each individual using a validated risk score for incident atrial fibrillation comprised of height, weight, systolic and diastolic blood pressure, current smoking, anti-hypertensive medication use, diabetes, history of myocardial infarction, and history of heart failure.

They found that the lifetime risk of atrial fibrillation after age 55 years was 37 percent was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of atrial fibrillation at the age of 55 years, those in the low polygenic and clinical risk tertiles, had a lifetime risk of 22 percent, whereas those in the high risk tertiles had a risk of 48 percent. Atrial fibrillation developed at an older age among individuals with a favorable clinical risk profile regardless of genetic predisposition. Nevertheless, the lifetime risk of atrial fibrillation in individuals with high genetic predisposition was substantial, even when the clinical risk factor burden was low. Thus, individualized projections of lifetime risk of atrial fibrillation may be refined by accounting for both genetic predisposition and clinical risk factor burden.

The final study tells us that in contrast to previous perceptions, Takotsubo cardiomyopathy has long-lasting clinical consequences. First and corresponding author Dr. Skally from University of Aberdeen in the UK and their colleagues did an observational case controlled study of 37 patients with prior Takotsubo cardiomyopathy and 37 age, sex, and co-morbidity matched controls. Although Takotsubo cardiomyopathy occurred 20 months before the study, the majority of patients had persisting symptoms compatible with heart failure and cardiac limitation on exercise testing. Despite a normal left ventricular ejection fraction in serum biomarkers, patients with prior Takotsubo cardiomyopathy had impaired cardiac deformation indices on echo cardiography, increased native T1 mapping values on cardio magnetic residence imaging and impaired cardiac energetic status on p31 spectroscopy. Taken together, these findings demonstrate that after Takotsubo cardiomyopathy, patients appear to develop a persistent long-term heart failure phenotype.

Well that wraps it up for our summaries. Now for our featured discussion.

Sudden cardiac death prevention and hypertrophic cardiomyopathy. Always such an important topic. I'm so pleased to have with us the author from our featured paper this week, Dr. Perry Elliot from University College London, nd our associate editor, Dr. Mark Link from UT Southwestern who also wrote a beautiful accompanying editorial with Tera Lynn Ho. So welcome both of you. Perry, I think to set us up, I'd really love if you could tell us a little bit more about the 2014 ESE guidelines for sudden cardiac death prevention and hypertrophic cardiomyopathy. And particularly pointing out how they may differ from the 2011 ACC AHA guidelines please.

Dr Perry Elliot: So, the 2014 guideline on sudden death prevention HCM, the aim of that guideline was to try to quantify the risk of sudden cardiac death. As you pointed out, sudden death is a significant complication of hypertrophic cardiomyopathy and one which we all as clinicians spend a lot of time trying to determine. If we look back over at, I don't know, a period of twenty, thirty years the approach we've developed is based upon the recognition of a number of clinical features of the disease that we know associate with a higher risk of sudden death. So things such as, you know, unexplained syncope or severity of hypertrophy. And it was that model of sort of taking those so called major risk factors which form the basis of the 2011 US guidelines and the essential model was the more of those things you have, the greater is your risk, and I suppose the higher indication for an ICD.

One of the problems with that approach was that it's not quantitative so you know, you could say, "Okay. Well I think you're at higher risk, but I can't say how much that risk is." And another problem with that way of doing things is when you start to think about some of the individual risk factors, it doesn't make a great deal of sense clinically.

And I suppose a good example of that is wall thickness. You know we have this magical number of 30 millimeters, above which we say you're at risk, but of course are we really saying that if your wall thickness is 29 millimeters you're at low risk? We know it doesn't really work that way in biology. So when we drew up the 2014 guideline we wanted to say, "Okay let's develop a model in exactly the same way that we do with atrial fibrillation or primary prevention in coronary disease so that we can say to the patient sitting in front of us, 'Based on your clinical assessment we think you've got a one, five, ten percent risk of something bad happening to you in the next five years.'" And then we can use that information to inform our decision about ICD implantation.

The model itself is not so revolutionary. I mean, it uses a lot of the conventional risk factors such as wall thickness, such as non-sustained VT on Holter monitoring, but what it did introduce was the factor of age, because we know that the age of the patient certainly determines their risk. We brought in [inaudible 00:10:12] obstruction because we've now got reasonable evidence showing that if you've got a big gradient, that certainly modulates your risk. And also probably for the first time, I suppose, left atrial size, which was one of those missing things I think in previous assessments. You know, it's a fantastic surrogate for restrictive physiology and certainly when we added it to the model it improved the predictive power of that model.

So I suppose in summary what we've done is to produce a tool which allows you to estimate risk and then use that to help you decide on whether an individual needs a defibrillator in the clinic.

Dr Carolyn Lam: You know Perry I believe you led those guidelines and I just want to congratulate you as well as that was such a beautiful explanation of what was going on behind those. Yup, but the proof is in the pudding isn't it? But you're providing that proof in today's paper. Tell us about it. So it's an external validation, a large international multi-centers study to actually validate these 2014 guidelines.

Dr Perry Elliot: That's right. I mean, I think when we generate these kind of models it's really important to test those models in different settings. The original model was based upon a relatively small number of European centers and I think what this paper does is it brings insights into different geographies and different health care systems. So we have participating centers from North America from the Middle East from the Far East and the idea here is to get as diverse a population as we can and just see if the model performs in the same way. And you know in a study just short of 4000 people, I think that we've shown that the model does indeed seem to behave in the same way. In fact, the numbers were remarkably similar. You know the ability of this model to discriminate between high and low risk patients was almost exactly the same as in the original paper, which I think gives us a level of reassurance that this model, this tool that we've developed, can be used in different health care settings.

Dr Carolyn Lam: Mark. I really enjoyed your editorial. I love the way that you started out with a case that really shows why this is so important. And I also love that you discuss some other studies that tried to validate the 2014 ESE guidelines as well. Could you just give us some of your thoughts there.

Dr Mark Link: Yeah. I first want to congratulate Perry and his fellow authors for this paper. I think it was a very nice paper. I was a champion of this paper from the time it got sent into circulation. And, you know, the big change in the 2014 European guidelines compared to the American guidelines is really the linear risk of age, wall thickness, and I'll put tract gradient. And as Perry says, I agree, it's not a simple you have it or you don't, it's a linear risk and I applaud them for including that in their risk factor stratifier. And if you look at the current paper, I mean it was very good at picking out high risk patients. So if you have greater than a four percent, six percent risk over five years, you did. And so for picking out the high risk patients it was very good. And for picking out the medium risk patients, it didn't function as well. It was best for separating out the high risk and the low risk population.

And I will say, based on this paper, I've started using the European risk stratifier in my clinical practice. So I do want to applaud them, you know, for the risk stratifier tool and this paper. But I do want to say, and I'm sure Perry will agree, that we're not there yet. We need better tools, because not only in this data set but in other data sets, because more of these individuals reside in the low risk population, more of the sudden deaths are in that population. And we need better tools. And over time they will come. You know, they may be MRI tools. They may be scar tools. They may be other tools that we aren't even aware of that are coming on the horizon, but we do need better tools as we move forward to identify those at risk for sudden death in hypertrophic cardiomyopathy.

Dr Perry Elliot: Yeah. No. I agree. I mean I think what I would say is if you sort of take a step back and look at the overall perspective in this paper, despite the fact that, you know, we've got nearly 4000 people and they're followed in different health care settings, the overall sudden death rate in hypertrophic cardiomyopathy pretty low. You know, so that's good for patients 'cause I think it shows that at least in managed populations, the risk of sudden death which is real and we've got to assess it, but I think it's really important to get that message over to patients that for most people with HCM they're at low risk. It is of course the challenge because when you're dealing with rare events, it's really hard to predict them. And this model is far from perfect. I would argue it's probably the best we've got for the moment, but you know, it's not that bad. It's not that bad.

I mean agree with you absolutely Mark, 'cause you know, either end it performs pretty well. In the middle there it's not as predictive, although what it tends to do is overpredict, rather than underpredict. So you know, I think if you use this model in your every day practice just the greatest risk is that you'd end up putting in probably more ICDs then you really need to rather than missing a lot of patients. You know, we really want to prevent every sudden death if we possibly can, but that's always going to be really hard I think and I think the fight goes on. We got to look for new risk predictors. It may be that we can interchange some of these predictors. They might be easier to assess in some practices, but I'm not a born optimist, but I really think it's amazing just how well in such a complex heterogeneous disease that this relatively simple assessment works. You know?

Dr Mark Link: Going forward, what do you think the future of HCM [inaudible 00:15:47] stratification will include? We've got the risk stratifiers in your calculator ready. And more specifically where do you think gadolinium enhancement will play a role in the future? So MRI findings of scar or gadolinium enhancement.

Dr Perry Elliot: The base we have at the moment show that the more scar you have, the greater risk of sudden death. It sort of makes sense, doesn't it? It's part of that substrate for ventricular arrhythmia. My own reading of it just so far is that I'm not sure what it adds to the existing way of doing things. I mean I think this is true of any biomarker, you know. I've got a new biomarker, what does it tell me that I don't already know? And with scar, we know the greater amount of scar, it often tracks with wall thickness. You're likely to have a thicker heart, you're more likely to have non-sustained VT. But I'm openminded on that front. The beauty about this model, for me, is that it's a tool to into which you can plug other things and you know, if we can get big enough data sets and we can use gads and the amount of scar and put that into the model and if it improves the performance of the model that's great. Those studies are underway at the moment and I think we eagerly wait the results of those studies.

For me, one of the missing things is the genetics. This is a heterogeneous disease with quite a complex genetic architecture, and despite the fact that you know it's 20, 30 years now since we identified the first gene, we haven't really factored that in to our risk models and I think that for me is one of the big challenges and opportunities over the coming years is to put together really large international data sets so that we can answer once and for all whether your mutation determines your prognosis.

Dr Mark Link: Yeah. I agree with the genetics also I think getting more information on that. And it’s been 30 years it still is not helping us prognosticate the risk of sudden death, but it should. I mean it really should. And I do think hopefully we will find other tools also as time goes on because it really is imprecise and it's very difficult when you're sitting there in front of ... You know, I just had a 20 year old yesterday come in with his family and he's got a three centimeter septum and he's got 12 percent scar and he's saying, "Gee what would you do and what would you do if I were your son?" And it's easy when you're looking at it in the aggregate. It's much more difficult when you're sitting there one on one with a patient in front of you.

Dr Perry Elliot: Of course. Of course. And I think another factor I think which is changing the dynamic of that kind of discussion is the evolution of ICD technology. You know, I think when you're dealing with young people the fear is long-term complications with leads isn't it? And I think with the advent of the SICD I sense it's already tipping the balance into perhaps a slightly more liberal approach to ICD implantation exactly in the kind of scenario you've just described Mark, you know you've got guy who's 20. He's got a really severe hypertrophy. Well you know, if you and mess ICD you know your threshold for implantation might be a bit lower.

Dr Mark Link: Yeah and in fact, after a two hour discussion that's what we decided on is that subcu ICD was the right thing for him. And everyone's very happy with that choice.

Dr Perry Elliot: Yep. I think it also raises another thing which I often think about is that as medics we're also probably not good at considering what acceptable risk actually is. You know? We develop models in different settings and hyeprtrophic cardiomyopathy, coronary disease, heart failure, and actually if you go back and critically look at the thresholds that are used to put in defibrillators, the absolute risks vary enormously. So you know, here in [inaudible 00:19:02] we're talking about an approximate annual risk of sudden death of about one percent per annum is sufficient to put in an ICD, but in long-QT world it's quite a different threshold that's used and of course that's because there is no defined number. You know the number's we used in the ESE model of greater than six percent you should have an ICD, well yeah that's the consensus number, there's nothing magical about it. There's nothing biological about it. And I think we've probably had greater debates at what acceptable risks really are.

Dr Mark Link: And that's become a big shared decision now in the States and actually everywhere. It's become a big word because it sued to be that the physicians would decide on who gets an ICD and who doesn't. And it's no longer that way it's a discussion with the patient, with the family. How much risk are they willing to take, both with an ICD and without an ICD, because there are issues with ICD, even though I'm a big fan. There are issues and especially with transvenous ICDs, but also with subcutaneous ICDs.

Dr Perry Elliot: Absolutely. Absolutely.

Dr Mark Link: You know, it's a different world now than it was 15 20 years ago.

Dr Carolyn Lam: Perry and Mark, this has been one of the most wonderful conversations I've had on these podcasts. I just can't thank you enough. I'm sure all our listeners are thanking you too. You've been listening to Circulation on the Run. You must tune in again next week for more beautiful conversations.

Circulation February 27, 2018 Issue

27 februari 2018 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. The new ACC/AHA hypertension guidelines are hotly discussed. So much so that we have invited perspectives of these new guidelines from around the world and authors will be discussing this right here on Circulation on the Run. Stay tuned, as it's coming right up after these summaries.

The first original paper this week is a translation study suggesting that the parasympathetic system may be a novel therapeutic target in pulmonary arterial hypertension. Co-corresponding authors Dr. Handoko and de Man from University Medical Center Amsterdam used heart rate recovery after maximal cardiopulmonary exercise testing as a surrogate for parasympathetic activity, and assessed white ventricular ejection fraction in 112 patients with pulmonary arterial hypertension. They found that patients with a lower right ventricular ejection fraction had a significantly reduced heart rate recovery compared to patients with a higher right ventricular ejection fraction.

Furthermore, they looked at tissues from the right ventricle of 11 patients undergoing heart-lung transplantation, and found that there was increased expression of nicotinic receptors with no difference in muscarinic receptor expression compared to controls.

Finally, in a rat model of pulmonary hypertension, they showed that chronic pharmacologic sympathetic stimulation by pyridostigmine, which is an acetylcholinesterase inhibitor, improved surviving right ventricular function and reduced pulmonary vascular remodeling.

In summary, the study shows that right ventricular dysfunction is associated with reduced systemic parasympathetic activity in patients with pulmonary arterial hypertension, with an inadequate adaptive response of the cholinergic system in the right ventricle. Furthermore, enhancing the parasympathetic activity in these patients may be a novel therapeutic strategy.

Dr. Carolyn Lam: The next study unveils a new mechanism by which pericardial adipose tissue coordinates immune cell activation and outcomes following a myocardial infarction. First author Dr. Horckmans, corresponding author Dr. Steffens, and colleagues from Institute of Cardiovascular Prevention in Munich identified larger B-cell clusters in epicardial adipose tissue of human patients with coronary artery disease compared to controls without coronary artery disease. Furthermore, they showed that infarcted mice had larger pericardial clusters, and a 3-fold up regulator numbers of GM-CSF producing B-cells within the pericardial adipose tissue, but not in the spleen or lymph nodes. This was associated with higher dendritic cell and T-cell counts in the pericardial adipose tissue.

Further experiments show that activated dendritic cells migrated from infarcts into the pericardial adipose tissue. Cytokines and growth factors released locally within the pericardial adipose tissue as well as systemically promoted immune cell proliferation and emergency granulopoiesis after myocardial infarction.

Finally, the enhanced fibrosis and worsened ejection fraction in mice was limited by removal of the pericardial adipose tissue.

In summary, these pre-clinical data suggest that pericardial adipose tissue may be a central compartment for innate and adaptive immune responses, which regulate post-myocardial infarction healing.

Dr. Carolyn Lam: The next study reports for the first time in a large, comprehensive national cohort study, the incidence of atrial fibrillation in children and young adults with congenital heart disease. First and corresponding author Dr. Mandalenakis and colleagues from University of Gothenburg in Sweden used data from the Swedish Patient and Cause of Death registers to identify all patients with a diagnosis of congenital heart disease who were born between 1970 and 1993. Each patient with congenital heart disease was matched by birth year, sex, and county with ten controls from Sweden. Follow-up data were collected until 2011.

The authors found that the risk of atrial fibrillation in children and young adults with congenital heart disease was 22 times higher than that in matched controls. Up to the age of 42 years, one in 12 patients with congenital heart disease had developed atrial fibrillation and one in 10 patients with congenital heart disease with atrial fibrillation had developed heart failure. In particular, patients with the most complex congenital malformations, conotruncal defects, had the highest risk to develop atrial fibrillation. These patients should be considered for targeted monitoring.

Dr. Carolyn Lam: The next study provides a novel and simple risk score for right-sided heart failure in adults undergoing Left Ventricular Assist Device implantation with the current mainstream devices. First and corresponding author Dr. Solomon and colleagues from University Medical Center Rotterdam studied almost 3000 adults who underwent continuous flow Left Ventricular Assist Device implantation in the largest EU registry of mechanical circulatory support devices. They derived and validated a right-sided heart failure prediction model that out-performed several published scores and well-known hemodynamic and echocardiographic individual markers of right-sided heart failure.

This prediction model included the following risk factors: need for three or more inotropic agents, inter-agency registry from mechanically-assisted circulatory support class one through three, severe right ventricular dysfunction on semi-quantitative echo cardiography, ratio of right atrial to pulmonary capillary wedge pressure of more than 0.54, and a hemoglobin level of less than 10 grams per deciliter.

These findings offer a step towards improving prediction of the risk of right-sided heart failure to target future optimal strategies aiming at early and intension right-sided heart failure management for the highest risk subgroups of patients undergoing Left Ventricular Assist Device implantation.

Dr. Carolyn Lam: Now, sharing a patient-level clinical trial data has been widely endorsed, but just how extensively have these data been used for cardio metabolic diseases? The final study this week attempts to answer this question. First and corresponding author Dr. Vaduganathan and colleagues from Brigima Women's Hospital extracted data from clinicalstudydatarequest.com, a large, multi-sponsored data sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.

They found that the median time from study completion to data availability was more than six years. Most data requesters of cardio metabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Only 15% of these trials had been accessed by investigators thus far, and few findings have reached publication. Most requests for shared data access focused on new hypothesis generating questions rather than validation of the original study findings. These data may allow anticipation of barriers to effective system implementation and shared data consumption in cardiology.

Well, that wraps it up for our summaries this week. Now for our feature discussion.

Dr. Carolyn Lam: We are having a truly global conversation today on a really global problem. That is hypertension. From Canada, we've got Dr. Ernesto Schiffrin from McGill University, from Europe we've got Dr. Giuseppe Mancia from university of Milano, from the United States we have Dr. Wonpen Vongpatanasin from UT Southwestern, our dear associate editor and regular voice on this podcast, and then of course from Asia, that's me. You know what we're talking about? It is the global impact of the 2017 ACC/AHA hypertension guidelines. So many novel aspects about these guidelines, including new definitions of hypertension and it's stages, new thresholds and goals of treatment, consideration of the global risks and treatment decisions, addition of classes of recommendations and levels of evidence. So much to talk about, and let's start right now.

Wanpen, you were the brainchild of suggesting these global perspectives. Perhaps say a few words about the ACC/AHA new guidelines first.

Dr. Wonpen Vongpatanasin: Yeah, so I think that this is the guidelines that actually incorporating the more recent evidence and trials, particularly SPRINT, and applying this into the threshold and the blood pressure goal across the board. There's three comprehensive guidelines, and obviously ... The first time, the threshold was lower across the board, and that leads to a lot of discussion and concern and trying to see how we're implementing this or is it appropriate to all the population? Particularly not just in the US and around the world. I guess that leads to us reaching out to many hypertension leaders across the globe and really get very interesting and very insightful feedback from the global experts, two of which is on podcast today. I'm really thankful and excited to have some more in depth insight from them.

Dr. Carolyn Lam: Yeah, exactly. The buzz has really been worldwide, I can see that even from where I'm sitting here in Asia. But maybe Ernesto, I'm just gonna jump straight to the core questions. How are these guidelines different from the hypertension Canada guidelines, and frankly do you think that the ACC American guidelines are going to impact hypertension care in Canada?

Dr. Ernesto Schiffrin: Well, there are quite a few differences. The definition of hypertension remains the classical one in Canada. We have different thresholds and goals, and interestingly, the hypertension Canada guidelines have adopted a SPRINT-based recommendation for high cardiovascular risk patients in contrast to the AHA/ACC hypertension guideline. Although it has intensified the goals for treatment, it has lowered ... Has introduced as you mentioned a category of elevated blood pressure, a new definition of hypertension equal to or above 130 over 80 in contrast to ours equal to or above 140 over 90. It has not really introduced a SPRINT-based recommendation. As well, I think that one of the major questions remains the measurement of blood pressure. In Canada, we have adopted the AOBP, the Automated Office Blood Pressure measurement, at least for high risk, SPRINT like individuals. In the AHA/ACC hypertension guidelines, there is emphasis on standardized blood pressure measurement, but the SPRINT-like measurement of blood pressure has not been adopted.

Dr. Carolyn Lam: Very interesting. In Canada, with the AOBP, how do you translate that? I suppose you estimate it as lower than what would otherwise be labeled?

Dr. Ernesto Schiffrin: That is indeed a problem, because the evidence for the relationship between the AOBP carried out in the absence of a health care professional and the standardized oscillometric measurement, or the osculatory manual measurement, is unclear. The evidence is weak. So we have not really provided a guideline or recommendation with respect to these differences.

In contrast, AHA/ACC provides at least a pragmatic expert-based recommendation on what the differences are between office blood pressure and out-of-office blood pressure measurement. But, as I mentioned, there is no recommendation regarding the SPRINT-like measurement of blood pressure, and that's important because there may be major differences in the order of ten or even 15 millimeters of [inaudible 00:13:32] systolic blood pressure. However, as I see it, the committee for the ACC/AHA hypertension guideline has adopted a prudent and pragmatic approach, and actually simplified thresholds and goals to 130 over 80, and in my view this is a prudent approach.

Will it impact Canada? I think in Canada, most physicians follow the hypertension Canada guidelines, and they are recommended as best practice by governments across the country, provincial and federal. I think that physicians will be aware, but will still carry out their practice following the hypertension Canada guidelines.

Dr. Carolyn Lam: I like that. Aware but perhaps not so practice-changing in Canada. Let's shift to Europe though. Giuseppe, do you agree with that? How do you think these American guidelines may impact physicians in Europe?

Dr. Giuseppe Mancia: The American guidelines have been received with interest, lots of interest. But also there has been some criticism. For example, the question of the SPRINT [inaudible 00:14:55], you read the question of how blood pressure was measured as professor Schiffrin mentioned. It was measured at least in large number professions, why they were [inaudible 00:15:10], I'm not sure. This means that values have lower worth than those obtained by conventional office blood pressure measurement. How much room is still debated, but it could be 10, 15 millimeter mercury, which means that you could compare these SPRINT-like values to conventional office blood pressure values. Probably the SPRINT values are not much lower than 140 millimeters to the mercury systolic.

Then there is the question that can SPRINT mutually [inaudible 00:15:50] at the start. Most of them with two hypertensive charts. So if it's difficult to decide the bounds of threshold to treatment, lower these pressures to the high-low of blood pressure range, less than 140 millimeters mercury systolic when you have patients already treated, because their original blood pressure was probably higher than 140 millimeters of mercury. This [inaudible 00:16:15], however there are other data suggesting that, at least in high-risk individuals, one might indeed start treatment when blood pressure is in the 140 millimeter of mercury. You'll see what the European guidelines will recommend ... They are going to be published in June ... But perhaps this fraction of the population will be a candidate for treatment.

One last point, however, collecting the data from SPRINT is what you wish for in this regard, is that there should be a definite reduction in the threshold blood pressure for treatment in the elderly. In Europe, this was about 160 millimeters mercury based on randomized trials but probably in the future it will be about 140 millimeters mercury. So a large fraction of the elderly population will be involved in [inaudible 00:17:14].

Dr. Carolyn Lam: You know a question I always get though, is what about the side effects? We talk about the benefits of lowering it further, but what about the side effects. I don't know, does anyone have any thoughts on that?

Dr. Ernesto Schiffrin: I would say that, when you look at SPRINT, although there were increased side effects in the intensive treatment group, actually side effects were relatively rare. Some of them were important, such as acute renal failure and hyperkinemia, and so on, and other electrolyte abnormalities and syncope. But they were rare, and when we are recommending intensified treatment for the elderly, for example, which is SPRINT based in the hypertension Canada guidelines, we do say that this approach should be a gentle and progressive one, very aware that particularly in the elderly orthostatic hypertension may occur. One has to be very careful about this intensification of treatment, but yet we believe that if using automated office blood pressure measurement unobserved, you are able to reach lower blood pressures and they are well tolerated around or below 120 systolic, this will benefit these patients as shown in the SPRINT trial.

Dr. Carolyn Lam: Yeah, indeed. That's very nicely put, and just brings up the gaps that we still need to answer, like the way blood pressure is measured, standardization. We may be accounting more about risk versus benefits, patient subgroups. Wanpen, have I missed out anything else? What is the other buzz that you've heard?

Dr. Wonpen Vongpatanasin: I think that we really need to do a better job in measuring blood pressure in basic clinical practice, particularly in the US where we allow only 20 minutes to see your follow-up patient. I don't think that it will be possible to do an AOBP in the US, but I think one thing that makes the issue a little bit murkier is the SPRINT group. I actually just had an abstract presentation at the last HA meeting, that said only half of that site measure in the intended way on AOBP.

Actually, at UT Southwestern we also SPRINT site and we actually did not use AOBP, and when that stratified the treatment side by using AOBP versus non-AOBP, the outcomes was still the benefit of intensive blood pressure reduction for what it's worth. I think that the AOBP story is still controversial, but I think that I agree that we hardly have patient, sit down quietly, for five minutes before we do the measurement. I think that's first and foremost, we need to be able to do that, and do at least two measurements. We'd be lucky if we'd get one measurement after sitting down immediately, that's what we usually get in clinical practice. I definitely agree with Dr. Schifferin that when we ... Particularly the elderly, we have to be careful about orthostatic hypertension. Particular in the SPRINT trial, they actually exclude anyone who had standing systolic blood pressure less than 110. These people who are high risk of having [inaudible 00:20:35] never get into those trials to begin with.

Dr. Carolyn Lam: I can't thank you enough, everyone, for joining me in this chat around the world. It has been a learning conversation for me, as I'm sure it has been for our listeners as well.

Listeners out there, you've been listening to Circulation on the Run. Thank you for joining us today.

Circulation February 20, 2018 Issue

19 februari 2018 | 16 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. This week’s issue is the Go Red for Women issue, my favorite discussions of the year happened during this podcast.

Today, I am so delighted to have with me, our Editor-in-Chief himself, Dr. Joe Hill, from UT Southwestern, as well as, of course, the editor that made this issue possible, Dr. Sharon Reimold, also from UT Southwestern. Joe, would you like to tell us a little bit about this year’s Go Red issue? From the birds eye view.

Dr. Joseph Hill: Well Carolyn, I share your enthusiasm. This is our second annual Go Red for Women issue and it is fantastic. It has generated great interest in the community. We had a number of papers coming in, unsolicited. Our frame of reference-type content. Original research articles. State of the art.

We clearly touched a nerve with this issue. As we will discuss further, we shine a bright light here on some of the very best science, focusing on sex-based differences in the biology of heart disease, the presentation of heart disease, how women function, and are treated in the academic environment. The ways in which they are impacted by psychological stress. It's an absolute bonanza of science, in this issue.

Dr. Carolyn Lam: You took the words out of my mouth. It is a bonanza issue. I mean, we had seven original articles. Lots of new stuff, but lots of good, important papers on plain old ischemic heart disease. What I really liked was that, three of these original papers focused on myocardial infractions, in the young, and their risk factors, prevention, and so on. Sharon, shall we go through those? I mean, there was the one on genetics, lifestyle, and LDL in young women.

Dr. Sharon Reimold: That would be great. That manuscript looked at, sort of, a distribution of lipids, in women, that would have otherwise expect to be healthy. They sorted them out by individuals that had extremely low LDL levels and those that had high LDL levels. They pointed out that the individuals with high LDL levels. Ended up having hypercholesterolemia heritable, but they also found genetic variance of related to those with low LDL levels. I think this manuscript points out the importance of screening younger women for lipid disorders and incorporating those data into their clinical management.

Dr. Carolyn Lam: Absolutely. Then, there was that paper that, again, talked about young women experiencing myocardial infarction, and the sex differences in their presentation, and perception. That was super cool. From the Virgo trial.

Dr. Sharon Reimold: There are several other papers, that are published, demonstrating that women tend to have multiple symptoms when they present with symptoms of ischemia. That's true for both myocardial infarction, as well as for other unstable syndromes. They certainly have more symptoms than men.

But what was very interesting about this particular paper, is that when women presented with multiple symptoms, providers were less likely to think that the symptoms were due to a cardiac etiology. So even when women are trying to tell their providers what is going on, sometimes, they're not taken seriously, because they have multiple symptoms. So I'm hoping that this resonates with our providers, clinical providers, and we think about this. Whether we're cardiologist, or emergency room providers, or even EMTs.

Dr. Carolyn Lam: Exactly. Then, the third original paper in these young women, kind of scary, mental stress induced myocardial ischemia.

Dr. Sharon Reimold: Right. So there's been a lot of interest in the myocardial infarction without obstructive coronary disease, in the last year or two. Because a lot of those individuals, even thought, they don't have typical atherosclerotic pathologies, they don't have good outcomes. So this article looks at the role that mental stress plays in inducing ischemia, by EKG, in these individuals.

I think we still need to understand more about how this contributes to the biology, and outcomes, in these individuals. Also, get a better understanding if this is also true in older women, who have ischemic heart disease.

Dr. Carolyn Lam: Exactly. You know, but speaking of the older women, it's not like the issue left out the older women this time either. I did think that the study on the metabolic predictors of incident ischemic events, in postmenopausal women, was really interesting, as well. Basically, the authors identified a cluster of novel metabolites, that were related to oxidative stress, that added to. you know?

They weren't correlated with the traditional biomarkers. Really suggesting that there may be a whole area of metabolites, and other biomarkers, that we may be needing to check, and to understand better, for risk prediction. At least, in older women. But, of course, in men as well. Then, finally, there was the data on sex differences from the STICH trial, on surgical revascularization. What did you think of that one?

Dr. Sharon Reimold: Well, I thought that this was a very important addition to the cardiology literature. Because we are accustomed to thinking of women as having poor outcomes, after they have cabbage revascularization surgery. Certainly, the STICH trial enrolled patients who were more sick than the average patient, with their underline LV dysfunction. They found that sex did not influence the outcomes in this trial.

So the importance of that, for the medical community, is obviously we should not consider sex as a barrier to sending women to surgery, even if they're at high risk, because they can have equally good outcomes.

Dr. Carolyn Lam: Exactly. Important message. Important paper. Then, moving from ischemic heart disease. We also had a paper focusing on stroke, which I thought was a really intriguing one, talking about atrial fibrillation, and questioning if being a woman is a risk modifier, or a risk factor. Do you want to elaborate on that one?

Dr. Sharon Reimold: So instead of the using the CHA2DS2–VASc algorithm they use the CHADS2-VA program and then looked to see how well that predicted risk, and how much the S and C, the gender actually influenced outcome. I think this is an important issue. I'll say it's for women, perhaps. because as a woman, you know, without doing anything, you start out with a risk factor of one. Then, once you get to a certain age you have a risk factor of two. That's even for somebody who has no other disease processes.

Dr. Carolyn Lam: Yeah.

Dr. Sharon Reimold: So I think it's a little different way to look at how the risk is modified. They propose that if your CHADS2-VA score is two, or greater, certainly, your risk goes up if you're also female. They propose, then, that you would treat those patients more intensively. It's just a little twist on the CHA2DS2–VASc and maybe will provide us different ways to refine our knowledge about outcomes in atrial fibrillation.

Dr. Carolyn Lam: Yeah. I love that paper, too, because it's quite different from the papers that we had in the first Go Red issue. Isn't it? But in the first Go Red issue, we had lots of papers on pregnancy. The current issue certainly has those papers as well.

Dr. Sharon Reimold: Yes. There are increasing number of pregnancy related complications. Both maternal, and offspring, complications that predict increased cardiac risk, down the line. This issue has a series of women who had, had preeclampsia during pregnancy, and found that 17% of their women had a coronary artery calcium score of greater than 95th percentile. While that doesn't entirely get you from the biology, in between those two, it at least gives you an idea of where to start going back, and taking a look at what's going on.

Dr. Carolyn Lam: What about the one in rheumatic mitral valve disease? Pregnancy outcomes in women with those?

Dr. Sharon Reimold: So rheumatic heart disease and pregnancy outcomes, you know, we don't see much written about it anymore. because most of the active disease is in certain areas, in the world. But obviously, these women can have symptoms related to their mitral stenosis and/or their regurgitation during their pregnancy, with heart failure being the most common presenting cardiovascular complication. While some of that is much more quantitative, than perhaps, it was in the past, which is useful.

I think that the take-home message from this particular trial is that you need to talk to these patients, and screen them, prior to pregnancy, if possible, to help achieve the best possible outcome. I think that the risk of heart failure was a little bit less than 2% during the trial, which is obviously much higher than the average woman's cardiovascular risk during pregnancy.

Dr. Carolyn Lam: this is still definitely an important issue, in many other parts of the world. I really appreciate that you invited this editorial, that gave that global perspective. The editorial, by Athena Poppas and Katharine French, really beautiful work there. You know, I have to say that one of my favorite papers, in this issue, was that in depth paper, regarding gender versus sex, as a social determinant of cardiovascular risk. I found that so intriguing, the first time I read it, and just love it.

Dr. Sharon Reimold: Social determinants of health is a hot topic, in a lot of different areas of medicine these days. But they point out some really interesting things, that I don't think I had thought about. One is the fact that, when you are a child, you know maybe 10 or 12, that boys are encouraged more to be physically active. Athletics and other sorts of activities. Whereas many girls, don't have the opportunity or are not as interested. Perhaps we set up an abnormal social situation very early in most people's lives.

Dr. Carolyn Lam: Yeah, that represents cardiovascular risk. I know. That stuck out to me too.

Dr. Sharon Reimold: Obviously, how and where people live, as children, can influence outcome. That can be influential for both boys and girls. But I think bringing the idea back to cardiovascular diseases, and risk, are really long term, lifelong processes, that we can make changes in, from a preventative standpoint, even in young people.

Dr. Carolyn Lam: Something we don't usually think about and I just love the way it was presented, so clearly, and I just love it. Now, to an area that really cuts close to the heart. Pun intended. That is the bias in research grants, bias in manuscript authorship. Joe you mentioned that, right from the introduction, I would love your comments on those papers.

Dr. Joseph Hill: The reality, that we all are aware of, is, in many countries, including the United States, 50% of medical students now are female. But as we move through the ranks, into the different subspecialties, and up the career ladder of academic cardiology, we see a thinning of female representation. Arguably, it's been improving, over the last number of years.

But the reality is, that there remains a bias against representation of women, in terms of extra mural grant funding, authorship on high-profile papers. This article digs into that, and analyzes those numbers, takes a snapshot of what it looks like at the present time. In some ways, I believe it's a call to arms on how we must do a better job of recognizing this and rectifying it, going forward.

Dr. Carolyn Lam: Sharon, did you have comments to add?

Dr. Sharon Reimold: Yeah. I mean, I think, I wholeheartedly agree with Joe about those sorts of things. I mean, we see the same types of issues in clinical cardiology as well as in the research components of what we do. we need to figure out how to do this better, so that we all can be productive, going forward.

Dr. Carolyn Lam: You know it's just such a beautiful issue. So rich, in so many ways. Was there anything else you might want to highlight to our listeners?

Dr. Joseph Hill: I might add that Sharon and I kicked off the issue with a brief introduction. Pointing out that the reality is, that one and four women will die of heart disease. Most women don't know that. Most healthcare providers don't know that. Many Cardiologist don't know that.

When you compare that to the realities of breast cancer, it's 1 in 40. It's 10 times different. Now, that community has done a fantastic job. The Susan G. Komen program, in the United States. The pink ribbons, that we see all around the world. That community has done a fabulous job of getting the message out about that grievous disorder.

We have to do better. We have to do better educating ourselves, educating the lay public, about the realities of heart disease in women. 1 in 4, around the world. We also have to do a better job of digging into the science. That's where this issue does an especially good job.

That the reality is that heart disease is different in men and women. It presents differently. It presents at a different age. The way in which women respond to therapies, can differ from men. So there's work to be done, in terms of awareness. There's work to be done, in terms of the underline biology. This is an especially exciting time in this arena.

Dr. Carolyn Lam: I couldn't agree more. I'd add to it, even sex differences and the perceptions about own symptoms, and that of women versus men with chest pain. Then, the whole gender, social element to it. Oh, just so much to discuss, so much to learn from.

Well, listeners you heard it right here. I want you to please send this episode, share it with as many other women as you can think of. Do help us to spread this message, it's such an important one.

Thank you so much, Joe and Sharon, for joining me today. Thank you, listeners, as well. Tune in again next week.

Circulation February 13, 2018 Issue

12 februari 2018 | 19 min

Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:

Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.

The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.

Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.

The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.

In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.

On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.

In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.

Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.

To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.

They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.

The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.

They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.

These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.

Well, that wraps it up for our summaries. Now for our feature discussion.

For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.

Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.

Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found?

Dr. Jason Weatherald: This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.

We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective.

Dr. Carolyn Lam: Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them?

Dr. Kelly Chin: I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.

The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.

Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.

I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing.

Dr. Carolyn Lam: Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.

The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason?

Dr. Jason Weatherald: Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.

What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.

I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration.

Dr. Carolyn Lam: Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.

Kelly, what do you think are the real take home messages from this?

Dr. Kelly Chin: I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment.

Dr. Carolyn Lam: Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason?

Dr. Jason Weatherald: I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.

At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.

I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic.

Dr. Kelly Chin: I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.

But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization.

Dr. Carolyn Lam: Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment?

Dr. Jason Weatherald: Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening.

Dr. Carolyn Lam: And Kelly, what do you think should be next steps?

Dr. Kelly Chin: I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.

But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies.

Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in again next week.

Circulation February 6, 2018 Issue

5 februari 2018 | 17 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In today's feature discussion, we are talking about external validation of the DAPT score, a discussion that's going to take us all the way to east Asia, but for now, here are your weekly summaries.

In this week's journal, two studies are presented which compare ductal stenting to surgical shunts in the current era of ductal dependent pulmonary blood flow. As background, infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt between the subclavian artery and either pulmonary arteries. This modified Blalock–Taussig shunt allows progress through early life to an age and weight at which repair or furthermore stable palliation can be safely achieved. However, these modified Blalock–Taussig shunts continue to present concern for post-procedure instability and early mortality.

Duct stenting has emerged as an alternative with potential for greater early stability and improved survival. In the first study, first and corresponding author Dr. Bentham from Yorkshire Heart Centre reviewed data from the National Congenital Heart Audit, comparing the outcomes of 171 neonates who underwent a modified Blalock–Taussig shunt and 83 who underwent attempted ductal stenting, all in the setting of duct dependent pulmonary blood flow between 2012 and 2015. They found that stenting the arterial duct was preferable over the modified Blalock–Taussig shunt in terms of survival to next stage surgery, early post-procedure hemodynamic stability and shorter intensive care and hospital stay. There was a high failure rate both early, with the inability to stent the duct and late, with a greater need for re-intervention on the stented duct compared to the surgical shunt.

The second study originated from four North American pediatric cardiology centers representing the Congenital Catheterization Research Collaborative. First and corresponding author, Dr. Glatz from Children's Hospital of Philadelphia performed a retrospective cohort study reviewing all infants with ductal dependent pulmonary blood flow under a year of age, having either a ductal stent or a modified Blalock–Taussig shunt between 2008 and 2015. Although the observed risks of the primary outcome of death or unplanned re-intervention to treat cyanosis was higher in the surgical shunt group, there was no significant difference between groups after adjusting for patient level factors. Furthermore, after adjusting for patient factors, other outcomes favored the stent group, including fewer procedural complications, shorter intensive care unit length of stay, less frequent need for diuretics and larger and more symmetric pulmonary arteries at last follow up.

These companion papers are discussed in an elegant editorial by Drs. Benson and Van Arsdell from Hospital for Sick Children in Toronto.

The next study tells us that there may be a higher risk of vascular dementia in patient who survive a myocardial infarction. First and corresponding author, Dr. Sundbøll from Aarhus University Hospital in Denmark performed a nationwide, population based study including almost 315,000 patients with myocardial infarction and found that the risk of vascular dementia was higher compared to a matched general population comparison cohort. The risk of vascular dementia was incrementally higher in patients who suffered stroke or developed severe heart failure during the first year after myocardial infarction and in patients who underwent coronary artery bypass grafting. There was no association with all caused dementia, Alzheimer's disease or other dementia sub-types. Take home message is that among one year survivors of myocardial infarction, attention should be placed to persistently higher risk of vascular dementia.

The next study identifies a novel mechanism whereby the RNA binding protein, fragile X mental retardation autosomal homologue one or FXR1, directly regulates gap junction remodeling, leading to dilated cardiomyopathy. Co-first authors Drs. Chu and Novak, corresponding author Dr. Gregorio and colleagues from University of Arizona studied human left ventricle dilated cardiomyopathy biopsy samples as well as mouse models of dilated cardiomyopathy. They found that FXR1 expression was significantly increased in human and mouse dilated cardiomyopathy. Up regulation of FXR1 in the heart altered the location and distribution of gap junctions, subsequently leading to ventricular tachycardia in mice.

Mechanistically, FXR1 associated with intercollated discs and directly interacted with integral gap junction proteins to regulate their expression in cardiomyocytes. Finally, loss of FXR1 in the heart led to dilated cardiomyopathy. Together, these results provide a novel function of FXR1, namely that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart. Thus, the authors concluded that FXR1 may be a promising target for therapeutic strategies to improve gap junction function in dilated cardiomyopathy.

Well everyone, that wraps it up for our summaries. Now for our feature discussion.

The dual anti-platelet therapy or DAPT score is widely used everywhere to estimate bleeding versus ischemic risk in patients undergoing percutaneous pulmonary intervention. However, very few studies have provided external validation of its utility. Well we have a very important paper in this week's journal that addresses just that in a Japanese population. So pleased to have with us the corresponding author, Dr. Takeshi Kimura from Kyoto University Graduate School of Medicine. Not just him, but also the editorialist for this paper, Dr. Shinya Goto, also an associate editor of Circulation from Tokai University of Japan and last but not least of course, our dear Senior Associate Editor of Circulation, Dr. Laura Mauri from Brigham and Women's Hospital. What an important topic. Takeshi, would you mind to please tell us about your study to start?

Dr Takeshi Kimura: Actually we thought about the utility of the DAPT score provided from the DAPT study in Japanese patient population. In a full cohort of three studies that are conducted in Japan, we compare the risks for ischemic and bleeding risks from 13 to 36 months after a PCI between patients with DAPT score (high-DS) and DAPT score

Circulation January 30, 2018 Issue

29 januari 2018 | 21 min

Dr. Carolyn Lam: Welcome to Circulation On The Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

In just a moment, we are going to be discussing the diagnostic conundrum of elevated high sensitivity cardiac troponin levels in a patient with renal disease, but also suspected of acute coronary syndrome. Aha! I bet I caught your attention. A very, very familiar diagnostic dilemma. So stay tuned right after these summaries.

Cardiac allograft vasculopathy is the leading cause of death in patients more than five years post cardiac transplantation. It has been hypothesized that cardiac allograft vasculopathy results from interrupted lymphatic drainage post surgery. Since the donor lymphatic vessels are not inesthimozed to that of the recipient during transplantation, thus the lymphatic system may play a crucial role in the alloimmune response.

Well, these hypothesis are addressed in the first paper in today's journal from first author Dr. Edwards, corresponding author Dr. Wong and colleagues from Kings College, London. These authors use spect CT lymphoscintigraphy in a pre-clinical model. And therefore provided objective quantification of lymphatic flow following transplantation and showed that this correlated to cardiac allograft vasculopathy. They demonstrated that cardiac lymphatic remodeling and lymphatic transport dysfunction post transplant was associated with cardiac allograft vasculopathy and transplant rejection.

They further showed that lymphatic flow was increased during chronic rejection. This in turn may have resulted in enhanced trafficking of antigen presenting cells to the local draining lymph nodes in an augmented alloimmune response. Now although the cause and effect of this phenomenon could not be fully established, these data provided the impetus for the investigation of lymphangiogenesis inhibition as a means to dampen chronic rejection.

The absorb bioresorbable vascular scaffold is known to completely resolve within three years after coronary artery implantation. However, what is the safety and effectiveness of these bioresorbable scaffolds during this critical three year period. First author Dr. Ali, corresponding author Dr. Stone and colleagues from Columbia University Medical Center performed an individual patient level meta analysis of the four randomized absorb trial and demonstrated that compared with metallic everolimus eluting stents, the bioresorbable vascular scaffold had higher rates of target lesion failure and device thrombosis cumulatively to three years and between one and three years. Multi-variable analysis identified the number of treated lesions, current tobacco use and previous cardiac interventions as independent predictors of three year target lesion failure. Whereas diabetes was predictive of three year device thrombosis in bioresorbable vascular scaffold treated patients.

The next paper reported the three year follow up of the FAME 2 trial, which compared PCI guided bi-fractional flow reserve with best medical therapy in patients with stable coronary artery disease to assess clinical outcomes and cost effectiveness. First and corresponding author Dr. Fearon and colleagues from Stanford cardiovascular institute showed that major adverse cardiac events at three years were significantly lower in the PCI group, compared with the medical treatment group. This difference was primarily as a result of a lower rate of urgent revascularization. Mean initial costs were higher in the PCI group, but by three years, were similar between the two groups. The incremental cost effectiveness ratio for PCI compared to medical therapy was more than $17,000 per quality adjusted life year at two years and $1,600 per quality adjusted life year at three years. Thus the authors concluded that percutaneous coronary intervention in patients with stable coronary artery disease and at normal fractional flow reserve may be advantages compared to with medical therapy alone, because it results in improved clinical outcomes and quality of life at no increased cost by the end of three years follow up.

The next study shows for the first time, that pioglitazone may prevent stroke as a single stand-alone outcome. Today's paper by first author Dr. Yaghi, corresponding author Dr. Kernan from Yale School of Medicine and colleagues was a secondary analysis of the iris trial, which showed that pioglitazone reduced the risk for a composite outcome of stroke on myocardial infarction among non-diabetic patients with insulin resistant and a recent stroke or transient ischemic attack. Now, the current planned secondary analysis used updated American Heart Association 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. The study found that pioglitazone reduced the risk by 25% by five years, with absolute rates of 8% with pioglitazone versus 10.7% with placebo. Pioglitazone reduced the risk for ischemic strokes, but had no effect on the risk of hemorrhagic events. These findings add to the evidence that pioglitazone may be a potent therapy for vascular disease risk reduction and may help inform shared decision making by providers and patients for the use of pioglitazone after ischemic stroke or transient ischemic attack.

Well, that ends it for our summaries. Now for a feature discussion.

The cardiac troponins have really revolutionized cardiology. We use them in of course the diagnosis of myocardial infarction and in fact the recent European Society of Cardiology recommendations say that the rapid zero and one hour triage algorithm for rule in or rule out of non STEMI should use high sensitivity troponins and interestingly irrespective of renal function. Now this latter point has caused some confusion, some questions, since we all know that patients with chronic kidney disease frequently have higher or increased levels of cardiac troponins, especially since we now can detect them with the high sensitivity essays. And this is even in the absence of an acute coronary syndrome.

Well, this week's journal contains two papers that address this topic so well. And I am delighted to have with us the corresponding author of the first paper, Dr. Christian Mueller from University Hospital Basel in Switzerland and the author of the second paper, Dr. Nicholas Mills from University of Edinburgh in Scotland. For the more, we have Dr. Torbjorn Omland, associate editor from University of Oslo in Norway.

Lot's to talk about. Christian, could I start with you? Could you say in your own words the rationale for looking at this vulnerable population and then perhaps describe what you did in your study?

Dr. Christian Mueller: I'm very thankful that Circulation shed a lot of light on the population of patients with renal dysfunction, because both as a clinician and as a researcher, I'm definitely convinced that they merit a lot of our attention for several reasons.

So first, it's important to be aware that the incidents of acute myocardial infarction among patients presenting with acute chest pain is much higher in patients with renal dysfunction, as compared to patients with normal renal function. And second, atypical clinical presentations also are more frequent in patients with renal dysfunction. Then possibly third, the ECG of course also a mandatory tool in our assessment is more often showing unspecific signs that may mimic or obscure the presence of myocardial infarctions and most of them are related to left ventricular hypertrophy. And in addition, patients with renal dysfunction are more prone to adverse events, both related to cardiovascular medication. For example, anticoagulation as well as our cardiovascular procedures, including PCI. Now again, as both papers have a strong focus on troponin, also cardiac troponin is a bit more difficult to interpret in patients with renal dysfunction related to exactly as you mentioned chronic elevations of cardiac troponin, TNI related to chronic cardiovascular disease.

And I think that's so important to stress, any troponin signal in a patient with renal dysfunction is real and should not be incorrectly attributed to just a problem of impaired secretion by the kidneys.

Dr. Carolyn Lam: So definitely an even greater need to diagnose myocardial infarction accurately in this very high risk population. So tell us what you did.

Dr. Christian Mueller: We assessed this challenging sub group within the APACE study. So APACE is a large international prospective diagnostic study that is run in five countries with 12 centers. And we actually enroll consecutive patients presenting with suspected myocardial infarction. And then all patients get a very detailed workup and then adjudicated final diagnosis. And the adjudicated file diagnosis is done by two independent cardiologists and is based on two enormous extensive sets of data. The clinical data set that has been obtained at the local site and of course includes cardiac imaging and standard troponin testing, ECG data.

In the second set of data that includes the study specific data sets, including serial measurements with high sensitivity carry troponin essay and a lot of details characterization of patients and patient follow up. So this is the reference standard against which the one hour algorithm the European Society of Cardiology evaluated. And the one hour algorithm has been derived and previously validated in overall population. Mainly patients with normal renal function. And so we tried to evaluate the performance of this predefined algorithm specifically in patients with renal dysfunctions.

So among a bit more than 3,000 patients, the prevalence of patients with renal dysfunction was 15%. So we had about 500 patients with renal dysfunction. And the interesting finding from our work is that first the prevalence of N-STEMI was nearly threefold in patients with renal dysfunction as compared to patients with normal renal function. And, fortunately the rule out part of the algorithm regarding sensitivity still works very well. It is, however, the efficacy of rule out that is lower in patients with renal dysfunction, simply because fewer patients really have very low troponin concentration and are therefore ineligible for rule out.

However, as a clinician, the main concern with troponin and renal dysfunction is the rule in part, and specificity. And as you would think, specificity of the one hour algorithm was in fact significantly lower in patients with renal dysfunction. It was still appropriate for therapeutic consequences, but it was lower as compared to patients with normal renal function, so the specificity was 89% in patients with renal dysfunction, as compared to 96.5% in normal renal function.

So the overall efficacy of the algorithm was lower in patients with renal dysfunction, however then when trying to create and derive optimized cut off levels, so all cut off levels optimized for use in renal dysfunction, we didn't really find alternative cut offs that would do a much better job than the official cut off levels recommended in the guidelines. So our conclusion is that in patients with renal dysfunction, the safety of the one hour algorithm still is very high, however the specificity of rule in and overall efficacy are decreased.

Dr. Carolyn Lam: Right. That's beautifully summarized. And also that different cut offs didn't really help to increase the efficacy of this algorithm. And just to clarify to our listeners, I believe you defined renal dysfunction as an estimated GFR of less than 60, which is so beautiful because it's perfectly consistent with the second paper.

Nick, could you please tell us about your study and your take home messages as well.

Dr. Nicholas Mills: So high stakes is our clinical trial that we're conducting across hospitals in Scotland to evaluate the best way to use high levels of cardiac troponin in clinical practice. One of the areas of uncertainty is whether these assets really add any additional value for patients with chronic kidney disease, where troponin concentrations tend to be higher. And the premise of a high sensitive test is that we can measure lower concentrations and improve the sensitivity. But is this just going to create uncertainty for clinicians?

So we evaluated 5,000 consecutive patients for performance of high sensitivity cardiac to put in testing. And those with and without renal impairment. And based upon what Christian, we identified that patients with renal impairment are less likely to have very low concentrations, but that you can rule out myocardial infarction safely in patients with renal impairment. And similarly that those with renal impairment are more likely to have an abnormal troponin concentration at presentation. Around about 40% of all patients have troponins above the upper reference limit. And whilst the specificity for myocardial infarction is lower, type one myocardial infarction or myocardial infarction due to plaque rupture or cardiac thrombosis remains the most common diagnosis in this group.

Finally we looked at one year outcomes. And this is really critical. Because we found that patients with renal impairment were two to threefold more likely to die from cardiovascular disease one year following their presentation than those without renal impairment. And I think that my general experience during these tests in clinical practice is that troponin elevations in patients with kidney disease are often ignored and there's a concern about what they mean, and therefore these patients don't get access to the fantastic treatments we have for coronary heart disease. So our take home message is that high sets of troponin testing in patients with renal disease does have value, it's useful for identifying low risk patients although there are fewer of them, and it performs well as a diagnostic test, highlighting in particular a group of patients that really have poor clinical outcomes.

As a cardiological community, we need to do better.

Dr. Carolyn Lam: What I really love about both or your papers is the consistency in the messages. Torbjorn, I want to bring you in on this. You managed both papers. Such a lovely pair of papers that we're so proud to be publishing and you had also invited an editorial by Dr. deFilippi and Seliger. Would you like to comment on your perspective and perhaps the clinical take home message to our audience?

Dr. Torbjørn Omland: Yes, I think this has been pointed very well out by both Christian and Nick. And I think it's worth recapitulating that renal dysfunction is a major problem that clinicians often try to explain by just lack of renal filtration. But that the closest probably are increased production and underlying cardiac disease. So in the editorial Dr. deFilippi Filippi and Dr. Seliger points also out in these things. Moreover they try to look forward and have made comments to recent studies that showed that in patients with renal dysfunction have different troponin fragments than patients with acute myocardial infarctions.

Dr. Carolyn Lam: I find that so fascinating. And it really, really relates to the field of heart failure and what we are also talking and thinking about with natriuretic peptides and their different fragments and the possible different meanings. And how different essays maybe non specific for different fragments.

Christian, you think a lot about these things. I'm curious, what are your thoughts on this and areas of future work that are very urgent?

Dr. Christian Mueller: I think Torbjorn very nicely addressed this. So the current high sensitivity essays for T and I that we use in clinical practice, they are designed kind of to detect everything in blood that looks like troponin, either T or I, including various fragments. And I think it's a fantastic new avenue of research, trying to find out that the biochemical signatures can be further differentiated and exactly that perhaps different troponin fragments or tricordinate products more prominent in patients having ischemic injuries like treat myocardial infarction, as compared to for example other modes of injuries. So I think that's very nice hypothesis and some early data. But at least from my perspectives and to the best of my knowledge until now, the diagnostic algorithms that we have other ways to approach this in clinical practice. And so it's the higher the blood concentration in patients with acute chest pain, the more likely it's acute myocardial infarction. It's not any chronic disease and again the higher the change from presentation to one hour or two hours, the more likely it's acute as a dynamic disorder resulting in an acute increase in cardiac troponin, as compared to the chronic release patterns typically seen in patients with renal dysfunction.

Dr. Carolyn Lam: Yeah. That's just so fascinating. Nick, we sadly are running out of time, but I do want to give you the last word. The clinical take home message, once again. What do you think listeners should take home that may change their practice, after listening to this podcast?

Dr. Nicholas Mills: I think the key message for clinicians, is that in a patient with suspected acute coronary syndrome and has renal impairment and elevated troponin concentration, serial testing is mandatory to differentiate between those that have chronic myocardial injury due to subclinical heart disease and those that are having acute myocardial injury as a consequence of a presumed acute coronary syndrome. Field testing is critical to inform which treatment path and what investigations we recommend for our patients.

Dr. Carolyn Lam: Wonderful. And to take any elevations seriously, because this is a high risk population.

Well, audience you heard it right here on Circulation On The Run. I'm sure you've enjoyed this. I certainly have. Don't forget to tune in again next week.

Circulation January 23, 2018 Issue

22 januari 2018 | 18 min

Dr. Carolyn Lam: Hello from the American Heart Association meeting in Anaheim. I'm Dr. Carolyn Lam, associate editor from Circulation at National Heart Centre in Duke National University of Singapore and I'm so pleased to be here with the Circulation team led by editor in chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior editor from Brigham and Women's Hospital, and Dr. Dharam Kumbhani, associate editor from UT Southwestern. Boy, we've got lots to discuss. I mean, I want to just first start with congratulating you, Joe. We have got quite a number of simultaneous publications here at the AHA.

Dr. Joseph Hill: I appreciate that, Carolyn. Don't congratulate me. We have a team that is a privilege to work with. One of the initiatives that we launched right from the start was a desire to foster and shine a bright light on emerging science at the major meetings around the world. Often, that involves simultaneous publication.

I'm proud to say that we have 11 simultaneous publications, a record for us here at AHA. Most of them are clinical trials. A few are clinical science, and two of them are young investigators who are competing in the various different competitions. We reached out to them a few weeks ago and offered them the opportunity to submit to us, of course with no guarantees, and our standard remains the same, but we promised that we would provide them with an external peer review. Two of them made it through the process and they will be simultaneously published with their presentations here in Anaheim.

Dr. Carolyn Lam: Wow, well you heard it. A record 11 simultaneous publications. We've got a lot to talk about. Let me just maybe group the topics a little bit. Let's start with talking about peripheral artery disease. I think there are at least three papers around that area, and then we'll talk about coronary artery disease, and almost focusing more on implementation science, papers, there are two there, and then of course we have to talk about heart failure. Dharam, could you start? Tell us about the FOURIER PAD trial.

Dr. Dharam Kumbhani: Yeah. It's very exciting to have clinical trials in the PAD realm. FOURIER PAD is certainly really well done sub-study of the FOURIER trial. As you remember, this was a landmark trial, which compared a PCSK9 inhibitor Evolocumab in two doses, two placebo. The overall trial was done in about 27,000 patients who were followed for a median of 2.2 years. In this trial, Marc Bonaca and investigators, they looked at the PAD subset, which were about 13% of the total cohort. Now, they specifically set out to look at how patients with PAD, during this trial and very gratifyingly, they also specifically assessed how patients with PAD did as far as limb events, not just cardiovascular events.

At the outset, not surprisingly, patients with PAD had a higher risk of cardiovascular events by, I think it was about 60% higher for the primary end point compared with patients who did not have PAD. There was really no, in fact, modification by PAD in that the benefit of Evolocumab that we saw in the overall trial was preserved among the patients with PAD as well as those without PAD. However, because patients with PAD had higher event rates, the absolute risk reductions were higher in patients with PAD.

Then, these investigators looked specifically at the incidents of major adverse limb events, which is a composite of acute limb ischemia, urgent revasc, and major amputations. What they show is that in the overall cohort, there is a 42% reduction in the risk of these major adverse limb events with Evolocumab compared with placebo. Obviously, the effect is significantly higher in patients with PAD. Although the benefit wasn't noted in the PAD subset specifically, the overall p-value for interaction was negative.

One of the really exciting things about this paper is that just like investigators have shown a monotonic reduction in cardiovascular event rates with LDL reduction, similarly, the investigators show a reduction in limb events, which is dose related and the same way in a monotonic fashion with Evolocumab. I think this is really exciting and I think this will be a very important paper for the field.

Dr. Carolyn Lam: Yeah. Dharam, that was beautifully summarized but once you start talking about the peripheral artery disease and this lack of interaction on effects and so on, I think of the CANVAS trial results that were reported at this meeting too. If I could maybe briefly summarize what the authors did in this circumstance, they looked at the more than 10,000 patients in the CANVAS trial who were randomized into Canagliflozin versus placebo in diabetic patients but this time they looked at whether or not there was a difference in effect with the primary prevention cohort versus the secondary prevention.

Primary prevention meaning those adults who had diabetes and risk factors but no established cardiovascular disease and the secondary prevention were those with peripheral artery disease, for example, and other established cardiovascular disease. The same thing, a lack of interaction, which I think is really important because it was the same sort of idea that the overall risk of cardiovascular events was lower in the primary prevention group. Looking at them as a subgroup alone, you didn't get the p-value that crossed the limit because the power was less in a lower risk group, but the lack of statistical interaction really gives us additional information, I think, that Canagliflozin and maybe the SGLT2s in general may be effective for primary prevention in diabetic patients. What do you think?

Dr. Dharam Kumbhani: Yeah. I mean, I think certainly, very interesting findings along those lines. As you pointed out, the event rates are much lower in the primary prevention cohort. All the confidence intervals overlap one, but because all the p-values for interaction for the three-point maze, the four-point maze, et cetera, one would say that there really isn't a difference between the primary and the secondary prevention subgroups. You would potentially have the same benefit in that subgroup as well.

Dr. Carolyn Lam: Fortunately or unfortunately, in that same study, they looked at the risk of amputations and there was a lack of interaction too for that meaning there was a higher risk of amputations with Canagliflozin versus placebo. That of course is a really hot topic now, isn't it? I just wanted to point out though, when you look at it in the primary prevention group, there are only 33 events. What do you think? It spells caution but further look needs to be done? Yeah. Contrast that with the EMPA-REG outcome PAD analysis. You want to tell us about it?

Dr. Dharam Kumbhani: Yeah. Once the Canagliflozin CANVAS findings came out showing a high rate of amputations with Canagliflozin, the Empagliflozin, the EMPA-REG outcome’s investigators went back and looked at the PAD subset in EMPA-REG outcomes. This was about 20% of the total cohort. I will say that unlike FOURIER, which we just discussed, the ascertainment of amputations was not prospectively defined for this trial and it was really obtained from the CRF forms.

However, having said that, it did not appear that amputation rates were higher with Empagliflozin. They did not break it down by the different doses but one assumes that the benefit is consistent between the two doses that they study. One would imagine the PAD patients would have a higher rate overall, which it was, but even in that group, it was about 6% over three years and there was really no difference between the patients who received Empagliflozin versus those who got placebo.

Dr. Carolyn Lam: That EMPA-REG outcome paper, I mean, interestingly, it was a research letter. Joe, you've been watching this whole field unfold right now and our journal has published so many good papers, including CVD REAL, all in this space. Could you comment on that a little bit and the research letter concept and the fact that we're publishing so many of these interesting papers in this topic?

Dr. Joseph Hill: Well, Carolyn, as you inferred, this field is evolving very rapidly. Now, the interface between metabolic disease and diabetes and heart disease is blurring. Some of these diabetic drugs are really emerging as heart failure drugs, it looks like and so there's a great deal of interest in exploring that and trying to find underlying mechanisms. It's an incredibly exciting time. In parallel with that, we are publishing research letters now for papers where, again, our bar starts with validity. Our bar doesn't change but if it's a story that can be communicated with really one multi-paneled figure and an 800word text, then that is a nice bite-size piece of information that we can get out to our readership. We're publishing one or two a week now. Overall, it appears to be well received and I think it's an effective vehicle for conveying certain types of our content.

Dr. Carolyn Lam: Frankly, it's such a delight to read, isn't it? It's hard to write. I think the shorter, the harder to write but this just goes to show how equally important they are.

Dr. Joseph Hill: Absolutely.

Dr. Carolyn Lam: That we're discussing it here. Well, let's go on to the next topic then, coronary artery disease. Regionalization of the care. I'll say that again, regionalization of the care. Would you like to comment on the two papers that are simultaneously being published? One would be the ACCELERATOR-2 trial. That's in the U.S. Then, a second from New Zealand, the ICare-ACS trial. Slightly different but-

Dr. Joseph Hill: Well, that's exactly right. Often, we know what to do but we don't do what we know we need to do in medicine. The implementation of what we already know is an area of hot research and is an area that's evolving rapidly. These two studies, ACCELERATOR-2 here in the United States, focused on regionalization of the interface between EMS systems and EDs, how to get patients identified in the hospital to their device, whether it's a stent or a balloon pump or whatever it is. The first medical contact to device was the metric and by implementing what we already know, the AHA mission lifeline principles, these investigators were able to optimize this regionalization, so there wasn't so much variability across these 12 metropolitan regions. As a consequence, the time to first medical contact to device was shortened, and there was in fact a striking, maybe even surprising, mortality benefit.

Dr. Carolyn Lam: Exactly. That was striking to me too.

Dr. Joseph Hill: From the street to the lab, another paper from New Zealand that you referred to called ICare-ACS focused on doing a better job in the emergency department with serial ECGs and serial high sensitivity troponins, risk stratification algorithms and they found that, again, by developing these clinical pathways within the ED, they were able to shorten the length of stay in the ED and the length of stay in the hospital.

Dr. Carolyn Lam: Yeah. I thought those were amazing and then also from different parts of the world, really strong public health messages as well. Laura, you take care of these ACS patients right on there. What did you think of these papers?

Dr. Laura Mauri: No, I agree. I think that we've, in the past, focused on science and focused on clinical trials but ultimately, none of that matters if we don't deliver the healthcare to the patient. I think this is just a growing field and I'm glad that we're emphasizing it in circulation.

Dr. Carolyn Lam: Absolutely. If we would now go to another area that is really increasing in prevalence throughout the world. Heart failure, and of course, heart failure with preserved ejection fraction.

Dr. Joseph Hill: Your favorite topic.

Dr. Carolyn Lam: Congratulations, Laura on the paper that you're presenting, that is being presented at this meeting, the REDUCE LAP trial. Could you tell us a little bit more about that?

Dr. Laura Mauri: Sure. Yes, as you know, it's a really challenging field, heart failure with preserved ejection fraction. There aren't a lot of therapies that we have. We really don't have great medical therapy. This study actually looks at a medical device to treat patients. It really is a feasibility study, so it's a relatively small trial, just over 90 patients but it's randomized. We know in the device arena, as in all trials, how important randomization is but also blinding. This was actually a sham-controlled blinded trial really designed to look at this interatrial shunt device in patients who have an elevated wedge pressure.

The REDUCE LAP stands for reduce left atrial pressure. That was the primary endpoint, was pulmonary capillary wedge pressure. This was not only looked at the safety, which showed that the device placement was very safe, but at the same time also looked at the proof of concept that by placing the shunt device, there was actually a reduction in wedge pressure over a period of exercise. It needs to be followed on. It's certainly just the first phase of trials but a pretty good standard with the sham control.

Dr. Carolyn Lam: Yeah, well, congratulations again. I mean, this follows … There was a previous publication of the single arm trial and now, this is the first randomized sham-controlled, and the results are consistent. It's a very difficult trial to carry out. HFpEF patients are notoriously difficult to recruit. Could you tell us a little bit about what it was like successfully completing this trial?

Dr. Laura Mauri: Yeah. Well, we had very enthusiastic centers and principal investigators, Ted Feldman and Sanjiv Shah. I think what it really required in this early phase was sites that were committed to characterizing the exercise physiology. The next stage of rolling this out to a broader number of sites and a larger number of patients to see if there's a clinical effect will really be more focused on the clinical endpoints and quality of life because ultimately that's the goal, is to improve symptoms in these patients.

Dr. Carolyn Lam: What I love about the design and the whole concept, it's so simple and elegant. We almost sometimes forget that HFpEF is heart failure, which means that by definition, there's raised filling pressures. It's hemodynamic at the end and this is just a simple concept of offloading the left atrium. That's so beautiful but it does come with some questions. Every time you mention this to someone, they go, “What about, I don't know, Eisenmenger's syndrome developing later?” The right side, volume overload, pulmonary hypertension, what about atrial fibrillation down the line? How about the safety parts of it?

Dr. Laura Mauri: Right, so the procedural safety was excellent but then I think you raise really important questions and these patients are still in follow-up but looking at the report here at this meeting, there was no pulmonary hypertension in excess in the shunt treated arm. The patient selection was towards patients who had higher wedge compared with right atrial pressure and among those patients, there was no evidence of RV overload. At least at this stage things look good to go on to the next step.

Dr. Carolyn Lam: That's wonderful and exciting. We definitely need a therapy for HFpEF. Joe, would you like to highlight any other trial? We have 11. We've discussed six.

Dr. Joseph Hill: Tonight at the editorial board meeting, we will be saluting these two young investigators who are presenting their work in this competition and simultaneously publishing their work. We've invited these young investigators and their mentor and they will present a short talk to the editorial board dinner. It's an effort to salute and recognize these early career investigators, to congratulate them on outstanding work. We're pleased and privileged to publish it, so I'm particularly excited about that.

Dr. Carolyn Lam: Wow, Joe. That is great. Thank you. I didn't know that was happening either. That's fabulous. Dharam or Laura, any other highlights that you may want to mention in this meeting?

Dr. Laura Mauri: I think that it's just been a wonderful kickoff to the meeting. We've covered, I think, many of the really important trials so it's really exciting to be able to see the work in print.

Dr. Carolyn Lam: That’s great, and to discuss it as well.

Dr. Dharam Kumbhani: Yeah, I agree. This is really exciting and hopefully, we can keep growing from strength to strength every year.

Dr. Carolyn Lam: Yep. You heard it right here everyone. We are going to grow from strength to strength under your leadership and with this great team, so thank you very much for joining us today.

Circulation January 16, 2018 Issue

15 januari 2018 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week's feature paper takes a deep dive into nitric oxide signaling, that extremely important pathway in cardiovascular health and disease. This time, taking a novel look at genetic predisposition, phenotypic consequences, and therapeutic implications. All that coming right up after these summaries.

The first original paper describes the derivation and validation of a novel model to stratify the risk of death due to circulatory etiology in patients resuscitated from cardiac arrest without an ST elevation MI.

First author, Dr. Bascom, corresponding author Dr. Setter from Maine Medical Center in Portland and their colleagues use the International Cardiac Arrest Registry to derive a novel model termed the CREST Model, which describes an incrementally high risk of circulatory etiology death with an increasing score.

Now, CREST is a simple score with components of C for prior coronary artery disease. R for non-shockable rhythm. E for ejection fraction less than 30% on admission. S for shock at the time of admission. T for ischemic time more than 25 minutes. The authors showed that this CREST tool may allow for estimation of circulatory risk and improve triage of cardiac arrest survivors without STEMI at the point of care.

The next study reports associations between usual sodium, potassium and blood pressure using gold standard 24-hour urinary data collected for the first time among a nationally representative sample of adults in the United States.

First and corresponding author Dr. Jackson from Centers for Disease Control and Prevention used cross-sectional data from 766 participants aged 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 national health and nutrition examination survey.

They found that there was a strong direct relationship between higher sodium excretion and higher blood pressure and hypertension. In addition, there was an inverse relationship between potassium excretion and blood pressure and hypertension. When added to the evidence based from longitudinal and interventional studies, these results support clinicians dietary advise to lower sodium intake and increase consumption of potassium containing foods.

The next two studies in this week's journal examine the utility of circulating biomarkers to aid in the diagnosis of acute aortic dissection. As a reminder, the AHA/ACC guidelines published in 2010, proposed using the aortic dissection detection risk score or ADD risk score as a primary screening tool based on scoring the presence of three categorical risks.

Number one, high risk conditions such as Marfan Syndrome, a family history of aortic disease, known aortic valve disease, known thoracic aortic aneurysm or previous aortic manipulation. Number two, The pain features such as chest, back or abdominal pain described as being of abrupt onset severe intensity or ripping, tearing. Number three, the examination features such as evidence of profusion deficit, systolic blood pressure difference, spoken neurological deficit or aortic diastolic murmur and hypertension or shock.

The presence of one or more markers within each of these categorical features is given an ADD score of one with a maximum cumulative score of three if all three categorical features are present. In the first of these two papers in this week's journal, first author Dr. Nazareen, corresponding author Dr. Morello and colleagues from Molinette Hospital in Italy performed the advised International Multi Centers Study, which prospectively assessed the diagnostic performance of standardized strategies integrating pre-test probability assessment and D-dimer in 1,850 patients from the emergency department.

They found that in patients with an ADD risk score above one and D-dimer less than 500 nanograms per milliliter, the rate of acute aortic syndromes was significant at one in 22 cases. Rule out strategies for acute aortic syndromes integrating an ADD risk score of zero or one with D-dimer less than 500 were found to miss only around 1 in 300 cases of acute aortic syndrome.

Integrating the ADD risk score with D-dimer could help to standardize diagnostic decisions on advanced imaging for suspected acute aortic syndrome balancing the risks of misdiagnosis and over testing. The authors concluded that patients at high probability of acute aortic syndrome such as with an ADD risk score above one should proceed to computer tomography and geography or other conclusive imaging irrespective of D-dimer levels. However, in those with an ADD risk score of zero or one, with a D-dimer of less than 500 were possible rule out diagnostic strategies for acute aortic syndrome.

The second manuscript in the present issue suggests that soluble ST2 might be an even better biomarker than D-dimer to rule out aortic dissection. In this paper by first author, Dr. Wang, co-corresponding authors, Dr. Du and Guo from Beijing Anzhen Hospital and Peking University respectively, the authors measured plasma concentrations of soluble ST2 using the R&D Systems assay in 1,360 patients including 1,027 participants in the retrospective discovery set and 330 patients with an initial suspicion of acute aortic dissection and ruled in a prospective validation cohort.

The proportion of acute aortic dissection, this acute chest pain cohort was high at more than 40%. The authors found that soluble ST2 measured using this research grade assay showed higher levels in acute aortic dissection than in acute myocardial infarction or in acute pulmonary embolism. The result suggested that soluble ST2 levels could be useful as a rule out marker possibly even to an extent moderately superior to D-dimer.

A cut-off level of around 35 nanograms per milliliters using the research grade soluble ST2 assay appeared to reliably rule out acute aortic dissection if used within 24 hours after symptom onset with a negative likelihood ratio of 0.01 and a negative predictive value of more than 99%. These intriguing findings are discussed in an accompanying editorial by Dr. Toru Suzuki from University of Leicester and Dr. Kim Eagle from University of Michigan. Well, that wraps it up for our summaries. Now, for our future discussion.

Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. In fact, the pharmacologic stimulation of nitric oxide pathway is emerging as a therapeutic strategy in cardiovascular medicine in many areas including in heart failure preserved dejection fraction.

Today's paper is therefore all the more intriguing because it seeks to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on the risk for cardiovascular disease as a way of informing of the potential utility of pharmacologic stimulation of the nitric oxide pathway.

Intrigued? Well, I certainly and I'm so glad to have with us the corresponding author, Dr. Sekar Kathiresan from Massachusetts General Hospital as well as a familiar voice, Dr. Peipei Ping, associate editor from UCLA here to discuss this paper.

Sekar, could I ask you as an introduction to tell us a little bit more of the general approach of looking at genetic predisposition as a way of perhaps forecasting potential utility of pharmacologic stimulation? Could you tell us a little bit more about that?

Dr. Sekar Kathiresan: Yes. I'm delighted to speak a little bit more about this idea of using naturally occurring genetic variation to understand if a medicine developed against a target is going to work in terms of efficacy and also potentially lead to on target side effect.

As you know, there are lots of variants for mutations in genes that eventually become targets for medicines. Over the last 10, 15 years, there's been an explosion in our understanding of human genetic variation, specifically in genes targeted by medicines.

The idea here is that if there's a naturally occurring mutation in that target gene, you can simply ask what are the phenotypic consequences of carrying that mutation. Also use that information to predict, as I said, the efficacy of pharmacologic manipulation and potentially on-target side effects. This approach has become a very powerful approach.

A famous recent example of gene, PCSK9, where mutation in this gene occur naturally. A lower function of PCSK9 and individuals who carry this mutations have lower LDL levels and lower risk of heart attack. This information has led to the development of medicine that mimic those mutations and those medicines have been proven now to lower LDL as well as lower risk of heart attack, a phenomenon anticipated by the genetics.

Dr. Carolyn Lam: If I understand it right then, with regards to today's paper, the idea is that if a genetic predisposition to enhanced nitric oxide signaling associates with reduced risk of cardiovascular disease, then that would support the hypothesis that pharmacologic stimulation of the nitric oxide pathway would prevent or treat the cardiovascular disease, right? Could you further expand? Because you also did a meditation analysis. How would we understand that?

Dr. Sekar Kathiresan: Let me walk you through the basics of this paper. Our hypothesis initially was a genetic predisposition to enhance nitric oxide signaling would actually affect a range of cardiovascular diseases. Nitric oxide is a well-known molecule, a regulator of a number of important processes; vascular tone, blood pressure, platelet aggregation.

A couple of important genes in the nitric oxide pathway are, one, nitric oxide synthase, the key enzyme that generates NO. Second is a soluble guanylyl cyclase that is a regulatory molecule involved in NO biology. One of the genes that is part of that pathway is called GUCY183, which is basically a subunit of the soluble guanylyl cyclase.

What we did was we looked at those two genes and asked, "Are there naturally occurring variations in those two genes that actually give us a sense that they gain function that they actually activate nitric oxide signaling. It turned out there are two polymorphisms. One in nitric oxide synthase and the other is in the soluble guanylyl cyclase subunit that are essentially gain of function. They're common polymorphisms.

We know their gain of function because the carriers of these DNA variants have lower blood pressure. An indicator that there's enhanced NO signaling. We use these two polymorphisms as an instrument to understand the phenotypic consequences of having lifelong enhanced nitric oxide signaling.

What we looked at was the relationship of individuals who carried both of the gene variants or gained a function and asked whether these individuals what the relationship of carrying the variant was to a range of cardiovascular diseases as well as a range of quantitative traits like blood pressure or kidney function.

We looked at this in extremely large human population samples where genotype and phenotype had been collated. Most important of these samples is a recent study of a population-based cohort study called the UK Biobank, which has involved about a half million people where genotype and have phenotype have been assembled.

What we found was that genetic predisposition to enhance nitric oxide signaling was associated with reduced risk of several important cardiovascular diseases. First, coronary heart disease. Second, peripheral arterial disease, and third, ischemic stroke.

That provide a very compelling evidence that atherosclerotic cardiovascular disease would be lower based on enhanced nitric oxide signaling. What was surprising to us is we also found a couple of other diseases where it seemed to benefit from enhanced nitric oxide signaling namely kidney function and pulmonary function. These were a little surprising to us, but I think it really suggest that NO plays an important role in a range of diseases.

In terms of your question about what aspect of NO biology is leading to be relationship to these diseases, is it simply the blood pressure effect for example or could you actually infer a mechanisms beyond the blood pressure? We looked at that specifically in the context of cardiovascular disease and we're able to show that the protection afforded by the enhanced nitric oxide signaling gene variants, that protection exceeded the amount predicted by the blood pressure change. In fact, by quite a bit suggesting that there are probably non-blood pressure mechanisms that are at play in terms of the protection afforded by enhanced nitric oxide signaling gene variants.

Dr. Carolyn Lam: Peipei, I have to invite your thoughts now. This is such an amazing paper. We had great discussions as an editor team. Tell us your thoughts.

Dr. Peipei Ping: The editorial team as well as the reviewers have been very impressed with the quality of the datasets and the value and detail, the metadata analysis together with the appropriate analytical approach. The study is done in our view in a very careful manner and the analysis was performed through the highest standards.

What we also recognized is the potential impact that this particular study may have on multiple areas of studies, in particularly with their findings, the spectrum of individuals, how they carry nitric oxide signaling trends. You could appreciate that the individual score or genetic score paired with the analysis of the genetic variance that they have done, they see from the mental idea that examine both genetic as well as phenotype of each individual is critically important for medicine to be prescribed in the next step of therapies.

Dr. Carolyn Lam: Building on that thought, Sekar, could I ask you? You found some rare inactivating variance. Are these the patients then you think should be targeted for NO enhancing therapies? What's the clinical implications of your findings?

Dr. Sekar Kathiresan: I think there are two ways to think about the implications of these findings. One is there's just a simple biologic insight, the pharmacologic activation of NO signaling maybe protective beyond pulmonary hypertension. As you know, there are actually compounds in the clinic right now that are pharmacologic activators of soluble guanylate cyclase. Those medicines work in the rare condition of pulmonary hypertension.

our work suggest that those medicines are likely to work in a broader range of indications including atherosclerotic cardiovascular disease, kidney disease and pulmonary function. At a simple level, those experiments, I think, should be looked at. Those indications should be looked at.

Whether we've identified a subset of a population that particularly will respond versus it will be a general phenomenon across a range of different individuals that have impaired nitric oxide signaling, I think time will tell. Certainly, one group to think about would be those who are indigenously deficient in nitric oxide signaling and we did find that there are small subset of patients who have inactivating mutations in these two genes and they have higher blood pressure and increased risk for cardiovascular disease.

It was a pretty rare phenomenon, so very small number of individuals would be relevant there. I'm not sure actually that you necessarily want to limit the potential benefit of NO signaling, enhanced NO signaling to just that subgroup. In fact, my prediction would be that the medicine would be relevant for a very large percentage of the population. That you do not need to limit the potential application of this therapy to just those who carry the inactivating mutations.

Dr. Peipei Ping: I agree largely of what Sekar has discussed. I would add that in situations where genetic information are available with the patients, what the study has offered is fairly clear in the patients where rare variance that inactivate the NOS3 or the guanylyl cyclase off the genes. Maybe a failure it is with a higher systolic blood pressure risk. I'm entirely supportive with the general conclusion that we have come to a time point where NOS outside signaling activation is a critical new element of therapy in cardiovascular health and disease.

Dr. Sekar Kathiresan: Thank you Peipei. Thank you Sekar for taking the time to share your thoughts with us. We are so proud to be publishing paper in circulation. So proud and happy to be chatting about this on this podcast. You've been listening to Circulation on the Run. Thank you for joining us and please tune in again next week.

Circulation January 9, 2018 Issue

8 januari 2018 | 23 min

Dr. Carolyn Lam: Welcome to "Circulation on the Run," your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke‐National University of Singapore. Our featured discussion this week focuses on the new 2017 ACC/AHA high blood pressure guidelines, and the potential impact of these guidelines on the U.S. population. A must listen, coming right up after these summaries.

The first original paper this week provides insights into how extracellular matrix remodeling contributes to in‐stent restenosis and thrombosis. First author, Dr. Suna, corresponding author, Dr. Mayr, and colleagues from King's College London, implanted bare metal and drug‐eluting stents in pig coronary arteries with an overstretch and then harvested the stented segments up to 28 days poststenting for proteomics analysis of the media and neointima.

The authors found significant differences by proteomics in the extracellular matrix of coronary arteries after stent implantation. Most notably, an upregulation of aggrecan, a major extracellular matrix component of cartilaginous tissues that confers resistance to compression. In fact, this study provided the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting. This opens a door to consideration of aggrecanase activity as new drug targets that may alter extracellular matrix remodeling in the vasculature.

The next paper tells us that empagliflozin could address a significant unmet need in patients with chronic kidney disease. First and corresponding author, Dr. Wanner, from Wurzburg University Clinic in Germany investigated the effects of empagliflozin on clinical outcomes in patients with chronic kidney disease in the EMPA‐REG OUTCOME trial, where patients with type 2 diabetes, established cardiovascular disease, and an eGFR above 30 at screening were randomized to receive empagliflozin or placebo, in addition to standard of care.

In the current study, prevalent kidney disease was defined as an eGFR of less than 60 or urine albumin/creatinine ratio of more than 300 at baseline. In these patients, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo, reduced the risk of all‐cause mortality by 24%, and reduced the risk of hospitalization for heart failure by 39%, and the risk of allcause hospitalization by 19%.

The effects of empagliflozin on these outcomes were independent of renal function or albuminuria status at baseline. Furthermore, the adverse event profile of empagliflozin was similar across subgroups by renal function at baseline. Adverse events of particular concern in this population, such as urinary tract infection, acute renal failure, hypokalemia or fractures, lower limb amputations or hypoglycemia were not increased with empagliflozin compared to placebo.

The next study provides mechanistic insights into exercise intolerance in heart failure with preserved ejection fraction or HFpEF. First author, Dr. Houstis, corresponding author, Dr. Lewis and colleagues from Massachusetts General Hospital, investigated the mechanism of exercise intolerance in 79 patients with HFpEF and 55 controls referred for cardiopulmonary exercise testing who were also studied with invasive monitoring to measure hemodynamics, blood gases and gas exchange during exercise.

These measurements were used to quantify six steps of oxygen transport and utilization in each HFpEF patients, identifying the defective steps that impaired each one's exercise capacity. The authors then quantified the functional significance of each pathway defect by calculating the improvement in exercise capacity that a patient could expect from correcting the defect.

The authors found that the vast majority of HFpEF patients harbored defects at multiple steps of the pathway, the identity and magnitude of which varied widely. Two of these steps, namely, cardiac output and skeletal muscle oxygen diffusion were impaired relative to controls by an average of 27% and 36% respectively. Due to interactions between a given patient's defects, the predicted benefit of correcting any single defect was often minor. At the individual level, the impact of any given pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects.

The authors concluded that a personalized pathway analysis could identify patients most likely to benefit from treating a specific defect. However, the system properties of oxygen transport favor treating multiple defects at once, such as, with exercise training.

What are the potential benefits or risks of intensive systolic blood pressure lowering in individuals with a low diastolic blood pressure? Well, the final paper today tells us. In this study by first and corresponding author, Dr. Beddhu, and colleagues from Salt Lake City in Utah, a post hoc analysis of the SPRINT trial was performed. Remember that the SPRINT trial was a randomized control trial that compared the effects of intensive versus standard systolic blood pressure control in older adults with high blood pressure at increased risk of cardiovascular disease. The current post hoc analysis examined whether the effects of the systolic blood pressure intervention differed by baseline diastolic blood pressure.

The authors found that there were U‐shaped relationships of baseline diastolic blood pressure with the primary cardiovascular disease outcome and all‐cause death. However, the beneficial effects of intensive systolic blood pressure lowering on the primary cardiovascular disease outcome in all‐cause death were not modified by baseline level of diastolic blood pressure.

Increased risk of kidney events and serious adverse effects of the intervention were consistent across baseline diastolic blood pressure quintals. Therefore, there was no evidence that the benefit of intensive systolic blood pressure lowering differed by baseline diastolic blood pressure levels.

These findings suggest that the reason for the observed associations of worse outcomes with lower diastolic blood pressure was due to underlying processes, such as increased arterial stiffness that lead to a decline in diastolic blood pressure, rather than the level of diastolic blood pressure per se. Furthermore, lower levels of diastolic blood pressure within the ranges examined in SPRINT, should not be an impediment to intensive treatment of hypertension, at least in those without diabetes or stroke.

Well, that wraps it up for our summaries. Now for our feature discussion. The ACC/AHA guidelines for the management of hypertension in adults has really been a hot topic. Just published this year, and it really updates the seventh JNC report, which was published in 2003. Well, today's feature paper deals directly with a comparison of these two guidelines and how it may impact our practice.

I'm so pleased to have with us today the first and corresponding author of this paper, Dr. Paul Muntner, from University of Alabama at Birmingham and a very familiar wonderful voice, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome!

Dr. Paul Muntner: Hi. Thank you for having me.

Dr. Wanpen Vongpatanasin: Hi, Carolyn.

Dr. Carolyn Lam: Paul, could I ask for you to start by painting the differences between the 2017 ACC/AHA guidelines and the JNC 7? We understand you were part of writing the guidelines, so who better than to draw our attention to the main differences.

Dr. Paul Muntner: I think that the new guideline, the ACC/AHA guideline, it was fairly comprehensive included 15 chapters, so there's a lot of new information in the guideline, everything from a dedicated section on the measurement of blood pressure to aspects of patient care.

The manuscripts featured in "Circulation" in this issue is focused on, in the past, there's different blood pressure thresholds in the guideline for defining hypertension, as well as recommendations for antihypertensive medication treatments, as well as blood pressure goals.

As everyone probably knows form JNC 7, hypertension was defined as a systolic blood pressure greater than or equal to 140 mmHg and/or a diastolic blood pressure greater than or equal to 90 mmHg, versus in the 2017 ACC/AHA guideline, these were lowered to 130/80.

In terms of treatment recommendations, there's really a fundamental shift with the new guideline, where the new guideline focuses not just on blood pressure levels, but also on overall cardiovascular disease risk. So going to the new guideline, people are recommended treatment if their blood pressure is above 140/90 but also there's a group with a blood pressure in the 130 to 139 range for systolic blood pressure, of 80 to 89 mmHg for diastolic blood pressure, who are recommended treatment if they have a high cardiovascular disease risk.

Finally, I'll just finish with this last note is that blood pressure control for people taking antihypertensive medication is now 130/80 so a goal blood pressure for people taking antihypertensive medication is systolic blood pressure less than 130 mmHg, and a diastolic blood pressure less than 80 mmHg.

Dr. Carolyn Lam: That was beautifully explained. Paul, I just really loved table 1 of your paper, and I want to refer our audience to it. It so nicely summarizes the differences between the 2017 guidelines and JNC 7. At risk of oversimplifying, when you compare the two in this approach, it's sort of comparing using a cardiovascular risk in conjunction with blood pressure‐type approach with a blood pressureonly number approach, isn't it?

Dr. Paul Muntner: Right. I think that's a key important piece of the new guideline and really CVD risk is used in conjunction with blood pressure levels to guide the recommendation to initiate antihypertensive medication. This decision was based on a wide variety of data from randomized trials, observational studies, as well as simulation or economic analyses that consistently showed the benefits of considering an individual's overall cardiovascular disease risk and providing effective and efficient treatment for lowering blood pressure.

Dr. Carolyn Lam: Right. And you analyzed the impact of this in the NHANES data in today's paper. Could you tell us a bit more about that?

Dr. Paul Muntner: The U.S. National Health and Nutrition Examination Survey, or NHANES, provides an opportunity to generate national representative point estimates on the prevalence of hypertension and treatment recommendations. So we're able to use data on about 9500 U.S. adults. Each person came in for a clinic examination where they had their blood pressure measured three times, and they were asked about their use of antihypertensive medication. What we found was the prevalence of hypertension, or the percentage of U.S. adults with hypertension according to the new guideline, is about 46%, which compares to 32% according to the JNC 7 guideline, so really a big increase in the prevalence of hypertension of about 14%. However, by using the combination of risk and blood pressure, we're not recommending treatment for everyone with hypertension but rather people with hypertension with very high blood pressure as well as those at high cardiovascular disease risk.

So antihypertensive treatment, pharmacological antihypertensive treatment, is now being recommended for about 36% of U.S. adults compared to 34% of U.S. adults according to JNC 7. The rest of the people with hypertension are recommended nonpharmacological therapies; exercise, diet, alcohol reduction, weight loss for people who are overweight and obese.

Really, it's an opportunity to treat people with pharmacological therapy if they're high risk. Then for people who aren't high risk, there's an opportunity for nonpharmacological therapies, so they can, hopefully, prevent the need for further treatment.

Overall, this equates to about 103 million U.S. adults with hypertension, so it's a very large number. However, only about 82 million of these individuals are recommended pharmacological antihypertensive treatment, so there's a big portion of the U.S. population who have hypertension, have high blood pressure, yet we think would benefit from nonpharmacological therapy.

Dr. Carolyn Lam: Wanpen, could I get you to chime in on what you think of the clinical implications of today's paper?

Dr. Wanpen Vongpatanasin: I think that this paper gives us at least reassurance that although we have 30 million more people with hypertension now, not all of them have to be started on medication right away. But it also put an emphasis on cardiovascular risk assessment, which we as the cardiologist are already doing this on a regular basis. It is a major step forward to incorporate cardiovascular risks as another way to gauge how people should be treated intensively, which we like that aspect of it.

Dr. Carolyn Lam: I agree. I think it's reassuring because most people think, "Oh, my goodness. We have got so much more hypertensives to manage." But then it tells us that a restratified approach really keeps it manageable, I suppose. But Wanpen, did you have some specific concerns or questions?

Dr. Wanpen Vongpatanasin: We look at the people who by JNC 7 calls prehypertension, which it's now some of them turn out to be a stage 1 hypertension. The question I have for Paul is that even though guidelines call for nonpharmacologic treatment first, the guidelines said give a try from three to six months, but what happens after that if they're still not reaching the goal?

Would people on the guidelines propose drug treatment eventually because, as you know, nonpharmacology treatment is easier said than done. Even though you might be able to tackle some aspect of it, but I doubt you can tackle everything; exercise, diet, sodium, weight loss all at the same time in a three to six month period.

Dr. Paul Muntner: It's a great question and it's something that the guidelines really spent a lot of time considering and reviewing the evidence. First, what the recommendation is that we recommend nonpharmacological intervention as you mentioned and the re‐evaluation. If the person's blood pressure remains in the stage 1 hypertension range and they're not a high cardiovascular disease risk, then they are recommended to continue attempts at the nonpharmacological interventions.

I've been asked several times since the guideline has been published, "What, are we supposed to just wait until people become high risk?" And my viewpoint on this is, it's hard enough to get people to adhere to their medications currently, let's be judicious about this, focus on the high‐risk people, and maybe if we can communicate with people that have high‐risk for cardiovascular disease, we can work with patients to improve medication adherence and really focus on the low‐risk people in preventing the need for lifelong therapy.

Dr. Wanpen Vongpatanasin: That's great, I think that's really helpful in clarifying this point. Because even if you say that 30 million doesn't need to be started on the drug right away, that eventually have to be started on drug in six months, I think that doesn't really give us a reassurance but, obviously, we still have to continue to

work on these patients who are on the fence of needing pharmacology intervention.

Dr. Paul Muntner: Right. I think what's interesting here is a lot of people since the guideline has been published have said to me, "Now this is done." I said, "No. Now we're really just starting. Now is the most important part of the guideline, which is implementation." And how are we going to implement the guideline, which, as we were just discussing, isn't just about initiating pharmacological therapy, but it's also about the nonpharmacological therapies as well as medication adherence and all these other issues that are in the guideline, proper measurement of blood pressure, etc.

I think that now is going to be the most important time to really have a big impact on our patients' lives by really using the evidence and now that it's in the guideline, we're using the evidence to direct treatment appropriately.

Dr. Carolyn Lam: Indeed, Paul. Just one thing. Along the lines of implementation, how about the issue of the lower target BP, to treat to? What did your study from NHANES show about that, numbers reaching targets, and do you see that as an issue?

Dr. Paul Muntner: It's an interesting question because the findings from our study found that it's currently over half of U.S. adults according to the new guideline, over half of U.S. adults on antihypertensive medication, have blood pressure above the goal in the new guideline. So in our study, 53% of U.S. adults taking antihypertensive medication had a blood pressure above 130/80. This represents an increase from the JNC 7 guideline of people with blood pressure above 140/90, of course, of about 14.4%. According to our estimates, there are about 8 million U.S. adults who are going to be recommended more intensive antihypertensive medication.

The blood pressure of less than 130/80 is a uniform goal for all people taking antihypertensive medication. This comes from several meta‐analyses that have consistently shown the cardiovascular and mortality risk reduction associated with achieving a blood pressure of less than 130/80. I think there's very firm evidence to stand on.

One interesting thing from the guidelines, it's in one of the tables, and I think it's a very important point to make, is that a lot of people who have above goal blood pressure, according to the new guideline, they're only taking one or two classes of antihypertensive medication. The vast majority of them are not taking multiple classes of antihypertensive medication, so we feel that these therapies can be optimized and we're not going to be pushing people into antihypertensive polypharmacy but rather they can receive substantial risk reductions without really giving them too many additional pills.

Dr. Carolyn Lam: Wow. Really about implementation. Wanpen, did you have any other comments before we close?

Dr. Wanpen Vongpatanasin: Yes, I think that is really interesting to see also with these guidelines how is this going to be embraced to the rest of the world. Actually, prior to this guideline, at least hypertension control rate in the U.S. is better than most countries, European countries, as well as in Asia. But now even lowering the bar, we use the same criteria for the rest of the world, that would be a lot worse control rate than now. I think it will be challenging, not only in this country but throughout the world.

Dr. Paul Muntner: That's a great point. Obviously, these guidelines are U.S. guidelines, however, new European guidelines should be coming out in 2018, is what I've heard. I think that even though these guidelines were developed by the American College of Cardiology and the American Heart Association, the data that we're using really comes from worldwide evidence. The evidence didn't stop at the borders. A lot of the evidence that was used in choosing the blood pressure levels to define hypertension, the blood pressure levels to recommend pharmacological interventions, as well as the blood pressure goals do come from other countries. A lot of data from Asia, Europe, Australia, so I think that the data used in these guidelines should be generalized when it's out of the United States.

I think there may be challenges with implementing these guidelines in different settings, and, obviously, a lot of things will have to be tailored to where they will be implemented. However, the overall goal is to reduce the burden of cardiovascular disease and renal disease related to hypertension and, hopefully, that can be a worldwide goal.

Dr. Carolyn Lam: What a great reminder. It is worldwide data, worldwide evidence for a worldwide problem. Well, listeners, you heard it right here on "Circulation on the Run." Thank you so much for joining us today and don't forget to tune in again next week.

Circulation Fellows-in-Training January 2018

2 januari 2018 | 22 min

Dr Carolyn Lam: (Music playing)...Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and his editors I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore. Today is one of my favorite podcasts as always because it is the fellows in training podcast.

This is where the center stage and we’re so pleased to have two brilliant fellows with us today. Dr. Tom Ford from University of Glasgow and Dr. Kevin Shah from UCLA and of course joining us today as well is our editor for digital strategies, Dr. Amit Khera. Hi everyone.

Dr Kevin Shah: Hi Carolyn.

Dr Carolyn Lam: Hey Kevin. Since you're there in wonderful bright and sunny California and going to talk about one of my favorite topics HFpEF. Could you please tell yourself and then please tell us also about the paper you chose?

Dr Kevin Shah: I am a third-year general cardiology fellow at UCLA. I have a career interest in advanced heart failure and transplant cardiology. I'm going to be doing a one-year fellowship in that next year at Cedars Sinai in Los Angeles.

The article that I picked to discuss was the Reduced LAP Heart Failure I Trial and it was specifically testing a novel device in a small cohort of patients to see if the creation of intraatrial septal connection in patients with HFpEF can improve their filling pressures as well as their symptoms with exercise.

Dr Carolyn Lam: Yeah so Kevin what about this paper stood out to you?

Dr Kevin Shah: The two biggest things that were impressive to me and that really stood out were 1) this concept that keeps coming up more frequently in contemporary research, which is the idea of using a sham trial. Specifically, in this study they did perform a one-to-one randomized trial. With one of the arms, if they did not receive the actual device, they underwent a complete sham undertaking including headphones in music and blind folding the patient who were not sure if they received the device or not.

I think it's an important concept because it does speak to the placebo aspect of procedures. It tries to really control for that when a patient doesn't know if they received a novel device, and we can still test them and see how they feel after-the-fact. I think that's an important strategy in modern trials.

Dr Carolyn Lam: Kevin, that is such a good point and really quite novel too. So we've discussed this paper before but not quite the aspect that you point out and I couldn't agree more. The REDUCED LAP follows its pilot study results, which was open label single arm right published in the Lancet. So this is a very reassuring results since knowledge sham controlled.

I suppose the lesson comes from other device trials that were sham controlled and then gave maybe slightly different results), right when we're talking about the renal innervation trials before. But you said that there were two points that stood out to you so what was the second?

Dr Kevin Shah: The other will also be endpoints and what they chose to target. It was a small trial but I think it's important in a disease state such as HFpEF to select specific endpoint that really reflect the physiology and pathophysiology and the authors should be commended. I think for selecting primary and secondary endpoint that will primarily focus on hemodynamics as well as symptomatic relief.

I know that they are working toward their stage 3 trial and I think in the vein selection of these type of endpoint. Probably more so than endpoints such as mortality are going to favor this disease state in terms of trying to carve out some sort of therapy that actually make patients feel better.

Dr Carolyn Lam: Great great points. For me to just knowing that a hemodynamic endpoint makes sense, because if we look at the Champion Trial and look at the HFpEF subgroup of the champion trial it also seems to show that if people just treated patients with HFpEF according to a hemodynamic guide and in the champion trial that was the pulmonary artery pressure reading. That actually appeared to keep patients out of hospital. And I have to agree with you that sometimes we forget that has HFpEF is about pulmonary congestion and that the end of the day it is a hemodynamic disease. It is heart failure in other words.

Kevin one last thing what do you think about using this sort of strategy in HFREF?

Dr Kevin Shah: That's a good question I can't say I know at least this device has been studied in this trial like you mentioned in one prior trial that was not randomized. I'm sure it's been at least investigated. I can't say I've seen any literature on it. I like to think that it would make some sense from a physiological standpoint, but I don't know if anyone is actually gone to the task of seeing how the device performs in HFREF.

Dr Carolyn Lam: As I said I think at the end of the day I think they're all part of the same heart failure family. And left atrial hyper tension is kind of the final common pathway. So I agree with you that maybe it's worth considering in HFREF too, but then on the other hand of course and have friends HFREF you've got all this great medical therapy. Well Kevin I really, really appreciate your selection. May I now switch over to Tom? Tom would you like to tell us a little bit about yourself ,and which paper you chose.

Dr Tom Ford: Sure thing my name is Tom Ford. I'm very interested in interventional cardiology, and my career path has been a bit unusual because I did my basic cardiology training in Sydney. And then from there I got a great opportunity to pursue a research degree, a PhD, which I’m currently halfway through. That's what Prof. Colin Berry and Prof. Keith Oldroyd here in Glasgow and that’s a British Heart Foundation Fellowship so it's a great opportunity. I went out for recent WOSCOPS Trial from posthoc analysis. In this is a really interesting study a lot of the readers and listeners will be familiar with the original publication. It was actually published 22 years ago. Published in the New England Journal of Medicine.

The WOSCOPS was a landmark trial that looked at statins for primary prevention. And this is the present analysis that looked at just over 2500 Mills with LDL-cholesterol above hundred and 190 mg/dL. So for those of you listeners in the UK 4.5 mmol per liter so quite the high LDL. They looked at these gentlemen without pre-existing vascular disease. There's guideline recommendation for this group but not much evidence. And what they showed was over a five-year period of follow-up that there was a reduction in cardiovascular death and all cause mortality with this treatment. That wasn't just for the period of the trial because of the study design we were able to get a legacy effect which was noted over 20 years of follow-up. So in summary a trial will show the benefits of statins and primary prevention mortality benefit for people without very high LDL to start with.

Dr Carolyn Lam: Carolyn awesome Tom. I love that she began saying that your into interventional cardiology but you chose an article about medical therapy and the importance of it, the statins. I fully agree with you. Amit did you have some for Tom?

Dr Amit Khera: Sure. First I want to commend you both I don't think you did this on purpose but Carolyn's heart failure HFpEF expert. I'm sure she loved the other trial and I'm a preventative cardiologists. So we certainly love you choices this week. Tom, thanks for the summary. It's an important article and one that we did highlight on the previous podcasts. You know there's so many things to talk about but certainly remind you that we have great data sets around that can answer unique questions that maybe are unanswerable today and I think this is an example of that.

Can you speak to this ideal of pulling an old 22-year-old child as you mentioned and how that provides insights and kind of as a PhD student ways to think about ways to be creative and research?

Dr Tom Ford: One of the reasons I chose this child because it's close to my heart looking at a population in the west of Scotland. Sadly over here we've got too high prevalence of cardiovascular morbidity and mortality. So what this trial speaks to is the benefits of a really carefully planned procedure. I mean these were outstanding researchers that thought ahead of their time, and as a result of their analysis. Over two decades later they are still multiple publications and there's kind of open approach where there's different research groups that have used this data set for number of different outputs.

I think a real outstanding example of what can be done with well-planned study.

Dr Amit Khera: Sounds like were in agreement about how to use a fruitful database and continue to learn from it as time goes on. The thing about this as you pointed out is the LDL above 190 component and what the authors say this is sort of the first clinical trial evidence for treatment. In your view, does this change practices or guidelines? Was this already what we were doing? Does this support what we were already doing, or how does this impact clinical care and guidelines currently?

Dr Tom Ford: I think it's a good point. People will say we were doing this anyways. I think now it's going to be helpful and practical inside the clinic. If you can say to a patient well actually look I know we’re asking you to take this tablet you've not actually had an event but, ultimately we know the natural history of people in your position may well be unfortunately that they’re high-risk, and that there is actually a mortality benefit to be had from these tablets that you don't necessarily want to take but definitely the benefit’s there.

Dr Amit Khera: The neat part as you pointed out also was dual components when they're looking at the on treatments during the trial. We see an improvement in events. What the WOSCOPS investigators have done so creatively over the years is this idea of a legacy affect.

The long-term impact in preventive cardiology – certainly a space for where were going was just looking beyond the short-term. There's obviously problems there too because that was not pre specified people were necessarily on assigned therapies. Tell me when you look at this long-term legacy effect what does that mean to you? How does that add be it the way you counsel patients or how you think about this treatment in patients with high LDL?

Dr Tom Ford: The effect of the statin assumes that all the patients are actually taking the drug. I think there has to be an analysis of these patients in this trial and obviously not everyone was compliant. So I think we can maybe extraopolate that for the that there might be in even bigger effect for those patients that were actually taking the drug. And I think if you were to take it for five year period. Obviously we don't know what happens after that. What we do know is the solid mortality data.

What it speaks to me is that if you take the drug and you are at high risk to begin with then potentially it's plaque stabilization, the pleiotrophic effects of statins that we know are beneficial and the hard endpoints are definitely reduced. That persists over 20 years of follow-up. So I think that’s really a great victory for preventive cardiology as you said.

Dr Amit Khera: That's a great point about biasing towards the know when you have people crossing over and that this may be conservative of what was seeing in the long term. I think that's a really important point. One last question for you. The West of Scotland trial - generations have changed and back then obviously part of it was trial design but LDLs on average were higher. The median or mean in the group was around 192.

If you look when they look above or below that 190. The people below were 178 or so - still pretty high LDL. So it does beg the question you know we have this paradigm of LDL above 190 should be treated regardless. You wonder if that should be 160 or whether the number should be lower. What are your thoughts about that?

Dr Tom Ford: I agree with you. I think it's always a challenge to kinda pass off dichotomous endpoints when you’ve got continuous variable like LDL. It's just a continuum of risk and divided using the figure 190 in the study. In fact the patients with LDL less than 190 they couldn't show statistically significant reductions in all cause mortality. But I think it's again personalization of meds and we may have to discuss the risk with individual patient.

Ultimately we do have to have a firm conclusion. I think in this study the data is quite clear that 190 does seem to be quite robust as the predictor who's gonna get the most benefit.

Dr Amit Khera: Listen I think protection article that you pointed out was close to home and you certainly discuss it very well and provided lots of important insights. And again I think it was an excellent choice and one that was really highlighted in the media as well. I think there was a broad allure to this article. If we make change gears now little bit we've heard about the science part know we want to talk about what it means to be a fellow in training.

I just want to say on behalf Circulation also speak for myself. It's so important for us to involve fellows in training into our activities and you're one of our major targets in terms of impact and goals for the journal. We're so delighted to do this twice a year and were always thinking about other ways we can get FITs involved. I mentioned just a couple of things the American Heart Association has of fellows in training program where people can sign up for free and get online access to the journal.

So I hope all fellows are taking part in that. We're starting a new initiative called FAVES where just like you both submitted articles of interest of the fellows can do the same. On Fridays we’ll post those on social media so these are a few ways that were getting FITS more involved and we really hope to continue that. Let me start by maybe asking Kevin to have a chat with you as much.

Kevin in terms of journals there's some me now we're getting inundated with information. I think that's a good thing. How do you consume the medical literature? There's old print journals; there's the online journal; there's a table of contents your social media tell us a little bit about how you consume the medical literature.

Dr Kevin Shah: I agree. We’re kinda getting to a space where now the amount of information that's coming out is tremendous. I think that finding a strategy to help filter out what appeals to your clinical and research interest is becoming more challenging. For me I'll say print journals are slowly kind of falling off. I don't subscribe to too many of them but they still do come to my doorstep. The main way that I would say I'm getting access to or at least becoming aware of articles that are kinda relevant to where I am in my training and what I'm doing is the social media. Some primarily at least for me is Twitter.

I'll say it's a helpful tool and that I can follow a group of individuals that have a similar professional interest as me and you can almost always rely on the fact that somebody will post an article that becomes relevant to a common interest. So between sharing on social media I think that's the primary way that I'm really catching my eyes to a major journal articles.

Aside from that I still subscribe by email to a couple larger journals and see their weekly or biweekly updates about what's being published. And the last at least in my institution our division chief Dr. Gregg Fonarow; he goes out of his way to send to the fellows and faculty new articles that are kind of pertinent to clinical practice. Which is very helpful for us.

Dr Amit Khera: That's so helpful and you know everyone has their own way of consuming the literature but I certainly appreciate your interest in social media. You know there are some luddites out there that think of it literally as just social and it really has a professional bent to it. Well rapidly you can figure out the most cutting-edge important articles in your field so I certainly appreciate your comments. Tom let me ask you now, at your stage of training. You've had an interesting training path as you said you sort of started as an interventional cardiologist and now you are doing a PhD. There so many different articles in Circulation. We have original research, state-of-the-art reviews. We have these opinion pieces and on my minds and different ones. Tell us a little bit about what articles appeal to you and which other novel formats maybe you'd be interested in seeing.

Dr Tom Ford: I think that the original research articles are great if it's in your chosen field. Obviously this is where we're going to a great deal of detail on specific topics but outside of that I think that the review articles are great form if it's something that’s a common clinical topic to kinda brush up on. Your On My Mind section I think is great because it gives you an opportunity to hear from key opinion leaders in the field. I think it was Morton Kern discussing invasive coronary physiological assessment.

So I think there’s different types of articles that can be quite helpful. To start with the original research ones. I’ll skim through the contents. I'll tend not to read the details if it's not in my chosen field.

Dr Amit Khera: Yeah great point. Obviously they are topical depending on what your main interest area and we always say reading around your field to get a broader perspective in cardiovascular medicine. I think you hit on the point about on my mind ones. We really want people be able to free associate and original article are sometimes more stiff and linear. So we really like those pieces as well. Carolyn we’ll give you second set ask a question or two to for today.

Dr Carolyn Lam: Actually Amit I just wanted to comment. Isn't it so encouraging to hear the variety of approaches and you know Circulation has enough that we’re meeting various different needs. I really wanted to take the opportunity to thank you as editor of digital strategies for just doing so many of these initiatives for Circulation. I think it’s just incredibly important for the Journal to keep up with the times in that sense. Amit, may I be cheeky ask you how do you consume the literature?

Dr Amit Khera: Carefully. You know the neat part in being on the editorial board of Circulation and one of the associate editors we get to see so many amazing papers that come through and I think obviously I get to see, essentially and also my digital strategies role I essentially see every paper that comes through that we end up publishing.

Obviously I get wide exposure to Circulation but obviously beyond that I get all the e-Table of Contents for almost every major cardiovascular Journal. Certainly looking at social media and I tend to find hotspots interventions and other areas and podcasts – let’s not forget podcasts. So there's some great podcasts out there. I know of one.

Dr Carolyn Lam: Oh I love it. All right but just one last question for both Tom and Kevin from me. I honestly would love to know what do you think we could do better or what would you like to see more from Circulation?

Dr Kevin Shah: I guess the question I have for Circulation is there any role or have fellows ever gotten involved in the review process for articles?

Dr Amit Khera: Listen that's really important because you learn a lot from doing that and obviously in institutions similar to ours where if you asked to review a paper you have a fellow contribute. I think you might be asking something sort of more formal and systematic with Circulation. I will say that one of our Circulation journals I believe it's Circ Heart Failure or Quality and Outcomes I'll check. It has a formal program where fellows essentially can be assistant editors if you will.

We have our cardiology fellows here at UT Southwestern involved in that process. And I think part of that process is just an IT issue of how to maintain confidentiality of our papers for our authors but yet still let fellows contribute meaningfully. And also timing because you know papers have cycles where you decide if he should go out for review but it'll come back and you never know when that happens you have to make the next level decision.

Then it goes potentially to a meeting and so being able to make sure that fellows can participate at every level, cause that's where the value comes in. We are certainly interested in learning from what our other Circulation of family journals is doing in that space and definitely an area that we've thought about some fellows contribute but need to do more.

Dr Carolyn Lam: And Tom how about you?

Dr Tom Ford: Just picking up on your point on what the sister journals are doing you know I see the Outcomes Journal is looking at more visual abstracts and video abstracts. You know I think it's really important that we increase the efficiency of learning. What's your take on that?

Dr Carolyn Lam: That is the greatest suggestion. I like first of all your phrase of increasing the efficiency of learning. Amit, I'm going to turf it to you again.

Dr Amit Khera: I'll tell you what's amazing you know when I started this role a bit ago. Both of you are obviously contributing to research and everyone on this call is and I think we forget that in the social media space we don't have a lot of data. Some things sound good or feel good. At Circulation my predecessor Carolyn Fox did a randomized trial called intention to tweet if you haven't read it. And there's a follow-up to that that was published. And essentially by randomizing articles to social media or not there was no increase in the views if you will of the article.

There's always limitations to every study but the point is, as you think about novel offerings, something we struggle or something we’ve seen as an opportunity, what works we tried a few things we tried certain videos and we look at what's the uptake and interestingly some things we thought that would be widely of interest really weren’t. Then other avenues we’ve tried have been.

I love what you said, and as Carolyn also felt, the idea of efficiency of learning. I think we need to do frankly in the social media and journal spaces is to continue not just to innovate but to study and figure out what works and what doesn't to help different learners.

Dr Carolyn Lam: (Music playing)....Thank you very much audience for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Circulation January 2, 2018 Issue

26 december 2017 | 20 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore. Our feature paper today focuses on LDL cholesterol results from non-fasting samples and a personalized novel method of LDL cholesterol estimation that you will surely want to know about. So stay tuned, coming up right after these summaries.

The first paper provides new evidence that RUNX1, a gene intensively studied in the cancer and blood research fields, has a critical role in cardiomyocytes following myocardial infarction. Co-first authors, Dr. McCarroll and He, corresponding author Doctor Loughrey and colleagues from University of Glasgow generated a novel tamoxifen-inducible cardiomyocyte-specific RUNX1-deficient mouse and showed that RUNX1-deficient mice were protected against adverse cardiac remodeling post-MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy and their cardiomyocytes exhibited markedly improved calcium handling.

At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by PKA and relief of sarcoplasmic reticulum calcium pump inhibition. Thus, these data identified RUNX1 as a novel therapeutic target with translational potential to counteract the effects adverse cardiac remodeling post-MI.

The next paper invites us to consider that some our resource-intensive quality improvement initiatives may not be fulfilling their intended goals or even justify their costs. In this paper by first author, Dr. Kutty, corresponding author, Dr. Chan and colleagues from St. Luke's Mid America Heart Institute, the authors evaluated the association between the implementation of pediatric medical emergency teams and the risk-adjusted mortality at the hospital level.

To do this, they looked within the pediatric health information system for freestanding pediatric hospitals and calculated the annual risk-adjusted mortality rates for sites between 2000 and 2015. A random slopes interrupted time series analysis was then used to examine whether implementation of a medical emergency team was associated with lower than expected mortality rates based on the pre-implementation trends. The authors found that before medical emergency team implementation, hospital mortality rates were decreasing by 6% annually across all hospitals. After medical emergency team implementation, the hospital mortality continued to decrease by 6% annually with no deepening of the mortality slope as compared with the pre-implementation trend for the overall cohort or when analyzed separately within each of the study hospitals. Five years after implementation across study sites, there was no difference between predicted and actually mortality rates.

Thus, in summary, the implementation of medical emergency teams in a large sample of pediatric hospitals in the US was not associated with a reduction in hospital mortality beyond the existing pre-implementation trends. This study's null findings on hospital mortality suggests that either medical emergency teams have no effect on mortality or are being poorly implemented in the real world. These issues are discussed in an accompanying editorial by Joshua Koch and Sandeep Das from UT Southwestern.

The next study tells us that carotid stent fractures are not associated with adverse events. First and corresponding author, Dr. Weinberg from Massachusetts General Hospital and his colleagues reported the stent fracture rate and its association with instant re-stenosis and adverse outcomes in the Asymptomatic Carotid Trial 1, which was a prospective multi-center trial of standard surgical risk patients with severe asymptomatic carotid artery stenosis randomized to carotid artery stenting or carotid endarterectomy. Stent fracture occurred in only 5.4% of patients and there was no association between stent fracture and in-stent re-stenosis or with the primary endpoint, which was a composite of death, stroke or myocardial infarction during the 30 days after the procedure or ipsilateral stroke during the 365 days after the procedure.

These findings suggest that routine surveillance for carotid stent fracture may be unnecessary and, if a fracture is identified in an asymptomatic patient, intervention may rarely be required.

Heart rhythm disorder management procedures are increasingly being performed and the next paper tells us important information on mortality and cerebrovascular events following such procedures.

Co-first authors Lee and Ling, corresponding authors Dr. Mulpuru and colleagues from Mayo Clinic in Phoenix, Arizona, performed a retrospective cohort study of all patients undergoing heart rhythm disorder management procedures between 2000 and 2016 at the Mayo Clinic from all three campuses in Rochester, Phoenix and Jacksonville. Among almost 49,000 patients undergoing a total of above 62,000 procedures, the overall mortality and cerebrovascular event rate was 0.36% and 0.12%, respectively. Lead extraction procedures had the highest overall mortality of 0.21% and the highest cerebrovascular event rates at 0.62%. However, most of the deaths and cerebrovascular events occurred after device implantation procedures due to the sheer volume of device implantation procedures, which represented 48% of all the procedures performed.

The most common cause of death directly related to these procedures was cardiac tamponade, being responsible for 40% of all directly related deaths. This highlights the importance of development of protocols for quick identification and management of cardiac tamponade, even in procedures typically believed to be of lower risk such as device implantation.

And that wraps it up for our summaries this week. Now, for our feature discussion.

Lipid testing plays a major role in our day-to-day management of our cardiovascular patients and fasting samples have long been the standard for assessing LDL cholesterol and triglycerides since fasting is believed to reduce the triglyceride variability and allow for a more accurate derivation of the commonly used Friedewald calculated LDL cholesterol. Well, I think that's an assumption we have taken for granted, I mean, since 1972 when the Friedewald calculation was first proposed, but in this day and age, several clinical guidelines from Europe, Canada and the US have now recommended non-fasting lipid testing for routine clinical evaluations and it's time to re-evaluate perhaps the Friedewald LDL or other methods for determining LDL.

Today's feature paper addresses this issue spot-on and we're thrilled to have with us the corresponding author of a very important paper and he is Dr. Seth Martin from the Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease and we also have with us Dr. Anand Rohatgi, associate editor from UT Southwestern. Welcome, gentlemen.

Dr. Anand Rohatgi: Thank you, Carolyn.

Dr. Seth Martin: Thank you.

Dr. Carolyn Lam: Seth, that was a super-long lead up from me, but I just find your paper so intriguing. Could you please paint the background of the idea behind your paper today and the rationale for questioning the Friedewald equation?

Dr. Seth Martin: Yeah, my pleasure. This was the first paper to look at directly fasting versus non-fasting using our new algorithm. To give a little background on the algorithm, we had recognized that the Friedewald equation, which had been the standard for decades as you mentioned, would really become problematic in the setting of low LDL concentrations. In fact, Dr. Friedewald himself and his co-authors said that in their original publication in 1972 because what's subtracted out is the LDL cholesterol and it's not a particularly accurate estimate by their equation, but at the time, it was viewed as acceptable because the concentrations of LDL weren't all that low.

Now, in the modern era, things are different. We treat the lower LDL. We're lucky to have new drugs that allow us to achieve low LDL levels and meanwhile we have many more patients with obesity and diabetes, leading to higher triglyceride levels, so this all means that that estimated component of the equation becomes a bigger part of the equation and that's what spurred us on to say, "Well, cane we estimate that better?" And we were very lucky to have access to a huge data set that had over a million patients and had directly measured VLDL cholesterol as well as triglycerides, so that allowed us to really more specifically address this estimated component of the equation.

To just give the brief details on what the equation does, is we take the original Friedewald equation from what I view is a one-size-fits-all approach where we divide triglycerides by 5 in milligrams per deciliter and now we just match the patient based on their lipid profile using the same data as the Friedewald equation with the more personalized factors, so taking it from one size fits all to a more precision or personalized fit and it's one of 180 different factors that the patient may get matched with and what we've found is that this type of approach is more flexible, so it's going ... as patients triglyceride levels go up in the setting of low LDL and as they go into non-fasting states, this type of approach can adapt to that better and provide a more reliable, accurate estimate of LDL cholesterol.

Dr. Carolyn Lam: That is so cool. It really is. It just makes so much sense in this day and age of proceeding towards personalized medicine, to make sure we apply equations that are personalized, so your paper essentially shows that applying this new equation works better than the traditional equation, particularly in the non-fasting states, right? And for states of low LDL cholesterol or perhaps high triglycerides. Would that be a good summary?

Dr. Seth Martin: Yeah, that's a great summary and this paper ... I'm really lucky. It was led by one of the fantastic Osler medical residents, Vasanth Sathiyakumar, who is going to be a future star in cardiology, I believe, and he did a great job leading our paper, which shows that in the non-fasting state, what happens is triglyceride levels are higher and this means that the Friedewald equation becomes less accurate and I think this has been a little bit overlooked in recent trends where there's been a big push to do more non-fasting lipid profiles, which really is great for patients, more convenient and it makes a lot of sense, but we have to be also, in an era of precision medicine, getting precise data and if we're going to be making clinical decisions based on LDL concentration, we want to make sure we have good information there and what our paper shows is that there should be some level of caution when using non-fasting Friedewald LDL at low levels, but our new algorithm does provide a more robust estimate in that setting.

Dr. Carolyn Lam: Anand, this is begging for the question, "What do you think are going to be the practical implications of this very important paper?"

Dr. Anand Rohatgi: I think the clinical implications are huge and I think that's why we were so excited when we received this, that sort of the potential impact was there. I can tell you personally my clinic is in the afternoon and so it's a struggle to try to get patients to get fasting lipid levels and often they can't do it when they're coming to see me and so the importance of non-fasting lipid levels is clear and what Seth's group has done is showed that we can actually accurately estimate the LDL levels. A lot of people struggle with trying to still calculate the non-HDL levels and, as Seth pointed out, oftentimes when you're non-fasting, the triglyceride levels are higher and the calculated LDL from Friedewald is artificially low, so it's very hard to combine the convenience of just looking at the lipid levels and having sort of a confidence in the actual calculated LDL, so in this case clinicians can have their patients get their lipid levels at any time and with this algorithm that's already being used by major laboratory services will have relatively high confidence that the LDL that they see is very accurate and then they can make a decision based off of that and they can counsel in real time based off of that, so it really changes the ability to engage with patients at any time and is not restrictive.

I can tell you many patients sometimes won't even get their lipid levels for weeks just because they can't arrange for it to be done on a fasting state and so this really liberates patients and it really enhances the doctor-patient relationship, I think.

Dr. Carolyn Lam: I agree, Anand. I like that word that you used, "liberate" the patient. Honestly, I think some of my patients cheat a little too and they don't really fast as they should before their fasting lipids and this is going to be incredibly helpful.

I have a couple of questions for you, though, Seth. In terms of understanding the limitations of what you may have tested in the current study, we all know that with triglycerides in the super-high level of more than 400, for example, the Friedewald equation breaks down. Did you test this with the new equation because I think you excluded this group as well in the current study, did you not?

Dr. Seth Martin: That's correct, yes. Traditionally, the Friedewald equation has excluded folks from calculation who have triglyceride levels, as you said, of 400 milligrams per deciliter or more and the reason for that is that's the setting where chylomicrons are more likely to be present and therefore we're trying to estimate VLDL cholesterol and it wouldn't make sense to do that if there's a lot of triglycerides and chylomicrons.

That being said, we did look at this previously and found that in that setting our equation works quite a bit better than Friedewald, but it's still inaccurate I would say about a third of the time due to the presence of chylomicrons, so it's an area where we should certainly be more cautious in estimating LDL cholesterol if the triglycerides are that high, but honestly in that setting, often the clinical priority is going to revolve around triglyceride lowering and the LDL may not be the most immediate priority for clinical treatment.

Dr. Carolyn Lam: And then just another question, recognizing that our podcast is heard throughout the world, in this day and age of precision medicine, how about accounting for potential ethnic differences, possibly? Did you account for differences in race, gender perhaps in these equations?

Dr. Seth Martin: What we found is that this really is a lipid-dependent phenomenon in terms of the ratio of triglycerides to VLDL in estimating LDL. We previously looked at age and sex and found that they contributed very, very little information to actually explaining this ratio and so I think that it is something that's likely going to be preserved across different demographic groups. I can say to our listeners in places ... in Asia that the equation has been validated over there and so there's some reassurance that even around the world and other places like Brazil, that it is holding up, so I think that largely this is going to be dependent on someone's lipid profile and it is quite simple in that regard, that we don't have to likely worry about too much differences between men, women, older, younger or different ethnicities.

Dr. Anand Rohatgi: I have a question for Seth. As we mentioned, this is an international audience and guidelines do differ on their emphasis on lipid targets now as everyone is aware, some still emphasizing them and others, like the American guidelines, de-emphasizing targets, so Seth, the question i had for you is based off of your work. Where do you see that fitting in with how the different guidelines and societies are trying to emphasize or de-emphasize lipid targets.

Dr. Seth Martin: The amazing thing is we're all ... really have access to the same data. We've worked together throughout the globe to generate clinical trial evidence that guides us as well as all sorts of other type of evidence to guide us in clinical practice, so just on a very broad conceptual level, my hope is that over time with the great exchange of information around the world that we're going to converge more on consensus recommendations and then, of course, there may be needs to adapt those recommendations to different cultures and that can be taken into account, so I'm hoping there'll be a push towards more consensus and as we get our updated American guidelines, it's looking like this upcoming year, I hope that we come into even more harmony with the rest of the world.

I think for a long time we've had this LDL goal in many different guidelines as less than 70, so that's part of the reason our work has focused on that level. The European guidelines have a target level for high-risk patients of less than 70 for LDL and I think what we saw in the recent consensus document on non-statins from the American College of Cardiology was a push to be thinking at that level when the LDL is 70 or above as a time to have a clinician and patient discussion about whether we should be intensifying therapy, so I guess would say the guidelines in my view, and Anand I would be curious of your view, are more alike than different, but I hope they become even more in harmony because really we're all basing our decisions on the same evidence base and I think it can be a bit confusing when we have disparate recommendations.

The same can be said for the issue of recommendations for fasting versus non-fasting guidelines, which have not been harmonized either, but Anand I'd be curious to your thoughts as well on this topic.

Dr. Anand Rohatgi: I would agree with you. I think they're more alike than different. It's just what may be the high level sort of things have come out to the lay public and others, but I agree with you. If you really read them, they're emphasizing risk reduction by the therapies and by controlling the risk factors, in particular the lipid levels, so I think that's where your work is really important and insightful and I think will be incorporated in all of the respective guideline revisions.

Dr. Carolyn Lam: I completely agree and we're so proud to be publishing your excellent work in circulation. Thank you, Seth. Thank you, Anand.

Thank you, listeners, for joining us today. Don't forget to tune again next week.

Circulation December 19/26, 2017 Issue

18 december 2017 | 20 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

This week's journal features two papers. One a research letter and the second an original article, both focusing on the effect of ionizing radiation on interventional cardiologists. I'm sure that cuts close to the heart, so please stay tuned. Coming up right after these summaries.

The first two original articles in this week's journal describe a metabolic adaptation that is good for the abnormal cell but bad for the patient. This is a shift in glucose metabolism called the Warburg phenomenon where there is failure of two fundamental pathways. Number one glucose metabolism and number two mitochondrial oxygen sensing. This Warburg phenomenon enables a reliance on glycolysis despite an abundance of available oxygen. These two circulation articles uncover new players in the Warburg phenomenon, both in the setting of pulmonary arterial hypertension. One in the pulmonary arterial endothelial cells, and the second in fibroblasts.

In the first paper, first and corresponding author Dr. Caruso and co-corresponding author Dr. Morrell from the University of Cambridge examined the microRNA and proteomic profiles of blood outgrowth endothelial cells from patients with heritable pulmonary arterial hypertension due to mutations in the bone morphogenetic protein receptor type two, or BMPR2 gene, and in patients with idiopathic pulmonary arterial hypertension. They demonstrated that reduced expression of microRNA-124 in pulmonary arterial hypertension endothelial cells was responsible for the dysregulation of the splicing factor polypyrimidine tract binding protein 1, and its target pyruvate kinase M2 or PKM2, which is a major regulator of glycolysis and which contributes to abnormal cell proliferation. Reduced BMPR2 levels were associated with reduced microRNA-124 expression.

In the second paper first author Dr. Zhang, corresponding author Dr Stenmark and colleagues from the University of Colorado studied pulmonary adventitial fibroblasts isolated from cows and humans with severe pulmonary hypertension. PKM2 inhibition reversed the glycolytic status of pulmonary hypertension fibroblasts, decreased their cell proliferation and attenuated macrophage interleukin beta expression.

Normalizing the PKM2 to M1 ratio in pulmonary hypertension fibroblasts by using microRNA-124 over expression, or by PTBP1 knockdown, reversed the glycolytic phenotype, rescued mitochondrial reprogramming and decreased cell proliferation. Finally, pharmacological manipulation of PKM2 activity or treatment with histone deacetylase inhibitors produced similar results. These findings provide new avenues for the treatment of pulmonary arterial hypertension and are discussed in an accompanying editorial by Stephen Archer from Queen's University in Ontario Canada.

The next paper tells us that the addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. First and corresponding author Dr. Bohula and colleagues from the TIMI study group investigated the efficacy of the addition of ezetimibe to simvastatin for prevention of stroke in the IMPROVE-IT trial where post ACS patients were randomized to placebo and simvastatin or ezetimibe and simvastatin and followed for a median of six years.

The current study focused on patients with a history of stroke prior to randomization. The authors found that the addition of ezetimibe to simvastatin reduced the frequency of ischemic stroke with a hazards ratio of 0.79, with a particularly large effect seen in patients with a prior stroke, where the hazards ratio was 0.52, compared to patients without a prior stroke where the hazards ratio was 0.84. Hemorrhagic strokes were rare and a non significant increase in hemorrhagic stroke was observed with the addition of ezetimibe. Thus, the authors concluded that it is reasonable to consider the addition of ezetimibe, a generic lipid lowering therapy with an acceptable safety profile, to a moderate to high intensity statin regimen for the prevention of ischemic stroke in patients with established ischemic heart disease, with or without a prior stroke.

Atrial fibrillation is the most common sustained arrhythmia in hypertrophic cardiomyopathy, but the influence of atrial fibrillation on clinical course and outcomes in hypertrophic cardiomyopathy had remained incompletely resolved. That is until today's paper in circulation. First and corresponding author Dr. Rowin and colleagues from Tufts Medical Center accessed the records of 1,558 consecutive patients followed at the Tufts Medical Center hypertrophic cardiomyopathy institute for an average of 4.8 years from 2004 to 2014.

20% of patients had episodes of atrial fibrillation, of which 74% were confined to symptomatic paroxysmal atrial fibrillation, while 26% developed permanent atrial fibrillation. They found that the timing and frequency of paroxysmal atrial fibrillation events were unpredictable with an average two year interval between the first and second symptomatic episodes but progressing to permanent atrial fibrillation uncommonly. They further found that atrial fibrillation was not a major contributor to heart failure morbidity, nor a cause of arrhythmic sudden death, and when atrial fibrillation was treated it was associated with low disease related mortality, no different than for patients without atrial fibrillation. Finally, atrial fibrillation was an uncommon primary cause of death in hypertrophic cardiomyopathy, but this was virtually limited to embolic stroke, thus supporting a low threshold for initiating anticoagulation therapy.

That warps it up for our summaries. Now for our feature discussion. This week's journal carries two papers that refer to the health risks of ionizing radiation to interventional cardiologists. Yes, you heard me right. You're going to want to listen up. These are going to send chills up our spine, or rather maybe chills into our brains and into our blood according to the papers.

To discuss these two papers I have with us associate editor from UT Southwestern, Dr. Manos Brilakis, as well as the corresponding author of the first paper Dr. Maria Andreassi from CNR Institute of Clinical Physiology from Pisa Italy. Maria, could you start us off by telling us what you found in your research letter?

Dr Maria Andreassi: In our study we evaluated the circulating microRNA profile in interventional cardiologists in order to provide insights into the molecular and the biological situation and the underlying association between occupational low dose radiation exposure in cath lab and the potential long term disease risk. The hypothesis of our study was based on the evidence that the microRNAs are crucial regulators of gene expression. And they have been shown to be dysregulated in many human disease. Moreover, the stability and the tissue selectivity of circulating microRNAs make them ideal biomarkers to explore disease potential clinical disease risk.

In summary, our findings exhibited the dysregulation and the down regulation of acute specific circulating microRNA, the brain specific microRNA-154 and the microRNA-2392. This tells us significantly involved in the deregulation of the three brain pathways and the brain cancer pathway as demonstrated by systematic analysis. In particular, the dysregulated labels so the brain specific microRNA-154 in interventional cardiologists support the notion that the brain damage is one of the main potential long term risk on unprotected head radiation in interventional cardiologists with possible long lasting consequences on the cognitive function.

Dr Carolyn Lam: That is really striking. Brain specific microRNA was shown to be dysregulated in interventional cardiologists compared to controls who were not exposed to radiation. As I understand it, these dysregulated microRNAs can be seen in certain forms of epilepsy and Alzheimer's disease and certain brain cancers and so the concern is very obvious for those of us who are interventional cardiologists. But your study did not actually relate these two specific adverse events. Is that correct?

Dr Maria Andreassi: You're right. Yes. microRNA-154 was first identified as a brain specific microRNA which is involved with inner synapse development and the directly implicated in [inaudible 00:12:15] and memory. Additionally, decreased expression of this microRNA class, was previously reported in several brain disorders including the thymus disease and bipolar disorder. This microRNA has also been shown to be down regulated in several brain cancers such as neuroblastomas. The reduced expression of the microRNA-154 is a predictor of progression and prognosis of human gliomas. This data strongly support it's important role in brain tumors. Our findings are of particular interest in relation the handle exposure to the pathology of the head, the [inaudible 00:13:13] 20, 50 millisieverts. The equivalent to 1,000, 2,000 chest x-rays and can reach a lifetime cumulative exposure around two sieverts for left hippocampus and one sievert for right hippocampus.

Dr Carolyn Lam: That really makes me go, yikes. But Manos, as an interventional cardiologist yourself, what are your thoughts? And also your thoughts please on that other paper that's in this week's journal?

Dr Manos Brilakis: First of all, let me just congratulate Maria Andreassi, she's been one of the leaders in this area and published several papers and this is one of them. It's really important to have these studies because unfortunately we as interventional cardiologists tend to forget about the negative affects of radiation because as you hear, people don't really see them and this can happen many years down the line. And by the time they happen, it's too late. It's really useful to have the studies to bring our attention the importance of keeping the radiation exposure to the patient and to ourselves as low as possible.

The other paper in addition to the one just discussed, is a paper that looks at DNA damage on operators performing endovascular aortic repair. As a preface, these are procedures demonstrated the aortic aneurism repairs which are very intense radiation wise. They are long procedures, fielding can sometimes be challenging for the operator. There is significant exposure of the operator to x-ray. What they did is they measured some markers of DNA damage and repair. Specifically gamma-H1AX and DDR, the DNA damage response marker and the pATM. They measured them in circulating lymphocytes in operators who performed the endovascular aortic aneurism. What they found is that there were significantly higher levels of those markers immediately after those operators performed those procedures. And they did the same thing after x-ray using leg shielding.

That's a very good reminder for us that the x-ray tube actually is not on the top of the table, but the x-ray tube, the generator, of the x-rays is actually on the bottom. Then the x-ray goes through the patient and the detector is at the top of the table and what happens is the x-ray comes from below the patient and gets scattered from the patient and coming towards the operator so actually it's the legs get the higher dose during any sort of x-ray guided procedure. Sometimes we're forgetting importance of shielding the legs 'cause we think the legs, whatever the muscles, the bones, they're fine. But as the study shows, it's not just the muscles and the bones there but the whole circulation blood gets exposed to x-ray in the lower extremity circulation and that can translate to many other potentially adverse events.

Dr Carolyn Lam: Manos, I love that you manage both these papers. What important messages for increase in risk awareness. This was really very, very well accomplished by both these papers. As well by the editorial that you asked for and that was so well written by Dr. Charles Chambers on both these papers. But beyond risk awareness, what I really love is what you brought up just a while earlier about risk reduction and methods that we can take, for example, in the second paper, by Dr. Modoari and colleagues about shielding the legs. What are the implications for example, wearing a helmet or shielding the head for interventional cardiologists? What do you think?

Dr Manos Brilakis: These are very, very good points. The reality is for the head there have been a couple studied that looked at shielding with lead caps or there's some lead free caps that can be worn and also there are radiation protective glasses. However, what was interesting, there was a paper earlier last year that showed that because the radiation actually comes from below the operator that wearing those helmets, although it seems appealing, it is simple to do obviously, it actually did not significantly reduce the dose to the brain and it only partially reduced the dose to the eyes. Though shielding is useful but may not be as good as we think it is.

In my mind, the starting point of all this is the basics of radiation safety which again, sound very simple and we learn about them in the beginning of training, unfortunately what happen is people tend to forget them as time goes by. These are things like don't step on the x-ray pedal unless you need to look at the pictures and that's very common done. People just have this heavy foot syndrome. They keep on x-raying when they don't need to. There's also the important things having the patient as high as possible and the detector as close to the patient so there is not as much distance for the x-ray to travel. Things like using low, not very steep angles so there is not as much radiation because they have to go through less amount of tissue. And there's some technologies actually coming along there's some technologies that focus the radiation beam only specific areas. And cut the overall dose. And there are x-ray machines that also can have much less radiation overall for the patient and the operator. As you said, having good shielding habits is very important.

Dr Carolyn Lam: Yeah, that's exactly it. That risk awareness should lead to action. I'm just curious, who do you think should primarily take hold of these risk reduction and safety procedures and the enforcement and so on? Us as a community, but what do you think of the role of things like professional societies, quality improvement programs, FDA even?

Dr Manos Brilakis: It's a great point. What we hear here Maria's comments on this as well. But my feeling is absolutely societies are very important for leading these efforts and they do have actually guidelines. There's procedural guidelines for radiation protection. But the end of the day it's the individuals themselves, the operators, each and every one who is in charge of this in their care or his own cath lab and their procedures.

Dr Maria Andreassi: I agree. We all of our findings can contribute to the increase of cross cultural assessment in cath lab and by promoting the diffusion but not the reduction technologies whereas diligent about your protection habits. Moreover it is important to let the design, the relationship between occupational radiation exposure, clinical risk and there are very important future studies studying larger population. We should focus on the molecular epidemiology studies by using biomarkers and this will be clinical and points as early predictors of a clinical event. Because this information is a model likely to better define the risk of radiation use disease at low doses as a comparative tool, the classical epidemiological approach that require a very large sample sizes spread over [inaudible 00:20:51].

Now it's time where largest studies involving scientific societies at an international level. Possible breaking the additional exposure in already recruited the Roth case. And by combining the conventional epidemiology, and the molecular studies and the expected results to better define the clinical risk as a good lesson to implement a more effective protection program. And better as the surveillance at the individual level.

Dr Carolyn Lam: That is wonderful. And thank you, this truly is an international call, isn't it? Another thing that we should keep in mind that all measures that we use to protect our patient from receiving excessive radiation is likely to help us as well as cardiologists.

Thank you so much, both of you, for joining me today on this podcast. What an important message and I'm sure that our listeners will agree. Thank you listeners for joining us. Tune in again next week.

Circulation December 12, 2017

11 december 2017 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke-National University of Singapore. Our feature discussion today centers on patients with acute stroke due to large vessel occlusion, and asks the question, "Does interhospital transfer prior to thrombectomy relate to delayed treatment and worse outcomes?" Well, stay tuned for more right after these summaries.

Our first original paper this week tells us that cardio protection is alive, and mitochondrial cardiomyocyte calcium-activated potassium channels of the BK type may be a promising target. In this study from first author Dr. Frankenreiter, corresponding author Dr. Lukowski, from University of Tuebingen in Germany, the authors used a combination of transgenic, pharmacologic and electrophysiological approaches to show that mice with a cardiomyocyte-specific knockout of BK channels had larger infarct size after 30 minutes of coronary occlusion, and 120 minutes of reperfusion, and were less protected by ischemic pre- and post-conditioning maneuvers, such as guanylate cyclase stimulators or activators and phosphodiesterase-5 inhibitors.

In a chronic infarct model, mice with cardiomyocyte-specific knockout of BK channels had more fibrosis and lower left ventricular function. Mechanistically, the activation of BK channels in the inner mitochondrial membrane by cyclic GMP and protein kinase G was identified by patch clamping, and resulted in reduced formation of reactive oxygen species and activation of cardioprotective signaling. In summary, deficiency of BK channels in cardiomyocyte mitochondria rendered the heart highly vulnerable to ischemic and reperfusion injury, whereas the beneficial effects of cardioprotective agents known to target the nitric oxide cyclic GMP pathway required these cardiomyocyte BK channels. This thus establishes these cardiomyocyte mitochondrial BK channels as a promising target for limiting acute cardiac damage and adverse long-term events following myocardial infarction.

The next study suggests that integration of maximal myocardial blood flow and coronary flow reserve, termed coronary flow capacity, may be helpful in predicting cardiovascular mortality in patients with stable coronary artery disease. First author Dr. Gupta, corresponding author Dr. Di Carli, and colleagues from Brigham and Women's Hospital, quantify myocardial blood flow and coronary flow reserve in more than 4,000 consecutive patients referred for myocardial perfusion PET scans from 2006 to 2013.

Maximal myocardial blood flow of less than 1.8 mLs per gram per minute, and coronary flow reserve of less than two, were considered impaired. Four patient groups were then identified based on the concordant or discordant impairment of maximal myocardial blood flow, or its coronary flow reserve. The authors found that in patients with known or suspected coronary artery disease, impaired coronary flow reserve with preserved maximal myocardial blood flow identifies patients at an increased risk of cardiovascular mortality, despite a lack of myocardial ischemia. Patients who may be targeted for initiation or intensification of lifestyle preventive therapies for cardiovascular risk reduction. Conversely, preserved coronary flow reserve, even in the absence of impaired myocardial blood flow, identifies patients at low risk, in whom the need for revascularization should be reevaluated.

The next study provides insights into cardiac regeneration, particularly with regards to using resident cardiac progenitor cells expressing the tyrosine kinase receptor c-Kit, which is being tested in clinical trials. In this study from first authors Dr. Chen and Zhu, corresponding authors Dr. van Berlo from University of Minnesota and colleagues, the authors used single-cell sequencing and genetic lineage tracing to show that there was innate heterogeneity within these c-Kit positive cardiac cells, where some have either endothelial or mesenchymal identity. Cardiac pressure overload resulted in a modest increase in c-Kit derived cardiomyocytes, with significant increases in the number of endothelial cells and fibroblasts. On the other hand, doxorubicin-induced acute cardio toxicity did not increase c-Kit derived endothelial cell fates, but instead induced cardiomyocyte differentiation.

Although the overall rate of cardiomyocyte formation from c-Kit positive cells was below clinically-relevant levels, the authors further showed an important role for p53 in the differentiation of c-Kit positive cells to cardiomyocytes. Thus, this paper shows that different pathologic stimuli induced different cell fates in c-Kit positive target cells. These are novel findings that could aid in the development of strategies to preferentially regenerate cardiomyocytes.

Since December 2014, a series of pivotal trials have shown that endovascular thrombectomy was highly effective in acute stroke management, prompting calls for reorganization of stroke systems of care. But how have these trials influenced the frequency of endovascular thrombectomy in clinical practice? Well, the last original paper in this week's journal tells us how. First and corresponding author, Dr. Smith from University of Calgary in Alberta, Canada, and colleagues, used data from the Get With The Guidelines stroke program to determine how the frequency of endovascular thrombectomy has changed in U.S. practice. They analyzed prospectively-collected data from a cohort of more than two million ischemic stroke patients, admitted to more than 2,000 participating hospitals between 2003 and the third quarter of 2016.

The authors found that the use of endovascular thrombectomy for acute ischemic stroke accelerated sharply after the publication of pivotal randomized control trials beginning in December 2014. The endovascular thrombectomy case volume doubled at hospitals providing therapy. In the third quarter of 2016, endovascular thrombectomy was provided to 3.3% of all ischemic stroke patients. This represented 15.1% of all patients who were potentially eligible for endovascular thrombectomy based on stroke duration and severity. In summary, endovascular thrombectomy use is increasing rapidly, however there are still opportunities to treat more patients. Reorganizing stroke systems to route patients to adequately resourced endovascular thrombectomy-capable hospitals might increase treatment of eligible patients, improve outcomes, and reduce disparities.

Coming right up, we will be discussing even more about endovascular thrombectomy in acute stroke management. Just hang on, our feature discussion is coming right up.

Endovascular treatment with mechanical thrombectomy is beneficial for acute stroke patients suffering a large vessel occlusion. And that is in the guidelines, however we also know that treatment efficacy is highly time-dependent. And so, will interhospital transfer to an endovascular-capable center help in cases of acute large vessel stroke? Well, today's feature paper really helps to present novel data to answer that question. And it is from the STRATIS study. I'm so delighted to have with us the first and corresponding author, Dr. Michael Froehler from Vanderbilt University Medical Center, who will tell us about his findings, as well as Dr. Graeme Hankey, associate editor from University of Western Australia, joining us today. Welcome, gentlemen.

Dr. Michael Froehler: Hello Carolyn.

Dr. Graeme Hankey: Thank you Carolyn.

Dr. Carolyn Lam: Thanks for making the time. Mike, tell us about the STRATIS study. What inspired it, what you found.

Dr. Michael Froehler: Well, the STRATIS study was actually a large registry of the use of the Solitaire device for large vessel occlusion. Those results, the primary results, were published separately. But what we did in this study is look at one key aspect of the system of care for stroke delivery, in terms of its effect on time to treatment and patient outcomes.

And so in short, what we found is that patients that are transferred from one hospital to another for mechanical thrombectomy take longer to receive treatment, and do worse in terms of functional outcome, compared to the patients that present directly to that thrombectomy center.

Dr. Carolyn Lam: Wow. Could you put some numbers to that?

Dr. Michael Froehler: Well, so we looked at 984 patients, almost a thousand patients. And what we found was that the time from stroke onset to revascularization, until the time the vessel was actually opened, was 202 minutes on average, for patients that presented directly to the thrombectomy center. Compared to over 311 minutes for patients that were transferred from one hospital to another. So that's a difference, on average, of over 100 minutes.

Dr. Carolyn Lam: And I really was impressed with this other analysis you did. So I was wondering if you could share, where you did a hypothetical bypass modeling. Could you tell us about that? Because I thought that was really practical with a feasible message as well.

Dr. Michael Froehler: I'm excited about that, and I should also share with you that we're working on a more in-depth bypass analysis, to really understand the implications of going to one center directly versus another. But the model that is built in to this publication is really designed to answer one or two questions. And the first is, how much time would we save if we went directly to the thrombectomy-capable center, compared to what actually happened? Meaning the patient was taken to a regional hospital and then subsequently transferred to the thrombectomy-capable center. And this was basically an ideal scenario.

So if they were taken to one hospital and then transferred to another, we simply calculated what the maximum driving time from the starting position to the thrombectomy-capable center would be. And that did rest on the assumption that you actually had to drive past the first hospital. We didn't take any shortcuts in terms of the driving, and probably that small amount of driving time is actually shorter than the number that we found in our calculation.

So the first question was, how much time would we save with that bypass? And the second question was, what kind of impact would that have on IV-tPA? Because, as a lot of us are thinking right now, with strong evidence in support of endovascular therapy for large vessel occlusion, if necessary how should we prioritize getting to endovascular treatment versus the standard therapy that we've known for 20 years, which is IV-tPA? And if you've got a choice, which one is more important?

I don't know the answer to that question, but to try and help lead up to it, we did this hypothetical bypass analysis to look at the impact of bypass, driving directly to the thrombectomy center, the impact of that on the time to delivery of IV-tPA. And so that was really the second question that we asked with this hypothetical bypass analysis.

Dr. Carolyn Lam: Yeah. I love that analysis, because I agree with you, it's a very, very practical question, and it's the way we clinicians think, right? So, tell us, what's the bottom line?

Dr. Michael Froehler: So, the bottom line is, you're gonna save about an hour and a half if you bypass the regional hospital and go directly to the thrombectomy-capable center. On average, you're gonna get to the ultimate treatment center 91 minutes sooner, compared to the transferred group. Contrast that 91-minute time savings with a delay of IV-tPA delivery of 12 minutes. So yes, tPA will be delivered a little bit later, but endovascular therapy will be delivered much sooner.

Now, that solution is probably not going to work everywhere, depending on your geography. So one of the other things we did within the hypothetical bypass analysis was limit that analysis only to patients who were transferred within a 20-mile radius. And that doesn't seem like a long distance, but actually there's a lot of patients in that group, that are still taken to the nearest hospital and then need to be transferred to another hospital that may be less than 20 miles away.

So if we looked at that group of patients, then thrombectomy is still performed an hour and a half earlier, in that analysis it was 94 minutes earlier, but IV-tPA was delayed by only seven minutes. So certainly, there is a large group of patients out there that are perhaps being taken to hospitals that are not necessary, it's not a necessary stop.

Dr. Carolyn Lam: Wow, Mike, this is really amazing results, it's starting to make me think of the old days of acute myocardial infarction treatment, when we were thinking of intravenous thrombolytics, comparison to primary PCI, an analogy and comparison that was also mentioned in the accompanying editorial that you invited. Graeme, would you like to share some of your thoughts on the implication of all this?

Dr. Graeme Hankey: Just to take a step back, of course this begins with a stroke occurring out in the field. And unlike acute coronary syndromes, where chest pain is the major symptom, there are many symptoms of stroke. And the first problem is trying to identify the patient who has actually had a stroke, and in particular, one of the 15% or so who's had a large vessel occlusion, who's amenable to large vessel mechanical thrombectomy. So in the field we have an issue with clinical triage, and trying to work out who's the one in six who really need endovascular therapy, and who are the five in six who perhaps don't.

And we're trying to develop clinical triage scales like the RACE scale to work out in the ambulance where someone should go. But we still haven't nailed that yet. Then you have scales that are very sensitive but not very specific, and have a high sort of false-positive rate. So then the question at the ambulance is, where does it go, to the hospital, the primary stroke center nearby, and give the patient the earliest opportunity to get tPA?

And that's the potential benefit of early transfer to a primary center, but tPA is not very effective in dissolving these big clots in large arteries. And so, of course the trials have shown a substantial benefit of endovascular therapy to remove the clots via thrombectomy. But those resources, they're only really limited to comprehensive stroke units, and that's what this paper was about. So the trade-off is early transfer to the primary center so you can get some tPA, versus delaying, as Michael has shown, by 1 1/2 to two hours on average, to get to a comprehensive center that can access the expertise of endovascular thrombectomy experts.

And this paper is really taking us forward in emphasizing again that time is brain, and we really don't want to delay. Perhaps there's a small trade-off in driving a little bit further, another 20 miles at the most perhaps, to get to a comprehensive center directly. And there may be some who are not shown to have a large vessel occlusion at that comprehensive stroke center, but the overall benefit is probably offset, the few who might miss out on tPA. And so this is a really important study, the largest registry of large vessel occlusion patients to observe and compare the outcomes after adjusting for all the different factors. And give us some clues, that perhaps we really need to be trying to focus on building our resources in comprehensive stroke centers, and also being able to more accurately identify those who are likely to benefit and go directly there.

Dr. Michael Froehler: I agree with everything Graeme said, and I would just amplify one thing that he said, that it does depend on distance, and those distances in turn depend on your own geography. We did an analysis of all our transferred patients and then limited it to those that were within a 20-mile radius. For Graeme in Western Australia, you know Graeme's mailbox is probably 20 miles away. And so there are huge distances in Western Australia to account for. And it may not be possible.

Dr. Carolyn Lam: Contrast that to me in Singapore. I think if I drive any bit more, and I'll be driving out of my country already.

Dr. Michael Froehler: I think that you make a great point though, Carolyn, that the solution that works for metro Singapore is not what's going to work for rural Western Australia. And we've seen this in New York City, for example. My colleagues at Mount Sinai are looking at different ways to deliver care across metro New York, which obviously is very different compared to myself in Nashville, Tennessee. So the right solution is not gonna be the same solution for everyone.

Dr. Graeme Hankey: And that's right Carolyn, because in rural places like out in Western Australia, we are learning now that another important message is to try and help upscale and reorganize our primary stroke centers, or just our medical centers out in the rural and remote areas. Because as Mike's paper shows, the delays once someone comes to a primary stroke center or a rural center, is about 30 minutes for diagnosis, about 30 minutes to arrange the transport, and about 30 minutes to actually do the transport.

So we need to once trying to develop comprehensive stroke units, also build up those peripheral hub and spoke centers to be more slick with their diagnosis, arrangement of transport, and transport times. And one of the important things I think is, we need our primary centers, when a stroke does come, to not just do a plain CT to exclude hemorrhage, but to do a CT angiogram at the time. And find out those who really do have an occlusion, rather than putting them all on the plane and sending them down, and quite a few of them don't actually have an occlusion by the time that they've got here. They haven't been fully investigated, it's just an extra five minutes to do the contrast CT angiogram at the time in the primary center if they're gonna go there.

Dr. Michael Froehler: I think the one other thing I should add, and this is just to reflect back on something Graeme said a minute ago, is that one of the differences we found that really came out of that bypass analysis is the impact on tPA was smaller than we expected. Because the door-to-needle times are actually much longer at the regional hospitals that are not thrombectomy-capable, compared to the thrombectomy centers themselves, that are not only obviously delivering mechanical thrombectomy, but are actually delivering IV-tPA much sooner in terms of door-to-needle times.

Dr. Carolyn Lam: So, room for improvement even for non-endovascular-capable centers, isn't it?

Dr. Michael Froehler: Right, I think it's another area where there's room for improvement.

Dr. Carolyn Lam: Please don't forget to tune in again next week.

Circulation December 5, 2017 Issue

4 december 2017 | 20 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. This week's journal features important information, that will aide identification of children with latent rheumatic heart disease, who are at highest risk of unfavorable outcomes. This important discussion is coming right up after these summaries.

The first original paper this week describes the largest study to date to examine payer approvals and rejections of PCSK9 inhibitor therapy, and describe the patient characteristics associated with successful prescribing. First author, Dr. Hess, corresponding author Dr. Yeh and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts, performed a retrospective descriptive cohort study utilizing nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The data set included over 220 million patients from all 50 states, and all pair types with more than 5,000 distinct health plans. PCSK9 inhibitor prescriptions were submitted for 51,422 patients in the pharmacy data set.

The authors found that among patients who were prescribed a PCSK9 inhibitor, 47% were approved for coverage by the payer. Variables that were associated with approval included age above 65 years, history of atherosclerotic cardiovascular disease, prescription by a cardiologist or a non-primary care provider, statin intolerance, longer statin duration, and non-commercial payers. Interestingly, higher LDL cholesterol levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates of 24 from 4% and Medicare had the highest at 60.9%. Thus, rates of approval for PCSK9 inhibitor therapy are low, even for patients who appear to meet labeled indications. While a combination of clinical characteristics increase the likelihood of approval, payer type is the most significant factor.

The next study identifies a novel mitochondrial localized protein that plays a role in cardiac dysfunction, remodeling, and heart failure. This protein is FUN14 domain-containing 1, or FUNDC1, a highly conserved outer mitochondrial membrane protein. In today's study, first author, Dr. Wu, co-corresponding authors, Dr. Xie and Zou from Georgia State University, and their colleagues, showed that in cardio myocytes, FUNDC1 bound to inositol 1, 4, 5-triphosphate type 2 receptor, to form mitochondria-associated endoplastic reticular membranes.

These, in turn, modulate a calcium release from endoplasmic reticulum into mitochondria and the cytosol. FUNDC1 deletion lowered the levels of calcium in both mitochondria and the cytosol. A reduction at intracellular calcium resulted in mitochondrial fusion, mitochondrial dysfunction, cardiac dysfunction, and heart failure. In summary, this study identifies FUNDC1 as a novel mitochondrial localized protein that plays a role in maintaining mitochondrial dynamics, and cardiac function, and may therefore be a therapeutic target in heart failure.

The next study takes a deep dive into the J-Curve phenomenon of systolic blood pressure by providing an experimental approach to an observational paradigm. First and corresponding author, Dr. Kalkman, from University of Amsterdam and colleagues assess the association between on-treatment systolic blood pressure levels, cardiovascular events, and all cause mortality in patients randomized to different systolic blood pressure targets in the pool database of the SPRINT-6 and ACCORD trials. For both the intensive blood pressure target of less than 120 millimeters mercury, and the conventional target of less than 140 millimeters of mercury, the authors found an identical shape of the J-curve was present with a [inaudible 00:04:44] for cardiovascular events and all cause mortality just below the systolic blood pressure target.

The advantage of the intensive treatment group persisted at any level of the difference between the intended target and the achieved blood pressure targets. As discussed in an accompanying editorial by Dr. Verdecchia from Hospital of Assisi in Italy, these data suggest that if two patients achieve identical low values of blood pressure during treatment, prognosis is expected to be better in the patient actually targeted to achieve low values. Conversely, the outcome might be worse in the patient randomized to a higher blood pressure target, because low values in this case possibly reflect masked or unmasked confounders linked to a poorer outcome.

Thus, physicians should not be reluctant in lowering blood pressure in their patients because of an expected detrimental effect of BP reduction on death or major cardiovascular events. Rather, they should carefully monitor the possible occurrence of other adverse effects linked to blood pressure lowering, such as syncope, renal impairment, or electrolyte disturbances. This study further suggests that the benefit or risk associated with intensive blood pressure lowering treatment can only be established via randomized clinical trials and should not be extrapolated from observational data.

The final study establishes a causal link between dysregulated Tryptophan metabolism and abdominal aortic aneurysm. In a series of elegant mouse experiments from first author, Dr. Wang, two corresponding authors, Dr. Liu] and Ding from Georgia State University in Atlanta, Georgia, the authors establish that 3-Hydroxyanthranilic acid or 3-HAA, a key Tryptophan catabolite of the Angiotensin II induced abdominal aortic aneurysm in vascular smooth muscle cells was indeed responsible for Angiotensin II induced abdominal aortic aneurysm in Vivo. 3-HAA activated nuclear factor kappa-B transcription factor, promoted matrix metallopeptidase 2 expression in vascular smooth muscle cells. Human abdominal aortic aneurysm samples had stronger staining with the antibody against 3-HAA, than those in the adjacent non-aneurysmal aortic sections of these samples.

The identification of 3-HAA in Angiotensin II triggered abdominal aortic aneurysm and in human patients with abdominal aortic aneurysms, suggests that Tryptophan derived metabolites may be a biomarker for abdominal aortic aneurysm diagnosis. Furthermore, agents that alter Tryptophan metabolism may have a therapeutic potential in preventing or treating abdominal aortic aneurysms. Well on that intriguing note, we're at the end of this week's summaries. Now, for our featured discussion.

Today's feature paper really reminds us that rheumatic heart disease remains the most common cardiovascular disease among the world's youth. These days, echocardiographic screening provides a promising tool for early detection. However, the utility of this tool really depends on knowing the natural history of screen detected rheumatic heart disease, so-called latent rheumatic heart disease. Now, that has remained clear until today's paper. I'm so pleased to have with us the first and corresponding author, Dr. Andrea Beaton, from Children's National Medical Center in Washington D.C., as well as Dr. Bongani Mayosi, Associate Editor from University of Cape Town, South Africa. Andrea, could you start by letting us know about your study and what you found?

Dr. Andrea Beaton: As you mentioned, over the last decade or so it's become clear that in addition to the substantial burden of clinical rheumatic heart disease that we see around the world in low and middle income countries, there's also an even larger burden of latent rheumatic heart disease or early rheumatic heart disease that we can see on echo. This brings up the question if echo screening might represent a very powerful tool for rheumatic heart disease control, but we can't move forward with that discussion until we understand the rate of progression of children who are found to have echo detected rheumatic heart disease, and if we can do something to intervene to prevent progression in that population.

That something is likely penicillin, which is known to prevent progression in clinical rheumatic heart disease. To start to address that question, we followed a large cohort of children who had been diagnosed with echo detected rheumatic heart disease through school-based screening in different areas of Uganda and had collected about 227 cases of children with latent rheumatic heart disease who had been in clinical followup between two and a half and almost six years.

Dr. Carolyn Lam: Great. Could you tell us what you found about the progression and risk factors perhaps of progression, which I think are most significant?

Dr. Andrea Beaton: Right, so this is the largest natural history cohort of children with latent rheumatic heart disease to date and four major findings emerged from our study. The first is that we find a lot of echo detected rheumatic heart disease in low income settings that is more advanced. What we found is that children, even if this is their first time of diagnosis at echo screening, if they had moderate to severe rheumatic heart disease on screening, if they had poor outcomes even if over a very short time period. In our study, children with moderate to severe disease, only 10% of those children improved over the study period and 10% had died after only two to five years of followup.

We also saw that kids with mild, but definite rheumatic heart disease, which is more criteria for rheumatic heart disease than borderline, showed worse outcomes. Although, both children with mild definite and borderline disease had substantial risk of progression. 25% progressed in the mild definite group and 10% in the borderline rheumatic heart disease group. That tells us that even with very minor changes on echo screening, there is substantial risk of progression to more severe rheumatic heart disease, because we had a larger cohort using a multi-variant model.

We also found that there were features of rheumatic heart disease that put children at higher risk of progression. In our cohort, if children had aortic insufficiency at the time of screening, or some specific morphological changes, or changes in the mitral valve at time of screening, then they had higher risk of progression. While older age at time of screening showed a protective effect against progression.

Dr. Carolyn Lam: Wow. Andrea, congratulations on this remarkable study and you've highlighted so many important public health messages just in this one study. Bongani, what do you think was the most important or significant finding?

Dr. Bongani Mayosi: The most important finding is the reflection of the progression even in the mild and borderline cases. I think there has been an understanding that the definite cases do have a higher rate of progression and on top of that, I think showing the fact that there are some predictors that can be detected on echo is also very useful. Those with more advanced disease categories, those with younger age, as well as those with morphological valve abnormalities, I think those are very, very valuable points. Of course, the other point that is not all here is the fact that the majority of the initial progression appears to occur early and this is brought out in this study because of the serial echos that were done, which is again, another very valuable and a unique aspect of the study.

Previous studies have only done an echo at the time of diagnosis and perhaps an echo at the end of the followup period. I think that these features really make this study a valuable one. There is one question though that I wanted to put to Andrea, the issue of auscultation is one that we realized very early was not very useful for screening patients with latent rheumatic heart disease. We missed too many. I'd like to ask you now, once we've identified patients with latent disease, do you think auscultation of those patients could in fact identify the ones with clinical disease? Presumably, the more severe aortic regurgitation, mitral regurgitation, may be audible using a stethoscope? In other words, now shifting the role of the stethoscope not so much for diagnosis, but for risk stratification. I just want to know if you looked at this issue at all in this particular cohort?

Dr. Andrea Beaton: That's a really good question, Professor. We did not specifically look at the role of auscultation in this cohort. Although, it stands to reason that children with moderate to severe rheumatic heart disease, which by our definitions meant at least moderate to severe regurgitation at one of the valves, or presence of mitral stenosis would be audible. In that way, I think separating out children with moderate to severe disease, versus children with mild definite and borderline disease, would be quite possible and reasonable by auscultation.

My worry with the use of auscultation is I don't think it would separate out well children with mild definite disease, who by definition could have no more than mild regurgitation at any one valve, from children with borderline disease. Whether that distinction is important, I think still remains to be understood, but it would not be a very sensitive way to follow children until they had progressed to the point of having much more significant disease. I think echo still remains incredibly sensitive compared to auscultation for minor progressions, which to be clear, were included here as counting as progression of disease, even minor changes on echocardiographic evaluation.

Dr. Carolyn Lam: I have a question along the same lines Andrea, what kind of expertise was required for these echocardiographic screening procedures, both of the acquisition and then the interpretation? I do notice that you had a trained pediatric cardiologist with expertise in rheumatic heart disease who actually re-reported some of the echos. Do you think this is needed? What do you think about that?

Dr. Andrea Beaton: This is a complicated question, but a good one. A lot of the research that we've done outside of this paper has been looking at the ability to task shift echo screening, so to have non-physicians, not experts conducting echo screening. What we found across the board, as well as other groups around the world have found, is that you can train non-experts in a relatively short period of time to both screen and diagnose, at least on a screening basis, the presence of absence of rheumatic heart disease. For the purposes of this study, we're using very precise and very detailed diagnosis. According to the World Heart Federation criteria, which do really require experts to interpret.

Dr. Bongani Mayosi: The other issue, Andrea, which you highlight in the paper is the whole issue of the definition of progression, and regression, and the fact that there isn't consensus in the field about how we handle that, which results in papers not being comparable among each other. What do you suggest is the way of taking this forward so that we can build a consensus and a way of actually following up this patients that will be comparable between studies?

Dr. Andrea Beaton: That's a really important question and something we struggled with while we were writing this paper. You'll note in our paper that we reported it in two different ways because we couldn't come to a consensus and we thought both had some legitimate importance. Most of the papers in this field have reported the groups as progression and as stable lumped together, versus regression or improvement of disease. We felt the most important endpoint and something we had the numbers to power, was progression by itself. How many children were getting worse over the study period? In one sense, we powered it progression, versus stable plus regression, trying to dichotomize it still.

Then on the other hand, we thought that it was important if you had mild definite disease, even if you remained stable and mildly definite, and so we reported differently on the second outcomes based on if you had definite disease where we grouped progression and stable together, versus if you had borderline where we only counted true progression as a change for the worse. I don't have the perfect answer of how this should be reported. Although, I think the more granular we can be as we report these studies going forward, the more we can separate out the data that is reported to make it comparable. A lot of the previous papers, I think, lack the granularity needed to compare in different ways.

Dr. Carolyn Lam: We're coming to the end of our time, so may I just wrap up by asking Andrea, what do you think are the next steps?

Dr. Andrea Beaton: That's a good question and something I feel strongly about. Another part of our paper showed that the other incredibly important outstanding question is if we can find these kids, can we change what happens to them over time, and does penicillin do that? Even with our large cohort of patients, we couldn't determine the effect of penicillin on progression or trajectory of these children over this time period. It's something that now that we have large numbers of children and still can't come to a conclusive response, I think warrants a randomized control trial to look at the effect of penicillin on children with echo detected rheumatic heart disease, because that's really what's going to drive the policy on if echo screening makes sense as a public health policy to reduce the global rheumatic heart disease burden.

Dr. Carolyn Lam: I'm sure listeners out there, you've appreciated this as much as I have. Tune in again next week.

Circulation November 28, 2017 Issue

27 november 2017 | 18 min

Our journal this week features novel data informing the choice between conscious sedation and general anesthesia for transcatheter aortic valve replacement. A very relevant discussion for those of us who see these patients. Stay tuned, that's coming right up after these summaries.

Subclinical hyperthyroidism is known to be associated with an increased risk of atrial fibrillation, but the association with thyroid function in the normal range or subclinical hypothyroidism is unclear. That is, until today's study, which shows us that variation in thyroid function within the normal range is associated with atrial fibrillation.

First author, Dr. Baumgartner, corresponding author, Dr. Rodondi and colleagues from University of Bern in Switzerland, conducted a systematic review and obtained individual participant data in more than 30,000 participants from 11 prospective cohort studies that measured thyroid function at baseline and assessed incident atrial fibrillation, which occurred in 8.6% of individuals.

They found that in youth thyroid individuals, there was a significant increase in the risk of atrial fibrillation with increasing free T4 levels within the reference range. Risks did not differ significantly by age and sex.

Conversely, there was no association between TSH levels within the reference range, or subclinical hypothyroidism and the risk of atrial fibrillation. Thus, free thyroxin levels might add to further assessment of atrial fibrillation risks. Further studies are needed to investigate whether these findings apply to thyroxine treated patients.

The next study provides insight into how exercise promotes metabolic remodeling in the heart. First author, Dr. Gibb, corresponding author, Dr. Hill and colleagues from University of Louisville, use radiometric, immunologic, metabolomic and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise.

They found that in the heart, glucose utilization via glycolysis was reduced during exercise and in the early recovery period after exercise. Low rates of myocardial glycolysis were sufficient to activate gene programs that instigate physiologic cardiac growth. Metabolic inflexibility of the heart, such as occurs in heart failure and diabetes, was sufficient to diminish mitochondrial function.

Phosphofructokinase mediated changes in metabolism appeared to regulate genes involved in processes critical for metabolic remodeling, transcription, cell division, differentiation, cell proliferation and contraction. Thus, this study provides important preclinical evidence, showing how exercise-induced changes in glucose metabolism may promote physiologic cardiac growth.

The next study addresses the question of whether antiarrhythmic drugs are safe and effective when non-shockable rhythms evolved to shockable rhythms during resuscitation for out of hospital cardiac arrests. In this study from first and corresponding author, Dr. Kudenchuk of University of Washington and his colleagues, patients who initially presented with non-shockable out of hospital cardiac arrests were randomized upon subsequently developing shock refractory VF or VT to receive amiodarone, lidocaine or placebo by paramedics.

The primary outcome was survival to hospital discharge, with secondary outcomes, including discharge functional status and adverse drug-related effects. The authors found that outcome from non-shockable turned shockable out of hospital cardiac arrest was poor, but not invariably fatal. Though not statistically significant, point estimates for survival showed a trend to greater survival after amiodarone or lidocaine than placebo without increased risk of adverse effects or disability. Together, these findings may signal a clinical benefit that invites further investigation.

The final study provides experimental data supporting the importance of a novel Cardiokine governing the local environment in infarcted hearts and determining the fate of implanted cells. This novel Cardiokine is C1q/tumor necrosis factor-related protein-9, or CTRP9, which is a novel pro survival Cardiokine that is significantly down regulated after myocardial infarction.

In today's study by co-first authors, Drs. Yan and Guo and co-corresponding authors Drs. Ma and Wang from Thomas Jefferson University in Philadelphia, mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells, CTRP9 or their combination. The authors found that administration of adipose-derived mesenchymal stem cells alone failed to exert significant cardio protection.

However, administration of these cells in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9, suggesting a synergistic effect. CTRP9 promoted adipose-derived mesenchymal stem cell proliferation, survival, migration and attenuated cardio myocyte cell death by signaling mechanisms that included binding with N-cadherin, activation of ERK, MMP9, and ERK-Nrf2 signaling and upregulation or secretion of antioxidative proteins.

In summary, these results suggest that CTRP9 is a Cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue. Well, that wraps it up for your summaries, now for our feature discussion.

Conscious sedation is very frequently used during transcatheter aortic valve replacement, or TAVR, but with limited evidence as to the safety and efficacy of this practice. Well, that is until this week's journal and this feature paper. We're so lucky to have with us the corresponding author, Dr. Jay Giri from Hospital of University of Pennsylvania, to discuss his novel findings, as well as Dr. Dharam Kumbhani, Associate Editor from UT Southwestern.

Jay, tell us your study findings and how this really helps us to characterize anesthesia choice and clinical outcomes of at least U.S. patients undergoing TAVR.

Dr. Jay Giri : We looked at 11,000 patients treated over a 15-month period in 2014 and 2015 with percutaneous transfemoral TAVR. Notably, this was a time period that was identified as the start of the era of conscious sedation for TAVR in the United States.

Also, this five quarter period that we looked at represented a time of relative technological stability where only two valve types, the Sapien XT and original Medtronic CoreValve were being used in America.

Looking at that 15-month period when conscious sedation was first being used in TAVR, we elected to compare those patients to a propensity matched group of patients who underwent TAVR by, what at that time was, the more traditional approach of general anesthesia.

Our primary outcome within hospital mortality, because we had complete followup for this outcome. We also looked at 30-day outcomes for which we had about 90% followup. What we discovered was actually an associated reduction in mortality, an absolute reduction of about 1% in the patients who were treated with conscious sedation.

We also noted that they had modest decreases in the hospital length of stay, as well as significant decreases in the rates of ICU length of stay and the rates of pressor or inotrope use during the procedure. Obviously, the most provocative of the findings was the fact that we seemed to discover, after propensity matching a slight improvement in in-hospital mortality that held true at 30 days, as well.

Dr. Carolyn Lam: Thank you, Jay. What important findings ... I mean, mainly because, we really didn't have much data, did we? About conscious sedation and TAVR before this. Now, it's observational data, and I suppose the question always becomes what about bias by indication? More well patients get selected for conscious sedation versus general anesthesia, perhaps? Or even the other way around. Could you elaborate a little bit on how you think that may have impacted results and the measures you took to look at that?

Dr. Jay Giri : I think it was something that we were highly aware of and I also have to give credit to Dr. Kumbhani and the editorial staff at circulation for pushing us on that issue of selection bias for the two procedures. The obvious concern here, when you saw that there was a potential mortality reduction with conscious sedation patients, was that perhaps the conscious sedation patients actually represented a healthier cohort to start with, or they were perhaps treated at centers that were more highly experienced and by operators that were more highly experienced with TAVR in general.

We tried to account for this in a number of different fashions. The first, as we mentioned, was with an inverse probability treatment weighted analysis that accounted for 51 co-variants that were balanced between the groups. Additionally, we did adjust for site characteristics and utilized a hierarchical method technique to take into account both the experience of sites and operators.

Finally and most importantly, we performed what's called a falsification end point analysis in a postdoc fashion to verify that it looked like other outcomes outside of things, like mortality, length of stay, things we would expect to be influenced by sedation type, ended up being equal between the two groups. Falsification end point analysis represents, essentially, a negative control. You're supposed to theorize for potential outcomes that you would think would not be influenced by your intervention. In this case, those outcomes we theorized were vascular complications, major bleeding and pacemaker implantation, which we theorized would not be influenced by sedation type. In fact, we discovered that those outcomes were similar after adjustment, even though they had some differences before adjustment.

Dr. Dharam Kumbhani: Jay, I want to congratulate you and your team on this paper. You guys really picked a very important topic to look at and then you jump ... as you outlined, you jumped through a lot of statistical hoops and try to really provide evidence for a field in which a randomized controlled trial is probably going to be just logistically probably hard to conduct, just given the sample size requirements, which also you've provided in your discussion.

I think all the metrics that you looked at as far as utilization of therapies and length of stay, things like that, I think many people believe that and you were the first one to systematically evaluate and show that.

As you alluded to, I think that mortality, and Carolyn mentioned that, as well. I think the mortality findings are very interesting. Again, it's always hard when you have observational data to really put a lot of stock into that and you guys, as you outline, looked at so many different ways of doing that.

Again, I guess, observational data are always inherently going to have that limitation, no matter what statistical rigor we put them through. They were definitely very thought-provoking and, as you outlined, it's definitely come at the right time as the field is exploding and more and more centers are getting facile at it.

The other thing that you mentioned, but which I want to make sure that people fully understand is that you also provided a very elegant analysis looking at site volumes, because traditionally the sites that are doing conscious sedation have done a number of TAVR's before and there is a very clear cumulative volume outcomes association, for TAVR.

By accounting for the totality of experience, so you adjusted for the cumulative volume that sites have been doing this, so these are not just the high volume, high throughput centers, which have a lot of experience doing 150, 200 TAVR's a year, that thereby have really good outcomes by virtue of being expert, both as operators and as sites, but rather potentially something that is related to conscious sedation aspect itself. You guys really stepped up and provided a very elegant analysis to try to dissociate the two issues here.

Dr. Carolyn Lam: Dharam, and you just provided a very elegant explanation of the thought processes that were going on with our editors about this paper. I join you in congratulating Jay. Just a question. This is the best available evidence now, what are we going to do about it? I mean, Dharam, you're an inventionist, what now?

Dr. Dharam Kumbhani: The issues were not so much related to efficacy, initially. The initial concerns were related to safety, and Jay's paper clearly addresses that. Then, in addition to that, it says, "Well, it's not just that it's a safe procedure, but it's also effective with potential patient level and hospital level benefits from having a robust conscious sedation program."

I guess the one question that I have about conscious sedation and, Jay, I would love to hear your thoughts on this, as well, is it is possible but it is usually not done, TEE's or transesophageal echos are typically not done when you're doing conscious sedation. It is possible, as I said. As you move towards lower risk patients, on the one hand, these would be ideal patients for conscious sedation because then it's almost like a day procedure, in some ways for them.

But on the other hand, the fidelity of being able to look for even small paravalvular leaks, things like that, may be harder with a transthoracic echo. I don't know, as we expand towards the oldest populations, whether we'll see a greater adoption of conscious sedation, or whether there'll be some scaling back.

Dr. Jay Giri : Two points on that. The first is, I totally agree that it's relatively unusual for a transesophageal echo to be performed in the setting of conscious sedation. There's no question, secondly that transesophageal echo allows for the most rigorous evaluation of paravalvular leaks.

It is striking, though, that the rates of paravalvular leaks, due to technological improvements to the valves, are significantly improving. Even since the time of our study two years ago, a new generation of valves is consistently coming out with leak rates in pretty well-conducted analyses that are in the low, single digit percentages for moderate leak or more.

Part of I think the move towards conscious sedation, even initially and especially as we go forward, is predicated on the fact of continuing technological improvements that essentially almost solve the leak problem.

I think it's true that there's always going to be a very small minority of patients that are stuck with concerns about paravalvular leak at the end of their TAVR procedure. For those who have moderate or greater leak, I think that the threshold for escalating care, even to intubation and TEE to evaluate that leak, I think should be relatively low in a lower risk population.

However, I think the point that you bring up about the potential harm of trace or trivial leaks, or mild leaks, which may not be perfectly interpreted with transthoracic echo and aortograms and [inaudible 00:16:41] assessments at the time of the valve placement. It's something we're going to have to keep a close eye on.

From a practical standpoint, I believe this train has left the station. Totally unscientific, but around the time they released the paper online. I just shot out a poll on Twitter and got about a couple of hundred responses from folks, what they're doing now.

Now, Twitter certainly, probably doesn't represent the average transcatheter valve operator in the world, but I was surprised to see that over 70% of the respondents favored a conscious sedation approach at this point in time, which obviously is much higher than what we saw in our paper from two years ago.

Dr. Carolyn Lam: Well, audience, I'm sure you enjoyed that. Thank you for joining us today. Don't forget to tune in again next week.

Circulation November 21, 2017 Issue

20 november 2017 | 18 min

Dr. Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week's journal features novel results from the NCDR IMPACT Registry that informs us on risk prediction in patients with congenital heart disease undergoing cardiac catheterization. We'll be taking a deep dive into this right after these summaries.

The first original paper provides pre-clinical data showing that delayed repolarization may underlie ventricular arrhythmias in heart failure with preserved ejection fraction or HFpEF. First author Dr. Cho, co-corresponding authors Dr. Marban, and Cingolani from Cedars-Sinai Heart Institute and their colleagues, induced HFpEF in Dahl salt-sensitive rats by feeding them a high-salt diet from seven weeks of age. They showed that susceptibility to ventricular arrhythmias was markedly increased in rats with HFpEF.

Underlying abnormalities included QTc prolongation, delayed repolarization from down-regulation of potassium currents, and multiple re-entry circuits during ventricular arrhythmias. These findings are consistent with the hypothesis that potassium current down-regulation may lead to abnormal repolarization in HFpEF, which in turn predisposes to ventricular arrhythmias and sudden cardiac death.

The next paper shows that genetic testing can help to identify patients with pulmonary veno-occlusive disease who were misclassified as pulmonary arterial hypertension. Now, heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II or BMPR2 are the commonest genetic cause of pulmonary arterial hypertension. Whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene or EIF2AK4 gene are described in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

In the current study, first author Dr. Hadinnapola, corresponding author Dr. Morrell, and colleagues from University of Cambridge performed whole genome sequencing on the DNA from 864 patients with pulmonary arterial hypertension, as well as 16 patients with pulmonary veno-occlusive disease all recruited to the NIHR BioResource – Rare Diseases study. They found that 1% of patients with a clinical diagnosis of pulmonary arterial hypertension actually carry the biallelic EIF2AK4 mutations. Patients who are diagnosed clinically with pulmonary arterial hypertension, but who had a transfer coefficient for carbon monoxide of less than 50% predicted and an age of diagnosis of less than 50 years were much more likely to carry these biallelic EIF2AK4 mutation. In fact, the diagnostic yield for genetic testing in this group was 53%.

Radiological assessment alone was unable to distinguish reliably between these patients and those with idiopathic pulmonary arterial hypertension. Importantly, these patients with biallelic EIF2AK4 mutations had a worst prognosis compared to other patients with pulmonary arterial hypertension. Thus in summary, younger patients diagnosed with idiopathic pulmonary arterial hypertension but with a low transfer coefficient for carbon monoxide, have a high frequency of biallelic EIF2AK4 mutations and should be reclassified as pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. They have a poor prognosis and genetic testing can therefore identify these misclassified patients allowing appropriate management and early referral for lung transplantation.

The next study identifies a novel molecular target for the treatment of pathological cardiac hypertrophy. This target is SIRT2 [inaudible 00:04:33] poorly characterized member of the Sirtuin family of proteins, which is a family of class III NAD-dependent deacetylases that regulate metabolism and age-related diseases including diabetes and cardiovascular diseases. In the current study, first authors Dr. Tang and Chen, corresponding authors Dr. Chen and Liu from the Chinese Academy of Medical Sciences in Peking Union Medical College used wild-type and Sirt2 knockout mice, and showed that SIRT2 protein levels and activity were reduced during pathological cardiac hypertrophy.

SIRT2 deficiency promoted aging and angiotensin II induced pathological cardiac hypertrophy, and blunted metformin-mediated cardioprotective effects. On the other hand, SIRT2 overexpression repressed pathological cardiac hypertrophy. The molecular pathway involved deacetylation of liver kinase B1 at lysine 48 by SIRT2 to activate AMP-activated protein kinase sickling, which prevented hypertrophy of cardiomyocytes. Thus, SIRT2 is a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.

The next study is the largest comparison of the prognostic value of coronary artery calcium with functional stress testing in patients with stable chest pain. In this study from first and corresponding author Dr. Budoff from Los Angeles Biomedical Research Institute and colleagues, authors looked at the PROMISE trial where patients with stable chest pain or dyspnea, and intermediate pre-test probability for obstructive coronary artery disease were randomized to functional testing or anatomic testing.

Their main finding was that these chest pain populations referred for testing had a low event rate and both tests had different strengths. Coronary artery calcium had a high sensitivity for future cardiovascular events whereas functional testing had a high specificity. The clinical implications are that a normal coronary artery calcium score has a very low event rate and perhaps maybe used to avoid further cardiac testing in a stable chest pain population. On the other hand, an abnormal functional test result including information on exercise and symptoms has a moderate prognostic value.

Of note, coronary CT angiography provided better prognostic and discriminatory power than either coronary artery calcium or functional testing. The implications of these important results are discussed in an accompanying editorial by Dr. David Newby from Edinburgh entitled, Can I Have My Cake and Eat It? On that intriguing note, we've come to the end of today's summaries, now for our feature discussion.

For today's feature discussion, we are talking about an increasingly important population that is pediatric and adult patients with congenital heart disease undergoing cardiac catheterization. A little bit out of my usual comfort zone, but then you see, I'm with two spectacular experts today, Dr. Gerard Martin from Children's National Health System in Washington DC, one of the authors of today's feature paper; and Dr. Gerald Greil, Associate Editor from UT Southwestern. Welcome gentlemen.

Dr. Gerard Martin: Thank you Carolyn.

Dr. Gerald Greil: Thank you Carol.

Dr. Carolyn Lam: Gerard, no that would be Dr. Martin. Enlighten people like me who don't think about this every day, why the importance of looking at cardiac catheterization, and adverse outcomes in this particular population?

Dr. Gerard Martin: Carolyn, that's because of the tremendous advances in medicine, and particularly medicine that's dealing with children with congenital heart defects. Cardiac catheterization was once purely a diagnostic study. Now, it's a less invasive definitive treatment option for many of our pediatric and adult patients with congenital heart defects. As you may or may not know, congenital heart defects are the most common birth defects that impact nearly one out of every hundred live births.

As I mentioned, we have these tremendous advances. As a result of that, there are now over a million children living with congenital heart defects. In the USA alone, improvements in care over the past 50 years, there are now more adults than children living with congenital heart defects.

Dr. Carolyn Lam: Wow. Now, I understand. I mean, cardiac catheterization not just meeting diagnostic but therapeutic, and such an important patient population. Tell us about your study?

Dr. Gerard Martin: As we said, cardiac catheterization is now replacing surgery for some of our defects. For some of the more complex defects, catheterization is providing treatments that make the surgery easier. Now in surgery, we've had registries for many years. These registries provided measurement of survival that allow comparison of programs, and we didn't have that ability with cardiac catheterization. The American College of Cardiology developed the IMPACT Registry. That was to solely provide measurements of the outcomes of catheterization procedures in the children and adults with congenital heart disease.

Now, one aspect of the quality of the program is your rate of adverse outcomes; but simply measuring the number of adverse outcomes does not provide enough discrimination to compare programs. I think you can probably imagine that adverse outcomes will increase based upon the complexity of the type of patients you see, or the types of procedures that you might be performing. What we wanted to do was to create a risk standardization tool for our population where we can measure variation and performance between programs. If we can do that, then we can learn from the best performers to improve all the others.

Dr. Carolyn Lam: That's beautifully put. Could you tell us what you found?

Dr. Gerard Martin: Sure. The IMPACT Registry began on about 2011 and has grown from 50 sites to 111 sites in 2017. That's the majority of the sites in the United States that perform cardiac catheterization on children. We have now over 115,000 procedures. What we wanted to do with this is to look at some of the early procedures that were included and to see how adverse events were occurring. When we created the registry though, we used data variables from a previous research study in Boston called the CHARM.

They created a tool to risk standardized outcomes during procedures. They did it by coming up with four categories of procedures, and some four markers of hemodynamic vulnerability. We tested their methodology with IMPACT, and it didn't really performed particularly well. In this study, what we did was to increase the number of risk categories. We took the nearly 200 types of procedures we do in the cath lab and divided them into six categories. We also increased the indicators of hemodynamic vulnerability from four to six.

Now, what I mean by hemodynamic vulnerability? What is the patient's oxygen level when they go into the procedure? What is their blood pressure when they're in the procedure? Do they have one ventricle, or do they have two ventricles? What is the resistance in the lung vessels? All these are critically important. Lastly, we looked at some baseline patient characteristics. In other words, was age important? Sex, genetic conditions, or other comorbid conditions like the level of mechanical support that the patients were on. Then we put all that into our model to see if we could come up with a risk score.

Dr. Carolyn Lam: Right. The final adjustment model? Which factors that they include in the end?

Dr. Gerard Martin: We did find that there are lot of adverse events that do occur. We found major adverse events occurring in about same 7% of our patients. Most common adverse events were bleeding, or rhythm disturbances that require some medicine, or cardioversion during the procedure, or death during the hospitalizations. We did find that these major events were more common in the youngest patients or neonates, children under a month of age, or in patients with genetic disorders, or single ventricle physiology, and also patients that went to the cath lab with their kidneys not working very well.

In the end, we did create a risk adjustment model that included the type of procedure that was done, the number of hemodynamic vulnerability indicators, and whether or not the patient had renal insufficiency, or single ventricle physiology, or coagulation, and we found really good discrimination. Our discrimination had a C-stat of 0.76 in the derivation cohort, and 0.75 in the validation cohort. The slope of the curve was excellent, so we really think we have something now that we can use as a tool.

Dr. Carolyn Lam: Gerald, you're a pediatric cardiologist. Could you give us your perspective on how important these results are?

Dr. Gerald Greil: I think it's the largest and the first study, which kinds of give us a calibration in our field how successful interventions are. How we can make centers better without finger pointing on specific centers, and how to advance the field as a whole? From that perspective, I'm quite excited that the group offered us to publish this paper in circulation. I was kind of asking a question to Dr. Martin because obviously, all essentials are closely monitored. There's obviously data publicly available. Do you think there's a risk that this way to monitor centers within the United States or probably worldwide, that it's potentially preventing innovation or risky procedures?

Dr. Gerard Martin: I think that, that's a good question. I think it's one thing that whenever we talk about transparency or public reporting, it's an argument against it. I think that having a model like this, actually levels the playing field. In other words, centers that are risk averse who aren't particularly innovative, you'll be able to look at those centers, see what type of patients they're doing and look at their adverse events for a low-risk population. Then, you can also look and see some other centers that are doing more complicated procedures, higher risk, and you can see what their adverse event rate is.

Certainly, this is only talking about the adverse events. This has to be put together with the outcome of the procedure. In other words, if you're trying to relieve an obstruction, did you relieve it? Did you meet the intended goal of the procedure? This is only half of the story. The other part of it is, did you get the intended goal of the procedure? When you put the two of them together, perhaps some of those centers that are risk averse have lower complications, but maybe their success rate is lower. This will be able to tell the public everything they know, and they'll be able to tell their providers what they need to know to get better.

Dr. Carolyn Lam: I have to agree. Your paper does highlight, I think. Gerard, just one other question. What do you think our next steps?

Dr. Gerard Martin: The next step is to test the data. We have a new version of IMPACT that has rolled out, version 2 that has new procedures in it. Now, we have to test the data and we actually have to look for variability. Can we see a variation between the programs? Then, once we see if there's variation, if we see there is best performers and those performers that could improve, a question then is how do we take from what the best performers are doing to try and lift those that need to improve up. That's going to be the true hard work for this registry.

Dr. Carolyn Lam: Thank you so much for publishing it with us. Thank you so much audience for listening with us today. Don't forget to tune in again next week.

Circulation November 14, 2017 Issue

13 november 2017 | 19 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and back-stage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center and Duke National University of Singapore.

What is the evidence we have for LDL-lowering therapy in primary prevention? For individuals with an LDL cholesterol above 190 mg/dL, well, you may think you know the answer, but today's featured discussion may surprise you like it did for me, and this is a must-listen in my opinion for those of us taking care of these patients. More soon right after these summaries.

How can we enhance the survival and therapeutic potential of human pluripotent stem cell-derived endothelial cells? Well, the first paper in today's journal tells us how. The first author Dr. Lee, corresponding doctor Dr. Yoon, from Emory University School of Medicine in Atlanta, Georgia, developed a novel, fully-defined, cell culture system to generate endothelial cells from human pluripotent stem cells. They not only showed that these endothelial cells had pro-angiogenic activities and exerted favorable therapeutic effects in repairing limb ischemia, but also showed that encapsulation of these cells in a biocompatible peptide amphiphile nanomatrix gel improved long-term survival of these endothelial cells in an ischemic environment and improved vessel-forming properties. This novel cell culture system and gel-mediated transplantation may serve as a novel platform for cell-based therapy.

The next study brings us one step closer to application of immunomodulatory therapies in pulmonary arterial hypertension. In the study, first author Dr. Saito, corresponding author Dr. Rabinovitch, and colleagues from Stanford University School of Medicine isolated lung immune complexes and pulmonary arterial hypertension target antigens from lung tissues from 16 patients with pulmonary arterial hypertension and 12 controls. SAM domain and HD1 domain-containing protein, which is an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from patients with pulmonary arterial hypertension. These immune complexes resulted from elevation in products of human endogenous retrovirus K. The human endogenous retrovirus K deoxyuridine triphosphate nucleotidohydrolase, or dUTPase, activated B cells, elevated cytokines and monocytes and pulmonary endothelial cells, and increased pulmonary arterial vulnerability to apoptosis, thus contributing to sustained inflammation, immune dysregulation, and progressive obliterative vascular remodeling. Furthermore, rats treated with the human endogenous retrovirus K dUTPase developed pulmonary hypertension. In summary, this study suggests that harnessing mechanisms that repress human endogenous retrovirus K expression and its sequelae could prevent and reverse pulmonary arterial hypertension.

The next study looked at the association of timing of coronary angiography with ischemic outcomes of non-STEMI who are at high risk with a Gray score of more than 140 in the TAO Trial. In this report from first author Dr. Deharo, corresponding author Dr. Steg, and colleagues from L'Hopital Bichat from Paris, France showed that in these high risk, non-STEMI patients, a very early invasive strategy of coronary angiography within the first 12 hours was associated with a lower risk of death in MI at 180 days compared to an early strategy of between 12 to 24 hours or a delayed strategy of between 24 and 72 hours. The bleeding risk was not different between patients managed with the very early, early, or delayed strategy. These observations deserve prospective confirmation in a randomized trial.

The next study provides contemporary mortality trends for STEMI and non-STEMI. In this paper from first author Dr. Puymirat, corresponding author Dr. Danchin, and colleagues from Hopital europeen Georges-Pompidou in Paris, France, the authors assess trends in the characteristics, treatments, and outcomes for EMI from five month-long registries conducted five years apart and spanning 1995 to 2015, including more than 14,000 patients admitted to cardiac intensive care units in metropolitan France. They observed major changes in the characteristics and management of both patients with STEMI and those with non-STEMI over the last 20 years. The mean age decreased in patients with STEMI and remained stable in patients with non-STEMI, whereas diabetes, obesity, and hypertension increased. At the acute stage, intended primary PCI increased from 12 to 76 percent in patients with STEMI. In patients with non-STEMI, PCI within 72 hours from admission increased from 9 to 60 percent. In parallel with these changes, six-month mortality consistently declined in patients with STEMI, whereas in patients with non-STEMI, six-month mortality reached a plateau after 2010. The authors concluded that future challenges will be to reduce pre-hospital mortality and to improve long-term survival after the acute myocardial infarction event.

That wraps it up for your summaries. Now for our feature discussion!

What evidence do we have from randomized trials supporting the benefit of LDL cholesterol lowering as primary prevention among patients with an LDL cholesterol above 190 mg/dL? You may be surprised to know that until today's journal, we had very little trial evidence supporting this. But I'm so pleased to have with us the corresponding author of our featured paper today, Dr. Kausik Ray from Imperial College, London, who's going tell us a bit more and discuss this very intriguing paper with our Editor for Digital Strategies, Dr. Amit Khera from UT Southwestern. Welcome, both.

Dr. Kausik Ray: Hi.

Dr. Amit Khera: Thanks for having us.

Dr. Carolyn Lam: Kaus, you are a familiar voice and so pleased to have you here. Please tell us, is this the first evidence we have from a randomized trial for primary prevention in those with LDL above 190? Tell us about it.

Dr. Kausik Ray: Yeah, it is. It really came about because we were interested in familial hypercholesterolemia and we used the level of 190 to talk about either primary hypercholesterolemia, which may have a genetic basis, or not. I kept hearing that there is no trial evidence, so you're not going to be able to ethically do a trial today despite the fact there's not much evidence, because most of us think that it's a bad thing to leave people on placebo in patients above 190, so I thought the only way to do this was to go historically to the WOSCOPS Study, which is, as you remember, 6,500 people, elevated LDL cholesterol. Interestingly, you go to WOSCOPS, the median LDL in that population is very close to 190. So, that gives a good starting point, thinking that we'll have at least half the population.

Now interestingly in WOSCOPS, although none of the patients had a history of myocardial infarction, a very small number of the 6,500, about 1,000 actually had evidence of some other vascular disease, so maybe a TIA, maybe angina, maybe some sort of ECG non-specific change of coronary disease. Today, you would say, well, actually, you've got to give these people a statin because there's evidence of vascular disease, PVD, et cetera. So we had to take those people out and that left us with 5,529. Once you break people down by LDLs above and below 190, you have 2,560. You could actually look at the randomized treatment effect of pravastatin, which was the statin chosen, over a five year period both above and below 190.

But interestingly, this was the first study and what we showed was that in this population, even with as little as 23% reduction in LDL cholesterol, over a five year period, you saw a statistically significant 27% reduction in CHD and if you take the usual 3 point MACE of current clinical trials, there was a 25% reduction, already statistically significant. We also had the ability to link data over 20 years. Remember, after the five year randomized treatment period, it becomes observational in nature, but what it showed was that when you gave nearly 40% in each arm statins and you followed people up this legacy effect, over a 20 year period, the people with the LDL above 190, that translated into this 28% reduction in CHD death. It translated into a 25% reduction in CV death, and actually an 18% reduction in all-cause mortality, which you didn't see in the population with slightly lower LDL cholesterol.

This is the best evidence we're ever going to get, really, and answer the question about what should we do in this patient population. Should we treat with lipid-lowering therapy? The answer, unequivocally, is yes, and the longer you treat, the more likely you are to see survival benefits.

Dr. Carolyn Lam: Oh, my goodness! I just love his paper. I have to humbly admit. I mean, it's in the guidelines already that we should treat these individuals with LDL above 190, and it really made me think how I'd taken for granted that there would be a whole body of evidence behind it from randomized trials, and you are right! This is the first, and likely going to be the last we're going to get, because we can't randomize them. So, congratulations. What you said just now, I can already hear myself playing this podcast to my patients. May I just ask, are there other remaining questions to answer, and then what do you also say to those that say, well what are the harms? How do you balance that with any potential harms?

Dr. Kausik Ray: In this particular study, given there was overall safety data observed in the WOSCOPS Trial population and in their extended follow-up in the overall 6,500 person cohort, we didn't go on and look at that. There was no evidence of harm in the extended follow-up of 6.500 people, so we didn't see the potential added gain in specifically looking for that. The main question we wanted to answer, because people had always pulled primary and secondary prevention patients together, and in fact, your best evidence is actually from CTT, pooling of primary and secondary prevention patients where they break the data down by an upper limit of about 175. With patients above 175, they don't specifically answer that question. So, to answer your question, we didn't look at that in the overall WOSCOPS Trial population. There was no signal for harm that was noticed. Even things like glucose elevation, if you remember in WOSCOPS, tended to be a little bit lower.

Dr. Amit Khera: Let me comment on a few things about this paper. First, I want to congratulate Dr. Ray and his colleagues. I was a history major and I think this is a great use of a historical tool. At this point, I think we can talk about WOSCOPS. It's 22 years old. It is part of the medical history and a very seminal article. I think they got creative because, as he mentioned. We have guidelines that support this treatment, but this is almost an unanswerable question, whether you say it's from ethics, or from equipoise, it was essentially unanswerable. So, they had to go back and take this historical study where practice patterns were different, to be able to look at this question. It was pointed out, there's pretty clear evidence in here and I think if you look at that during the five-year study period of the randomized period, pretty clear evidence that treating participants with LDLs above 190 without vascular disease certainly lowers cardiovascular disease events.

One of the best things about working on the editorial board is being able to work closely with authors, and I have to also thank Dr. Ray and his colleagues for being so gracious in working with us closely in some modifications as this went along. We hope, and I hope he feels this way, too, that at the end of the day, the product ends up being even better than where we started. That's our goal is to really help and work with authors in that way and they were incredibly responsive. The two things I thought they did really well that were insightful to the US guidelines and beyond. One is they also restricted to the group without diabetes, without ASCVD less than 7.5%, and some other parameters to really hone down on what we have in the current US guidelines and still the finding was consistent that the statin therapy benefited that group.

The other part was just acknowledging that the legacy part, the long-term effect, is really valuable. They published heavily in this area, but at that point, it becomes an observational component. It's not part of the randomized period. The reason that adds value, if you look at our guidelines above the age of 21, an LDL above 190 can be treated with a statin, there would be less controversy if your LDL was 200 and you're 55, but if you're 22 or 23, I think there may be more angst. That's where the long-term data is important, because we're not looking necessarily always at 10 years, but we're looking at 20 or 30 or 40 or 50 years. I think this does at least shed some light. I appreciate the study population was older, but a least it helps us look at maybe some of the long-term benefits.

If I may, Carolyn, I would love to ask Dr. Ray a question. Kaus, when you guys did this, the group with the LDL less than 190 had essentially similar benefit. The p-interaction was no. I think we have to acknowledge that the LDLs were higher in that group than what would seem because the lowest level was 155. Is it above 190, or should it be above 160 where we treat patients with statins?

Dr. Kausik Ray: Yes, and I really want to thank the editors, because there were certain things that you pushed us with analyses and I think that you could make the case that if you have a LDL cholesterol above 155, over a five-year randomized treatment period, there was a significant reduction in CHD and MACE as well. So, you could make that point that actually the cutoff should perhaps be pulled down even further to about 155. What's interesting is, these groups, when you broke them down, age was identical, BMI was identical, blood pressure, and everything else. The only thing that was different, really, was the LDL cholesterol, which impacted on total cholesterol. TGs, HDLs were absolutely identical. I think you could probably make the case.

I think the one thing that we didn't see, although it's observational in those with slightly lower LDL cholesterols, is that over the 25 year period, they seem to get slightly less mortality benefits. Now, that could be a chance finding, because it's observational. We don't really know the implications of that, but I think over a five-year period, this is the best evidence you're going to get for primary prevention, right?

Dr. Amit Khera: Agreed. The US guidelines do say above 160, it's a point of consideration. It can be a factor to consider as we think about treatment, so perhaps this helps bolster that point as well.

Dr. Kausik Ray: It's not just the American guidelines. In the European guidelines, when they use score, if you look at LDL cholesterol levels, the European case fatality 10 year risk is 2.5%, which is equivalent roughly to 7.5% fatal and non-fatal MI in the pooled cohort equation. There they still have diet and lifestyle, but it says, "Consider pharmacological," and one of the things I thought was really interesting is if you did a 10 year risk calculation in this group, 67% of the population with an LDL above 190, you would have said the predicted 10-year risk was below 7.5%, but the 10-year observed risk was double that. It was 15%. If you did the same thing for the group between 155 and 190, your ten-year risk predicted would be in most of these people, you would have said about 90% actually are less than 7.5%, so you wouldn't have given them a statin. But, their observed event rates in the placebo group was about 11%.

So, I think that it tells you if you have an isolated elevated cholesterol above 155, you're probably going to be underestimating risk if you're using global risk score, and perhaps a discussion with the patient about risks and benefits in the way that most of us try to do and citing data like this might encourage patients to actually start that therapy earlier, which most of us probably believe from genetic and legacy effect is probably beneficial. That's one of the other implications of this.

Dr. Amit Khera: This is why one has to read not just the abstract, but all the details, because there are so many kernels of interesting findings in this paper beyond just the highlights that we hit upon.

Dr. Carolyn Lam: Thank you both for just a marvelous discussion of an incredible paper that is really, really going to be extremely clinically relevant. We're so proud to be publishing this in Circulation this week.

Audience, you heard it right here. Don't forget to tune in again next week as well to Circulation on the Run for even more hot news.

Circulation November 7, 2017 Issue

6 november 2017 | 18 min

In just a moment, we will take a deep dive into the issue of age and its association with outcomes of primary prevention ICDs in patients with non-ischemic systolic heart failure.

Yes, a long-awaited discussion from the Danish trial. That, in just a moment. First, here's your summary of this week's Journal.

The first original paper provides evidence of a true association between disturbed genetic imprinting and Preeclampsia. This paper is from co-first authors, Dr. Zadora, and Dr. Singh, and co-corresponding authors, Dr. Izsvak, from the Max Delbrück Center for Molecular Medicine; Dr. Hurst, from the University of Bath; and Dr. Dechend, from the Experimental and Clinical Research Center of Berlin.

These authors performed an unbiased analysis of genome-wide molecular data on raw characterized patient material, from normal controls, and patients with Preeclampsia, and identified DLX-5 as an imprinted target gene, with novel placental function in Preeclampsia. Due to loss of imprinting, DLX5 was upregulated in 69% of placentas from Preeclampsia patients. Levels of DLX5 correlated with the classical Preeclampsia markers.

DLX5 was expressed in human, but not in urine trophoblast, underlying the known human specificity of Preeclampsia. Finally, DLX5-induced overexpression if trophoblasts faithfully modeled Preeclampsia in a cell culture system. In summary, this paper shows that disturbed imprinting is common, and may play a causal role in Preeclampsia.

The next study affirms that stenosis severity is better discriminated using coronary invasive physiologic indices, than using coronary angiographic assessment. First author, Dr. Lee, corresponding author Dr. Koo, colleagues of Seoul National University Hospital, studied 115 patients with left anterior descending artery stenosis, who underwent both ammonia positron emission tomography, or PET, an invasive physiologic measurement.

Myocardial blood flow measured using PET, and invasively measured coronary pressures, were used to calculate microvascular resistance, and stenosis resistance. They found that both fractional flow reserve, or FFR, and instantaneous weight free ratio, or IFR, decreased as angiographic stenosis severity, resistance, and pressure gradient increased, and hyperemic myocardial blood flow decreased.

When the presence of myocardial ischemia was defined by both low hyperemic myocardial blood flow, and low coronary flow reserve, the diagnostic accuracy of FFR and IFR did not differ, regardless of cutoff values for hyperemic myocardial blood flow, and CFR. However, at any given stratum of a given stenosis, physiologic classification of stenosis severity using FFR or IFR showed better discrimination of a unique relationship between absolute myocardial blood flow, and pressure gradient, than anatomic classification using angiographic percentage.

In summary, by demonstrating coronary physiologic responses to coronary stenosis, these authors showed that stenosis severity is better discriminated, using invasive physiologic indices, than using angiographic assessment.

The next paper identifies a previously unknown angiogenic growth factor that can be enhanced therapeutically to repair the heart after myocardial infarction. This novel growth factor is endoplasmic reticulum membrane complex, Subunit 10, or EMC10, which the authors previously identified by bioinformatic secretome analysis in bone marrow cells.

In the current paper, from co-first authors Dr. [Rabel 00:04:35], and [Krof Clengobill 00:04:37], and corresponding author Dr. Wollert, from Hanover Medical Center, and colleagues, the authors investigated the angiogenic potential of EMC10, and its mouse homologue, in cultured endo fetal cells and infarcted heart explants. They found that EMC10 and its mouse homologue signal a virus, small GTAPases; p21-activated kinase; and p38 mitogen-activated protein kinase, to promote endothelial cell migration.

In mice with acute myocardial infarction, bone marrow derived monocytes and macrophages produced EMC10 endogenously, to enhance infarct vascularization, tissue repair, and heart function. Furthermore, subcutaneous treatment with recombinant EMC10 for one week, after myocardial infarction, augmented infarct vascularization and repair, and led to a sustained improvement in heart function and survival.

The next study is the first prospective randomized trial of screening for atrial fibrillation, with a smartphone-based, single-lead, electrocardiographic system in 1,001 patients, aged 65 years and above, with a CHA2DS2-VASc score of two and above, and without a history of atrial fibrillation.

In this paper, from first and corresponding author Dr. Halcox, from Swansea University Medical School, in the United Kingdom, and colleagues, patients were randomized, either to biweekly electrocardiographic recordings with the iPhone device, or to routine over a 12-month period.

The smartphone-based electrocardiographic approach was at least three times more likely to identify incident atrial fibrillation, than routine care, and at a cost of just over $10,000 per case identified, and was judged to be a highly acceptable approach in this group of patients. These results support consideration of evaluation in an appropriately-powered, event-driven randomized trial, to confirm the clinical and cost effectiveness of such an approach to stroke prevention in atrial fibrillation.

Well, that wraps it up for your summaries. Now for our feature discussion. The Danish trial really created a huge splash last year, when it was reported that a primary prevention ICD in patients with non-ischemic systolic heart failure, may not actually reduce all cause mortality. Something that we had, perhaps, taken for granted, and in fact, entered our guidelines.

Now, however, there was a pre-specified subgroup analysis at the time, that suggested a possible age-dependent association, between ICD and mortality, in the Danish trial. This week, we are so pleased to be discussing an in-depth analysis of the association between age and outcomes in the Danish trial.

I'm so pleased to have the first author of today's featured paper, Dr. Marie Bayer Elming, of Copenhagen, Denmark, as well as Dr. Sana Al-Khatib, who's not only an associate editor of circulation, but also the author of an accompanying, and she is from Duke, Durham, North Carolina. Welcome, ladies!

Dr. Bayer Elming: Thank you. Happy to be here.

Dr. Sana Al-Khatib: Thank you so much.

Dr. Carolyn Lam: Sana, could you start by framing why this paper is so important, and why we've been looking forward in anticipation to these results?

Dr. Sana Al-Khatib: Absolutely. As you know, data on the outcomes of primary prevention ICDs in patients with non-ischemic cardiomyopathy started emerging in the early 2000s, or so. Then in 2005, the sudden cardiac deaths and heart failure trial was published, that included a large number of patients with non-ischemic cardiomyopathy, and absolutely showed survival benefits from primary prevention ICDs in those patients. Of course, there were also patients with ischemic cardiomyopathy.

But really, that trial formed the basis of the guidelines, recommendations, that have informed our practice for the last 12 years, that basically tell us that we should consider implanting a primary prevention ICD in patients with non-ischemic cardiomyopathy, who have an EF of 35% or less, who have Class II or III heart failure symptoms. As long as they are on optimal care at the end, they have a reasonable life expectancy.

So that's what's we've been doing for years, and then, the Danish trial was published this past year, that really called into question the prior findings, and the current practice. Because Danish, as you stated, showed no survival benefit with primary prevention ICDs, but there are many aspects about the trial that people need to pay attention to, to put the results in perspective.

The fact that 58% of patients in the trial, in those arms, received cardiac resynchronization therapy ... the fact that the trial required that patients have an elevated NTproBMB level, to be considered for enrollment ... that may have biased the results toward a higher risk of non-sudden cardiac deaths, so on, so forth.

I think what was really interesting, and caught people's attention, when the paper was published, was this subgroup analysis that showed that younger patients may benefit more than older patients. I think, many of us, Carolyn, were really awaiting the results of a more dedicated analysis, looking at age in Danish, and Dr. Elming and her colleagues did a great job looking at this very closely in their paper, and showed great results, and probably will let Dr. Elming share those results with us.

Dr. Carolyn Lam: Yes, absolutely, Sana. Actually, I just wanted to echo how surprised everyone was, and the immediate thing was, "Oh, my goodness. What do we do with the guidelines?" Maybe we should get back to that later, and Marie, please share with us, what did you do, and what did you find this time?

Dr. Bayer Elming: The reason why we did this study was that, in this main Danish trial, age was the only one of the 13 pre-specified subgroups that had a significant treatment by a subgroup interaction. This suggested that a younger patient might have a survival benefit from ICD ... the implication, even though the overall study was neutral. So we wanted to further investigate this relationship between age and effective ICD implantation.

What we did was to look at the relation between age and effective ICD, and we found that there was this linear relation, for each year of younger age, that was associated with a reduction, a 3% reduction in the hazard ratio, for the benefit of ICD.

Also, we did this selection impact curve, which is a bit technical, but what it does is to describe the expected survival for the population, on as a whole, for the different age cutoffs for ICD treatments.

So, if we take into account, both the patients receiving an ICD, and those who did not, we could see why we would get the highest survival for the population as a whole. What we found was that, when no one in the population received an ICD, around 70% would survive.

If everyone in the population received an ICD, only 72% would survive, but if we chose 70 years as the age cutoff ... so, patients younger than 70 years received an ICD, and patients older than 70 years did not receive an ICD, we got the highest survival for the population, and 75% would survive.

Dr. Carolyn Lam: Thank you, Marie. What important results. So, maybe, still consider ICDs for primary prevention ... in our non-ischemic systolic heart failure, patients were less than 70 years old. Is it as simple as that, Sana? You wrote a beautiful editorial. Tell us, what are the clinical implications?

Dr. Sana Al-Khatib: This is an important question. Danish was an important trial, but in my mind, it truly doesn't refute the role of primary prevention ICDs in patients with non-ischemic cardiomyopathy. As I mentioned earlier, the majority of patients enrolled in Danish received a CRT device. And so, you end up questioning, what does that actually mean, for those patients who are not eligible for cardiac resynchronization therapy?

So, I actually believed that, and as you know, Carolyn, and maybe Marie knows, as well, there have been several meta analyses that have been published, combining data on patients with non-ischemic cardiomyopathy only, and excluding patients with cardiac resynchronization therapy from Danish, that have actually now shown, consistently, a significant improvement in survival, with a primary prevention ICD ... including one that was done by our group.

So, no, I don't think that, based on the results, we should say, "No, we shouldn't be offering primary prevention ICDs to patients with non-ischemic cardiomyopathy," and this beautiful analysis that was done by Marie and her group actually shows that, at least for those patients who are 70 years of age and younger, I think we should absolutely continue to consider them for the therapy, and offer them the therapy, if they're appropriate candidates.

Then, of course, if the patients are older than 70,, and they meet criteria for cardiac resynchronization therapy, I think it will be important for us to be talking to the patients about ... is the RTD with a defibrillator, versus a CRTP only, with a pacemaker, and talking about the pros and cons, and everything else? But in those patients who are older than 70, who don't meet criteria for CRT, I think more research is needed, to really understand the role of primary prevention ICDs in those patients. We definitely need more data there.

Dr. Bayer Elming: I definitely agree that, of course, for the patients older than 70 years were not candidates for CRT treatment. These patients, we do not know very much about 'em, and this study that we did, do not answer that question. Based on the Danish study, and this further analysis of the age inspection, the guidelines in Denmark also state that patients younger than, we say, 68 years, because that was the age cutoff used in the '08 Danish trial, you should definitely think of giving patients with non-ischemic cardiomyopathy an ICD.

But for the older patients, it depends on a variety of co-factors, such as co-morbidity, or frailty, and it should be an individual assessment of the patient. So, I agree with you, Sana.

Dr. Carolyn Lam: That's wonderful. Hey, just one more question. Sana, I'd like you to put on your AE hat, now, and sort of think with me. In circulation, we don't ... well, we're careful about publishing subgroup analyses, so to speak, right, of results. You articulated, in your editorial, reasons why this, perhaps subgroup analysis, may be different from others. Could you elaborate on that a bit?

Dr. Bayer Elming: Yeah, and absolutely, that's a great question. As you pointed out, I mean, you really ... the conventional wisdom in clinical research is to be careful, interpreting subgroup analyses. I think there are some strengths in this particular analysis, as Marie stated: "Here's what we specified." The other thing is, I believe that Marie and her group then came, and did their very robust statistical methods, and really, probably most importantly, if you look at their findings, they actually really align well, and support their main conclusion.

For example, looking at the fact that older patients had the higher presence of co-morbidities, that they had a higher level of [Co-BMP 00:17:00], they had had a longer duration of heart failure ... I mean, all those things most likely had an impact on their mode of death, really making it more likely for those patients to succumb to non-sudden cardiac death. I think the whole story makes a lot of sense.

Dr. Bayer Elming: If I can elaborate a bit on this, I think one of the important findings from the study is that we show that mode of death varied according to age. So, the rates of sudden cardiac death were almost similar, between the younger and the older part of the population. But the rates of non-sudden death were almost twice as high in the older part of the population. This is a really good explanation why the ICD implantations have less impact in the older patients.

Dr. Carolyn Lam: Yeah, because ICDs would definitely not be expected to reduce non-sudden cardiac deaths. Really, really, well put. Oh, thank you so much, Marie. We're so proud to be publishing your beautiful paper, as well as your editorial, Sana, and thank you for this great conversation.

Well, listeners, I'm sure you enjoyed that as much as I did. Thank you for joining us this week, and don't forget to tune in next week.

Circulation October 31, 2017

30 oktober 2017 | 20 min

This week's journal is really special. It is the 2017 cardiovascular surgery-themed issue of "Circulation." To summarize this issue, I am so privileged to have the editors, Dr. Marc Ruel from University of Ottawa Heart Institute, as well as Dr. Timothy Gardner from Christiana Care Health System. Welcome gentleman.

Dr. Timothy Gardner: Hello.

Dr. Marc Ruel: Hi, Carolyn. Glad to be here.

Dr. Carolyn Lam: Thank you for another beautiful themed issue, Marc. I see that there are four general themes within this theme, if I may. The first of which are a collection of papers on coronary disease and coronary surgery. Could you maybe start by giving us an overview of that?

Dr. Marc Ruel: One of the main topics that have been looked at in the surgical-themed issue this year is coronary surgery. We all know well that 2016, 2017, the academic year was quite fertile in providing new information around coronary surgery, especially with the release of the ART trial had actually scientific sessions of the American Heart Association the last November with simultaneous publication.

Interestingly, the cardiovascular surgical-themed issue has several coronary papers and one that deals with essentially with graft failure, if you will. There's an in-depth review written by Mario Gaudino, who is well known and does fantastic work at Cornell, who essentially put a team together looking at several aspects of coronary graft failure. I guess we can say that these are looked in quite great depth, and they deal with several aspects of what would lead to a coronary bypass graft to fail.

First and foremost, Mario and the team look at the blood components. Then the artery and the native bed itself. Then they focus a lot on the conduit, not only the nature of the conduit being a venous versus arterial conduit, but also the way of storing the conduit prior to performing the bypass. Also, the technique that's used around the use of that conduit.

Finally, I'd say that the review culminates with the patient bioreactor, for lack of a better term, aspect. Endothelial dysfunction in the patient with diabetes, age, gender, hypertension, dyslipidemia, etc., all these things that do act as a significant substrate for the fate of the conduit vessel.

A very unique, I think, first-time, in-depth review that, certainly, the "Circulation" editorial team and reviewers were very excited about. I think this will be quite impactful and provide very, very detailed information for future research and future improvement and fate of the coronary graft conduits.

Dr. Carolyn Lam: And, Dude, I agree. It's the new look at perhaps a classic, old, central surgery, the cardiovascular surgery. Very nice, indeed.

Dr. Marc Ruel: Precisely, thank you. We also have a couple of important, seminal original papers within the realm of coronary surgery. In fact, these also deal, to some extent, with the fate of conduits and certainly how they work in the patient population in long ago bypass surgery.

One is a randomized control trial, a single center randomized control trial that was performed in South Manchester. It's called the VICO trial, a study comparing vein integrity and clinical outcomes. Essentially, the study looked at open vein harvesting versus two types of endoscopic vein harvesting for coronary artery bypass grafting.

The study was performed at a single center in England with three sound methods, having three groups of 100 patients who were compared with regards to the vein harvest technique. The primary outcome was with regards to actual vein integrity, looking at muscular damage and endothelial function and integrity on microscopy.

Surprisingly and actually quite reassuredly that there were very few differences between endoscopic vein harvest and open vein harvest. Certainly the investigators also looked, as one of their secondary outcomes, at quality of life. It was quality of life that was gained in patients who had endoscopic vein harvest versus those who had open vein harvest.

Overall, there was no difference in major adverse cardiac events. Therefore, showing at least in an internally valid fashion that these investigators at their center could do endoscopic vein harvesting as well as open vein harvesting.

Dr. Carolyn Lam: I know that there are other original research papers, perhaps. Would you like to highlight any of them?

Dr. Marc Ruel: Yes, for sure. Carolyn, there's also one more coronary surgery paper, which I wanted to highlight and that is the paper entitled, "Does Use of Bilateral Internal Mammary Artery Grafting Reduce Long-Term Risk of Repeat Coronary Revascularization?"

This is a multi-center analysis with first author is Iribarne from Northern New England. Essentially, seven medical centers got together and took about 20 years of consecutive CABGs with a total number of 50,000 operations, or just shy of 50,000 operations.

The median duration of follow-up was 13 years, and these patients were well matched together using a propensity matching scheme. I think this paper and this research is unique and of high impact. Even though it does have shortcomings of not being a randomized control trial, it is very welcome information, especially in light of the recent ART trial, which, as you know, did not show any difference at five years analysis between single and bilateral internal thoracic artery use.

The particularity of the Iribarne paper is that it is a very large data set up with close to 50,000 patients. It is multi-centered, therefore, it is real life. It is a consecutive series. The patients are extremely well matched, and it is remarkable to hear that the patients, in fact, had no difference in mortality until about five years after the operation.

As opposed to many previous series where single versus bilateral internal mammary grafting shows a mortality difference very early on, which always raises the suspicion of poor matching or confounding by indication, if you will, this paper did not have that.

Finally, the follow-up was quite long and at about six years, there was really a mechanistic signal with regards to repeat revascularization events, which seemed to match the difference in late mortality. There was no difference in early and five-year mortality, but afterwards as repeat revascularization events started to occur more frequently in the single mammary group, this was matched by a difference in mortality, as well.

I think a very useful, large, long follow-up mechanistically-based information that I think adds very significantly to the current information we have about bilateral versus single mammary use.

Dr. Carolyn Lam: Thank you, Marc. Two original papers, highlighted, dealing with really very important modern controversies in this area. Open vein versus endoscopic vein harvesting, single versus bilateral mammary artery bypass. Excellent.

Let's move on now to the next sub-theme, if you will. And that is the collection of papers on "Adult Congenital Heart Conditions," really, really an increasingly important and growing population that we're seeing. Tim, would you like to summarize maybe some of the highlights of the papers there?

Dr. Timothy Gardner: The first paper, as you point out, is focused on adult patients with repaired tetralogy of Fallot. This series came from the UK and it examines the course of almost 60 patients, at a mean age of 35 years following a repair of tetralogy as infants or young children, developed right heart failure and required pulmonary valve replacement.

This is a common scenario that we're seeing, successfully repaired children who appear to do well but as they get into their late 20s and 30s, their pulmonary valve function, which is often inadequate or not even present valve, require an intervention.

The important learning here is that pulmonary valve replacement, either surgically or by catheter technique, was shown to be highly effective in salvaging right ventricular function. That is based on imaging studies as well as hemodynamic studies of right ventricular function. There was an almost, in this group of patients, almost an immediate reverse remodeling of the right ventricle after placement of the valve, that continued to improve over time.

This was, I think, quite reassuring. There, historically, was a bit of a reluctance to operate on these patients as their right heart was failing, despite the fact that without some intervention to take the volume load off of the RV, the patients didn't do well. This is good news for an important group of patients who we are all seeing, who oftentimes present to the adult cardiologist because of this right ventricular failure problem. A nice, reassuring study.

Actually, the other two congenital papers are, again, focused on the infant. They both deal with the infant with hypoplastic left heart syndrome or single ventricle pathology. The first paper seems sort of specialized in terms of its focus, "The Optimal Timing of Stage-2-Palliation for Hypoplastic Left Heart Syndrome." This was a report from the NIH Pediatric Heart Network. They had a single ventricle reconstruction trial.

This network is comprised of about 10 North American centers, both in the U.S. and Canada and has provided excellent data about the management of pediatric heart disease but, in particular, the single ventricle trial has been excellent.

In this particular paper, they look at the optimal timing for stage-2 repair. Just to remind ourselves, the first part of the three-stage treatment for hypoplastic left heart syndrome is the Norwood procedure, which has to be done shortly after birth, as the patent ductus arteriosus closes and converts, essentially, the single right ventricle into the systemic ventricle.

The stage-2 comes along, usually done with a Glenn-type of shunt, increases pulmonary blood flow and stabilizes these infants until they can reach the age for, and the heart function for definitive repair. This has been a particularly difficult problem for the congenital heart surgeons. What is the optimal timing?

This study, which involved over 400 patients, identified optimal timing for the second stage between three and six months after the Norwood. I think this was very reassuring, is reassuring or supportive for the congenital heart community in terms of both patients and also good evidence base that a delay of three to six months does, in fact, produce the best transplant-free survival.

In fact, the other aspect of this observation was that infants who developed the need for another second stage operation sooner than that did not do well, and the reasons for the required earlier surgery could be failure of the initial operation or additional anatomic risk factors. But this, I think, was an important, large series, multi-center study that will prove to be very helpful in sorting out this complex timing of a three-stage repair.

Just to comment, again, for readers who don't deal with infant congenital heart treatments very often, there's been a remarkable amount of success over the last two decades in salvaging and saving these very difficult infants with the hypoplastic left heart syndrome. In fact, an additional paper in this surgery-themed issue, comes from the UK and is, in fact, a report on the findings from the UK-wide audit of the treatment of infants with hypoplastic left heart syndrome.

In fact, their findings, in this sort of real world, not in the Pediatric Heart Network trial group, is very similar. They found that infants who got to the second stage without additional refinement of the initial Norwood procedure and were able to be successfully treated with a Glenn shunt somewhere in the four-to-six-month age range, did well. They actually made the point that the anatomy was more of a determinant than anything else.

I think that this particular review will reinforce what the congenital heart surgeons have learned about optimal timing for this three-stage treatment of what previously were unreconstructable children.

Dr. Carolyn Lam: Thank you so much, Tim. Isn't it wonderful the way papers come in and they're actually complementary and consistent with one another. We're just so lucky to be publishing all of these great, high-quality, impactful papers in "Circulation."

Moving on, the next paper actually reminds us why this is a cardiovascular surgery-themed issue and not just a cardiac surgery-themed issue. Didn't we just say that earlier, Marc? This one is on abdominal aortic aneurysm treatment. A population-based landscape of this. Could you tell us a little bit more about that one?

Dr. Marc Ruel: Absolutely. Carolyn, you're entirely right. We must remember that "Circulation" is also about peripheral vascular disease, saying this earlier, or cardiovascular surgery and anesthesia consult also when it encompasses vascular surgery. Precisely to that effect, one of the papers in our cardiovascular surgical-themed issue is a landscape population based analysis from Finland that looks at the incidence of abdominal aortic aneurysm between the years of 2000 and 2014.

Finland has a population of about 5.5 million and remarkably has a very circumscribed healthcare system. They do not have an organized system of AAA care as some other countries have shown to have and potentially benefit from, but rather they have a treatment of this condition at several institutions, many of which may not be high volume.

I think the paper is remarkable is that it is very well nested in terms of a population. It provides a comprehensive landscape of where this condition has evolved to over the last few years. Obviously, we see in the results from the authors that the mortality has decreased quite a bit, but also the incidence, probably as a result of better control of risk factors. And also the incidence of rupture outside the hospital.

One thing that came out of this paper, as well, is a potential cohort of the benefits gained from developing an organized system of AAA care, from the reason that the mortality of AAA rupture in Finland was still quite high, despite this being a modern series. In fact, when you include ruptures, before arrival to hospital and at arrival to hospital, the overall mortality was almost 80% for ruptured AAA.

Perhaps one message that comes out of this is that there may be a benefit in having specialized centers dealing with these conditions, especially as they are in the process of rupturing. One last observation was, obviously, the increasingly prevailing role of endoscopic vascular repair in the treatment of this condition, which, in fact, has now surpassed open repair as the dominant method of elective repair.

I think, overall, a very comprehensive, well-nested, country-wide with good follow-up landscape of the AAA condition in a country that has essentially a similar socioeconomic status to much of the western world. Therefore, with external generalized ability to some extent.

Dr. Carolyn Lam: Exactly, and contemporary data. I really enjoyed that you paired those with an excellent editorial, as well. Finally, before we wrap this up, I have to ask Tim to comment on this next paper, and it's on ventricular assist device malfunctions, I love the title, "It's More Than Just The Pump." Of course, as a heart failure physician, this one's very close to my heart. Forgive the pun. But, Tim, could you tell us about that?

Dr. Timothy Gardner: This paper comes from the University of Pittsburgh and their artificial heart program. Robert Kormos is the first author and he's been one of the stalwart leaders in the use of LVADs and other pump devices. He reports on their experience with over 200 both HeartMate and HeartWare ventricular assist devices.

It was interesting when we reviewed this paper by the editors, there was some thought that maybe this was a little too engineering focused and so on, but I think the point of the paper is that, as they say in the very first line in their report, reports of LVAD malfunction had focused on pump thrombosis.

But they point out very appropriately that, in fact, controller failure, battery failure, cable failure and other causes of device failure, which can be critical and life threatening and so on, are engineering issues. It reminds us that when we're managing this difficult group of patients, and we're seeing many more patients today with getting LVADs than 10 or 20 years ago, we need to have the bioengineering abilities and resources available.

Even the surgeon and the critical care physician who is dealing with these patients either has to acquire this kind of knowledge or capacity himself or herself, or needs to have a good bioengineer nearby.

What's interesting, I think, that all of us define that these mechanical failures were more common in this pretty big experience than what we've more clinically worried about, which was thrombosis of the pump.

Dr. Carolyn Lam: Exactly. That's so wonderful. And you know it just leads me to really thank you both, Marc and Tim, for this extraordinarily excellent selection of original research, state-of-the-art and perspective articles and editorials on congenital, coronary, vascular and heart failure surgery. This really appeals not just to the cardiovascular surgeons but really to the vast readership of "Circulation."

Thank you for a wonderful themed issue and thank you for this great podcast.

Dr. Timothy Gardner: Well, thank you.

Dr. Marc Ruel: Thank you very much, Carolyn.

Dr. Carolyn Lam: Listeners, don't forget to tune in again next week.

Circulation October 24, 2017 Issue

23 oktober 2017 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today's feature discussion centers on the population burden of sudden death associated with hypertrophic cardiomyopathy. These are novel data from the ongoing Oregon sudden unexpected death study, results that may surprise you. Stay tuned and that's coming up right after these summaries.

The first original paper in this week's journal tells us that risk reductions from air pollution control yields health benefits comparable to the control of systolic hypertension and smoking in a high risk segment of the urban Chinese population. First author Dr Huong, corresponding author Dr Gu and colleagues from Fu-Wai hospital in Beijing China projected the life years gained if urban China were to reach one of three air quality goals. First, Beijing Olympic games level. Second, China class 2 standard. Third, the WHO standard. They further compared projected air pollution reduction control benefits with the potential benefits of reaching WHO hypertension and tobacco control goals.

Now to do this, the authors used the Cardiovascular Disease Policy Model: China, which is a computer simulation state transition mathematical model of coronary heart disease and stroke incidence, prevalence, mortality, non-cardiovascular deaths, and costs of health care in the Chinese population. They found that air quality improvement under the different scenarios could lead to a great health benefit, ranging from 241,000 life years gained to much greater benefits, benefits that were greater to or equal to the combined benefits of a 25% improvement in systolic hypertension control, and a 30% smoking reduction. Thus, the authors called for joint efforts of the whole society for air quality improvement in China.

The next study describes six differences and similarities in atrial fibrillation epidemiology, risk factors, and mortality in the community. First author Dr [Magnusson 00:02:42], corresponding author Dr [Schnabel 00:02:44] and colleagues from University Heart Center Hamburg Eppendorf studied 79,793 individuals without atrial fibrillation diagnosis at baseline from 4 community-based European studies, namely, FINRISK, DanMONICA, Molisani, and Northern Sweden, all followed for a medium of 12.6 years. They found that cumulative incidence increased markedly after the age of 50 years in men and after the age of 60 years in women. The lifetime risk was similar in more than 30% for both sexes.

Subjects with incident atrial fibrillation had a three and a half fold higher risk of death compared with those without atrial fibrillation. Among the classical risk factors, body mass index explained the largest proportion of atrial fibrillation risk. Six interactions were seen for the risk associations of body mass index and total cholesterol, wherein body mass index was associated with a greater risk increase in men than women, whereas total cholesterol was inversely associated with incident atrial fibrillation with a greater risk reduction in women than men.

The next study describes a novel circular RNA as a potential target in diabetic proliferative retinopathy. Circular RNAs are a novel class of non-coding RNAs that regular gene expression and they're characterized by closed loop structures with neither five-prime, nor three-prime polarity nor a polyadenylated tail. In today's study, first author Dr [Shah 00:04:33], corresponding authors Drs. [Yen 00:04:33] and [Zhao 00:04:36] from Shanghai Medical College Fudan University in China characterized the expression and regulation of the circular RNA, circHIPK3 in retinal endothelial cells and diabetic retinal vascular dysfunction.

CircHIPK3 expression was significantly up regulated upon high glucose stress in vivo and in vitro and regulated retinal endothelial cell function and vascular dysfunction by acting as an endogenous microRNA 30A-3P sponge that sequestered and inhibited its activity. In summary therefore, the circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking microRNA 30A function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that the circular RNA may be a potential target for diabetic proliferative retinopathy.

The next study identified important new principles of endogenous chromatin structure that have key implications for epigenetic therapy. In this study from first author Dr Rosa-Garrido, corresponding author Dr Vondriska, and colleagues of David Geffen School of Medicine in UCLA, the authors examined changes in chromatin configuration in cardiomyocytes isolated from mouse hearts subjected to transverse aortic constriction or hearts subjected to Tamoxifen inducible cardiac specific excision of CTCF, which is a ubiquitous chromatin structural protein.

There was several important findings from this work. Firstly, the authors found that depletion of CTTF was sufficient to induce heart failure in mice and human heart failure patients receiving LVADs also showed increase CTCF abundance. Pressure overload or CTCF depletion selectively altered the boundary strength between topologically associated domains, which are regions of DNA in which physical interactions occur frequently. The authors showed that there were changes in the compartmentalization of active chromatin and inactive chromatin segments, which is a measure of genomic accessability.

Heart failure involved decreased stability of chromatin interactions around disease causing genes. In summary, these finding provide a high resolution chromatin architectural resource for cardiac epigenomic investigations and also demonstrate that global structural remodeling of chromatin underpins heart failure.

The final study is the first to provide insights into the fluid mechanics of transcatheter valve thrombosis. First author Dr Midha, corresponding author Dr Yoganathan and colleagues from Georgia Institute of Technology and Emory University in Atlanta analyzed post-procedural four dimensional volume rendered CT data of transcatheter aortic valve replacement, or TAVR patients, enrolled in the Resolve trial, excluding patients on anticoagulation. Patients were classified as having transcatheter heart valve thrombosis if there was any evidence of hypoattenuated leaf thickening. The authors studied the flow characteristics within the neo sinus which is formed followed deployment of a transcatheter valve into a native aortic valve.

The authors found that post deployment valve geometry and final implant position affected the flow within the neo sinus, which in turn, may affect the predisposition to thrombus formation. The impact of geometry and position varied according to the different valve types. A supra-annular transcatheter heart valve deployment resulted in a nearly seven fold decrease in stagnation zone size when compared to an intro-annular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. In summary, deployed transcatheter heart valve geometry may have implication on the occurrence of thrombosis and a supra-annular neo sinus may reduce thrombosis risk due to reduced flow stasis. While additional prospective studies are clearly needed, these results may help identify patients at higher thrombosis risk and aid in the development of the next generation of devices with reduced thrombosis risk.

Well, that wraps it up for our summaries. Now for our feature discussion.

Sudden death in hypertrophic cardiomyopathy has been and still is a very hot topic in cardiology. Of course it's understandable given all the high profile deaths that have occurred in young athletes ascribed to hypertrophic cardiomyopathy and the fact that these deaths may potentially be preventable with implanted defibrillators. However, we're so proud to have in this week's journal, some of the first data on the population-based burden of sudden death associated with hypertrophic cardiomyopathy. I'm so happy to have with us the corresponding author of this research letter, Dr Sumeet Chugh from Cedar Sinai Medical Center, as well as Dr Mark Link, associate editor from UT Southwestern. Welcome, gentlemen.

Dr Sumeet Chugh: Thank you.

Dr Mark Link: Thank you.

Dr Carolyn Lam: Sumeet, you know as I said in the introduction, sudden death in hypertrophic cardiomyopathy, we've talked about it a lot. There's been lots published. What makes your data so novel?

Dr Sumeet Chugh: There is indeed a large body of work related to hypertrophic cardiomyopathy but most of it came from registries. Probably what's a bit unique about our work is that it was done in one large, US community over a number of years.

Dr Carolyn Lam: Indeed. So population-based statistics, not just of hypertrophic cardiomyopathy, but of sudden death related to it, isn't it?

Dr Sumeet Chugh: That's correct, Carolyn.

Dr Carolyn Lam: I think the other thing that we were just actually chatting about is the fact that it's contemporary. Could you tell us maybe the period you're looking at and then give us your findings?

Dr Chugh: Yes. The study was initiated in 2002 and is now in it's 16th year, so this particular analysis was conducted between the time period 2002 and 2015. What we do in the process of this community-based work is that we track prospectively every cardiac arrest that happens in the community centered around Portland, Oregon in the USA. The work in performed in the process of doing a multiple-source ascertainment where we take the help of the first responders or the ambulance personnel, the hospital emergency rooms, as well as the police, and the coroner network. It's a fairly comprehensive way of ascertaining sudden cardiac arrest.

Dr Carolyn Lam: That is a very unique and valuable data set. Could you summarize the top line results, because they were rather surprising?

Dr Sumeet Chugh: We are already learning that over time, with more awareness, education, and modern management of hypertrophic cardiomyopathy, the risk of sudden cardiac arrest and the overall morbidity from hypertrophic cardiomyopathy may be on its way down. What this study is showing is, that actually the risk of sudden cardiac arrest and the burden of sudden cardiac arrest from hypertrophic cardiomyopathy in the community may be quite low. Those are the main findings.

Dr Carolyn Lam: Yeah. In fact, I was just so impressed because first of all, you excluded the individuals in this population and found that hypertrophic cardiomyopathy was responsible for 1 in 30 of the cardiac deaths, but that the incidence of the sudden deaths were 0.2 to 0.3% among these hypertrophic cardiomyopathy patients, perhaps less than others may have expected.

Mark could I bring you in on this for a moment? What do you think are the take home messages for something like this, because in a young and middle age population, is any rate really too low?

Dr Mark Link: I think this is great data because it encompasses an entire population, so it gets us good data on the true incidence of sudden cardiac death. In the study, if you look at the total number of patients that either had an ECHO or had an autopsy, about 5%, a little over 5% of them, had hypertrophic cardiomyopathy. Roughly 5% of the individuals dying suddenly, under age 60 are dying secondary to hypertrophic cardiomyopathy. That's the sort of data that we really didn't have before because we didn't have such a nice population-based study.

It was interesting also, they tended to be younger, 10 years younger than the others dying suddenly, so it was a younger cohort. They more often had ventricular fibrillation or ventricular tachycardia than the others dying suddenly. It really does give us some nice data on the true incidence of sudden death due to HCM in the community.

Dr Carolyn Lam: What I thought was also valuable was the fact that the diagnosis of hypertrophic cardiomyopathy was quite often missed prior to the cardiac arrest and I'm trying to wrap my head around about what that implies.

Dr Sumeet Chugh: That's a very important point, Carolyn. These findings also give us the message that our risk classification methodology continues to need more work. The fact remains that a significant proportion of patients with hypertrophic cardiomyopathy are also going to be asymptomatic. Sometimes they just don't come to our attention.

Another important point, however, that's related to this work is that there may have been during the course of this time period, at least a few patients in this community who would have received an implantable defibrillator and their sudden cardiac arrest would have been averted, so we're not able to count those individuals who were already found and managed.

Dr Mark Link: That's a very important point because if a person is found with HCM and has risk factors, they would get a implantable defibrillator. Those individuals would not show up in this database because they wouldn't die.

Dr Carolyn Lam: Mm-hmm (affirmative)-

That's a very, very important point. Thank you for highlighting that. I think it goes back to why these data are so important, because they are contemporary as well and we really need such estimates, so congratulations Sumeet and thank you for giving us these valuable data.

I'd like to switch tracks a little bit though, and point out this was a research letter, a big data set, important findings, but published as a research letter. Should I even say but? Mark could you comment a little bit about research letters in circulation versus original articles?

Dr Mark Link: We increasingly are using research letters in circulation for original research that drives home a basic single point. If that basic single point can be made in 1,200 words, we actually like the research letter format. It's a quick read, people remember it, it's cited. It is something that authors that we ask to turn a full length manuscript into a research letter, should be taking that as a positive sign, because that means that we're interested in the topic and would like to see it in print.

Dr Carolyn Lam: I completely agree and in fact, Sumeet, if I could ask you to weigh in. Sometimes it's harder, isn't it, to write a research letter than to write a full length manuscript? How was your experience?

Dr Sumeet Chugh: I have to admit that the first responses as you said, where you feel, "Oh, I've spent a lot of effort in writing this large paper, and now I have to squeeze it into 1,200 words," but the second thought for me was, "The fact is that this is a one bullet message and why not make it shorter and snappier as it is?" I think I've come around in the appropriate situation to appreciating this opportunity of writing a research letter.

Dr Mark Link: when you read the research letters, they're very succinct. I actually like them. They get the message across quickly and I think it's a great way to produce science and to show what you've done.

Dr Carolyn Lam: Yeah. The thing is that we also restrict to a single figure, or a single table and I cannot tell you how many times I've referred to that single figure because it usually tells the full story and it's beautiful summary.

So, listeners, you've heard about the research letters in circulation. Please have a look at them. I'm pretty sure that you will fall in love with the format just like we all have.

Thank you so much, Sumeet and Mark for joining me today. I'm afraid our time is up, but I've so enjoyed talking to you. Thank you, listeners, for following us today. Don't forget to tune in again next week.

Circulation October 17, 2017 Issue

16 oktober 2017 | 21 min

Our feature discussion this week centers on the temporal changes in natriuretic peptides preceding heart failure hospitalizations and patients at high risk. Data that are really novel and have implications for the way we perhaps monitor and categorize these high risk patients. Well, more soon right after these summaries.

The first original paper this week provides the first epigenome-wide association study in patients with heart failure. Now, epigenetics refers to biochemical DNA modification such as methylation of gene bodies, and post-translational modification of histones, which is increasingly recognized to play a crucial, regulatory interface between genes, environment, and the transcriptome.

The lack of availability of myocardial specimens from patients has been a major roadblock for elucidating the impact of such epigenetic changes on complex cardiovascular traits. However, in today's paper from first author, Dr. Meder, corresponding author, Dr. Katiz and colleagues from University of Heidelberg, Germany. The authors performed the first multi-omic study in myocardial tissue and blood of patients with dilated cardiomyopathy compared to controls.

They detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy, with three of them reaching epigenome-wide significance. 29 of these loci could be replicated in independent cohorts and authors further linked a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression.

Finally, they identified distinct epigenetic methylation patterns that are conserved across tissues. Thus representing novel, epigenetic biomarkers for heart failure.

The next study is the first to assess a diagnostic and prognostic value of cardiac myosin binding protein-C in patients presented with possible acute myocardial infarction or AMI. Cardiac myosin binding protein-C is a cardiac restricted protein that is more abundant than the cardiac troponins and is released more rapidly following AMI.

In today's paper, first author, Dr. Kaya, corresponding author, Dr. Marber and colleagues from the Rayne Institute In St. Thomas's hospital in London evaluated cardiac myosin binding protein-C as an adjunct or alternative to cardiac troponins in the early diagnosis of AMI in 1,954 unselected patients presenting to the emergency department with symptoms suggestive of AMI.

The final diagnosis of AMI was independently adjudicated in 340 patients. The authors found that concentrations of cardiac myosin binding protein-C at presentation were significantly higher in those with versus without an AMI. The discriminatory power for AMI quantified by the area under receiver operating curve was comparable for cardiac myosin binding protein-C to high sensitivity cardiac troponins T and I, and even superior to standard sensitivity cardiac troponin I. The use of cardiac myosin binding protein-C more accurately classified patients with a single blood test and to rule out or rule in categories in early presenters, meaning those with chest pain of less than three hours.

The improvement in rule in or rule out classification with cardiac myosin binding protein-C was larger compared with higher sensitivity cardiac troponins T and I. Finally, cardiac myosin binding protein-C was superior to high sensitivity and standard troponin I and similar to high sensitivity cardiac troponin T at predicting death at three years. Thus in summary, this paper shows that cardiac myosin binding protein-C at presentation provides discriminatory power comparable to high sensitivity troponins T and I in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset.

The next paper describes the discovery of a novel candidate cardiomyopathy or arrhythmia gene. First author, Dr. Barryfield, corresponding author Dr. McNally from Center of Genetic Medicine in Chicago and colleagues studied a family with dilated cardiomyopathy and associated conducted system disease in whom prior clinical cardiac gene panel testing was unrevealing. Whole genome sequencing however, identified a premature stop codon in the gene encoding a novel myo filament component, the myosin binding protein-H-like.

Having identified this gene, they turned to experimental approaches. The myosin binding protein-H-like gene was found to have high atrial expression with low ventricular expression. The truncated protein failed to incorporate into the myo filament. Human cell modeling demonstrated reduced expression of the mutant allele. Heterozygotes and nullumites exhibited a reduction in fractional shortening and increased diastolic ventricular chamber size, aberrant atrio-ventricular conduction and an increased rate of arrhythmia associated with the expression of the myosin binding protein-H-like in the atria, as well as in discrete puncta throughout the right ventricular wall and septum.

These findings therefore support that myosin binding protein-H-like truncations may increase the risk for human arrhythmias and cardiomyopathy.

Transplantation of cells into the infarctant heart has significant potential to improve myocardial recovery. However, low efficacy of cell engraftments still limits the therapeutic benefit. In today's paper, authors describe a method for the unbiased, in-vivo selection of cytokines that may improve Mesenchymal stromal cell engraftment into the heart. In this paper from first author, Dr. Bortolotti, corresponding author Dr. Giacca, and colleagues from University of Trieste in Italy, an arrayed library of 80 secreted factors were individually cloned into adeno-associated viral vectors.

Pools from this library were then used for the batch transduction of bone marrow derived Mesenchymal stromal cells ex-vivo, followed by intra myocardial cell administration in normal and infarctant mice. Three weeks after injection, the vector genomes were recovered from the few persisting cells, and identified by sequencing DNA barcodes that were uniquely labeled for each of the tested cytokines.

Using this novel, competitive, engraftment screening methodology, the authors identified that the most effective molecule was cardiotrophin-1 a member of the IL-6 family. Intra cardiac injection of Mesenchymal stromal cells preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size parallel to the persistence of the transplanted cells in the healing hearts for at least two months after injection. Thus, preconditioning with cardiotrophin-1 might represent an efficient manner to improve the currently poor cell retention in patients treated with Mesenchymal stromal cell therapy.

The final paper presents results of the early myo trial, a non-inferiority trial comparing a pharmacoinvasive strategy with half-dose alteplase versus primary PCI in patients with STEMI, presenting six hours or less after symptom onset but with an unexpected PCI related delay.

First author, Dr. Poole, corresponding author, Dr. Hua and colleagues from Shanghai Jiao Tong University in China randomized a total of 344 patients from seven centers to a pharmacoinvasive arm or a primary PCI arm. They found that pharmacoinvasive strategy was non-inferior to primary PCI for the primary endpoint of complete epicardial and myocardial reperfusion after PCI defined as TIMI flow grade 3, TIMI myocardial profusion grade 3, and ST-segment resolution of more than 70%.

There was no significant differences in the frequency of the individual components of the combined endpoint. Infarct size and left ventricular ejection fraction were similar in both groups and there was no significant differences in 30-day rates of total death, re-infarction, heart failure, major bleeding events, or intracranial hemorrhage. However, minor bleeding was observed more often in the pharmacoinvasive group.

Thus the authors concluded that a pharmacoinvasive approach with reduced dose alteplase seems to offer effective and safe reperfusion in low-risk patients with STEMI with an unexpected PCI related delay. Further large, randomized control trials powered for clinical endpoints are needed.

Well, that wraps it up for your summaries. Now for our feature discussion.

The measurement of natriuretic peptides BNP, NT-proNP have certainly become the cornerstone of heart failure management. We measure these levels by guidelines in patients who are presenting with symptoms and suspected heart failure, in patients who are hospitalized. We measure them for prognostication purposes at discharge. However, what we don't really know is how the preceding changes in natriuretic peptides may precede heart failure hospitalization in patients who are at high risk of developing heart failure.

For example, patients with a recent coronary event or type-2 diabetes. And this is the very subject of our feature paper today, and I am so pleased to have the corresponding author of today's paper which is really a research letter. Dr. Brian Claggett from Brigham and Women's Hospital as well as Dr. Biykem Bozkurt who's our senior editor from Baylor College of Medicine.

Welcome both, and maybe I could start, Biykem could you let us know, what are the unanswered questions in heart failure relating to natriuretic peptides and how do you see this paper falling in, clinically?

Dr. Biykem Bozkurt: Carolyn, this is a wonderful I think prelude to perhaps preventing heart failure events. And as you are aware, we in the recent year changed our guidelines at the ACC, AHA, and the HFSA incorporating screening high risk patients for development of incident heart failure. And the study that resulted in this consideration was a STOP-HF trial which was utilizing natriuretic peptides in high risk patients to determine whether their closer follow up in a multidisciplinary fashion would result in earlier detection and prevention of heart failure, and which it did.

And this study I think is straddling the concept of high risk or stage A or B patients because they are individuals who have had heart attacks, coronary events, and they have type-2 diabetes so they are definitely high risk. And doing natriuretic peptides as an outpatient, whether that would predict the heart failure hospitalizations.

And in essence I think it's a good concept. Perhaps the challenging concepts are how often should we screen our patients, and what will be the threshold of the rise that would potentially make us act in either earlier diagnostic strategies, or management strategies. I think those are the two unanswered questions that remains.

How are we gonna screen our patients? Our high risk patients to determine when they are developing heart failure before they become symptomatic? So, what threshold are we going to use?

Dr. Carolyn Lam: That is a perfect set up. I just wanted to add as well in addition to STOP-HF there was the PONTIAC study in diabetics which is very relevant to today's paper that also sort of used NT-proBNP to risk stratify patients for prevention of heart failure. But neither of these studies talked about the temporal changes in natriuretic peptides. And I think a lot of the reason for that is, is that the methods, I mean the statistical methods to do that sort of thing are mind-blowing.

And so Brian, could you now please share with us what you did, the methodology and basically what you found before we discuss the two questions that Biykem brought up?

Dr. Brian Claggett: What was really interesting is the method that we came up with to look at these questions. It's something that we like to believe will be generalizable and can be used in other scenarios and for other biomarkers. But the idea that we have is that we are always used to thinking about the design of a clinical trial as being very regimented. So, you see a patient once at baseline, and then maybe six months later, and then maybe six months after that, and so on. And so it's hard to know what's going on, on a day to day or week to week basis.

But if you think backwards, and you think backwards from the time of any sort of event, because those events whether they're hospitalizations or MIs or death, they happen not on that same schedule. And so odds are at the end of a trial, you had a patient who came to a scheduled visit and then had an event the next day. And you probably had a patient who came in for a visit two days before an event, and another patient who came in a week before an event. So if you start thinking on that time scale, you can piece together all these different time frames when you do have data collected and try to reconstruct something that looks like an actual continuous natural history of what that biomarker would have looked like over say a two year period, if it had been measured continuously.

Dr. Carolyn Lam: So, tell us what you found. First of all, let's just make sure that everyone knows you were looking at the ELIXA cohort, right?

Dr. Brian Claggett: Yes, the data that we had available for this analysis comes from the ELIXA trials, it was 6,068 patients all with type-2 diabetes and a recent ACS event. Recent meaning within the last 180 days. And they were randomized placebo versus a diabetes drug, lixisenatide. And they were followed up for cardiac outcomes.

Beyond that, the natriuretic peptides were measure systematically at baseline, month 6, month 18, and month 24 in all patients who were participating in the trial. So this was the richest collection of a large number of patients being measured multiple times, systematically and not in just a sub-sample of the population. So, we felt like this was a great opportunity to learn something about what happens. What can you learn when you measure these natriuretic peptides over and over again.

And even more interesting than that, the fact that this wasn't a heart failure trial meant that some of the patients already had heart failure at baseline. Other patients didn't have heart failure, but as the trial went on, they developed or were hospitalized for heart failure for the first time. And so we were able to also look at differences between patients experiencing their first heart failure, versus those with more long standing disease.

Dr. Carolyn Lam: And that was very, very unique methodology that you spoke about. And I fully agree that it's going to be used more. I am staring at your beautiful figure one right now. That really, really says it all. Could you walk us through the results?

Dr. Brian Claggett: Sure, I think our key finding is that, I guess no matter when you measure patients. Patients with a higher level of NT-proBNP, or a higher level of BNP at any given time are going to be at higher risk of developing heart failure in the future.

But as we start looking at this as a temporal process, what we see is that there seem to be a noticeable acceleration in these increases, specifically in the last six months before development of heart failure. Or, before a hospitalization for heart failure. And that increase in the final six months seems to occur both in patients who had no prior history of heart failure and also in patients with a history of heart failure. So that six month window I think is something that we learned that we didn't necessarily know before.

Dr. Carolyn Lam: But, going back to Biykem's questions, do you think we have answers to how often we need to survey natriuretic peptides in these high risk patients and what threshold we need to act on?

Dr. Brian Claggett: I think both are very important. I think maybe the timing and the thresholds are somewhat separate questions. I think we're better able to answer the timing question. At the very least we can say that if dramatic changes are happening over a six month window that measuring patients only once every six months probably isn't enough. Whether that means it needs to be every three months, or two months, or one month, or something more than that, I think it's hard to know exactly what the right answer is. But I think we are confident in saying that things happen relatively quickly and we need to be measuring these things more frequently.

As far as the question of thresholds, I think that's maybe even a more difficult question. Or even the idea of a threshold means that we think that there's some magic number and I am not sure that we know for sure what's more important, the absolute number or is it the ... if someone starts relatively low and that relatively low number doubles over the course of six months. That might still be prognostically just as important as someone who's been consistently edging just below or just about that threshold level.

I'm not sure that we're confident enough to say that the changes, the speed of the changes, or the relative changes, or some absolute threshold is the most important thing to be paying attention to. But, I think where these two are related is the more ... that we can start to collect this data more frequently and be able to analyze it. I think that gives us a lot better chance of being able to successfully answer that question about thresholds.

Dr. Carolyn Lam: Indeed. Stuff for future work, huh? Biykem, what do you think?

Dr. Biykem Bozkurt: I wanted to point out two things from Brian's study which was quite interesting. One is the trajectory of the rise, or the delta changes in the natriuretic peptides was quite different in the patients with no history of heart failure compared to those with a history of heart failure. The trajectory, or the linear rise, or the delta changes were more prominent in the individuals with no history of heart failure. Probably intuitively expected so because their baseline levels are not as high as the individuals with history of heart failure.

So, it almost gives the impression that maybe in low low risk, the screening or the frequency may need to be lower, and if low, then probably the likelihood of the rise may be less. But those individuals who, as you said, are edging upward, then maybe the frequency may need to be higher and there may be perhaps a linear rise or a more prominent rise about six months before the incident event.

So, it's an interesting concept just to look at people's trajectories. But, as you said, probably individualization and monitoring or targeting may need to be individualized according to personal risk and other features. And one then wonders futuristically if this would be a concept that would be point of care testing maybe done by the patients similar to glucose monitoring. And in the event that we were to be able to carry the platform to self-test.

Dr. Brian Claggett: You're talking to a statistician, so I am always going to be in favor of collecting more data all the time. So I agree with that.

Dr. Carolyn Lam: Wow, what an insightful discussion. Thank you both for joining us on this podcast today.

Ladies and gentlemen out there, you heard it right here in Circulation on the Run. Tune in again next week.

Circulation October 10, 2017 Issue

10 oktober 2017 | 19 min

We know that excessive sedentary time is bad in terms of health outcomes, but does it matter how that sedentary time is accrued, whether in short or long bouts? Today's feature paper gives us some answers. More soon, right after the summary of this week's journal.

The first original paper in this week's journal provides insights into the mechanisms underlying neointima formation in arterial restenosis. Co-first authors, Dr. Cheng and Shi, corresponding author Dr. Li from Wuhan University in China, and their colleagues, performed an elegant series of experiments in which they demonstrated that interferon regulatory factor 4, or IRF4, which is a member of a family of key, innate, immune regulators known to play a role in cardiometabolic disease, actually protects arteries against neointima formation.

They further probed the mechanism underlying this protective effect and found that IRF4 promoted the expression of Krüppel-like factor 4 by directly binding to its promoter. Genetic over-expression of Krüppel-like factor 4 in smooth muscle cells reversed the neointima promoting effect of IRF4 ablation. Whereas, ablation of Krüppel-like factor 4 abolished the protective function of IRF4, thus indicating that the protective effects of IRF4 against neointima formation were Krüppel-like factor 4 dependent.

These findings suggest that the previously undiscovered IRF4 Krüppel-like factor 4 axis plays an important role in vascular proliferative pathology and thus may be a promising therapeutic target for the treatment of arterial restenosis.

The next paper highlights that high-spacial resolution in gene expression signatures can reveal new regulators, genetic pathways, and transcription factors that are active in well-defined regions of the heart.

Now we know that traditional genome-wide transcriptome analysis has been disadvantaged by the fact that the signals are derived from tissue homogenates. Thus, the authors of this current paper, including Co-First authors Dr. Lacraz and Junker, corresponding author Dr. Van Rooij from University Medical Center Utrecht in the Netherlands used tomo-seq to obtain genome-wide gene expression signature with a high spacial resolution, spanning from the infarcted area to the remote areas to identify new regulators of cardiac remodeling.

Using this technique, they identified SOX9 as a potent regulator of cardiac fibrosis. In vivo loss of SOX9 reduced the expression of many extracellular matrix genes, which coincided with a blended cardiac fibrotic response upon ischemic injury.

These data therefore were able to unveil currently unknown relevance of SOX9 as a key regulator of cardiac fibrosis, thus underscoring that tomo-seq can be used to increase our mechanistic insights into cardiac remodeling, and to help guide the identification of novel therapeutic candidates.

The next paper reports the primary results of the effect of ferric carboxymaltose on exercise capacity in patients with iron deficiency and chronic heart failure, or EFFECT-HF study, which is a randomized control trial of intravenous ferric carboxymaltose, compared to standard of care on the primary end point of change in peak Vo2 from baseline, to 24 weeks in patients with symptomatic, chronic heart failure with reduced ejection fraction and iron deficiency.

In this report from Dr. van Veldhuisen from University Medical Center Groningen and colleagues, intravenous ferric carboxymaltose was shown to significantly increase serum ferritin and transferrin saturation. At 24 weeks, peak Vo2 had decreased in the control group, but was maintained in the group receiving intravenous ferric carboxymaltose.

Although a favorable effect on peak Vo2 was observed with ferric carboxymaltose, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak Vo2 among patients who died.

They also reported that patient's global assessment and functional class, as assessed by New York Heart Association, improved on ferric carboxymaltose compared to standard of care.

Whether ferric carboxymaltose is associated with an improved outcome in these high risk patients, deserves further study.

The final study provides important long term clinical data to guide lead management decisions in patients with cardiac implantable electronic devices.

Dr. Pokorney from Duke University Medical Center in Durham, North Carolina, and colleagues, analyzed over 6,000 Medicare patients and found that device extraction was associated with a lower adjusted five year infection rate, compared with a cap and abandon strategy. There was a lower absolute five year mortality with extraction, but after adjustment there was no association between extraction and a lower five year mortality.

In summary, therefore, elective lead extraction for non-infectious indications in this Medicare cohort had similar long term survival, but lower risk of device infections at five years, compared to capping and abandoning leads.

Patient and provider preferences are critical to decision making when considering extraction versus capping and abandonment of leads.

Well, that wraps it up for your summaries. Now for our feature discussion.

For today's feature discussion, we are talking about sedentary time and a metabolic risk of having too much of it. But, today's paper is so interesting because it tells us that it's not just the total amount of sedentary time that may matter, but how we accrue the sedentary time. Very, very novel concept in my point of view and I'm so pleased to have the first and corresponding author of this paper, Dr. Keith Diaz from Columbia University Medical Center with us, as well as Associate Editor from Johns Hopkins, Dr. Wendy Post.

So pleased to have you both. Keith, could we just dive right into it? Tell us what population you were looking at, and what you found.

Dr. Keith Diaz: Sure, so we were studying a population of participants enrolled in the Hispanic Community Health Study, so it's a US populations of over 16,000 Hispanic adults. And essentially what we found was that sitting for prolonged bouts, so sitting for one, two hours at a time, was associated with poor glucose regulation.

Dr. Carolyn Lam: Well, yikes. I've actually been sitting for a few hours in a row right now, actually. I think these results are phenomenal, but could you maybe expand a little bit on the details, like how long is too long? And, how often a break needs to happen for you to see differences in the metabolic risk?

Dr. Keith Diaz: It's a good question and, to be honest, we don't know. I think that's where the research needs to head, but right now it seems to be that taking a break every 30 to 60 minutes could be beneficial. I think that's what we've found thus far.

Dr. Wendy Post: Keith, we were really excited to get your paper in. I think everyone on the Associate Editorial Board was especially interested in it because we can all relate. As Carolyn said, she's been sitting for a long time and when we have these meetings we have two hour meetings at a time and maybe we need to start saying that in the middle we should all stand up and take a break. So we can all relate to this.

But I think one the biggest questions that we had related to data itself, was the association between the total sedentary time and the sedentary bout duration. Maybe you can tell us a little bit more about those correlations in the interaction and tell us also how you also measure sedentary bout duration and total sedentary time in this observational cohort.

Dr. Keith Diaz: Sure, so I'll start with that latter question. So, we measured sedentary time [inaudible 00:09:32] subjectively. So we actually used an activity monitor called an accelerometer to see how sedentary they are. And how we quantified sedentary bouts is we just looked at how long consecutively a person sat without moving. That was considered sedentary bout. In terms of correlation, what we found is that there are very closely linked. So, people who sit for long hours during the day for total volume, also sit in long bouts. And so what we wanted to do was try to figure out and piece apart, which one is more important? When we're trying to ... If we're thinking about guidelines and what we should be doing about our sedentary time, is it important to reduce our volume or interrupt our bouts? And so what we found is that they're not independent, and that they're in many ways synergistic. And that the association of prolonged sedentary bouts with glycemic biomarkers varied according to how much total volume you sit and vice-versa.

Dr. Wendy Post: Can you expand a little bit more on that? So tell us about the interaction that you found between sedentary bout duration and total sedentary time.

Dr. Keith Diaz: Sure, so we did find that there was a specifically significant interaction between the two variables and so what we tried to do is actually categorize people as to whether they were high for both characteristics or high for just one of them. And so what we found was that those participants who are high for both, so they had high volume and sat in long bouts, they had the worst glucose regulation, and that those individuals that were high for just one of the characteristics had a little bit better glucose regulation. And so really what we thought the take home message was when thinking about how do we improve our sedentary behaviors is that it's targeting both. It's not sitting for large volumes during the day, but also making sure to take frequent breaks every 30 or 60 minutes.

Dr. Wendy Post: And tell us about the glucose measures that you included in your study.

Dr. Keith Diaz: Yep, we had a couple glucose measures. One we had people do a two hour glucose tolerance test, so they took a glucose drink and then we measured their blood sugar levels two hours after having that drink. We also measured their H1Ac levels as well as their fasting glucose and fast to link insulin measures from which we can then derive measures of something called HOMA IR, which is a measure of insulin resistance.

Dr. Wendy Post: And the associations that you saw were primarily with the HOMO IR and the two hour glucose levels but less with the hemoglobin A1c?

Dr. Keith Diaz: Correct.

Dr. Wendy Post: So it really appears to be that insulin resistance that's most affected by the total sedentary time and sedentary bout duration. Tell us about potential confounders and how you factored that into your analysis.

Dr. Keith Diaz: Yeah, there was quite a number of potential confounders between this relationship of sedentary behavior and glycemic biomarkers. One of them in particular that we were concerned about most were things like body mass index or exercise or physical activity levels. And so we took a look at what we adjusted for those confounders how the relationship changed. And what we did find was that there was an attenuation and association between sedentary behavior and the glucose markers, but there was also ... were still statistically significant. So suggestive that maybe they're partly in the pathway of body mass index or exercise but they didn't make the relationship go away. I should add that we looked at a couple other confounders, we looked at things like inflammation, C-reactive protein, as well as whole bunch of other measures of cardiovascular risk factors. I'll stop there.

Dr. Wendy Post: And what about the fact that study is cross-sectional, are there any caveats related to the study design that you'd like to point out to the audience?

Dr. Keith Diaz: Yeah, I think that's an important point, that this is cross-sectional, so by no means can we infer causality that sedentary behavior causes glucose dysregulation, it's just purely an association. So I think anyone listening to this podcast should keep that in mind when reading this paper or listening to this podcast.

Dr. Wendy Post: So if you were writing the next set of guidelines what would you recommend in terms of how you implement these findings into guidelines? Not to imply that we think that these cross-sectional observational data mean that we're ready to change guidelines but, if these were replicated in randomized trial or some other more objective data study design, how do you think we should use these results to change our behaviors?

Dr. Keith Diaz: I think these guidelines point ... or, with the current guidelines are, sit less, move more, where the guidelines that came out from AHA in October of 2016. In part, they were not as specific because we don't have quite the quality of guidelines or data that we need for more qualitative guidelines, or quantitative guidelines. I think if we're able to replicate these data with [inaudible 00:14:10] or point us towards at least is, also, that we should be interrupting our sedentary bouts. And so what I'd like to see hopefully if we can replicate something I'd like guidelines that say every 30 minutes or every 60 minutes of sitting you should stand up and move. And hopefully with future studies that are coming out that we can make them even more specific and something along the lines of every 30, 60 minutes you stand up and walk for 5 minutes or you just stand up for 1 minute. That's where I'd like to see the science head and I think this study points us in the that direction of maybe we have to start thinking about breaking up our sedentary bouts.

Dr. Carolyn Lam: All right you guys, I don't know about you, but I am literally standing up right now while I'm listening to you both. This is so interesting and I love the way, Wendy, you reflected the robust discussions we had as team when we were working through this paper. Congratulations again, Keith, for just this remarkable paper. Actually, maybe I could just ask, Wendy, what do you think? What do you think our next steps that may need to get these kinds of recommendations, perhaps into guidelines?

Dr. Wendy Post: I think as was alluded to before, these are observational data so they're important for hypothesis generation, but really to have evidence that would lead to changes in guidelines maybe having a randomized trial, where obviously you can't have very hard outcomes, but randomized trials of some duration that could potentially lead to changes and important outcomes, would then maybe lead to changes in guidelines. But there isn't anything that we would lose from trying to implement these kinds of behavior, changes into our lifestyle since the downside and the risk is pretty low. So even if they don't make the strongest level of evidence at this point, I think we can still all be mindful of this and so.

One thing that we've been trying to do in our preventive cardiology group at Hopkins is trying to implement walking meetings. In fact, I just had an email discussion with one of my colleagues about meeting tomorrow and she said, "Well, where do you want to meet?" And I said, "Well, why don't we go for a walk? The weather should be nice." And so I think if we're all mindful of trying to, not only increase our amount of physical activity, but trying to limit the sedentary bout duration by being creative and trying to change, sort of, long standing traditions of having meetings sitting in an office, then that could be helpful.

So, just something for our audience to think about as well.

Dr. Carolyn Lam: That's brilliant. You know, the one thing that I was thinking, though, just thinking about the reception of these data in my country, in where I practice, in Asia. This was a purely Hispanic or Latino population. I suppose there is a perception that that population may be predisposed to cardiometabolic disease and so on, and so you know, what's the applicability to us in Asia? So, I'm really happy, particularly to hear how you've taken it on. I mean, it's a simple thing, why not, right? Just to be more active. There's surely can't be something wrong with that. What do you think of that?

Dr. Wendy Post: Totally, I think it's important to emphasize the unique nature of these data and that they come from a Hispanic study, which is a really important addition to our literature in epidemiology and cardiovascular disease and certainly there are significant differences in lifestyle among different communities within the United States and across the globe, as you've experienced having lived in different countries. And so, I think we need obtain more data about how there might be differences based on various traditions and different lifestyles, and try to target those who are at greatest risk.

Dr. Carolyn Lam: Keith, did you have anything to add to that?

Dr. Keith Diaz: Yeah, I think Wendy is right on and certainly I don't think we have any reason to suspect that sedentary behavior acting differently in Hispanics versus other populations, and so I still think going forth with this notion that we all should be reducing our sedentary behaviors is important to highlight.

Dr. Carolyn Lam: Fantastic. Well, thank you both for a really wonderful discussion. This is really cool, I think a lot of people will be talking about this.

Listeners, you've heard it first, though, in Circulation on the Run. Thank you for joining us today and don't forget to tune in next week.

Circulation October 3, 2017 Issue

2 oktober 2017 | 20 min

Today's issue features striking results from the ASSERT 2 trial of the prevalence of subclinical atrial fibrillation detected with implantable monitors in a group of high-risk older individuals. Much more soon, right after these summaries.

The first original paper in this weeks' journal shows for the first time that myocardial edema, in the week after STEMI in humans, is a bimodal phenomenon. First off, there is Dr. Fernandez Jimenez and Barreiro-Perez, corresponding author Dr. Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that the time course of edema reaction in 16 patients with anterior STEMIs successfully treated by primary angioplasty compared to 16 matched controls using cardiac magnetic resonance and assessing its implications for myocardium at risk quantification. The STEMI patients were scanned serially within the first three hours after reperfusion and at, one, four, seven and 40 days, while controls were scanned once. Furthermore, they performed an experimental study of 20 pigs undergoing 40 minute ischemia reperfusion, followed by serial cardiac magnetic residence exams at 120 minutes, one, four and seven days after reperfusion.

The authors found that am initial wave of edema appeared abruptly at reperfusion, but it was significantly attenuated by 24 hours. The initial wave of edema was followed by a second or differed healing related wave of edema several days after reperfusion, reaching a plateau around four to seven days after myocardial infarction. Of note, cardiac magnetic resonance myocardium at risk quantification at 24 hours post-reperfusion severely underestimated the infarct size.

In summary, post-MI edema in patients follows a bimodal pattern, which affects cardiac magnetic resonance in estimates of myocardium at risk. The dynamic changes in post-STEMI edema, highlight the need for standardization of cardiac magnetic resonance timing to retrospectively delineate myocardium at risk and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day four and seven, post-MI, seems a good compromise for standardization. However, further studies are needed to study the effect of other factors on these variables.

The next paper sheds light on molecular mechanisms underline the progression of atherosclerosis, involving multiple inflammatory events, as well as the counteraction by inflammatory responses in cells such as the endothelium, circulating monocytes and resident macrophages in the arterial wall.

Co-first authors, Dr. Li and Martin, corresponding author Dr. Shyy from Xi’an Jiaotong University Health Science Center and University Health Science Center and University of California, San Diego and colleagues, analyzed RNA seek data to identify cholesterol oxidation and e-flux genes regulated by Kruppel-like factor 4, which is a key anti-inflammatory transcription factor. They found that Kruppel-like factor 4 upregulates cholesterol 25 hydroxylase and liver X receptor in vascular endothelial cells and macrophages. In further in vitro and in vivo experiments, they show that access enhanced reverse cholesterol transport from the vascular wall, mitigated inflammation through suppression of sterile regulatory binding protein two and NOD-like receptor family hiring pyrin domain containing protein three inflammasome in endothelial cells and also promoted cholesterol e-flux in M1 to M2 transition in macrophages.

In summary, Kruppel-like factor 4 trans-activates cholesterol 25 hydroxylase and liver X receptor, promoting the synergistic effects between individual cells and macrophages to protect against atherosclerosis susceptibility, and this may therefore be a therapeutic target for cardiovascular disease.

The next study provides data on the safety and efficacy of a novel cobalt alloy-based coronary stent eluting the antiproliferative agent, ridaforolimus, for treatment of patients with coronary artery disease.

Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia and colleagues, reported the primary results of the bionics trial, which was a prospective international, one-to-one randomized trial conducted to evaluate in a noninferiority design, the relative safety and efficacy of ridaforolimus-eluting stents compared to slow release zotarolimus-eluting stents among 1,919 patients at 76 centers undergoing PCI. At 12 months, the primary endpoint of target lesion failure was 5.4% for both devices, thus meeting the prespecified criteria of noninferiority of ridaforolimus stent compared to the zotarolimus stent.

Angiographic and intravascular ultrasound measures of restenosis, late lumen loss and nepintimal hyperplasia measured at 13 months, were similar in both devices. Treatment with the ridaforolimus-eluting stent resulted in low rates of myocardial infarction, repeat revascularization and stent thrombosis, and results were consistent in predefined patients and lesion groups. The authors therefore concluded that these results support the safety and efficacy of ridaforolimus-eluting stents in patients representative of every day clinical practice.

Well, that wraps it up for your summaries. Now, for our future discussion.

Today for our future discussion, we are going to talk about a true global public health problem. It's a condition that affects 33 million people worldwide, a number that is expected to double by 2050, and what we're talking about is atrial fibrillation. Those are the numbers of just what we know of detected atrial fibrillation, but today's paper deals with silent subclinical atrial fibrillation and the results of the ASSERT 2 trial. I'm so pleased I have the first and corresponding author with us today, Dr. Jeff Healey from Population Health Research Institute at McMaster University in Hamilton, Ontario. Welcome, Jeff.

Dr. Jeff Healey: Good morning.

Dr. Carolyn Lam: Also on the show today is Dr. Sami Viskin, associate editor from Tel Aviv Medical Center. Hi, Sami.

Dr. Sami Viskin: Hi. Hello, everybody.

Dr. Carolyn Lam: Jeff, from ASSERT to ASSERT 2, could you give us a bit of the picture of what made you do ASSERT 2 and what have we learned?

Dr. Jeff Healey: The ASSERT trial was a large 2,500 patient trial in patients in with pacemakers and also implantable defibrillators and it was really an easy first place to study this entity of sub-clinical atrial fibrillation because, of course all of these patient had implanted devices with electrodes in their atrial where they could report all of the internal activity continuously for many years at a time. This was done with really no incremental costs or inconvenience to the patient, the data were already being collected, so in ASSERT we asked the question, how common is atrial fibrillation as it is not detected clinically and is it associated with stroke? What we found was that over time, somewhere between 30% and 40% of patients with an implemented device developed atrial fibrillation, which we termed subclinical atrial fibrillation, because this was not detected by the usual clinical mean. Great results, very interesting, but begged the question, is this a unique entity that we see only in pacemaker patients or if you just took older individuals in the more general population, would you see subclinical atrial fibrillation as well? That was really the impetus for doing that ASSERT 2 trial in patients who are over the age of 65, had cardiovascular condition, placed them at increased risk or stroke in atrial fibrillation, but did not have implanted devices.

Dr. Carolyn Lam: Indeed, Jeff. That's a beautiful set up. The ASSERT was really quite a landmark study suggesting that what we know as clinical may be just the tip of the iceberg, isn't it? Now you've extended it, and I think it'd be really important for the audience to understand that ASSERT 2 was really a high risk cohort. Could you maybe tell us a little bit more of what you did and what more we learned?

Dr. Jeff Healey: Sure. These were typical patients who might be attending a cardiology clinic, an outpatient general medicine clinic who did not have pacemakers and did not have any history of atrial arrhythmias, but you're right, they were high-risk. These were patients over 65 who have had clinical risk factors, things like hypertension, or diabetes, but also some other marker of increased risk such as a BNP that was elevated or left atrial enlargement.

Dr. Carolyn Lam: Yeah and your findings were so striking. Tell us.

Dr. Jeff Healey: What was quite was surprising was, indeed, we found that in the non-pacemaker, non-defibrillator population from ASSERT 2, we also found high prevalence of subclinical atrial fibrillation. This was really quite surprising. In fact, it was many times higher than we had predicted. We found that over time, the annual risk of developing atrial fibrillation in this cohort was 34.4% per year, which is truly astounding number of patients who developed atrial fibrillation.

Dr. Carolyn Lam: That's like one in three of such patients experiencing at least one of these episodes lasting at least five minutes? That's really impressive.

Dr. Jeff Healey: It was high. You could look into that study and find groups where the risk was even higher, so we chose to cut off left atrial volume of 58 millimeters and not correspondent with the median volume of the population series of Olmstead County for people over the age of 65 who came in for an echocardiogram, and that was the minimum left atrial size to get into the trial. If you then looked at within the ASSERT 2 trial and looked at the volumes within the trial, somewhere around 72 1/2 milliliters, if you looked at the patients who had the top of atrial size, that risk was as high 50% per year, so one in two.

Dr. Carolyn Lam: Another thing I noticed though about your results is that the frequency of these episodes, it's not that frequent, and so what we would do typically in a 24-hour monitoring or even a seven-day monitoring would have captured only a small proportion of these. Isn't that the case, Jeff? Could you give us some numbers there?

Dr. Jeff Healey: Yes, of course. The episodes that qualified were at last five minutes in duration, we then do longer episodes in course, but these were much less frequent in the single digit percent risk, and what we found was there were, as you say, quite infrequent. So with the standard 24-hour halter monitor, for example, you would have had a very low pickup. It really goes to show that the longer you monitor, the more you will find. I think that's the key message out of this study and other studies like it.

I think conversely, you also have to realize that the more you look, or the harder you look, you may be uncovering atrial fibrillation that behaves differently than atrial fibrillation you find, for example, in the single 12 lead ECG. We have found, and others have found, that the risk of stroke we find when we would have short episode picked up only with long term continuous monitoring is real but it's much lower than we see with atrial fibrillation that was picked up by ECB where patients are presenting in emergency rooms stroke with symptoms.

Dr. Carolyn Lam: That's such relevant points, and it really brings up the unanswered questions perhaps, exactly what is the correlation with stroke risk? What should we do about it? Sami, I'm sure you have other questions when you handle this paper and we had so many discussions among the editor, would you like to just start the ball rolling in some of these considerations?

Dr. Sami Viskin: Well, actually, we understood from the beginning of the study was not powered to show any difference in outcome by intervention, by treating any of these patients that had discovered atrial fibrillation with anticoagulation, so we took this paper as what it is, a paper that shows the unexpectedly high privileges of atrial fibrillation in patients who have neither symptoms nor electrocardiographic documentation of atrial fibrillation when they undergo implantation of our recording device. So we took this paper for what it is, a very interesting finding that opens the door for new studies, testing perhaps the value of intervention with anticoagulation at an earlier stage.

Dr. Carolyn Lam: Yeah, I agree. I'd love to hear Jeff’s thoughts on what those next steps may be, but just to point out to the audience, I mean, at the moment, our decisions on whether to anti-coagulate, like the CHADSVASC score and so on, doesn’t really take into account the type of atrial fibrillation or the duration of atrial fibrillation? Does it? What do we do now? What do we do in the context of the fact that results, like the COMPASS trial, that maybe just based on the presence of vascular disease, we should anti-coagulate, right? Jeff, how about your thoughts? What are the next steps?

Dr. Jeff Healey: You're right. I mean, is there a value for empirically anticoagulating individuals. That's really going to boil down to the individuals with an absolute risk of stroke and how well they do on anticoagulants. Good question.

In the post-stroke world or post-cryptogenic stroke, which we now report to as [inaudible 00:16:48], these individuals are being evaluated with two large clinical trials, looking at this idea of just empiric anticoagulation with low dose, NOAC in comparison to aspirin. These trials are ongoing, and they expect to report findings by the end of 2018.

In the general population, no such large scale trial is ongoing at the present time. You mentioned COMPASS and the big COMPASS results were clearly a big result at the European Society meeting, but it must be clarified that the dose of NOAC or rivaroxaban used in COMPASS was not the typical dose that we would use in the treatment of patients with atrial fibrillation, so much lower. I think we have to be careful when we're talking about doses that may be different 5 to 10 fold and what is then coagulating a patient and what is not. I think, certainly, I would not consider the COMPASS tests right now to be an effective atrial fibrillation dose, but as we've discussed, subclinical atrial fibrillation is different and we may have further data in the future.

Now, how do we get there? I think many people are aware of two ongoing trials, the ARTESIA trial, which is run by our group, the NOAH-AF Trial run by Kirchof and the group from Birmingham and the AF-NET organization, and these two ongoing trials have taken this question back again, so the pacemaker population that we are enrolling thousands of patients with pacemakers and defibrillators who have these short episodes, and they're being randomized treatment with a full dose new oral anticoagulant vs aspirin. These trials are ongoing, and I think these trials and the pacemaker population will actually give us the answer to what is the risk benefit for treating, so interesting course of event. We started in the pacemaker population to show there was risk for these short episodes, that this was hotly debated 10 - 15 years ago, and now we take ASSERT 2 and other trials into the non-pacemaker population to show that this is actually a problem for older individuals in general, and now the third step, go back into the pacemaker clinic again and to do trials to study the effectiveness in therapy.

Dr. Carolyn Lam: Great point and great takeaways. How about, Sami? What do you think would be the take-home message for clinicians at this moment based on what we know now and based on this new data?

Dr. Sami Viskin: Well, the message is clear, the message is that atrial fibrillation is far more prevalent than what we think it is, the message is that for every event of atrial fibrillation that we feel we probably have many events that we don't feel we should be distrustful about judging the decision to anti-coagulate or not based on symptoms, and I'm referring now to patients who already have one event documented of atrial fibrillation and are waiting until they feel the next one, before they start taking anti-coagulations. This is another warning about how we should be careful about trusting symptoms when deciding to treat and when not to treat. I just said this opens a new door for a new line of studies, looking at how early to intervene with anticoagulation, what dosage should be used for these patients who probably have lower burden of atrial fibrillation. If you can see that the patients who have atrial fibrillation documented on the electric cardiogram, as patients who simply have a higher burden and therefore they are more likely to come up with documentation on a regular ACG, so perhaps those only have subclinical atrial fibrillation have a lower burden, perhaps they can benefit from lower doses of anticoagulation, but these are all fit, that need to be proven by trials.

Dr. Jeff Healey: It is not only an issue for implanted devices but with the implantable cardiac monitors, this is now relevant for many other patients who have these devices implanted for things like syncope, but also there's been a lot of progress in the last 5 to 10 years on surface-attached based monitors or other types of monitors that can be with patients for days, weeks and even months, and we're all grappling with this in clinical medicine, what to do with a person with 25 beats of an atrial tachycardia or 37 seconds on a 30-day monitor? It's all an issue of the density, the burden of arrhythmia, and we do believe there is some gradience in the risk of stroke ... You're right, the treatment is not obvious, but we should take our treatment for patients who are in atrial fibrillation a lot or all the time, and simply apply it upstream like, that we may have very different treatment or approaches that are more tailored to individual patient risk.

Dr. Carolyn Lam: Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff. We discussed a lot of other questions that need to be answered, but you've really opened the door to look at some of these questions with your paper today and we're really very proud to be publishing your paper in this week's journal.

Thank you very much, listeners for joining us this week. Don't forget to tune in again next week.

Circulation September 26, 2017 Issue

25 september 2017 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on new data from the Framingham Heart Study that addresses the question of the prognosis of pre-hypertension among individuals who never progressed to hypertension as well as the role of early versus late onset pre-hypertension in this context. Well, more soon, right after your summary of this week's journal.

The first original paper provides mechanistic insights on the relationship between low and oscillatory wall shear stress, together known as disturbed flow, and atherosclerotic arterial remodeling and stiffness. Co-first authors doctors Kim and Pokutta-Paskaleva, co-corresponding authors Dr. Brewster and Jo from Georgia Institute of Technology in Emory University in Atlanta, Georgia used a novel mirroring model of disturbed blood flow to stimulate arterial stiffening through collagen deposition in young mice. They discovered a critical role for Thrombospondin 1, or TSP1 in activating TGF beta and stimulating arterial stiffening, all of which was significantly attenuated in the TSP1 knockout animal.

Blockade of TSP1 activation of TGF beta decreased the up regulation of pro-fibrotic genes that contributed to arterial stiffening. Furthermore, they show that TSP1 localized to regions of disturbed flow in arteries from patients with peripheral artery disease and these arteries had similar increases in collagen gene expression. Thus, this work links TSP1 up regulation to arterial stiffening and identifies TSP1 as an important promoter of pathologic arterial remodeling in peripheral artery disease.

The next study provides international insights on the degree to which secondary prevention treatment goals are achieved in clinical practice among patients with diabetes and cardiovascular disease. First and corresponding author, Dr. Pagidipati from Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina, looked at 13,616 patients from 38 countries with diabetes and cardiovascular disease in the TECOS trial. They found that only 30 percent of patients met all 5 secondary parameters of aspirin use, lipid control, blood pressure control, angiotensin-converting enzyme-inhibitor, or ARBUs, and non-smoking status.

Only 58 percent of individuals with diabetes and cardiovascular disease attained blood pressure control. Furthermore, the degree to which secondary prevention goals were met in this trial varied by the world region and country. In summary, patients with diabetes and cardiovascular disease are still being undertreated globally with respect to secondary prevention, and especially with regard to blood pressure control. These gaps in care provide clear opportunities for improvement in this high risk population.

The next study is the first to directly compare data from an electronic data research network to a large cardiovascular disease cohort. First author Dr. Ahmed, corresponding author Dr. Allen from Northwestern University in Chicago and colleagues sought to evaluate the degree of agreement of electronic data research networks compared with data collected by standardized research approaches in a cohort study. To achieve this goal, authors linked individual level data from the multi-ethnic study of atherosclerosis, or MESA community based cohort with Healthlink, a 2006 to 2012 database of electronic health records from 6 Chicago health systems.

They identified areas of agreement and disagreement between blood pressure, cardiovascular risk factor diagnosis, and cardiovascular events between the two data sources. The correlation was low for systolic blood pressure, compared with MESA, Healthlink overestimated systolic blood pressure by 6.5mm mercury. Conversely, there was a high correlation between body mass index in MESA and Healthlink. Healthlink underestimated body mass index by 0.3 kilograms per meters square.

Using ICD-9 codes and clinical data, the sensitivity and specificity for Healthlink queries for hypertension were 82.4 percent and 59.4 percent. For obesity these figures were 73 percent for sensitivity and 89.8 percent for specificity and for diabetes they were 79.8 percent for sensitivity and 93.3 percent for specificity.

Finally compared with adjudicated events in MESA, the concordance rates for myocardial infarction, stroke, and heart failure were at 41.7 percent, 61.5 percent, and 62.5 percent, respectively. These findings therefore illustrate the limitations and strengths of electronic data repositories compared with information collected by traditional standardized epidemiologic approaches for the ascertainment of cardiovascular risk factors and events.

The next paper helps physicians and patients to make an informed decision about whether or not to stop low dose aspirin use. First and corresponding author Dr. Sundstrom from Uppsala University in Sweden and colleagues investigated whether long term low dose aspirin discontinuation increased the risk of cardiovascular events in a cohort study of more than 600,000 users of low dose aspirin for primary or secondary prevention in the Swedish prescription register between 2005 and 2009.

They found that patients who discontinued aspirin had a 37 percent higher rate of cardiovascular events than those who continued, corresponding to an additional cardiovascular event observed per year in one out of every 74 patients who discontinued aspirin. The risk increased shortly after discontinuation and did not appear to diminish over time. Thus, in long term users, discontinuation of low dose aspirin in the absence of major surgery or bleeding seemed to be associated with a more than 30 percent increased risk of cardiovascular events, thus adherence to low dose aspirin treatment in the absence of major surgery or bleeding may be an important treatment goal.

The final study raises the possibility of using Histone Methyltransferase Inhibitors for the treatment of heart failure. Dr. Papait from Humanitas Clinical and Research Center in Italy and colleagues focused on G9A, a histone methyltransferase that defines a repressive epigenetic signature. Using normal and stressed cardiomyocytes from a conditional cardiac specific G9A knockout mouse, and a specific G9A inhibitor, they showed that the histone methyltransferase G9A was important in defining the epigenetic landscape that maintained the transcription program of the cardiomyocyte. It was also important for the regulation of gene expression reprogramming during cardiac hypertrophy.

Furthermore, impaired G9A function promoted cardiac dysfunction. Thus, these findings suggest that G9A may represent a therapeutic target for early stages of cardiac hypertrophy.

That wraps it up for your summaries, now for our feature discussion.

For today's feature discussion, we're talking about the very important topic of the prognosis of prehypertension without progression to hypertension. Now, we've always known that mild blood pressure elevations that we call prehypertension are associated with cardiovascular risk. However, this risk could be attributable to the fact that these patients with prehypertension eventually progress to overt hypertension. But, what happens to the patients with prehypertension who do not progress to hypertension, and what is the role of early versus late onset prehypertension?

Well, we have some answers today and I am so pleased to have the first and corresponding author with us, Dr. Teemu Niiranen, from Boston University's Framingham Heart Study. Welcome, Teemu.

Dr. Teemu Niiranen: Thank you very much, great to be here.

Dr. Carolyn Lam: And to help us along in this discussion, we have a familiar voice. Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back, Wanpen.

Dr. Wanpen Vongpatanasin: Thank you Carolyn. Happy to be here.

Dr. Carolyn Lam: Teemu, you know, I sort of set the background that you so nicely articulated in this research letter, but could you tell us a little bit more of what you were looking at, how you did it, and what you found?

Dr. Teemu Niiranaen: My boss, Dr. Vasan, was also a coauthor in this paper, he already showed some 15 years ago that prehypertension carries greater cardiovascular risk than perfectly normal blood pressure. However, it's pretty much unclear what happens to people who are prehypertension but never go on to develop hypertension because even the name suggests that if you have prehypertension you will get hypertension. We also looked at what effect does the age of developing prehypertension and hypertension have in this context.

We used a case cohort setting in the Framingham Heart Study in the way that we only looked at 5 1/2 thousand decedents. These were people who had already passed away. Then we categorized those decedents into 5 categories, people who never got prehypertension or hypertension, people who developed prehypertension late in life, who never developed hypertension, and people who developed early onset prehypertension but never developed hypertension, and then people who went on to develop late or early onset hypertension. We used a cutoff of 55 years as the definition of early onset versus late onset.

Then, in a case cohort setting, we estimated case versus controls, adjusted case versus control odds ratios, for the 4 prehypertension/hypertension categories versus those who died without ever developing prehypertension.

Dr. Carolyn Lam: Teemu, could I just stop you here before you share the intriguing results. I just wanted to remark that it's so amazing how the Framingham Heart Study really enables analysis like this, simply because of the long follow up and just the great detail and the standardization of blood pressure measurements and so on. I mean, as I said, I worked at the Framingham Heart Center, and we were trained to do this in a standardized fashion.

Define prehypertension and hypertension, just in case, and then please tell us your results.

Dr. Teemu Niiranaen: Prehypertension was 120 to 135 systolic blood pressure, and a diastolic blood pressure of 80 to 89 millimeters mercury, and then hypertension was 140 over 90 millimeters mercury, or antihypertensive medication, and yes, your correct that the Framingham Heart Study provides a very unique setting. Especially for defining early versus late onset hypertension because we can define the age of hypertension or prehypertension or prehypertension onset objectively because these people have been followed up, they have attended so many exams, especially the original cohorts.

But, to the results, so we observed that basically people who develop prehypertension, either early and especially late in life, but did not ever develop hypertension, their risk, or odds of dying of cardiovascular disease versus non-cardiovascular disease was pretty much similar to those who never develop prehypertension or hypertension, while conversely the people who went on to develop either late or especially early onset hypertension, or developed early onset hypertension they had considerably greater risk of cardiovascular death versus those who developed either prehypertension or hypertension. That's our main result. I won't go into conclusions yet.

Dr. Carolyn Lam: Okay, but maybe at this point, I could ask Wanpen to share some thoughts. I mean, this is very striking findings. Curious what you think the clinical implications were, and especially as we discussed among the editors.

Dr. Wanpen Vongpatanasin: It is very important study that, as Teemu outlined it, to look at the fate of people with prehypertension and I think that's the first time we had this kind of data to show whether the earlier versus late prehypertension and even hypertension itself. I don't think people have looked at in the large number in terms of outcome people who have early versus late onset hypertension. I found the result to be fascinating.

Dr. Carolyn Lam: Yeah, what does this mean though when we see a patient with this sort of borderline hypertension, you know, falling in the prehypertension range. We don't know whether they're going to develop hypertension. What do you think the clinical implications are? Teemu?

Dr. Teemu Niiranaen: Unfortunately a lot of the people who develop prehypertension as the name suggests they go on to develop hypertension, but there is still a considerably great part that never develop hypertension, and our study shows basically that if you are able as a doctor or a patient to prevent progression to hypertension you are much better off and this really hasn't been previously shown, so it just should motivate patients and also doctors to strive to, if they see a prehypertensive individual, try to through lifestyle and other interventions try to prevent the progression to hypertension.

Dr. Carolyn Lam: Yeah, I think that was one of the take home messages for sure. Were there any other plans for future work you think that needs to be done?

Dr. Teemu Niiranaen: There's the everlasting problem with observational studies, so definitely it would be great if our results could be taken into clinical trials or anything to test whether interventions, A, that preventing the progression from prehypertension to hypertension could then impact cardiovascular outcomes.

Dr. Carolyn Lam: Indeed, and if I may comment, I've always wondered about ethnic differences when it comes to this. The one thing that Framingham, you know, it's difficult to see from there, is what happens in other ethnicities other than white ethnicities, isn't it? Still, very striking findings. Wanpen did you have any other comments or questions from Teemu?

Dr. Wanpen Vongpatanasin: Well, I think that one thing also that's interesting to me is even the people who had early onset prehypertension, although the number of CHD deaths were not significant, but the odds still 28 percent higher than the control that will never have prehypertension so, I think that that the signal is there but perhaps because the number of people who had prehypertension but never really progress to prehypertension is relatively small. It could be underpowered to see the significance and I think that from this study, it tells me that the exposure to blood pressure to our life, I think is the blood pressure lowered on the cardiovascular system, I think that's the one that really determine the cardiovascular outcome the most. I think that we should not discount that this is not a truly benign phenomenon, I think hopefully they'll be some more data from the Framingham group or other group.

Also, I think that this study also very important to show that early onset hypertension actually have the worst prognosis, and often time when people come to see a doctor when they're 30 and 40 years old, they don't really want to take medicine, and the physician often time are reluctant to prescribe the drug, and I think that this study say that we probably need to be a little bit more serious about it, because they actually have the most cardiovascular events.

Dr. Carolyn Lam: What excellent points, and you know what? At this point I just want to highlight that beautiful figure that you have in your research letter, Teemu. I think it says it all. It highlights that point estimate for the prehypertension groups is not exactly 1. If anything, it is above 1, right? For the odds of poor outcomes, so I do take Wanpen's point as well. Beautiful figures, and I also actually want to use that to ask you a different question Teemu. You have 1 figure, because this is a research letter that only allows 1 figure and 800 words, and you've put so much important information into that space. I'd love for you to share that experience with our listeners too, of a research letter versus a full paper. Why did you choose to submit yours as a research letter, and how was that?

Dr. Teemu Niiranaen: One of the important take home messages from this was the differences between early onset versus late onset hypertension that we'd been also recently publishing on, so we wanted to delve more in depth on this prognosis of prehypertension versus hypertension so we don't have to be repetitive too much. We decided to focus on this very small topic most intensively, therefore we decided that maybe a research letter would be the most effective way so we could communicate all the really novel stuff that we have in just one figure. Well, it has 3 panels, but it still counts as 1 figure.

I just wanted to point out that maybe the early onset prehypertension, yeah the confidence intervals are somewhat wide, but the panels sees for coronary heart disease versus non-cardiovascular disease deaths, so that's maybe a bit more underpowered than the back panel B, so the CHD deaths are part of the CBD deaths, so with CBD deaths, the early onset prehypertension, the odds ration was 1.09, but still of course the confidence intervals reach up to 1.49. Just to clarify the difference between panel B and panel C, so B's better powered.

Dr. Carolyn Lam: It's a very nice figure, and indeed, I think it works very, very well as a research letter, and I think the fact that we're discussing it right now shows that length doesn't dictate importance. Wanpen you had a few comments about that. What do you think of a research letter format?

Dr. Wanpen Vongpatanasin: Yes, I think this research letter is a really important part of articles in Circulation. I think that all the others should be aware that we're trying to enter at submission if it's suitable, just like this one. It actually show up in the pub med exactly like the full article and gets cited as much and sometimes much more than a regular article because it capture the essence of one more focused problem and the figures and table allow to show only one or two at a time, so they really capture the essence or the guts of the article and the reader can go through that quickly and grasp the concept and learn within flipping through a few pages.

I think we should have many more interesting research letter like this.

Dr. Carolyn Lam: Congratulations again Teemu for a beautiful paper, a very important one. Thank you Wanpen for shepherding this one.

And thank you listeners for joining us today. Don't forget to tune in again next week.

Circulation September 19, 2017 Issue

18 september 2017 | 23 min

Today we will be discussing the cost effectiveness of statin use guidelines for the prime and prevention of coronary heart disease and stroke. Comparing the 2013 American College of Cardiology American Heart Association guidelines with the adult treatment panel three guidelines. A very important and current discussion that you don't want to miss. All coming up right after these summaries.

The first original paper in this week's journal is the largest study yet reported that assessed the long term outcome of Takayasu's Arthritis. First author, Dr. Comarmond, and corresponding author Dr. Saadoun and colleagues from Hospital Pitie-Salpetriere in Paris performed a retrospective, multi-centered study of 318 patients from the French Takayasu network including patients with Takayasu Arthritis fulfilling the American college of Rheumatology and/or Ishikawa criteria. They found that, firstly, 50% of Takayasu arthritis patients relapse and experienced a vascular complication at ten years. Secondly, male sex, elevated CRP, and carotidynia were independently associated with relapse and with a two-fold higher risk of relapse. And thirdly, patients at high risk for vascular complications could be identified according to presence of two or more of the following risk factors: progressive clinical course diagnosis, thoracic aortic involvement, and or retinopathy. In summary, these factors identify patients with a high risk of relapse or vascular complications and may therefore serve to adjust more aggressive management and close follow up in Takayasu's Arthritis.

The next study provides experimental evidence for a pathogenic role of the transcription factor interferon regulatory factor five or IRF-5 in atherosclerosis. In this study from co-first authors, Dr. Seneviratne and Dr. Edsfeldt, corresponding author Dr. Monoco from Kennedy Institute of Rheumatology in Oxford, United Kingdom, and colleagues. The authors showed that atherosclerosis prone apple-E negative mice who were also deficient in IRF-5 showed reduced atherosclerosis lesions and necrotic core formation. They found that the development of the lesion necrotic core was controlled by IRF-5 through impairment of macrophage dead cell removal, or spherocytosis. They further demonstrated that the CD-11C gene was a direct target of IRF-5 in macrophages and that IRF-5 was important in maintaining CD-11C positive macrophages in atherosclerotic lesions. In summary IRF-5 was shown to be a potential therapeutic target since its inhibition could reduce plaque inflammation and necrotic core size, thus potentially promoting a stable plaque phenotype with a lower risk of acute clinical complications.

The next study is the first to assemble a transcriptomic framework of multiple cardiac cell populations during post natal development and following injury, thus enabling comparative analysis of the regenerative or new natal state, compared to the non regenerative or adult state. In this study from first author Dr. Quaife-Ryan and co- corresponding authors Dr. Porrello from the Royal Children's Hospital and Dr. Hudson from the University of Queensland, Australia. The authors isolated cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarct and non infarct neonatal and adult mouse hearts. The then performed RNA sequencing on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair and regeneration. They further, surveyed the epigenetic landscape of cardiomyocytes during post natal maturation by performing deep sequencing of assessable chromatin regions. This comprehensive profiling of cardiomyocytes and non myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non regenerative time points. The majority of transcriptional changes in all cardiac cell types resulted from development maturation from neo natal stages to adulthood. Rather that activation of a distinct regeneration specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state.

But in contrast cardiomyocytes failed to reactive the neonatal proliferative network following infarction which was associated with loss of chromatin accessibility around cell cycle genes during post natal maturation. In summary these findings are significant because they defined a regulatory program underpinning the neonatal regenerative state and identified chromatin modifications in adult myocytes that could restrict cardiac regenerative potential after birth and may need to be overcome to facilitate cell cycle re entry in adults.

The final study reports results of two studies investigating the pharmicokinetic and clinical outcomes of a new drug coated balloon to treat femoral popliteal disease. The first study is the Illuminate pivotal study in which 300 symptomatic patients were randomized to stellarex drug coated balloon or standard angioplasty. The primary safety outcome was freedom from device and procedure related death through 30 days and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency through 12 months. The second study was the illuminate pharmicokinetic study in which paclitaxel plasma concentrations were measured after last balloon deployment and at pre specified times until no longer detectable. In this report my first in corresponding Dr. Krishnan from Mount Sinai Medical Center in New York. In the pivotal study the primary safety endpoint and the primary patency rate was significantly higher with the drug coated balloon. The rate of clinically driven target lesion revascularization was significantly lower in the drug coated balloon cohort. pharmicokinetic outcomes showed that all patients had detectable Placitexal levels after drug coated balloon deployment that declined within the first hour.

In summary these findings demonstrate the safety profile and superior patency of the stellarex drug coated balloon for femoral popliteal disease compared to standard angioplasty. This therefore suggests that this drug coated balloon may be a valuable treatment option for patients with superficial femoral and popliteal artery disease.

Well those were your summaries now for our feature discussion.

Today we are discussing the highly relevant and also highly controversial issue of Statins for primary prevention of cardiovascular disease and when do we start a statin. How cost effective is it, and of course all this discussion really began with the 2013 ACC/AHA guidelines that expanded the recommended statin use. I am so pleased because this week’s journal actually provides, for the first time, some cost effectiveness data that may help us in making this decision and in facing our patients. I can't tell you the number of times I've had an individual patient come to me and just want to discuss all the pros and cons of starting a statin for primary prevention and I'm sure, listeners out there you identify with this. Well hang because today we have the corresponding author of today's feature paper Dr. Kirsten Bibbins-Domingo from University of California, San Francisco as well as the editorial list on this wonderful paper, Dr. Rodney Hayward from University of Michigan and VA Ann Arbor. Welcome Kirsten and Rod.

Dr. Kirsten Bibbins: Thank you.

Dr. Rodney Hayward: Great to be here.

Dr. Carolyn Lam: Kirsten, could you please tell us the top line results of what you found in this paper, it's such an important paper.

Dr. Kirsten Bibbins: We use simulation modeling to compare three approaches to giving Statins for primary prevention. The older guideline in the US called ATP-3, the one that you mentioned in your introduction the ACC/AHA guideline that broadened the use of Statins to many many more people and then an even broader strategy where we don't look at cardiovascular risk, and in each of these approaches we found that the use of Statins for primary prevention was very effective and in fact cost saving, when we did a cost effectiveness analysis. And regardless of the assumptions that we made about more side effects then we had known from the literature or could anticipate or regardless of the parameters that we put into the model we found that, pretty much that the broad use of these medications is effective and, in fact, cost saving.

Dr. Carolyn Lam: Could you give us an idea of what you used in that simulation model, what population was it, how applicable is it to people outside the US, for example.

Dr. Kirsten Bibbins: Simulation modeling is a way to take the evidence that we have from multiple types of studies and to try to synthesize that evidence and apply it to, in this case, the population of the US. So our simulation model uses the demographics of the US and takes the primary studies and the effect rises that we know from those studies and using that model we found that each of these three approaches had both health benefits and cost saving benefits. It's applicability might be somewhat variable if this were applied to a different population, but the effects are pretty substantial and so it suggests that Statins are likely to be beneficial using these approaches in a broad array of populations.

Dr. Carolyn Lam: Could you give us an idea of the estimated effect size, you know, when you say cost effective, for example, how, how much and for what. Give us everyday clinician some kind of take home of numbers that would make sense for them.

Dr. Kirsten Bibbins: One way to think about these types of cost effectiveness analysis is that often times they give us numbers that suggest that we have to pay a certain amount to get the type of health benefit that we want. In this case because we found that they were cost savings, it actually suggests that the amount that we pay for Statins, to give Statins to a broad population of individuals actually saves us money. It saves us money in terms of the heart attacks that are avoided, and the other types of health care costs that are avoided and probably a number that might be relevant to your audience might be that the number that one would need to treat in order get one additional year of life, through using these Statins for primary prevention, is on the order of about 35 individuals and so that's a small number that we would be treating in a primary care practice in order for an additional quality adjusted year of life.

Dr. Carolyn Lam: I thought that was really one of the most remarkable figures, you know, that the ATP-3 guidelines would result in 8.8 million more statin users than the status quo and that was an entity of 35 per quality of life. Was that correct?

Dr. Kirsten Bibbns: That's exactly right.

Dr. Carolyn Lam: Whereas the ACC/AHA guidelines could potentially result up to 12.3 million more statin users than the ATP-3 guidelines with a marginal number needed of 68 per quality of life. So very, very useful figures, but you know, I began by saying my individual patient. These feel like population bases statistics, you know, and my individual patient kind of wants to know but for me, what's a long term risk and so on. And these are issues that you have discussed so elegantly, Rod, in your editorial. Could you enlighten us a bit on these considerations.

Dr. Rodney Hayward: Sometimes decisions that we have to make in policy are inherently population based decisions, like putting fluoride in the water, in which the average benefit of cost for population is what you have. Cause you can't treat individual separately with that type of intervention, but with a statin, the average that a population gets is not the important thing to our patients across the room. And it's sort of the number needed to treat for them, how likely are they to benefit. And what I think this paper establishes very well, and I think it's important to start with why the areas of agreement here, this establishes that the new guidelines are a great idea. There's no assumptions in this model that would change that starting people on a statin between 7.5 and 10 % ten year risk isn't a good idea. And that aspect of the paper even some of the issues I have about some of the assumptions are not going to be relevant, where it starts to become concerning, and will always be controversial is how low of risk to start it at. Do we go from 7.5 to a 5% risk? Do we start putting everyone at age forty on a statin?

And at that case, certain elements of this simulation model are very important, the likelihood of an individual benefiting becomes very, very small. And even a small dislike of the medicine, would outweigh that. But also you have to assume in this model that we know all the bad things of a statin at 20-25 years, because you're starting to put people on a daily medicine that's biologically active for 30 years. And it's impossible statistically, epidemiologically, to know with any degree of certainty whether or not being on these medicines for 20-30 years would have unheard effects. We don't have that ability, currently, even if we had the databases so how should individuals think about that, well my feeling is that is part of the shared decision making of how much a patient worries about unknowns, about being on a medicine long-term versus they worry more about the potential for a heart attack prevention which are likely there. I want to emphasize again these are not relevant concerns when we're talking about the current guidelines, these are only concerns when we start pushing it down to a 5% risk or everyone over 40 where you're extending to tens of millions more people, in which the population benefits would be substantial.

As long as people don't mind taking a pill every day at those ages and we know all of the harms being on a statin for 20 years. And that's something that no one knows.

Dr. Carolyn Lam: Rod that was just so eloquently stated, and listeners out there, you just have to read this editorial. It states these things very clearly, and I think it's really helpful in our thinking of what to tell patients when we do see them. Kirsten, I'd love to invite your thoughts on what Rod just said, you acknowledge this, fully in your paper. Curious, any steps you took to maybe address this and what you would say as a take home message for clinicians?

Dr. Kirsten Bibbins: I think that Rod's bringing out exactly the point. And, I think, we have seen the shift from the earlier guideline to the most recent guideline in putting more people on Statins and these medications certainly have the benefit, but as you bring more and more people on who have lower overall cardiovascular risk, their likelihood of benefiting while there, is always smaller. And so then other things do come in to play, and I think the thing that probably was most surprising to us as we put this work together, was how sensitive our results were to, essentially, a patients preference as we moved down into including more of these lower risk individuals. That means that an individual who's lower risk may not directly benefit or their likelihood of benefiting in terms of avoiding a heart attack is lower, and so therefore the facts that their tolerance for taking a daily medication is in fact, then becomes relevant in to their particular trade off for taking this medication. And I think that is clinically important as we think about including more and more lower risk people into these types preventative guidelines, the threshold for any given individuals tolerance for taking a daily medication and of course, as Rod said, if you're doing this over many years and decades the fact that we don't actually know what will happen over the long term, also becomes relevant.

Dr. Carolyn Lam: Just maybe one last question for both of you. What do you think our next step is here, what more do we need?

Dr. Kirsten Bibbins: I just think we still want to continue to expand our understanding of what the long term effects and side effects of daily use of statin therapies are, again I'd want to emphasize as you said it's always important to understand patients preference, but, as Rod said, our current guidelines which really have focused on higher risk individuals, I wouldn't want it to be lost that these medications are in fact very effective and so I think having an understanding of the long term use of these medications and what the potential side effects when used over a long period time are, I think that's a critically important area. As well as really developing continuing to develop the tools that can help doctors and patients together engage in the conversation about the trade off for given individual.

Dr. Rodney Hayward: I would definitely agree with that, but I would focus on three bits of science. That are critically important for refining this issue. The one is something we currently don't have and that's post marketing surveillance of medicines long term. That when you look at the data we have, that, most of them follow patients either a short period of time and don't have enough continuity or their smaller studies in which outcomes that are long term might be found. And this is a place where big data, but also combining and sharing data across health systems could really help us monitor. This is not just an issue for Statins but as more medicines are recommended for younger individuals with life expectancy we need to work on that. Two the results are insensitive meaning that it always looks good, for people in the current guidelines but two elements of the model for people at a 5% risk or starting people at age 40 are assumptions that are being made with the best available data now, but have some considerable concerns and could be improved.

One is, we don't know the impact of a non fatal heart attack on future outcomes, my personal opinion is the assumption in this model, is probably an overestimate. Unimportant for the current guidelines but would be critically important for these younger risk people and ways to really understand the impact of non fatal events on future risk are epidemiologically tricky and it's very easy to pick up things that are markers that aren't causal and then when you run your models you think you're extending life years where you really aren't. And the other is we still don't know how much a Statins relative benefit varies by a persons LDL level, that might seem astounding but there's evidence on both sides. That it is related to baseline LDL and it's not. This is a completely solvable question, the CTT group has the data and we really need them to publish and tell us how much the relative risk of a statin varies by that. The current assumption in the ACC/AHA guidelines is that it is not correlated, the assumption in Kirsten's model is that it is.

Either could be correct, my personal opinion is it's probably in between, those two, but that would help us in terms of thinking of extending to the lower people. If LDL is a partial factor that probably should be considered, if it's not then only risks should be considered. That is completely answerable for those that have access to the RCT data and I'm hoping that this paper may encourage that publication.

Dr. Carolyn Lam: Wow, those were such insightful comments, I can't thank you enough, Rod and Kirsten for joining us today.

Listeners I'm sure you enjoyed that and learned so much just like I did. Don't forget to join us again next week.

Circulation September 12, 2017 Issue

11 september 2017 | 17 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week contains novel data from the TOPCAT trial, this time relating physical activity to prognosis in patients with heart failure and preserved ejection fraction. A great discussion coming right up after this weeks' summaries.

Our first paper tells us that pericarditis may be a marker of occult cancer and augurs increased mortality following the cancer diagnosis. Authors, Dr. Sogaard and colleagues from our host university hospital in Denmark used the Danish medical databases to conduct a nationwide cohort study of all patients with a first-time diagnosis of pericarditis from 1994 to 2013. Among 13,759 patients with acute pericarditis, 1,550 subsequently were diagnosed with cancer during followup.

Patients with newly-diagnosed pericarditis had higher risks than age and sex match members of the general population of being diagnosed with lung cancer, Non-Hodgkin lymphoma, and myeloid leukemia during the first three months following a pericarditis diagnosis, but increased risks for lung cancer and Non-Hodgkin lymphoma and bladder cancer persisted beyond one year following a pericarditis diagnosis. The increased cancer risk was not restricted to patients with pericardial effusion.

Furthermore, pericarditis was a prognostic factor for survival after lung cancer, breast cancer, and bladder cancer. Thus, the clinical take-home message is that patients with pericarditis, particularly when complicated by pericardial effusion, may need to be considered for workup targeted at diagnosing or ruling out cancer.

The next paper provides insights into mechanistic processes leading to stent thrombosis in the largest contemporarily available series of patients undergoing optimal coherence tomography, or OCT imaging, during stent thrombosis presentation. The first author, Dr. Adriaenssens, corresponding author, Dr. Byrne from Munich, Germany, and colleagues of Prestige Consortium, performed a prospective multicenter study to evaluate OCT findings in consecutive patients presenting with stent thrombosis enrolled in a registry that was using a centralized registration system.

In 231 patients with stent thrombosis undergoing OCT, uncovered and malapposed struts were frequently observed, with the incidents of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to the time intervals from index stenting. Uncovered struts and stent underexpansion were the most common observations in acute or subacute stent thrombosis, whereas neoatherosclerosis and uncovered struts were the most common findings in late or very late stent thrombosis. The impact of dedicated clinical strategies for the prevention and treatment of mechanisms underlying stent thrombosis should be investigated in future clinical studies.

The next study identifies a new type of capillary malformation, arteriovenous malformation. Now, we know that most arteriovenous malformations are localized and occur sporadically. However, they also can be multifocal in autosomal dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation arteriovenous malformation or CMAVM. RASA1 mutations have been identified in 50% of patients with CMAVM.

In the current study, first author, Dr. Amyere, corresponding author, Dr. Vikkula from Brussels, Belgium and colleagues studied non-RASA1 patients and found that EphB4 mutations occurred in patients with multifocal capillary malformations associated with arteriovenous malformations. This phenotype named CMAVM2 mimicked RASA1-related CMAVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120-RasGAP was a direct effector of EphB4. Furthermore, the study implicated EphB4-RAS-ERK signaling pathway as a major cause of arteriovenous malformations. Thus, patients with multifocal capillary malformations need to be screened, not only for an inherited RASA1 mutation, but also for EphB4.

The final study identifies a novel potential therapeutic target in the treatment of atherosclerosis, and that is Dickkopf-related protein 3, or DKK3, a secreted protein previously known for its involvement in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but very little studied in atherosclerosis. In the current study, first author is Dr. U.N. [inaudible 00:05:51], corresponding authors, Dr. Qu from Capital Medical University in Beijing, and Xu from Kings College London used both epidemiological and experimental approaches to test the hypothesis that DKK3 was atheroprotective.

In the prospective population-based Bruneck study, they found that the level of plasma DKK3 was inversely related to carotid artery intimal medial thickness and five-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, they demonstrated that DKK3 promoted re-endothelialization in murine models of atherosclerosis and wire-induced femoral artery injury, thus revealing its atheroprotective role.

They further explored the mechanism of DKK3-induced endothelial cell migration, which was via noncanonical Wnt signaling pathways. The study, therefore, provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair with potential therapeutic implications.

That wraps it up for our summaries. Now for our feature discussion.

For today's feature discussion, we are talking about physical activity and prognosis in heart failure with preserved ejection fraction, or HFPEF. To discuss this paper, which contains really neat results from the TOPCAT trial, we have none other than the first author, Dr. Sheila Hegde, corresponding author, Dr. Scott Soloman, both from Brigham and Women's Hospital, as well as Dr. Jarett Berry from U.T. Southwestern, who was the editorialist on this paper. Welcome, everyone.

Dr. Scott Solomon: Thanks, Carolyn.

Dr. Sheila Hegde: Thank you.

Dr. Jarett Berry: Thank you, Carolyn.

Dr. Carolyn Lam: Hey, Scott. Could you set the background a little bit and let us know what was the rationale of looking at physical activity in TOPCAT?

Dr. Scott Solomon: As you well know, heart failure with preserved ejection fraction is a disorder in which we don't currently have a therapy, or for which we currently don't have a therapy, and we know that people would also have a lot of comorbidities. Sheila has been extremely interested in the role of physical activity in heart failure and patients with heart failure, has studied this in the atherosclerosis risk in community studies, and we thought TOPCAT would be a great overall trial dataset to understand the importance of physical activity in HFPEF patients and the relationship with outcomes.

As you know, TOPCAT is a study that was funded by the NIH in patients with heart failure, preserved ejection fraction. Patients were randomized to spironolactone or placebo and then followed for outcomes, and it was a very rich dataset for which we have a lot of physical activity information.

Dr. Carolyn Lam: Indeed, and I wasn't even aware of the extent of the physical activity information in TOPCAT. Sheila, could you explain a bit how physical activity was captured and graded, and tell us about your findings?

Dr. Sheila Hegde: Each participant’s physical activity was assessed by self report. Subjects were asked about the amount of heavy, medium, and light exercise in the preceding two weeks. They were given some examples of what those might be and what we did was, we converted these to AHA, American Heart Association categories of poor, intermediate, and ideal activity. As you know, the ideal activity category corresponds to 150 minutes of moderate intensity activity per week or 75 minutes of vigorous activity per week. What we found, using these categories, was that the majority of subjects actually met criteria for poor activity, so at least 75%. Also, a majority were New York Heart Association Class II heart failure.

Those with poor activity were more likely to be women, have diabetes, chronic kidney disease, and a previous history of heart failure hospitalization. Interestingly, there was no significant difference in history of myocardial infarction, stroke, atrial fibrillation, or COPD. The median follow-up time for this group was 2.4 years, and we did sort of focus on the first two years because there was an interaction with times and randomization and, using Cox regression models, we found that those with poor or intermediate activity had approximately a two-fold higher risk of a primary composite outcome, which was heart failure hospitalization, cardiovascular mortality, or aborted cardiac arrest.

Dr. Carolyn Lam: Wow! You know what the question is? Chicken or egg? Does this mean those who were exercising had better outcomes or they were just better and, therefore, they could exercise?

Dr. Sheila Hegde: That's a very good question. This is a post hoc analysis, so it will be difficult to say, but we did sort of look at excluding those with a history of stroke or MI and found that the same two-fold increased risk of outcomes existed for those with poor intermediate activity.

Dr. Scott Solomon: This is always the problem, as you know, Carolyn, with observational data. We don't know if the patients who are exercising more are doing better because they're exercising more or is it that the people who feel better can exercise more? You try to adjust as much as you can, but I don't know that there's any way to determine that for sure without doing a randomized trial of exercise in patients with HFPEF.

Dr. Carolyn Lam: Certainly and, in fact, I thought that was one of the good messages, that it's time that we do a proper trial of that, don't you think? Jarett, would you have some questions for Sheila and Scott, too?

Dr. Jarett Berry: I was really interested in your figure 3, this dose response analysis. In figure 3, you divided the exposure into deciles. You don't begin to see a decremented risk until you begin to see the ninth and tenth decile of exercise. If you look at other observational data, you really see this different pattern where just getting off the couch seems to be beneficial in other observational data for preventing coronary disease events but, both in our work and also in this paper here, particularly your figure 3, you see that this higher dose of physical activity was required to see a reduction in risk. I don't know if you could comment a little bit on that.

Dr. Sheila Hegde: I agree that there is a difference in what appears to be a dose response at lower levels of activity. In this analysis, we actually included amount of light intensity of activity since the majority of people had no moderate or vigorous intensity activity to account for. In that sense, there's even sort of a higher threshold, perhaps, required to achieve benefit and reduction of risk, and it may be that heart failure has a different mechanism for physical activity in terms of achieving those benefits.

Dr. Jarett Berry: I'm wondering, I guess getting back to Carolyn's original point there about, and Scott's comments, as well, about the need for a trial. If you look back at HF-ACTION where we saw some relatively modest benefit for exercise training and heart failure with reduced ejection fraction. Some of our prior work would suggest that, actually, the benefit of exercise is much more apparent in HFPEF patients. When you train HFPEF patients, they tend to improve much more dramatically with regard to VO2 peak, compared to heart failure with reduced ejection fraction. I'm just wondering what your thoughts were about the next steps. It seems like a trial of some type would be of great interest. What are your thoughts about that?

Dr. Scott Solomon: I agree with you 100%. It would be a great idea for a trial. There have been small trials, as you know. Dalane Kitzman did a trial and Frank Edelmann and Burkert Pieske did a trial, and I think they're actually even doing another one now. The relatively small numbers of patients do show improvement in myocardial oxygen uptake, improvement in quality of life, and some improvement in some measures of echocardiographic measures of diastolic function, as well, with exercise training which is, frankly, more than we've gotten with drug therapies, so I agree 100%.

It's also important to note that it's actually hard to get our patients with HFPEF in the United States into cardiac rehab because it's currently not paid for by Medicare, and I'm hoping that will change, as well.

Dr. Carolyn Lam: You know, that's so well put, Scott. I've got a question, though. Every time you think TOPCAT, you think regional variation, right? How did this look in the different regions, in the U.S. versus elsewhere?

Dr. Scott Solomon: First of all, let me just tell the audience that TOPCAT was a study in which we enrolled patients both in the Americas, which was the U.S., Canada, Argentina and Brazil, and in Russia and the Republic of Georgia. As you know, when we unblinded the trial, we found that the event rates in Russia and the Republic of Georgia were considerably lower, about five-fold lower than they were in the Americas. We believe that many of these patients may not have had heart failure.

We've also recently found that many of these patients probably weren't taking spironolactone, as well. For many of our TOPCAT analyses now, including this one, we excluded the patients in Russia and Georgia and just focused on the Americas. Sheila, did you happen to look at the results in Russia and Georgia, just as a tweak?

Dr. Carolyn Lam: I can tell you that the majority of patients were active, so very much different than our majority in active patients in the Americas region.

Dr. Jarett Berry: This is an amazing study that really puts forward an important hypothesis that needs to be tested. Before, I know we've discussed that a couple of times already, but I really believe that we are exercising the wrong heart failure patients. As the Director of Cardiac Rehab here at Southwestern, we are including a lot of heart failure with reduced ejection fraction but, as Scott points out, there aren't currently funding available or billing is not allowable for patients who have heart failure with preserved ejection fraction.

I think it's only studies like this that are going to move the field for it and how we can begin to think about caring for these patients and treating their comorbidities and treating their disease process through what we believe is probably one of the most important therapeutic strategies we have that we're not using, and that would be the exercise training, so I think this is a fantastic study and a wonderful contribution as we begin to think more about the future of treatment for patients with HFPEF.

Dr. Carolyn Lam: Thank you so much, everyone. Listeners, I'm sure you enjoyed that conversation as much as I did. Don't forget to tune in again next week.

Circulation September 5, 2017 Issue

5 september 2017 | 21 min

Dr. Carolyn Lam: Welcome to "Circulation On The Run", your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today's feature paper looks at the early use of N-Acetyl Cysteine with nitrate therapy in patients undergoing primary PCI for STEMI. More soon right after this week's summary of original articles.

The first paper identifies a novel association between Phosphatidyl Choline Transfer Protein, or PCTP expression, in the blood, and death or myocardial infarction in patients with cardiovascular disease. Now, PCTP regulates intermembrane transfer for phosphatidyl choline. Platelet PCTP expression has been shown to be associated with increased platelet responses upon activation of protease-activated receptor four thrombin receptors. In today's paper, first authors Dr. Mao and Songdej, corresponding author Doctor Rao, and colleagues from the Temple University School of Medicine in Philadelphia used DNA protein binding studies and human erythroleukemia cells, as well as luciferase reporter studies to show that PCTP is a direct transcriptional target of RUNX1, a major hematopoietic transcription factor that regulates platelet production and function. Furthermore, in 587 patients with cardiovascular disease, the authors showed that PCTP expression in the blood correlated with RUNX1 expression and was independently associated with future death or myocardial infarction. Thus, regulation of PCTP by transcription factor RUNX1 may play a role in the pathogenesis of platelet-mediated cardiovascular events.

The next paper provides molecular insights into cardiac fibrosis and shows that bone marrow cells are involved in cardiac fibrosis during pathological stress. Drs. Kishore, Verma and colleagues from Lewis Katz School of Medicine and Temple University of Philadelphia hypothesize that interleukin-10 inhibits pressure overload-induced homing of bone marrow fibroblast progenitor cells to the heart, and inhibits their trans-differentiation to myofibroblasts, thus attenuating cardiac fibrosis. To test this hypothesis, the authors used pressure-overload in wild-type and interleukin-10 knockout mice by transverse aortic constriction, and used chimeric mice to determine bone marrow origin. They further isolated fibroblast progenitor cells from mouse bone marrow for mechanistic studies.

They found that, in addition to resident cardiac fibroblasts, bone marrow-derived fibroblasts significantly contributed to progression of pathological cardiac fibrosis, and that pliotropic antiinflammatory interleukin-10 inhibited the recruitment and trans-differentiation of bone marrow fibroblast progenitor cells in the pressure-overloaded myocardium. At a molecular level, they showed that interleukin-10 inhibited TGFβ SMAD2-3 signaling in activated bone marrow fibroblast progenitor cells. Furthermore, inhibition of TGFβ SMAD2-3 signaling mediated micro-RNA21 maturation was a novel mechanism by which interleukin-10 inhibited bone marrow progenitor cells-mediated cardiac fibrosis. Thus, selective inhibition of bone marrow cells homing to the heart and of fibrotic signaling using interleukin-10 or selective RNAs might inhibit the transition of physiological hypertrophy to heart failure, and may be a potential therapeutic target to treat or prevent the development of hypertrophic remodeling.

The next study looks at the risk of major bleeding in patients receiving ticagrelor compared to Aspirin after a TIA or Acute Ischemic Stroke in the SOCRATES study. As a reminder, the SOCRATES trial was the first outcome study with ticagrelor in patients with Acute Ischemic Stroke or TIA, who were given ninety days of monotherapy with ticagrelor, 90 milligrams, twice daily and compared with those given aspirin 100 milligrams daily. The trial found that ticagrelor was not superior to aspirin in reducing the primary composite endpoint of stroke myocardial infarction or death. In today's study, Dr. Easton and colleagues from University of California San Francisco aimed to describe the bleeding profile of monotherapy with ticagrelor versus aspirin in this population of patients with Acute Ischemic Stroke and TIA, to characterize major bleeding based on the PLATO, TIMI and GUSTO bleeding definitions, and to identify factors associated with major bleeding.

They found that PLATO major bleeds occurred in 0.5% of patients on ticagrelor and 0.6% of patients on aspirin. The most common locations of major bleeds were intracranial and gastrointestinal. Intracranial hemorrhage was reported in 12 patients, or 0.2%, on ticagrelor and 18 patients, or 0.3%, in aspirin. Independent of bleeding classification, PLATO, TIMI or GUSTO, the relative difference between treatments for major or severe bleedings was similar. However, non-major bleeds were more common on ticagrelor. Thus, this paper contributes important data on the bleeding profile of ticagrelor in patients with acute cerebral ischemia, provides some reassurance that there's no increased risk of major bleedings with ticagrelor compared to aspirin, including intracranial bleeds, however, a numerical increase in minor bleedings with ticagrelor.

The next paper tells us that single 24-hour urine collections may be useful for estimation of average sodium intake in populations. However, for a reliable estimation of cardiovascular and renal risk, multiple 24-hour urine collections may be needed. First author, Dr. Olde Engberink, corresponding author, Dr. Vogt and colleagues from Academic Medical Center Amsterdam selected 574 adults with EGFR above 60, an outpatient 24-hour urine sample, and at least one collection during a seventeen year follow-up. Sodium intake was estimated using a single baseline collection, and the average of samples that were collected during a one, five, and fifteen year follow-up.

They found that estimates of daily sodium intake changed more than 0.8 grams in half of the subjects when using multiple follow-up collections instead of a single baseline collection. The way of estimating sodium intake significantly affected the observed relationship between sodium intake and long-term outcome. Hazard ratios for cardiovascular and renal outcomes changed up to 85% when multiple follow-up 24-hour urine collections were used, instead of a single baseline collection. Thus, in summary, relative to a single baseline, the use of subsequent 24-hour urine samples resulted in different estimations of an individual's sodium intake, while population averages remained similar. This had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcome.

That wraps it up for your summaries this week. Now to our featured discussion.

Today for our featured discussion, we are talking about approaches to cardio protection. Now, we all know that the mortality rates in STEMI has improved over the last few years, because we've gotten better at reperfusion therapy with primary PCI, as well as effective secondary prevention therapy. However, the incidents and severity of heart failure following STEMI has been rising and thus, cario-protective therapies are of great interest to prevent heart failure and improve overall clinical outcomes following STEMI, following primary PCI. Over the years, a number of cardio-protective therapies have been tried, but have either been unable to reduce MI size or improve clinical outcomes following STEMI, but in this week's journal, we have an exciting trial, very interestingly of two old cardio-protective therapies showing a lot of promise in this area. And to do discuss this, I am so pleased to have the corresponding author, Dr. John Beltrame from University of Adelaide in Australia, as well as associate editor from Brigham and Women's Hospital in Boston, Massachusetts, Dr. Laura Mauri.

John, you know, in my introduction I said this is very interesting. You're actually combining two old therapies, N-acetylcysteine and nitroglycerin in your approach in this trial. Now, both these drugs have been around for a long time. Please share with us what led you to think that a combination would work, what made you test the combination, and what makes your trial different from the other reperfusion studies before.

Dr. John Beltrame: So, nitroglycerin, of course, has been utilized to treat myocardial infarctions for many years, has been shown to reduce the chest pain in that scenario, but little reward in perhaps reducing infarct size. And one of the main benefits of that people don't know is the vasodilation effect that it has on the coronary arteries, as well as reducing the wall stress. So, what we thought to combine it with N-acetylcysteine, which potentiates nitroglycerin effects, but also is a free radical scavenger. So therefore it would actually also work on reperfusion injuries. So these have a very synergistic effect, and therefore we expected to have good benefits.

The ... because we're also looking at an anti-ischemic therapy with a reperfusion protective therapy, we wanted to introduce it as soon as possible. And so this drug was initiated in the emergency department as patients arrived, and then taken off to the cath lab where it was continued. We also began to ensure that we had adequate N-acetylcysteine, which I'll probably refer to as NHC from now on, as much on board as possible before we actually opened the artery. We gave high dose N-acetylcysteine at 20 milligrams in the first thirty minutes, and then at a slower rate for the next twenty-four hours. So for the first hour we gave it at 20 milligrams a minute, and then thereafter 10 milligrams a minute. And then, the actual study. We had patients randomized and double-blind placebo control trial, multiple sites here within South Australia with the primary endpoint being myocardial infarct size on early cardiac MRIs.

So they got to see the opportunity to have a smaller sample size than many of the conventional infarct studies, and the key finding was in that early MRI, we saw an absolute 5% reduction in infarct size, which was an exciting find for us and this we expect to translate to a significant reduction in cardiovascular events and that's where I guess we're going in the future, is that we need to now undertake a study where we show that the combination of these two drugs also impacts on cardiac events.

Dr. Carolyn Lam: How beautifully summarized, John. And really, congratulations on such an impactful and elegantly done study. I like the way you highlight it, though. Basically, you gave this drug earlier than most other trials of reperfusion therapies, because you gave it even before the primary PCI procedure as most cardio-protective strategies were tried within the cath lab. Would that be accurate?

Dr. John Beltrame: Exactly right. So, whereas a number of the studies would take the patient with the STEMI to the cath lab, undertake the diagnostic angiogram and the diagnostic angiogram would then confirm that this was occluded, then they would introduce the cardio-protective agent and then proceed on to open up the artery. Whereas we had an opportunity for sort of ... at least twenty to thirty minutes before the artery was opened to actually have those drugs on board. And so, in a number of cases, we improved the patency of the vessel when we got to the diagnostic angiogram. So it's a two-point strategy, one anti-ischemic and one cardio-protective in terms of reperfusion injury. And we think that future trials in this area need to address both those conditions.

Dr. Carolyn Lam: I can think of no better person to comment on being able to do these trials and the future of these trials than Laura. Laura, what are your thoughts?

Dr. Laura Mauri: Thanks Carolyn. John, that was a great summary and I think you're really to be commended, because this is just such a challenging area to be doing trials in, but that's really what we need. And you know, most of the trials have focused on early procedure success for therapies that we currently use, rather than showing documented benefit in longer-term endpoints. But as you mentioned earlier, Carolyn, we really do still have patients who would benefit from therapies that may reduce infarct size. I think it's really remarkable, John, that your study was able to intervene early in the emergency room, as we know as clinicians that's not easy to do, not only to activate the quick pathways of care that we need for STEMI, but then on top of that to lay on a randomized trial, but I think it's incredibly important.

What are you foreseeing as the challenges? As you think about your next steps in rolling this out to a ... potentially a larger trial and implementing such a study?

Dr. John Beltrame: As with many trials, it's ways of recruitment, because a study like this is not gonna be funded by industry, you need to be looking at ... here within Australia, be looking at government authorities to put in an application for funding and then, it's a matter of recruiting. That's one of challenges we came across in doing this particular study, and this relates particularly, I guess, to the MRI endpoint, is the number of patients that were claustrophobic and therefore we couldn't actually perform the cardiac MRI, and so your primary endpoint ... you missed out. And so again, there's going to be frustrations like that and a much larger trial, which will need to involve even more centers. But funding that's ... for much of the research, I guess, it will be the challenge, because we've got two agents as Carolyn mentioned in the beginning that have been around for a long time and are certainly unlikely to attract any industry funding.

Dr. Carolyn Lam: John, I have a question about the design as well. Of the current and maybe a future trial, because I'm left with the question, was it your early intervention? Was it the outcome you chose? Or was it one drug or the combination? And so, you did not do a factorial design in this trial. Are there plans to look at that, or do you the combination ... it's so obvious that two separate drugs don't need to be tested?

Dr. John Beltrame: Very good question. So, you're quite correct, we can't be absolutely confident in terms of the mechanism, because we had one opportunity, I guess, to do the study and so we wanted to keep a simplified design, and that's what we gave everyone; a background of nitroglycerin and then just randomized the N-acetylcysteine. But we think it's actually the combination of the two that makes the benefits, because as you would be aware, the synergistic benefits is that the N-acetylcysteine potentiates the effect of the nitrates, potentiates the vasodilating properties, potentiates it's anti-platelet properties also. And so we think it's a combination of the two.

Dr. Laura Mauri: John, it's interesting ... the use of the cardiac MRI endpoint, as we've all seen, it's being used more and more frequently, but at the same time, it's new for us, right? So you've raised some of the challenges and the practical execution of getting patients who can tolerate it, especially after an acute hospitalization. But the classical endpoint has been SPECT imaging as a surrogate endpoint for mortality in myocardial infarction. Of course, that's based on very large trials showing correlation, but the MRI should really give much better resolution, so I think that's really a very logical next step. But I think the more data that we get across multiple different trials, the better we can validate that endpoint and see how it might differ from the classical surrogate endpoints that we've had for myocardial infarction.

Other than the efficiency of looking at MRIs, do you have other observations when you look at MRIs at endpoint compared with some of the traditional endpoints like SPECT?

Dr. John Beltrame: Not SPECT so much, but to follow on exactly what she was saying, we all also measured serum creatine kinase, so CK, values. And because of the larger spread of the data and therefore the need to have a larger sample size, although we certainly saw a trend of improvement in CKs as a marker of infarct size, we didn't achieve statistical significance, but with the MRI because we had more precise measurements, that gave us a smaller margin of error and therefore, we were able to see a difference between the two treatments. So certainly I think in the future, the MRI is certainly a very good way to evaluate agents in this particular area.

Dr. Laura Mauri: It's nice to see the consistency that you saw across the different endpoints.

Dr. Carolyn Lam: That's true, but I do have a question though, as an Echo cardiologist here, your three-month assessment of the ventricular remodeling, if I read it right, there was no change detected at three months. Would you like to comment on that?

Dr. John Beltrame: What we saw in terms of the infarct size, we still saw a difference. I think what you might be referring to, the infarct size was a little bit smaller, so that's just ... over time the we feel like the scar contracts down. But I'm not sure if you're also referring to the ...

Dr. Carolyn Lam: LV dimensions and injection fraction.

Dr. John Beltrame: The injection fraction's interesting, because when we looked at that ... because we found no difference in the injection fraction. Now, if you take a look at the actual values, they're almost normal and I think that says something to where we are in terms of the management of acute STEMIs, because we preserved the left ventricular function, because there were normal ejection fractions, so we couldn't make them better than what we had in placebo, so that is something to primary PCI, I think.

Dr. Carolyn Lam: That's a great answer. Thank you, John. And Laura?

Dr. Laura Mauri: John, your group is really to be commended for conducting such a high-quality trial in this very challenging area. We've been victims of our own success, I think, in this space because the mortality rates have obviously declined after MI, infarct size is on the decline with early reperfusion. Getting in there with attempted therapies is a race when you're also trying to achieve fast door-to-ballon times, but it's still an important area and one we can only address with careful, randomized trials with important therapies. So I want to congratulate you and your group, it's really a step in the right direction.

Dr. Carolyn Lam: You've been listening to "Circulation On The Run", thank you so much for joining us, and don't forget to tune in next week!

Circulation August 29, 2017 Issue

28 augusti 2017 | 17 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week tells us more about aortic wall inflammation, and how this predicts abdominal aortic aneurysm expansion, as well as need for surgical repair. Much more, right after these summaries.

Our first original paper sheds light on a novel mechanism for adult cardiac regeneration. This is a paper from first authors Drs. Wang, and Lee, and corresponding authors Dr. Chen, Houser, and Dr. Jeng from Third Military Medical University from Chongqing, China.

In an elegant series of experiments using mouse models, the authors showed that mature adult cardiomyocytes could re-enter the cell cycle and form new cardiomyocytes though a three-step process: of dedifferentiation, proliferation, and redifferentiation. Intercellular calcium signals from neighboring functioning cardiomyocytes through gap junction induce the redifferentiation process. Furthermore, they showed that this mechanism contributed to new cardiomyocyte formation in post MI hearts in mammals. In summary, this study contributes to our understanding of adult cardiac regeneration and could lead to novel strategies to repair the injured heart.

The next paper provides mechanistic data that may explain why thrombotic complications are more prevalent in patients with diabetes, and why some anti-platelet drugs may have limited efficacy in patients with diabetes. In this paper by first author, Dr. Hu, corresponding author Dr. Ding, and colleagues from Fudan University in Shanghai, China, the authors show that platelets of patients with Type 2 diabetes express high levels of activated P2Y12 receptor.

The P2Y12 inverse agonist inhibited P2Y12 activity of platelets from diabetic patients and rats, more than Cangrelore, leading to a stronger in-vivo antithrombotic effect in thrombosis rat models with diabetes. Increased platelets P2Y12 receptor expression in diabetes was mediated by a high-glucose reactive oxygen species, NF-kappaB pathway. In summary, platelet P2Y12 receptor expression was shown to be significantly increased, and the receptor was constitutively activated in Type 2 diabetic patients, which contributed to platelet hyperactivity, and limited anti-platelet drug efficacy in Type 2 diabetes.

The next paper tells us that the majority of cardiovascular disease events are now occurring amongst adults with a systolic and diastolic blood pressure of less than 140 over 90 millimeters mercury. Prior data have shown us that the majority of incident cardiovascular disease events occurred among U.S. adults with higher systolic and diastolic blood pressures of above 140 over 90. However, over the past several decades, blood pressure has declined and hypertension control has improved. Thus, in the current study, Dr. Tajeu and colleagues from Temple University College of Public Health in Philadelphia estimated the percentage of incident cardiovascular disease events that occur at blood pressures below 140-90 in a pooled analysis of three contemporary U.S. cohorts: the Reasons for Geographic and Racial Differences in Stroke, or, REGARDS study, the Multi-Ethnic Study of Atherosclerosis, or MESA study, and the Jackson Heart study.

In these three U.S. cohorts that enrolled after 2000, more than 60% of incident cardiovascular disease events occurred among participants with blood pressures below 140 over 90 millimeters mercury. In the 2001 to 2008 National Health and Nutritional Examination survey mortality follow-up study, 58% of cardiovascular disease stats occurred in U.S. adults with blood pressures below 140 over 90. Among participants taking anti-hypertensive medication, with blood pressures below 140 over 90, only one-third of those who are eligible for starting treatment were taking one, and approximately 20% met the SPRINT eligibility criteria.

In conclusion, while higher blood pressure levels are associated with increased cardiovascular disease risk, in the modern era the majority of incident cardiovascular disease events occur in U.S. adults with blood pressure below 140 over 90. Although absolute risk and cost effectiveness should still be considered, additional cardiovascular disease risk reduction measures for adults with blood pressure less than 140 over 90, and at high risk for cardiovascular disease, may be warranted.

Well, that brings us to the end of our summaries. Now, for our feature discussion.

Dr. Carolyn Lam: On today's podcast discussion, we will be talking about aortic wall inflammation as a possible functional, or biological, imaging bio-marker that may add to the usual structural measurements of size that we use to predict abdominal aortic aneurysm expansion and rupture. Now, to discuss this very important paper, we have the corresponding author, representing the MA3RS study investigators, Professor David Newby from the Center for Cardiovascular Science in Edinburgh, as well as a familiar voice now, Dr. Joshua Beckman, associate editor from Vanderbilt University. Welcome, gentlemen.

Professor David Newby: Hi, there.

Dr. Joshua Beckman: So great to be here again, thanks for having me.

Dr. Carolyn Lam: So great that you're back again, Josh! But David, let's start with you. Could you just summarize what this trial was about and your main findings?

Professor David Newby: Sure, so this was a major clinical trial that we undertook in the U.K. and Scotland. We approached patients who were in a surveillance program who had an abdominal aortic aneurysm, and we asked the question, "Is there anything we can do better than just serial ultrasound measurements that currently are stunned to this care?" So, in Edinburgh, we developed a technique using ultrasmall, superparamagnetic particles of iron oxide, which is a bit of a powerful ... so we shortened that to USPIOs; these are really small iron particles that are so small they can cross vascular spaces and they get gobbled up by tissue resident macrophages, and then causes a signal that we can detect on magnetic residents' scanning MRI.

So we were really asking the question, "Can we do better than ultrasound by using what we call USPIO-enhanced MRI?"

Dr. Carolyn Lam: So a biological or functional imaging parameter versus just structural. And so, what were your main findings?

Professor David Newby: We recruited around 361 patients and ultimately 341 went into the trial because of various exclusions, et cetera. And we followed these patients up for, on average, around three years. And so we were following it up every six months with ultrasound, with other various assessments, and ultimately what we found was that the USPIO-enhanced magnetic residents' scan was positive in around half of patients, and in those patients that took up the USPIOs in their abdominal aortic aneurysm wall, those patients, their aneurysms expanded quicker. So rate of expansion was higher, and they went on the have the primary event of either elective repair, or rupture. And, don't forget, that the clinicians who were looking after these patients, they didn't know the results of the MRI so it didn't influence their clinical minds, when this was completely independent of the clinical team.

So, for the first time, we demonstrated that imaging or tracking macrophages in the abdominal aortic wall could, indeed, predict both disease progression and clinical outcome.

Dr. Carolyn Lam: And Josh, you know, no one can say it better than you: could you just describe what we discussed as the editors about the significance of such a finding?

Dr. Joshua Beckman: I think there's a few things to take home from these three that are really incredible. First, David, were you surprised at the concordance between the USPIO-enhanced imaging and smoking, or was that something that you expected?

Professor David Newby: That was a big surprise. That was, actually, as we discussed in the manuscript, quite an interesting finding, and as always with an interesting find, we dig around in the background, and it actually gets more and more exciting and plausible because of the mechanistic work that we'd seen in the pre-clinical science that preceded our trial. So yes, it was a surprise, but actually the more we got into it, the more it made sense.

Dr. Joshua Beckman: One of the other things that I think is really important to talk about is how you get this study done, and one of the things I found incredibly impressive ... I am unaware of any other multi-sensor MRI study like this. How did you organize this amongst the different institutions?

Professor David Newby: It can be a bit of a challenge. So I've done quite a few multi-sensor trials in Scotland, and imaging trials, and the community in Scotland actually is very, very supportive and we got a good network of folks. So the three centers are actually two imaging centers: one in Edinburgh one in Glasgow, a further recruitment center in a city just in the center of Scotland, Sterling. And the patients ... we were able to obviously make sure the scanners did the same protocols; fortunately, they were the same scanner, make and model. So that all obviously helped, but we had a lot of inundation, phantom work, to make sure both centers got things right.

But there was a huge motivation to get this done, and I'm indebted to Charles Riditi and Colin Barrie in Glasgow for doing the, and supporting the, imaging work, and also a medical physicist here in Edinburgh, Scott Semple, who'd done a lot of the work to get this to happen. So there's a teamwork in Scotland and the NHS, where the access to patients are in the screening program as well, which made recruitment really well and very efficient. And we started exactly to target, which is pretty unusual in clinical trials, often takes longer to recruit patients, but it was a great team effort. The imaging quality, we checked, verified, centrally read, and it was really good to see it delivered in that way.

Dr. Joshua Beckman: Do you think that agent, the iron oxide particles, is going to be the contrast agent, I guess, of the future, or do you think because it is now so consistent with smoking, it's gonna be more of an investigational tool?

Professor David Newby: So there's a couple of things to say here on ferumoxital, which is the USPIO we used. It's currently licensed in the U.S. for the treatment of anemia and chronic renal failure, but it can also be used as an imaging agent and actually this, I think increasingly, might have a role; not just in aneurysms, but elsewhere. So the first thing you can do is actually do angiography with this agent. [Obviously gadolinium is getting a lot of press at the moment, with problems with warnings coming out, of residual brain deposition, and so on. With the USPIOs, you can use this in renal failure patients, so again, another contraindication for us to concern about: NSF in renal failure patients. So actually, for angiography, I think it's going to have an increasing role.

For imaging of inflammation, we've previously demonstrated that you can track inflammation post-myocardial infarction, so you can see air is lighting up following myocardial infarction. We have some papers out on that, and I think, if you are in the business of looking at cellular inflammation, macrophage trafficking, then this technique really can be helpful.

When we come to aneurysm studies, I think it is less clear because ultimately, doing a quick ultrasound, in fact can give you the information together with all of the clinical risk factors, like smoking, and you get to the same end point without doing the MRI. Then, clearly, it's not going to be that impactful. Having said that, I think sometimes we will have patients who've got all this information and we're not sure which way to go. So I think it could be used as an almost umpire test, if you're not sure whether to proceed with surgery or not. And I think, also, if we discover new agents that are anti-inflammatory that may impact on disease progression, with a normal therapy, then clearly this might be a good buyer market to use in future therapeutic trials.

Dr. Joshua Beckman: Yeah, I actually see a huge potential for the testing of new agents, to see whether or not it reduces the inflammation that's associated. I'm gonna ask you a theoretical question, if that's okay with you. Part of the inflammatory process in the aneurysm is based on oxidative stress, but I've always wondered if you provide more oxygen, which may enhance the oxidative stress reaction, are you actually worsening the reaction at the time you're doing the study? Is that possible, or am I just concerned about nothing and making it up?

Professor David Newby: Well, obviously your [inaudible 00:13:19] stressors is important in all of cardiovascular disease, and if you increase oxygen supply, maybe you indeed induce more oxidative stress. In the context of an aneurysm, often there's quite an hypoxic state in the aneurysm wall, because obviously the intraluminal thrombus can buffer the wall itself from it, obviously the vasovasorum come in, but they may not be as efficient in doing that. Some of the areas that we're seeing light up probably are quite hypoxic, so they'll be in an oxygen-deprived state. So I think that needs to be put in the balance, too, and there has been some suggestion that iron particles can increase oxidative stress, and it has been suggested maybe harmful; we've not seen that, we've had absolutely no adverse reactions at all in all of our patients. We had one patient whose blood pressure fell a little bit, but we didn't have to medically intervene at all, so it was just observed and it passed; of course it might be due to many things.

We've also studied this in patients with myocardial infarctions, I've said, also bypass surgery, people who've had bypass surgery. We've also published on using these agents there, and again, we've seen absolutely no adverse reactions. And you would've thought, in the context of those situations, if you were going to see an adverse effect you would've seen it behind.

Dr. Carolyn Lam: David, I've got a question for you. I think you mentioned, a little bit earlier, that end of the day this enhanced MRI did not improve the risk stratification beyond the current predictors of clinical outcome in abdominal aortic aneurysms, but what are the next steps for you?

Professor David Newby: There's a couple of things, which we've been thinking through. Firstly, I think the primary end point of the trial was mostly driven by repair, and when we looked at the emergent events, so dying, and rupturing, the signal got stronger and very close to statistical significance. And obviously when you've got a population of patients whose elective surgeries mostly dominated by the ultrasound scan decision, therefore makes it difficult to prove, on top of that, the MRI will have value. So it's quite high, and on a difficult bar to cross, so some of the thoughts we've had are thinking about predicting rupture, rather than repair. And there will also be potential for actually doing a trial, where we actually base decisions on the aneurysm, and if you've got an intermediate category of patient, where you're not sure which way to go, those patients you then do use as an arbiter, and that might have, therefore, proof or value for it.

And the final area that we're probably thinking about exploring is, "Okay, paths for macrophages." Is there other pathophysiological processes that we might want to explore with other agents, that might predict aneurysm growth and rupture even stronger, and macrophage inflammation? So those are some of the thoughts that we've had about where the next steps will be.

Dr. Joshua Beckman: This is an incredible amount of work and I always think it's important to make clear to everybody who's listening to this podcast that, even though we may not all do the same kinds of research, it needs to be made clear that having a multi-sensor study in this topic, with this technique, is incredibly impressive. And the physiology that was brought forth, in addition to the clinical stuff that we just heard about, I think is what makes this worthy of a podcast.

Dr. Newby, thanks so much for participating.

Professor David Newby: Thank you so much, that's very kind. And just to reiterate, it has been a long journey and a huge effort, but we're reaping the rewards now, and it's nice to see the data being published in circulation.

Dr. Carolyn Lam: Gentlemen, it has been so wonderful having you here to discuss this. Thank you so much for your time.

Circulation August 22, 2017 Issue

21 augusti 2017 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. And Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University at Singapore.

What is the effect of obesity and underweight status on perioperative outcomes of congenital heart operations?

Our feature paper this week sheds light from the Society of Thoracic Surgeons Database. More soon, right after these summaries.

The first original paper highlights the role of micro RNAs in metabolic remodeling and heart failure. As a reminder, micro RNAs are small, noncoding RNAs important in post transcriptional modification and influencing many cellular processes simultaneously.

First author, Dr. Heggermont, corresponding author, Dr. Heymans, and colleagues from Maastricht University in the Netherlands use mice subjected to pressure overload by means of endotension to infusion or transverse aortic constriction. They show that micro RNA 146A was up regulated in whole-heart tissues in these murine pressure overload models, as well in left ventricular biopsies of aortic stenosis patients. Over expression of micro RNA 146A in cardio cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of micro RNA 146A blunted the hypertrophic response and attenuated cardiac dysfunction in Vivo.

Mechanistically, micro RNA 146A reduced its target dihydrolipoyl succinyltransferase or DLST, a mitochondrial protein that functions as a TCA cycle transferase. DLST protein levels were reduced in pressure overload mice, while they were partially maintained in micro RNA 146A knockout mice. Furthermore, overexpression of DLST in wild type mice, protected against cardiac hypertrophy and dysfunction in Vivo. Thus, micro RNA 146A and its target DLST are important metabolic players in LV dysfunction. These results also opened the door to novel therapies to treat metabolic disturbances and improve energy efficiency of a failing heart.

Program cell death is critically involved in ischemic cardiac injury, pathologic cardiac remodeling, and heart failure progression. Our next paper sheds light on the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure. Using genetic mouse models, first authors Dr. Guo and Yin, corresponding author Dr. Liu, and colleagues from University of Washington in Seattle, identified a critical role for a tumor necrosis factor receptor associated factor 2 or TRAF2 in myocardial survival and homeostasis by suppressing necroptosis.

The authors delineated an important TRAF2 mediated NF-KB independent pro-survival pathway in the heart by suppressing necroptotic signaling. They identified novel molecular mechanisms whereby TRAF2 suppressed TNF receptor 1 mediated, receptor interacting protein 3 dependent necroptosis, which is critical for myocardial survival and homeostasis. Thus, this finding suggests that the necroptosis suppressing TRAF2 signaling pathway and its effectors may serve as novel therapeutic targets for pathologic cardiac remodeling and heart failure.

Our next paper tells us that cerebral hyperperfusion may be associated with accelerated cognitive decline and an increased risk of dementia in the general population. First author Dr. Walters, corresponding authors Dr. Ikram, and colleagues from Erasmus University Medical Center in Rotterdam, The Netherlands, measured cerebral blood flow by 2D phase contrast MRI in non-demented participants of the population based Rotterdam study. A 4,759 participants with a median age of 61 years, and a median follow up of 6.9 years, 123 participants developed dementia.

Lower cerebral perfusion was associated with higher risk of dementia and this risk was even higher with increasing severity of white matter hyperintensities on MRI. At cognitive reexamination after an average of 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition, which was similar after excluding those with incident dementia, and again, most pronounced in individuals with higher volumes of white matter hyperintensities.

Thus, lower cerebral perfusion was associated with accelerated cognitive decline and increased risk of dementia in the general population. This association was modified by hypertension and cerebral small vessel disease, possibly reflecting impaired arteriola and capillary function. This paper calls for further long term study and evaluation of optimizing cerebral perfusion as a means to prevent cognitive deterioration, for example, in patients with heart failure or carotid artery stenosis.

Well, that wraps it up for our summaries. Now for our feature discussion. For today's feature discussion, we will be looking at data from the Society of Thoracic Surgeons Database. This time looking at the effect of body mass index on perioperative outcomes of congenital heart operations in children, adolescents, and young adults. To discuss this, we have none other than the first and corresponding author, Dr. Michael O’Byrne from Children's National Medical Center in Washington D.C., as well as Dr. Naveed Sattar, Associate Editor from University of Oxford. Welcome gentlemen.

Dr Michael O’Byrne: Good morning.

Dr Naveed Sattar: Good morning.

Dr Carolyn Lam: Michael, we know that extreme body mass indices, very high or very low, has been associated with increased risk of at first, perioperative outcomes in mainly older adults undergoing cardiac surgery. We also know about the obesity paradox in conditions like heart failure, so why was it important to look at this specific group of patients? Congenital heart patients and children, adolescents, and young adults?

Dr Michael O’Byrne: Yeah, I think that as a pediatric cardiologist, a lot of the data that we use to guide our management is extrapolated from adult studies. However, in this particular case, it wasn't clear necessarily that adult data would necessarily be applicable to children and adolescents and young adults. We are aware that there are epidemiologic trends that congenital heart disease population ages and there are also in increasing problems of obesity among children in the United States.

The convention wisdom among surgeons in the United States is that obesity would increase perioperative risk and the thought is that some combination of exposure to hypertension and diabetes and peripheral vascular disease might impede wound healing and that body habit as itself might be a risk for the technical approach in wound healing. Acknowledging that there's a lot of evidence both for extreme BMI being a risk in surgical patients and adults, but also the idea that obesity paradox might be important in children because the biological mechanisms might be different.

Children themselves are exposed, their sort of dose response or dose exposure is less, they're younger, and so haven't been obese for a prolonged period of time, so that the integrated effect of having diabetes, hypertension, and obesity might be less. At the same time, we also acknowledge that in children with heart disease, we have congenital cardiac disease, the same issues with cachexia and frailty are present. i.e. that children with very low body mass index might be assigned to their own medical frailty, or a part of a heart failure cachexia syndrome.

One of the challenges in dealing with children with congenital heart disease, however, as you know is that its rarer than cardiac disease of the aging and additionally, that the population is very heterogenous in terms of the actual defects that are present and the surgeries that are performed. It was relevant to look and see over a wide range of sort of technical complexity surgeries with a wide range of sort of intrinsic preoperative risk of perioperative outcome, whether or not BMI would be associated with an adverse outcome. Either operative mortality in this case, or a composite outcome of mortality, major adverse events, and wound infection.

Dr Carolyn Lam: Wow, that makes a lot of sense and congratulations. This is not just the first, it's huge and really comprehensive. Could you just tell us a little bit more about what you did and what you found?

Dr Michael O’Byrne: I think as this point, I'd have to acknowledge that the challenges that we described in terms of both a sample size and in terms of getting a representative sample, is a constant challenge in our field and we have to give credit to my co-authors Marshall and Jeff Jacobs for their work in developing the collaboration that allowed for the STS Congenital Heart Surgery Database to exist. Also, on top of shepherding the database, their research, along with the people at Duke Clinical Research Institute, they've developed a robust risk stratification model for mortality that we utilize as part of this study. Without that, this would be really be very challenging.

What we did is performed an observational cohort study using the STS Congenital Heart Surgery Database to look at the risk of perioperative mortality and composite outcome in patients undergoing surgery in the United States between 2010 and 2015. We looked at both the actual events, the sort of observed events, in terms of mortality and adverse events, and then created multivariate models to adjust for the known covariance.

We hypothesized that extreme BMI, either very high or very low, would be associated with increased risk of mortality and increased risk of that composite outcome. What we found that operative mortality and that perioperative adverse events occurred more frequently in obese and severely underweight subjects. However, because they have an unequal distribution of potentially important covariance, we used multivariate modeling to adjust for those covariance.

Our multivariate models for death, however, the severely underweight subjects had an odds ratio of 1.4 and obese subjects had an odds ratio of 1.3, but neither was specifically significant in that context. We sort of anticipated that with a possibility given the very low event rate. That's the reason we've used a composite outcome, a higher event rate.

For that composite outcome, in both different versions of the multivariate model that we used, the severely underweight subjects had an odds ratio of 1.5, underweight subjects had an odds ratio of 1.3, and obese subjects had an odds ratio of 1.2. An increased risk in all three of those populations of interest relative to normal weight or just overweight subjects.

Dr Carolyn Lam: We're always saying that at circulation we do want to publish papers that have direct and important clinical implications, so Naveed, could you share some thoughts on what this means clinically?

Dr Naveed Sattar: Yeah, I think they went through the review process and I think the paper was very well written. I think Michael and his colleagues clearly understood the strength and the limitations of the data so that you can only ever itself prove associations here and therefore, clinically when we push them on trying to make clinical inferences, I think clearly they recognize that once they find associations between obesity and adverse outcomes and underweight.

What they need to do next, now this is a paper that then leads you to think, "Well actually, I need to do some clinical trials to prove that module ..." You're preventing these outcomes or in very under knowledge where they're actually increasing the BMI but improving their nutrition, cannot also improve outcomes following surgery. Now those are tough things to do. Michael, what do you think from some of the clinical inference? My inferences were the associations were there, particularly for the normal [inaudible 00:12:35] outcomes, but actually to prove that, to make a difference, you probably might need to do some intervention trials or is that how you take it as well?

Dr Michael O’Byrne: I agree with you 100%. I think that as an epidemiologist, I think that what we see in an observational study like this is an association. The two next levels of research that are necessary at this point are to see whether or not in this population BMI is a modifiable factor in the short run before surgery, or even in the long run. And the second question to answer is whether those adjustments in BMI, if they are achievable, affect outcome with surgery. Absolutely.

It's a tremendous challenge, both logistically in organizing a study, and honestly, in terms of capturing a cohort that would be large enough, given that this is almost 100% of the surgeries that occurred over a six year period in the United States.

Dr Naveed Sattar: I looked at it and thought, "Well, the mortality association once you adjusted were not quite significant but are there any individuals you would not do surgery on based on their BMI based on these results?

Dr Michael O’Byrne: The motivation for the study is exactly to try to begin to shed light on that kind of question. I think that it might be what I would call a tiebreaker potentially, if you have a situation where a patient is near meeting criteria but isn't quite at a place where you need to do surgery at that point. It might dissuade you from proceeding immediately potentially pursuing a course that might adjust their BMI in the correct direction.

At the same time also, in a patient who's underweight particularly to evaluate whether their medical regimen has been optimized and if there are other residual lesions that can be addressed in a non-surgical or medical fashion.

Dr Naveed Sattar: I suppose the other trick with this type of research research is always trying to make sure that people understand these are the associations and not trying to attribute causality because it's always physical, isn't it? But I think you and your team did that very well and I'm sure we had a back and forth with review but I think your discussion section, your limitation section, is beautifully written and covers those kinds of caveats, which I think is important as well.

Dr Michael O’Byrne: I thank you for that. That's very complimentary and we certainly strived for that, but I think that you as an editor, and also in terms of the reviewers also, were very helpful in that sort of collaborative process to try to make sure that we're communicating it. It's not always clear in a project that takes months and years to finish when you're writing it necessarily, you may be constantly aware of trying to be clear in your communication but it's also helpful to have a reviewer from the outside carefully read the study.

Dr Carolyn Lam: That's wonderful and Michael, may I just join Naveed in congratulating you on beautiful paper? And maybe just one other little question, did you have any insights into the mechanisms of increased risk for composite events in the extremes of BMI?

Dr Michael O’Byrne: I think it's an important question. There's been a tremendous amount of research in adult cardiac disease about whether it is the BMI as a steady state or BMI changes immediately before and after surgery that are relevant in this case. From this kind of observational study, it's very hard and very challenging to try to make any sort of inferences about the causes. It would be an important part of any study moving forward to include ways to investigate that, and honestly, as an interventional cardiologist and epidemiologist, I probably would defer to Naveed, he might have more cogent and logical ideas about that than I do.

Dr Naveed Sattar: We've had lots of research from a whole variety of researchers. We all understand it's finally serious but recognize it's difficult, so one of the ways moving forward and I think Michael and his colleagues have this is if you have serial BMI data prior to surgery, that could try and inform on reverse causality because of the low BMI, but in terms of the mechanisms, remember these are associations, but I think mechanisms are well covered if you are obese and clearly you have risk factors for death, across the vasculature, across the cardiac functions, across the whole variety of things.

We know those mechanisms, question is, to what extent are they actually operating and causing increased risk in the surgical arena and that's a really tough ask. I think people can come up with a multitude of mechanisms. I think the key things, like this particular paper, is that there are potential mechanisms but these are associations ... Look, this is what we found, and clinically now we need to try and address this within the following types of interventions or at least provide some guidance to colleagues and clinicians.

Exactly as Michael says, if there is somebody who is approaching surgery whose quite obese, perhaps they should try and intervene to try and lessen their weight for a short period of time prior to [inaudible 00:17:07], you know what happens. It would be nice to do some big trials but I think doing trials in this area is going to be really tough, but with imagination, with good collaboration across centers, trials are not impossible. I think they can be done.

Dr Michael O’Byrne: Naveed, I think, actually articulated what I think is both the difficulty of doing that trial but also the importance of it. I think that looking at ... In these databases, we don't have a serial BMI and I think that's an important missing piece of information that we tried to address in our discussion and I think it's something that would be really valuable moving forward. And certainly testing interventions, whether they're medical, interventional, or surgical, to help these patients who are obese either lose or maintain an appropriate weight is the next step.

On the converse side, this research highlighted to me the prevalence of chachectic or underweight patients in our population and it's something that outside of the infant period, we don't necessarily think about tremendously and we don't think about it as a modifiable factor. I think that's another group of patients who also deserve some attention.

Dr Carolyn Lam: Listeners, you've been listening to Circulation on the Run. I'm sure you learned a lot as I did. Don't forget to tune in again next week.

Circulation August 15, 2017 Issue

14 augusti 2017 | 19 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our podcast today highlights an important perspective piece on charting a future together and turning discovery science into cardiovascular health. You don't want to miss this, coming up right after these summaries. The first original paper tells us about the importance of changes in exercise capacity following transcatheter aortic valve replacement or TAVR.

First author, Dr. Altisent, corresponding author, Dr. Rodés-Cabau, and colleagues from Quebec Heart and Lung Institute in Canada studied a total of 305 patients undergoing TAVR with baseline and six month followup exercise capacity assessments by six minute walk tests. They found that close to one-third of patients undergoing TAVR failed to improve their exercise capacity despite an optimal hemodynamic result post-procedure.

Factors associated with a lesser exercise capacity improvement included patient characteristics such as older age, female sex, non-cardiac comorbidities, such as chronic obstructive lung disease, peripheral artery disease and bleeding episodes resulting in reduced hemoglobin levels. Importantly, the absence of an improvement in physical performance at six months post-TAVR was an independent predictor of mortality and adverse cardiovascular outcomes during the ensuing four years and particularly among patients with a greater impairment of exercise capacity pre-TAVR.

Thus, implementing exercise capacity assessment pre and post-TAVR may help to improve patient risk stratification and augment the accuracy of the prognostic information given to patients, helping to identify those requiring more intensive followup assessment. The next study provides mechanistic insights into the adverse health outcomes associated with particulate matter exposure in the air. First author, Dr. Lee, corresponding author, Dr. Kahn, from Fudan University in Shanghai, China and colleagues conducted a randomized double-blind crossover trial in 55 healthy college students in Shanghai. Real and sham air purifiers were placed in participant's dormitories in random orders for nine days with a 12 day washout period.

Serum metabolites were quantified using gas chromatography mass spec and ultra-high performance liquid chromatography mass spec. They found that higher particulate matter exposure led to a significant increase in cortisol, cortisone, epinephrine and norepinephrine. Between treatment, differences were also observed for glucose, amino acids, fatty acids and lipids. They also found that higher blood pressure, hormones, insulin resistance and biomarkers of oxidative stress and inflammation were present among individuals with higher exposure to particulate matter.

Thus, this study showed that activation of the hypothalamus-pituitary-adrenal and sympathetic-adrenal medullary axis may contribute to the adverse cardiovascular and metabolic effects of particulate matter exposure in the air. In China, indoor air purification may be a practical way to reduce personal exposure to particulate matter. The next study shows that N-acetylcysteine may be new effective thrombolytic treatment. First author, Dr. Lizarrondo, corresponding author, Dr. Gauberti and colleagues from Inserm, France hypothesized that N-acetylcysteine might cleave the von Willebrand factor multimers inside occlusive thrombi, thereby leading to their disillusion and arterial recanalization.

To test this hypothesis, the authors used experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of Laser Doppler Flowmetry and magnetic resonance imaging. They showed that intravenous and acetylcysteine administration promoted lysis of arterial thrombi that were resistant to conventional approaches such as recombinant TPA, direct thrombin inhibitors and anti-platelet treatments. Furthermore, through in vitro and in vivo experiments, they provided evidence that the molecular target underlying the thrombolytic effects of N-acetylcysteine were principally the von Willebrand factor that crosslinked platelets in arterial thrombi.

Co-administration of N-acetylcysteine and a non-peptidic GP2B3A inhibitor further improved its thrombolytic efficacy essentially by accelerating thrombus disillusion and preventing rethrombosis. In a new large vessel thromboembolic stroke model in mice, this co-treatment significantly improved ischemic lesion size and neurological outcomes. Importantly, N-acetylcysteine did not worsen hemorrhagic stroke outcome suggesting that exerted thrombolytic effects without significantly impairing normal hemostasis. Thus, in summary, N-acetylcysteine was shown to be an effective and safe alternative to currently available anti-thrombotic agents to restore vessel patency after arterial occlusion.

The clinical implications of the study are wide reaching considering the very wide availability, low cost and apparent safety of N-acetylcysteine. This is discussed in an accompanying editorial by Dr. Lillicrap from Queens University, Kingston, Canada. The final study identifies a novel mechanism for regulation of cardiac fibrosis that revolves around plasminogen activator inhibitor type 1 or PAI-1. First, author, Dr. Flevaris, corresponding author, Dr. Vaughan and colleagues of Northwestern University, Feinberg School of Medicine in Chicago, Illinois showed that cardiac fibrosis was detected by late gadolinium enhancement cardiac MRI in two otherwise healthy humans with complete PAI-1 deficiency due to a homozygous frameshift mutation in serpene 1.

They further performed a series of mouse experiments to show that treatment of young PAI-1 deficient mice with angiotensin 2 induced extensive hypertrophy and fibrotic cardiomyopathy. Ventricular myocytes were found to be the important source of cardiac transforming growth factor beta or TGF beta and PAI-1 regulated TGF beta synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. PAI-1 deficiency significantly enhanced multiple TGF beta signaling elements and transcriptional targets. Thus, in summary, this study show that PAI-1 is an essential repressor or cardiac fibrosis and access a molecular switch that controls the cardiac TGF beta access and its early transcriptional effects that lead to myocardial fibrosis.

Modulation of the cardiomyocytes TGF beta access represents a unique therapeutic strategy that may abrogate fibrotic signaling and cardiac fibrosis. Well, that wraps it up for your summaries. Now for our featured discussion. We are incredibly privileged today to have the director of the National Heart, Lung and Blood Institute, Dr. Gary Gibbonss with us on the podcast, as he talks about his perspective piece entitled "Charting Our Future Together: Turning Discovery Science into Cardiovascular Health." Also, joining me today is our editor in chief, Dr. Joseph Hill from UT Southwestern. Joe, I know you share my incredible excitement and enthusiasm at having Dr. Gibbonss on this podcast with us.

Maybe could I invite you to say a few words to frame just how important this perspective piece is for Circulation?

Dr. Joseph Hill: We all know that cardiovascular medicine and science are evolving at an unprecedented pace. The challenges we face are evolving and yet the opportunities and the tools and the resources at our disposal are unprecedented in their scope and vision. We're very pleased that Gary has provided strong leadership at NHLBI now for several years and has laid out in this perspective piece here where he thinks the next steps are specifically around this strategic vision that focuses on precision medicine and data science. I would love to hear Gary provide additional perspective on that vision.

Dr. Gary Gibbons: Well, thank you, Joe. As the director of NHLBI, clearly we're public servants and we're accountable stewards of the nation's investment in heart, lung and blood and sleep disorders. This piece gave us an opportunity to outline some of the opportunities that lay ahead in a strategic visioning process. First, I should note that a key part of the legacy of the NHLBI is to make strategic investment with enduring principles in mind to really support investigator initiated discovery science as really the core foundational element of our research portfolio, as well as to maintain a balance portfolio to really expands to spectrum of basic translation clinical population and implementation science.

In this piece, we particularly want to highlight our strategic visioning process in which we encourage the broad input of the NHLBI community that actually included over 4,000 participants in this process from every state in the country. Indeed, 42 countries around the world to provide the most compelling questions and critical challenges that the field faces around strategic goals of understanding normal human biology, reducing disease, accelerating translation and preparing a biomedical workforce and resources for the discovery science of the 21st century.

Out of that strategic vision, we focus in on two elements that emerged that relate it to precision medicine and data science for this piece and really that was the central core of what we wanted to share with the Circulation readership about how these two areas we think are going to be transformative in the years ahead.

Dr. Carolyn Lam: Dr. Gibbons, you know, when the term precision medicine is used, sometimes it's a bit fuzzy I think in the minds of a lot of people. Could you maybe give a few examples or perhaps a specific idea that comes to mind?

Dr. Gary Gibbons: You're right. There's often a lot said about it than probably a bit of hype about it. In some ways you could see this as a legacy of cardiovascular medicine and science. It could be argued that the definition of cardiovascular risk factors that came out of the Framingham Heart Study many years ago was the first sort of forerunner of precision medicine. It helped us indeed define those individuals who are at the greatest risk of having a heart attack and that to this day has played a role in directing targeted preventive treatments of the highest risk individuals in order to prevent heart attacks. That has continued to evolve.

I think what's new now is that we have, as Dr. Hill mentioned, new modalities of both imaging and analytics of computational science, as well as novel biomarkers and genetic markers that can help us be even more precise in that risk assessment. That's really I think the greater opportunity to further subcategorize patient populations to get the right drug to the right patient at the right time with a more strategic treatment approach.

Dr. Joseph Hill: Gary, that's very exciting. I think your vision is absolutely compelling. I like how you categorize the NHLBI as a catalyst for the future. I'd like to think that the Biomedical Journals, the AHA Portfolio of Journals and Circulation are also catalysts that will partner with NHLBI and other entities to chart the course for the future. That again the challenges that we face now are different than they were back in the era when Framingham first got started after World War II. The tools that we have are also evolving rapidly and certainly our perspective from Circulation is that we are stewards of helping chart that course, helping identify and bring forth the best science around the world. In many ways we look to you as a partner.

Dr. Gary Gibbons: Oh, absolutely. The NHLBI really can't fulfill our mission of turning discovery science into the health of the nation and indeed around the world without a circle of partners and that certainly includes the platforms of disseminating new knowledge like Circulation, as well as partner organizations such as American Heart Association. We definitely appreciate the value that your organ brings to really enhancing our efforts to not only take discovery science, but make that knowledge available to practitioners and researchers and patients.

I think a key part of the 21st century is how we not only can discover and generate new knowledge, but how we can facilitate that movement of data to knowledge and from knowledge to action that actually enhances the lives of patients in the real world context. Again I believe your journal plays an important role in helping to do that.

Dr. Carolyn Lam: You both mentioned critical challenges that we're facing and will face. The Chinese for these challenges or crisis, the word is actually wéijī. Okay? Wéi is actually meaning danger, whereas jī is for jīhuey which is opportunity. In every challenge, there's always this new opportunity and I just really would like to ask what are the greatest challenge and perhaps the greatest opportunity?

Dr. Gary Gibbons: I think the challenge that we probably face is the emerging epidemic of non-communicable diseases typically cardiovascular disease throughout the world. Not only in the most industrialized nations, but indeed mainly the developing nations. This will quickly surpass communicable infectious diseases as the major burden and causes of mortality worldwide. We're dealing with a global challenge. Increasingly, we recognize that scientific discovery and analysis is often siloed in various packets. Our vision for the future is really to promote the creation of a global reach of what we're calling a Data Commons. That is that a disease has no borders. Science should not be limited to national states.

It is part of the commonwealth if you will of information and knowledge that really should transcend national borders. We say this is a global community of data and information and knowledge exchange and collaboration. As part of this global community, it's that we think this diverse and inclusive approach will be critical to the best minds and best practitioners of the world learning from each other and contributing to this commonwealth of knowledge. We're excited because the opportunity on the other side of that challenge is that it's an unprecedented capability of power to communicate now. We I think are communicating with you from Singapore and we're in a digital age in which this notion of communication and knowledge exchange should be more fast than it's ever been before.

Indeed, we can create computer platforms that are similar to what exist for a Facebook or a Google that are global in scope. The vision is really to say what would happen if we could turn that toward biomedicine and make biomedicine part of this data science such that we have global contributions to our understanding, knowledge exchange and really create that sort of global sandbox if you will of knowledge exchange and discovery. That's part of this notion of creating a Data Commons and really advancing data science as an element of a strategic vision.

As we move forward with precision medicine and data science, our most sacrosanct stewardship is for the next generations. A critical element is to ensure that we're providing them with the tools and training to really lead the charge of advancing these exciting areas of science and that indeed will be a global enterprise.

Dr. Joseph Hill: That's very exciting, Gary. I take my hat off to you for the leadership that you have maintained at the NHLBI during these times that are once very challenging and at the same time exhilarating. I look forward to working with you through our journal and partnering with you to bring to fruition much of what you had laid out in your vision.

Dr. Gary Gibbons: Thank you, Joe. We look forward to our ongoing partnership.

Dr. Carolyn Lam: Thank you, listeners, for joining us today. Do join us again next week.

Circulation August 8, 2017 Issue

7 augusti 2017 | 17 min

Later on in this podcast, we will be meeting Dr. Nancy Schweitzer, Editor-in-Chief of the new Circulation Heart Failure. We will be discussing today's feature paper on acute myocarditis as well as hearing about her visions for the journal. All that coming right up after these summaries.

The first original paper this week suggests that day-to-day blood pressure variability may be a significant risk factor for dementia. First author Dr. Oishi, corresponding author Dr. Ohara, and colleagues of Kyushu University from Fukuoka, Japan, studied a total of 1,674 community-dwelling Japanese elderly without dementia, who were followed up for five years, and had home blood pressure measured three times every morning for a median of 28 days.

They found that the age and sex adjusted incidences of all-cause dementia, vascular dementia, and Alzheimer's disease increased significantly with increasing day-to-day variability of home systolic blood pressure. These associations remained unchanged after adjusting for potential confounding factors, including average home systolic blood pressure. The study, therefore, suggests that the measurement of day-to-day blood pressure variability, using home blood pressure monitoring, may be a useful way to assess future risk of dementia, irrespective of dementia subtype.

The next paper is one of the first studies to directly target a gene within the fibroblast of a mammalian heart and show a direct role in regulating cardiac fibrosis. Co-corresponding authors Dr. Molkentin from Howard Hughes Medical Center and Cincinnati Children's Hospital Medical Center and Dr. Davis from University of Washington and colleagues performed an elegant series of mouse experiments to show that the gene-encoding p38 alpha mitogen-activated protein kinase was required to mediate fibroblast activation in the mouse heart following injury.

They also showed that forced activation of p38 within fibroblasts, using a transgenic approach, was sufficient to drive fibrosis in multiple tissues of the mouse, including the heart.

In totality, their findings indicated that p38 mitogen-activated protein kinase was a nodal signaling effector within the cardiac fibroblast that drove both wound healing and long term fibrosis in heart failure. In other words, it appears to play a crucial role in the control of both physiological and pathological processes. The clinical implications are that pharmacologic inhibition of p38 mitogen-activated protein kinase in heart failure could reduce progressive fibrosis. However, the same inhibition during acute myocardial infarction injury may inhibit wound healing and be detrimental. These issues are discussed in an accompanying editorial by doctors, Stratton, Koch and McKinsey.

Receptors, well known for their roles in angiogenesis and cancer, may play a role in atherosclerosis, as shown in the next paper, which looked at the Eph-family of receptor tyrosine kinases. These are the largest family in the mammalian genome, which interact with ephrin ligands on adjacent cells to mediate cell adhesion repulsion signaling.

First author, Dr. Finney, corresponding author, Dr. Orr, from LSU Health Sciences Center, Shreveport, and colleagues assessed the role of EPHA2 in atherosclerosis by deleting the EPHA2 in a mouse model of atherosclerosis and by assessing EPHA2 function in multiple vascular cell culture models.

The authors identified a novel role for EPHA2 in atherosclerosis by regulating both plaque inflammation and progression to advance atherosclerotic lesions. Cell culture studies suggested that endothelial EPHA2 contributed to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas, smooth muscle EPHA2 expression regulated the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition.

The clinical implications are that blunting EPHA2 ligation may selectively reduce plaque-associated inflammation. Since the effect of EPHA2 on smooth muscle proliferation appears to be largely ligand independent, unlike its effect on inflammation, the blunting of EPHA2 ligation may limit inflammation while leaving smooth muscle fibroproliferative remodeling intact.

Well, that wraps it up for our summaries. Now, let's go to our feature discussion.

Our feature paper today may cause us to think a little bit differently about fulminant versus non-fulminant acute myocarditis because the findings are actually in contrast with previous studies and are extremely insightful.

And, to discuss this, I am so pleased to have the corresponding author, Dr. Enrico Ammirati from Niguarda Hospital in Milan, Italy, as well as Dr. Nancy Sweitzer, Associate Editor of Circulation from University of Arizona, who managed this paper. But importantly, also, the Editor In Chief of Circulation Heart Failure. Welcome, Enrico and Nancy.

Enrico: Hello.

Nancy: Thank you, Carolyn.

Carolyn: Enrico, could I ask you to start by clarifying the conditions that we're talking about here? When we say acute myocarditis or fulminant myocarditis, and non-fulminant myocarditis, what exactly are we referring to?

Enrico: We refer to an acute condition and fulminant myocarditis is a myocarditis inflammation of the myocardium that's a media anatomic or mechanical support due to an anatomic instability, while non-fulminant myocarditis it's a condition where the patient remains hemodynamically stable. Previous records have suggested that despite their dramatic presentation of patient with a fulminant myocarditis might have better outcome than those with acute fulminant myocarditis.

Now in this study we have over 55 patients with fulminant myocarditis and in particular, 34 patients with fulminant myocarditis with viral genomes within two weeks from the onset of symptoms, whereas in the previous record, in particular from [inaudible 00:07:38] we have shown in 15 occasions of fulminant myocarditis, that fulminant myocarditis as quite a good prognosis.

But what we believe it is that gives disparity between our results that connected all acute patients admitted to the emergency department with [inaudible 00:08:01] and symptoms onset within one month to two weeks before. Is the main difference comparing [inaudible 00:08:11] this study [inaudible 00:08:13] patient with onset of symptoms since one year before the onset of symptoms. And we believe that we enroll acute patients.

Whereas in the other study, there was sort of selection by us. It was true that in those previous studies, they have all just patients who we were endomyocardia biopsied performed whereas in our study we did not perform endomyocardia biopsies in that case. But we feel that we have a snapshot of the acute stage of a fulminant myocarditis, so we connected all the patients, whereas in previous study, maybe some of the patients they had acute symptoms died before evaluation from the other researchers.

Carolyn: Indeed, it makes a lot of sense that there may be some survival bias involved. For example, if the sickest patient didn't get a biopsy, for example.

Nancy, when you were managing this paper, what were the kind of the discussions that occurred at the editorial discussions?

Nancy: I think that Dr. Ammirati pointed it out really well. The editors felt that this was a very important paper because it really looked inclusively at myocarditis in the modern era, and showed us where perhaps bias in prior studies had led us astray in terms of our beliefs about, particularly the outcomes in this syndrome. Not only the outcomes in the fulminant patients, who have a very profound and important early mortality risk, but also the outcomes in the non-fulminant patients, who in this study, really do extremely well and do not progress to LV dysfunction, which has been a long-held belief, I think. So understanding much better the full spectrum of myocarditis was made much easier because of the comprehensive look Dr. Ammirati and his colleagues took.

Carolyn: Enrico, I do congratulate you on a beautiful paper. As I said, as a heart failure cardiologist myself, it has changed my thinking. Could you maybe share just a bit more details of what your study found and how this is important clinically?

Enrico: What we have found it is that hospital deaths or heart transplantation was about 25 percent in fulminant myocarditis compared to ten percent in non-fulminant myocarditis and despite greater improvement in the left ventricle injection fraction [inaudible 00:10:56] in fulminant myocarditis compared to non-fulminant forms. The proportion of patients with the left ventricle injection fraction below 55% [inaudible 00:11:09] was higher in fulminant myocarditis comparing it to non-fulminant myocarditis. So we have to pay great attention to do this form of myocarditis not thinking that this is a condition that can simply recover with time but we have to aggressively manage this condition, and we have to see about trials designed [inaudible 00:11:39] in this specific setting to improve the [inaudible 00:11:50] outcome and to reduce myocardial injury during the acute phase.

Carolyn: True. And Nancy, I mean you see tons of these patients too. How has this impacted you?

Nancy: It's interesting, it definitely has impacted me. I like everyone, taught and taught on my teaching rounds for many years that the fulminant patients we were seeing, despite how ill they were, would have better outcomes than those who were non-fulminant. And also, many patients who present with dilated cardiomyopathy who are non-ischemic are told after searching for some viral illness in the year prior to their presentation that probably they had a virus attack the heart or an inflammation of the heart. I've stopped saying those things, and I continue to see review of papers that I'm handling about myocarditis refer to these misconceptions. So I think this is going to be a really important paper, and clarifying our understanding of how this disease evolves over time.

Enrico: I fully agree, I fully agree with this message, and [inaudible 00:12:54] but I believe that the traditions that are involved in [inaudible 00:13:00] maybe can be misleading for other cardiologists.

Carolyn: Nancy, I'm gonna switch tracks a little bit, I mean your explanation of that already gets me so excited about the kinds of papers that are gonna get to be seen at the new Circulation Heart Failure under your leadership. So could you just tell us a little bit more about your vision as editor-in-chief.

Nancy: Well Carolyn, Circulation Heart Failure is an excellent journal Dr. [inaudible 00:13:33] has stewarded it beautifully in its first decade of life. In many ways I don't want to change the journal, I want the very best science that's helping us have a deeper understanding of the disease processes and therapies that affect our patients. That said, I would say we have a couple new initiatives, or sort of slight differences in how we're going to manage the journal going forward. I must say, the content we get is spectacular, and we're so fortunate to be able to look through the papers we get, and try to choose the very best science. It's an amazing privilege for me and the new team.

We're really interested in young investigators and those people who are starting out in their career. The emerging scientists who are producing the best heart failure science. Early in your career you might not have the weight of data behind you to merit publication and circulation proper, but we hope that with good science well thought out excellent hypotheses, Circulation Heart Failure will be an appropriate target for those emerging investigators.

We found some great pleasure in approaching young scientists at meetings, and discussing their work, and asking them to send it to our journal. And that's been great fun and we've seen wonderful yield from that. We've been getting submissions from people we've spoken to whose work we admire, and we really hope to build that part of the journal up. Hand in hand with that is an effort at building our social media presence. We're an entirely online journal. We're very interested in visually appealing content. We do have an images in case report section. And we're going to work to try to build an online community for our young investigators who may not have the money to travel internationally, but who really needed global community of heart failure research colleagues, and we hope to be a place to build that.

And finally, we're interested in some areas that maybe, are emerging or underrepresented in other journals. Areas like ... the way technology is transforming heart failure mechanical circulatory support devices, wearable devices, the other technologies we're using increasingly in our patients. And the world of pulmonary hypertension, and right ventricular dysfunction, which is sort of searching for a journal home, and we hope that we can be that journal home. And of course representing the full spectrum of therapies for heart failures including transplantation. I already mentioned mechanical circulatory support, you know, all the richness that is the evolving field of heart failure, and how we ... I think as professionals in that field think about and treat our patients a little differently than other people caring for heart failure.

Carolyn: Listeners, you just heard it right here, on Circulation on the Run.

Thank you so much for joining us this week. Tune in again next week for even more exciting news.

Circulation August 1, 2017 Issue

31 juli 2017 | 17 min

Dr. Carolyn Lam: Welcome to Circulation on the Run your weekly podcast summary and backstage pass to the Journal and it's editors. I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.

Our feature paper this week provides important mechanistic insights into oxidative stress and inflammation with aging. More of that soon right after the summary of this week's journal.

The first paper contributes to our understanding of the genetic and functional relevance of soluble guanylyl cyclase activity for coronary artery disease. As background, a chromosomal locus at 4q32.1 has been associated with coronary artery disease risk with genome wide significance. The locus encompasses GUCY1A3, which encodes the alpha one subunit of the soluble guanylyl cyclase, a key enzyme of the nitric oxide cyclic GMP signaling pathway.

In today's study from co-corresponding authors Dr. Kessler, and Dr. Schunkert from Munich, Germany and colleagues the authors showed that the GUCY1A3 locus has regulatory properties with the risk allele leading to reduced expression of GUCY1A3. The lead snip modulated finding of the transcription factor ZEB1 resulting in reduced expression of GUCY1A3 in carriers of the risk allele. As a consequence risk allele carriers demonstrated impaired inhibition of vascular smooth muscle cell migration and platelet aggregation after stimulation of the soluble guanylyl cyclase.

In summary, this study suggest that modulating soluble guanylyl cyclase activity or inhibiting the effects of reduced expression of GUCY1A3 may be promising therapeutic strategies for individuals with the high risk alleles of GUCY1A3.

The next paper reports the outcome associations between adding a radial arterial graft to single and bilateral internal thoracic artery grafts in the arterial revascularization trial or ART. As a reminder, ART was designed to compare survival after bilateral internal thoracic artery over single left internal thoracic artery bypass with about 20% also receiving a radial artery graft instead of a saphenous vein graft.

In the current paper, first author Dr. Taggert from University of Oxford and corresponding author Dr. Benedetto from University of Bristol in the United Kingdom and colleagues showed that the primary endpoint of ART which was a composite of myocardial infarction, cardiovascular death and repeat revascularization at five years was significantly lower in the radial artery group when compared to the saphenous vein graft group. This association was present when the radial artery graft was used to supplement both the single internal thoracic artery as well as the bilateral internal thoracic artery grafts.

In summary this post-hoc ART analysis showed that an additional radial artery was associated with lower risk for mid-term major adverse cardiac events when used to supplement single or bilateral internal thoracic artery grafts.

The next study addresses the questions of whether intensive blood pressure lowering beyond usual targets recommended by guidelines would lead to more lowering of left ventricular hypertrophy in patients with hypertension and whether reducing the risk of left ventricular hypertrophy explains the reported cardiovascular benefits of intensive blood pressure lowering.

To answer this question Dr. Soliman from Wake Forest School of Medicine in North Carolina and colleagues studied the 8,164 participants with hypertension but no diabetes from the Systolic Blood Pressure Intervention or SPRINT Trial. They showed that among SPRINT participants without baseline left ventricular hypertrophy, intensive blood pressure lowering was associated with a 46% lower risk of developing left ventricular hypertrophy compared to standard therapy. Similarly, among SPRINT participants with baseline left ventricular hypertrophy blood pressure lowering intensively was associated with a 66% greater likelihood for regression or improvement of their left ventricular hypertrophy. Furthermore, adjusting for left ventricular hypertrophy as a time-varying covariate did not substantially attenuate the effect of intensive blood pressure therapy on cardiovascular disease events.

In summary these findings add further evidence of the benefits of the intensive blood pressure lowering in patients with hypertension and suggest that these benefits go beyond reducing the hemodynamic stress on the cardiac structure. Further research is needed to understand the mediating factors and mechanisms by which intensive blood pressure lowering impacts the cardiovascular system.

Well that wraps it up for our summaries, now for our feature discussion.

We are going to talking about aging, oxidative stress and inflammation today and really taking a deep dive into potential mechanisms. I am so pleased to be here with the corresponding author of our feature paper in this week's issue. And that is Dr. Mustapha Rouis from INSERM University Paris six in France as well associate editor from University of Rochester Dr. Charlie Lowenstein.

Welcome gentlemen.

Dr. Charlie Lowenstein: Thank you for having us.

Dr. Mustapha Rouis: Thank you very much.

Dr. Carolyn Lam: Mustapha, what inspired you to actually look at the Thioredoxin system in looking at this aging question? What were your hypotheses?

Dr. Mustapha Rouis: Actually our laboratories working on cardiovascular diseases for several years. We have been trying to understand why oxidative stress and inflammation increase with age despite the presence of a variety of antioxidant proteins in the body. So among the antioxidant proteins the Thioredoxin-1, isoform one which is a small ubiquitous incytocylic protein called our attention because it's a multi functional protein. It can exert an antioxidant role, anti-inflammatory and anti-apositic role. So therefore we wanted to know whether the increase in the oxidative stress and inflammation with age is it due or at least in part to a deficiency of Thioredoxin-1. If so is there increases due to a decrease in protein synthesis or to increase in its degradation.

For this purpose we have constituted a cohort of young and old subject, male and female. They want to focus on this particular point because this is very important point it has not been easy to achieve and we took a lot of time to sort and to keep only subject meeting our criteria. Those who we wanted to enroll consisting of people free from any history of diseases such as cardiovascular diseases, diabetes, obesity, inflammation, any kind of inflammation, cancer et cetera. In addition we wanted subject without any risk factor for cardiovascular disease except of course the age. No smoking, no hyperlipidemia and no taking any medication.

This really very hard to achieve. Then once we have enough subject we evaluate the Thioredoxin-1 using commercially available very specific kit, ELISA kit and showed that the plasma level of Thioredoxin-1 decreased significantly with age. Since it has been described for several years that Thioredoxin-1 can be cleaved at the C terminal level, the cleavage has been described to be occur after lysine at position eight. This will generate a truncated called Thioredoxin-80. We measured the plasma concentration of Thioredoxin-80 in this sample, in this same sample of the selected subject using an ELISA method developed in our laboratory because there is no commercially kit for Thioredoxin-80.

The result showed that Thioredoxin-80 increased with age therefore the decrease in the plasma concentration of the full length Thioredoxin-1 observed in the old, in the elderly is probably due to an increase in its cleavage and not to a decrease in its synthesis. Of note we observed an increase of the expression and activity of two alpha secretases ADAM-10 and ADAM-17 two enzyme responsible for the cleavage process in the peripheral blood mononuclear cells of the old subject. Our results consolidate our interpretation.

Dr. Carolyn Lam: Wow, what a beautiful set of studies that included human samples and then also included some very elegant mouse experiments. I remember the excitement among the editors when we discussed this paper. Charlie could you just share a little bit of what went on when we looked at this?

Dr. Charlie Lowenstein: First I'd like to put this study into context which is that oxidants increase during aging and it's been known for a long time that animals that have high metabolic rates have short life spans and one of the things that goes along with high metabolic rate is a lot of radical production. And since the 1950's there's been this theory, the free radical theory of aging that radicals damage cells. And so the question is, are radicals bad? What do they do in aging? And what defenses do we have against them? So that's one of the contexts of this article.

Secondly we also know that oxidants are associated with diseases. Increased oxidants during cancer, during inflammatory diseases and during atherosclerosis so that's why this study is important. It's important for two reasons. First of all there's a theory that as you age there's more radicals and radicals might actually cause part of the problem in aging. Secondly radicals are also associated with inflammatory diseases like atherosclerosis.

When the editors got this article, it was very exciting for several reasons. First of all, the short form of Thioredoxin, TRX-80 might explain why older people have more oxidative stress. Secondly this short form TRX, TRX-80 might be a new bio-marker for aging. And thirdly, the short form of Thioredoxin might help us monitor different antioxidant therapies when people have too many radicals. So for a number of important clinical reasons our editors were very excited when we received this important manuscript.

Dr. Carolyn Lam: Mustapha, what are your next steps when it comes to this?

Dr. Mustapha Rouis: Well several studies have shown that Thioredoxin-1 can reduce inflammation and can protect the body against several pathologies which has an increased interest in its use for therapeutic purpose. However its cleavage in the generation of the Thioredoxin-80, limited research work in this direction so I just remember you that the Thioredoxin-80, the truncated form in contrast to the full length Thioredoxin-1 exerts a pro-oxidant, pro-inflammatory angiogenic and carcinogenic effect. So nevertheless in order to counter these difficulties we plan to synthesize some Thioredoxin limited peptides such as catalytic site containing peptides and these peptide used it in therapy could show significant biologic activity. This peptide could lose constitute maybe an alternative to the full length Thioredoxin.

Dr. Carolyn Lam: Wow, that is exciting. Charlie, what do think is the take home message for clinicians listening to this?

Dr. Charlie Lowenstein: Scientists and clinicians all agree that an excess of radicals is bad. But there's an antioxidant paradox which is when patients take antioxidants like vitamin E, those antioxidants don't help. In a large clinical trial suggesting that vitamin E and other antioxidants don't help. So the question is, maybe antioxidant therapy helps some patients but doesn't help others. One of the interesting aspects of this study that maybe the presence or absence of TRX-80 might determine whether antioxidant therapies will help. Furthermore, maybe TRX-80 levels might be able to guide patients as to whether or not they should take antioxidant therapy. There are many important aspects of this study that point toward future studies.

Dr. Mustapha Rouis: We thought about inhibiting the ADAM-10, ADAM-17 alpha secretase enzyme to prevent the cleavage process and I know that many drug companies are trying to find the specific inhibitors but the problem is these two enzyme are benefit in brain for enzymatic disease. So waiting to have a specific inhibitor for this enzyme that do not cross the hematoencephalic barrier to use it in humans but until that we may be the use or conceive the peptides it's better approach.

Dr. Carolyn Lam: I'm just loving this discussion because it's really bringing out a lot more to this paper than I realized as a clinician. Charlie could you end by just saying a few words about how we look at basic science papers in Circulation and the importance of the clinical translation element that we keep saying is our primary focus.

Dr. Charlie Lowenstein: Circulation is a great journal that covers important clinical topics. There's a lot of basic science that underlies some of these clinical topics so whenever we get a paper that gives us insight into a disease or reveals a new therapy and it's at the basic level we look very carefully at it. We want to know, will it help our readers understand something about the clinical process, clinical disease, diagnostics [inaudible 00:16:00] So when we get a paper we look at it very carefully and emphasize it has to be a basic paper that reveals a mechanism that's important to clinicians. That clinicians can understand and appreciate and gain insight about what's going on with their patients. I'm both a clinician and a scientist, I am charged with trying to figure out what basic concepts are relevant to our clinical audience.

Dr. Carolyn Lam: Thank you Mustapha, thank you Charlie and thank you listeners for tuning in this week. Don't forget to tune in again next week.

Circulation July 25, 2017 Issue

24 juli 2017 | 17 min

Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our journal this week features an in-depth review on transcatheter therapy for mitral regurgitation, a very, very hot and interesting topic. You have to listen on, coming up right after these summaries.

Our first original paper this week sheds light on the influence of aging on aldosterone secretion and physiology. First author Dr. Nanba, corresponding author Dr. Rainey and colleagues from the University of Michigan in United States, examine the relationship between age and adrenal aldosterone synthase in 127 normal adrenals from deceased kidney donors. The donors' ages ranged from nine months to 68 years. The authors found that adrenals from older individuals displayed less normal aldosterone synthase expression and zona glomerulosa, and greater content of abnormal foci of aldosterone synthase expressing cells.

Furthermore, older age was independently associated with dysregulated and autonomous aldosterone physiology, in an ancillary clinical study of subjects without primary aldosteronism. This study therefore suggests that aging may be associated with a sub-clinical form of aldosterone excess and provides at least one potential explanation for age related cardiovascular risk.

The next study shows, for the first time, that the chemokine receptor, CXCR4, in vascular cells, limits atherosclerosis. The CXCL12 and CXCR4 chemokine ligand receptor axis is known to control cell homeostasis and trafficking. However, its specific in atheroprotection has thus far been unclear. This is addressed in today's study by first author Dr. During, corresponding author Dr. Weber, and colleagues of The Institute for Cardiovascular Prevention in Munich, Germany. In hyperlipidemic mice, the authors showed that cell-specific deletion of CXCR4 in arterial endothelial cells, or smooth muscle cells, marked the increase atherosclerotic lesion formation. Mechanistically, CXCR4 axis promoted endothelial barrier function through VE-cadherin expression and a stabilization of junctional VE-cadherin complexes. In arterial smooth muscle cells, CXCR4 sustained vascular reactivity responses, and a contractile smooth muscle cell phenotype. Whereas, CXCR4 deficiency favored the occurrence of macrophage-like smooth muscle cells in atherosclerotic plaques and impaired cholesterol efflux.

Finally, in humans, the authors identified a common allele variant within the CXCR4 locus that was associated with reduced CXCR4 expression in carotid RG plaques, and increased risk for coronary heart disease. Thus, the study suggests that enhancing the atheroprotective effect of arterial CXCR4 by selective modulators may open normal therapeutic options in atherosclerosis.

The next paper is the first to study the effects of rosuvastatin on carotid intima-media thickness in children, with heterozygous familial hypercholesterolemia. First author Dr. Braamskamp, corresponding author Dr. Hutten, and colleagues from Academic Medical Center Amsterdam in the Netherlands, study children with heterozygous familial hypercholesterolemia aged 6 to less than 18 years, with LDL cholesterol more than 4.9, or more than 4.1 millimoles per liter in combination with other risk factors, who received rosuvastatin for 2 years, starting at 5 milligrams once daily, with uptitration to 10 milligrams for children aged 6 to 10 years old, or 20 milligrams daily for those aged 10 to 18 years old.

Carotid intima-media thickness was assessed by ultrasonography at baseline, 12 months and 24 months in all patients and in age-matched, unaffected siblings. Carotid intima-media thickness was measured at 3 locations, the common carotid artery, the carotid ball, and the internal carotid artery in both the left and right carotid arteries. At baseline, the mean carotid intima-media thickness was significantly greater for the 197 children with heterozygous familial hypercholesterolemia compared with the 65 unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid intima-media thickness in children with heterozygous familial hypercholesterolemia than in the untreated, or unaffected siblings. As a result, there was no difference in carotid intima-media thickness between the two groups after two years of rosuvastatin. These findings, therefore, support the value of early initiation of statin treatment for LDL cholesterol reduction in children with heterozygous familial hypercholesterolemia.

The final study highlights the therapeutic potential of a novel alpha calcitonin gene-related peptide for the treatment of heart failure. First author Dr. Aubdool, corresponding author Dr. Brain, and colleagues from King's College London in United Kingdom, tested the stable alpha analog of calcitonin gene-related peptide in 2 models ... First, an angiotensin 2 infused mouse, and secondly, pressure overload cardiac hypertrophy mouse model using suprarenal aortic ligation. They showed that systemic colon injection of the alpha analog blunted the angiotensin 2 induced rise in blood pressure, as well as the vascular and cardiac remodeling, changes in water consumption, and renal injury, that are normally associated with angiotensin 2 infusion. Furthermore, protective effects were also seen when starting the alpha analog treatment, only during the last week of the 2-week angiotensin 2 infusion, in other words, when hypertension was already established. Finally, the alpha analog preserved heart function, and diminished the degree of hypertrophy and fibrosis in the aortic ligation model.

Thus, these results demonstrate the therapeutic potential of the alpha calcitonin gene-related peptide pathway, and the possibility that this injectable alpha analog may be effective in cardiac disease.

Well, that wraps it up for this week's summaries! Now, for our featured discussion.

For our feature discussion this week, we're talking about trans-catheter therapy for mitral regurgitation, a very hot field and a field in which there have been a lot of advances. To help us break it down, and get right into the insights, the challenges, and potential solutions, I am so pleased to have the first author of this in-depth review paper, Dr. Paul Sorajja from Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital, as well as Dr. Manos Brilakis, associate editor from UT Southwestern, here with us today!

Paul, could I start with you, and just ask you first to give us an idea of what we're talking about here when we talk about mitral regurgitation ... There are different kinds, which are we referring to, and what are the challenges involved in a trans-catheter therapy for mitral regurgitation?

Dr. Paul Sorajja: I think there are a number of challenges, I think the first thing is that MR is often thought of as one disease, but it's really an incredibly heterogeneous disease ... Broadly, we talk about primary versus secondary MR, but the mitral valve is so complex, with multiple different components, any one of which can disrupt and cause MR. When we're talking about trans-catheter therapy, it's often very easy, again, to think we could have one therapy that could treat a simply insufficient valve, but it's way more complex than that, and as a result, there have been many different approaches that have been developed, adding to the complexity of how we manage these patients.

Dr. Carolyn Lam: Right, and in your paper, I loved the way you grouped them, very logically, under those from mitral valve repair, and that for mitral valve replacement ... And then, under repair, you grouped it into leaflet versus targeting the LV ... Could you maybe give us some top-line insights on these techniques?

Dr. Paul Sorajja: Yeah, there are a number of different approaches that have mechanistically gone after the different components through the pathophysiology of MR, where there is leaflets, where there's analysts, cords, or ventricular approach ... I think it's somewhat simplistic to think of it that way, but as catheter-based technology, we are technically limited by what we can do from a catheter standpoint. I think it's inevitable to think about these catheter technologies as eventually being combined, rather than singular, in order to approach what surgeons do in the OR.

Dr. Carolyn Lam: Right, but then even going further, you spent quite a bit of the paper talking about trans-catheter mitral valve implantation ... So, replacing the mitral valve, that's really cool, could you tell us a bit about that, and about that important issue brought up about patient selection.

Dr. Paul Sorajja: Yes, it's a very good point, I think in terms of trans-catheter mitral replacement, I think that that's really where the future is going to go ... The simple analogy is that people think that it will follow the route of TAVR, but I think it will follow the route of TAVR more quickly so, because when you look at how the mitral valve is currently treated in the OR, sometimes, a lot of the times, patients can end up worse. Whereas, a trans-catheter solution actually, I think in terms of the safety margin, actually will equate a degree of safety relative to surgery, if it's done and developed correctly, as opposed to how TAVR's done. I think for TAVR, it's been a number of years for our field to be equivalent or superior to surgery, whereas I think with mitral, I think there's a lot of potential for mitral to have equated a degree of safety. As an example, in the Tendine Feasibility Study, it was published this past January ... A high-risk population, there was not a single procedure death, out of 30 patients ... And for these patients who would go to the OR with an eject fraction of 30 to 40 percent, I think that's quite remarkable.

Dr. Carolyn Lam: Wow, that's really exciting indeed! Manos, you handled this paper, and it's just so beautifully laid out ... That flow chart, I just want to refer all our listeners to the flow chart in Figure 7, that talks about maybe an approach that can be considered. Manos, could you share some thoughts on how this developed?

Dr. Manos Brilakis: Yeah, absolutely, and obviously Paul is the expert on this, but I think it's very important about this paper, and through discussions with Paul and through the development of the paper, is that there's more of a collaboration between the surgeons and the interventionists. So instead, if it's additional style of ... Or the interventionists are doing one thing and the surgeon is doing another, I think the key to success in the mitral field is working very closely together ... Many of those valves right now, the percutaneous valves, are done through a cut down and a typical approach, so working very closely to addressing the anatomic components of the mitral valve problem is a big plus.

The other thing I think that is very important is the new emergence of imaging, trying to understand whether the new mitral valve is going to create issues with LVOT obstruction or not. I think that's leading to a whole new understanding of when and how patients are even candidates for this approach, and I think Paul can elaborate more on this, but as things evolve, fewer and fewer patients are going to be excluded from these new technologies.

Dr. Carolyn Lam: Paul, would you like to take that? What do you think is happening and will happen with patient selection?

Dr. Paul Sorajja: There has been a challenge in current feasibility studies, in terms of getting patients in, the anatomical restraints are exactly what Dr. Brilakis has outlined. There's a certain bulkiness and size to the valve, which essentially poses risk for LVOT obstruction if the valve is too big ... As a feasibility study that's still early, or a field that's still early in its development, there's been a really conservative approach in terms of patient selection to ensure that LVOT obstruction doesn't happen. I think we're pushing the boundaries for that, and I think we've learned a lot from CT imaging, in terms of predicting LVOT obstruction, and I think the valves are also getting to be shorter in profile, which makes it less likely ... But that is definitely one of the limitations, and it's a limitation that exists, not just for trans-cat therapy but also for surgical therapy.

Dr. Carolyn Lam: Right, and then maybe a question for both of you ... What do you think the future is going to hold? What do we need to make this more mainstream, and where do you think this will leave surgical approaches? I know you said a combined approach, but maybe you could elaborate a little bit more?

Dr. Paul Sorajja: I do think, and I agree, I think Manos' point is spot on about that ... This will have to be multidisciplinary, the surgeons and cardiologists absolutely need to continue to work together, that's what's led to the successful development of TAVR, and I think that will be even more so for mitral, because the mitral valve is just infinitely more complex, and we have a lot to learn from the surgeons. But I think going forward, the collaboration is going to be a requirement, and then the training is also going to be a significant portion ... Putting in a mitral valve is much more complex than putting in an aortic valve ... I think if there's a safety margin that's demonstrated, I still think that it will be more appealing and more rapidly adopted than aortic disease.

Dr. Carolyn Lam: Well, Manos?

Dr. Manos Brilakis: No, I completely agree with Paul on that respect. I think, in my mind, at least, an again, this is from an early standpoint, the next big step would be to make it completely percutaneous, right now, you still have to do the cut down, and it's a little more invasive, although still safer than the completely open surgery, but maybe having a complete percutaneous system would be the next big step ... There's no question in my mind, as well ... And watching very closely how Paul and the surgical team are handling this, I think this is definitely the way for the future. Sometimes, in TAVR, it's not as technically demanding, and you don't really need to have too many people in the room, but for this procedure, it's definitely more important to have everyone in the room, and benefit from everyone's expertise.

Dr. Carolyn Lam: Manos, could I switch tracks for a moment now, and ask you to comment on the question that I get a lot ... You're an Interventionist, you handle a lot of the interventional papers for Circulation, and a lot of people are wondering, what makes papers like Paul's ... What makes interventional papers something that we would want to publish in Circulation? Could you share some thoughts?

Dr. Manos Brilakis: Absolutely, thanks Carolyn ... That's a big part, I think, of the appeal of Circulation right now. We're really trying to communicate to people that cutting-edge, clinical science is actually at the heart and the core of Circulation, and clinical content is what drives a lot of editorial ... Especially in intervention, where particularly interesting and new, cutting-edge technologies, new trials, observational studies ... But essentially, things that are cutting-edge, and are going to have a specific implication and impact in the way the field is going ... And this is part of Dr. Sorajja's paper, showing where the future lies in terms of trans-catheter mitral technologies, but along the same lines, we love to have cutting-edge papers on various aspects ... Coronary, peripheral, all aspects of interventional cardiologies, as well as interventional imaging ... The goal, again is to make the submission easy, there are not many honors requirements for submitting the papers, it's very simple to submit, and there's an answer going out very quick, so we're looking forward to receiving more and more interventional papers on cutting-edge science.

Dr. Carolyn Lam: Thank you so much for joining us today, and don't forget to tune in again next week.

Circulation Jul 18, 2017 Issue

17 juli 2017 | 17 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center and Duke-National University of Singapore.

Now, the SGLT2 inhibitor, empagliflozin, has been shown to improve outcomes in the EMPA-REG OUTCOMES trial. But do these benefits also apply in the real world, and to other SGLT2 inhibitors as a class? Well, we may just have some answers this week in the CVD-REAL study. More soon right after these summaries.

The first original paper this week uncovers the mechanism of beneficial action of T-cells for proper healing after myocardial infarction. Now, the pro-inflammatory danger signal, adenosine triphosphate or ATP, is released from damaged cells, and degraded by the ectonucleotidase CD73 to the anti-inflammatory mediator, adenosine.

Using newly-generated CD4-CD73 null mice, first author, Dr. Borg, corresponding author, Dr. Schrader, and colleagues from Heinrich Heine University of Düsseldorf in Germany, showed that a lack of CD73 on T-cells enhanced tissue fibrosis and worsened myocardial function in the remodeling phase after myocardial infarction.

T-cells migrated into the injured heart and upregulated their enzymatic machinery to enhance the extracellular degradation of ATP to adenosine. T-cells lacking CD73 showed accelerated production of pro-inflammatory and profibrotic cytokines. Finally, the adenosine 2B receptor was upregulated on cardiac immune cells in the remodeling phase.

In summary, therefore, local adenosine formation by CD73 on T-cells appears to be the body's own defense mechanism to control inflammation induced by myocardial infarction. This is a mechanism that might be exploited to promote healing or remodeling by specifically targeting the adenosine 2B receptor in the infarcted heart.

The next paper provides insights on genetic determinants of susceptibility to peripheral artery disease, and specifically puts the spotlight on Bcl-2-associated athanogene-3, or Bag3, which is a cell chaperone protein previously identified in a genetic screen for determinants of tissue loss with hindlimb ischemia.

In the current study, Dr. McClung from East Carolina University, Brody School of Medicine in Greenville, North Carolina, and colleagues, used adeno-associated viruses to show that an isoleucine to methionine variant at position 81 in Bag3 was sufficient to confer susceptibility to ischemic tissue necrosis in BALB/c mice.

In a series of elegant experiments, they demonstrated that Bag3 was a modulator of ischemic muscle necrosis and blood flow. In summary, this study provides evidence that genetic variation in Bag3 plays an important role in the prevention of ischemic tissue necrosis, and highlights a pathway that preserves tissue survival and muscle function in the setting of ischemia.

The next study provides insights into inflammatory atherogenesis by studying psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction. First author, Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI, National Institutes of Health in Bethesda, United States, and colleagues, hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of non-calcified plaques with high-risk features.

To test this hypothesis, they compared total coronary plaque burden, non-calcified coronary plaque burden, and high-risk plaque prevalence between 105 psoriasis patients, 100 older hypolipidemic patients eligible for statin therapy, and 25 non-psoriasis healthy volunteers. All patients underwent CT coronary angiography, and a sample of the first 50 psoriasis patients were scanned again at one year following therapy.

The authors found that patients with psoriasis had greater non-coronary burden and increased high-risk plaque prevalence compared to healthy volunteers. Furthermore, compared to older hypolipidemic patients, patients with psoriasis had elevated non-calcified burden, and equivalent high-risk plaque prevalence. Finally, improvement in skin disease severity was associated with an improvement in non-calcified coronary burden at one year.

The clinical implications are that patients with psoriasis have similar coronary artery disease risk as hyperlipidemic patients one decade older, and these patients with psoriasis should be screened earlier for cardiovascular disease and educated about their elevated risks. Further investigations focus on the longitudinal impact of psoriasis treatment on high-risk plaque morphology, as well as on the extent of cardiovascular risk mitigation in randomized trials.

Well, those were your summaries. Now for our feature discussion. Now, we've heard of the EMPA-REG OUTCOME trial, that prospective randomized, controlled trial, showing a substantial reduction in cardiovascular death and hospitalization for heart failure with the sodium-glucose cotransporter 2, or SGLT2 inhibitor, empagliflozin, and that's, remember, that was in patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

Well, our paper today really extends our knowledge and tells us a bit more about the role of SGLT2 inhibitors in real-world clinical care. And I'm so please to have with us the first and corresponding author, Dr. Mikhail Kosiborod from Saint Luke's, Mid America Heart Institute, as well as Dr. Gabriel Steg, associate editor from Paris, France, joining us today. Hello, gentlemen.

Dr. Gabriel Steg: Hello.

Dr. Mikhail Kosiborod: Hi. Good morning, Carolyn.

Dr. Carolyn Lam: Mikhail, I am going to say what I said to you at the ACC and at the ESC Heart Failure: Congratulations on CVD-REAL. Please tell us about CVD-REAL.

Dr. Mikhail Kosiborod: Right, well, we know, as you just mentioned, that the EMPA-REG OUTCOME trial showed substantial reduction in cardiovascular death, and hospitalizations for heart failure in patients with type 2 diabetes and established cardiovascular disease. We were all very excited once that data got presented in September of 2015 in Stockholm, but there were several very important questions that weren't really addressed, and truly, could not be addressed, in EMPA-REG's trial.

The first, actually, and probably the most important is, we all know that clinical trials, while we regard them as the gold standard of evidence, as we should, they do have their own set of limitations, the most important of which is that they examine a relatively small sliver of patients; and many patients we see in the clinic, in the hospital, don't look like patients in clinical trials. I think the most important questions we tried to address was, "Will this translate to real-world clinical practice?"

The second was, as you recall, again, all patients on EMPA-REG had established cardiovascular disease, so we wanted to know whether the benefits associated with the use of SGLT2 inhibitors could potentially extend to lower-risk patients with type 2 diabetes without established cardiovascular disease, a much broader spectrum of patients.

And finally, and also very importantly, I think, the third question was, "Is it an empagliflozin-specific effect or is it a class effect?" These are all the critical questions we tried to address in the CVD-REAL study.

Dr. Carolyn Lam: Great. Could you give us the topline results, please?

Dr. Mikhail Kosiborod: Right. So, just as a reminder, we collected data from well-established registries in six countries, so the United States and some five countries in Europe, Sweden, Norway, and Denmark, and also, the United Kingdom and Germany. And really, the inclusion/exclusion criteria for the study were quite broad, you just had to have type 2 diabetes and be newly started on either an SGLT2 inhibitor or any other glucose-lowering medications, which was the comparative group.

And after we did the one-to-one propensity match to make sure, comparable samples, we ended up with about 154,000 patients, and each treatment group, over 300,000 patients overall. What we actually observed was a marked and highly significant reduction in the risk of hospitalization for heart failure that was associated with use of SGLT2 inhibitors versus other glucose-lowering drugs.

In fact, the magnitude of reduction in risk that was associated with SGLT2 inhibitors, so that outcome was quite similar, about 39% relative risk reduction, quite similar to what we see in the EMPA-REG OUTCOME trial. But this, of course, was for the entire class of SGLT2 inhibitors, so patients in the study were treated primarily with canagliflozin and dapagliflozin, with a small proportion being treated with empagliflozin.

We also saw dramatic and highly significant associated reduction in the risk of all-cause death with SGLT2 inhibitors versus other glucose-lowering drugs, about a 51% relative risk reduction, and the composite of those two outcomes, obviously, there was significant associated reduction in risk as well.

So, again, the hazard ratio estimate that we saw for these outcomes were quite similar, and in some cases, almost identical to what we've seen in EMPA-REG, but for a patient population that was much broader, in fact, about 90% of patients, close to 90% of patients in our study did not have established, documented cardiovascular disease. And, of course, as I mentioned before, important implications to these findings, in my opinion.

Dr. Carolyn Lam: Yeah, that is just remarkable. Gabriel, could you share some of the discussions that happened among the editors about this paper?

Dr. Gabriel Steg: We were really excited by this paper. I think this is truly a landmark paper for a number of reasons. It's a very large, multinational study, but even more than the size, I think what's interesting here are a couple of key aspects. First of all is data on all-cause mortality, which is a highly reliable outcome when you look at many of the observational studies.

Non-fatal outcomes can easily be skewed or biased in ascertainment or assessment, but this is relatively reliable. And here, we have a very large multinational cohort that finds benefits on death, heart failure, and their composite, which are remarkably consistent internally, consistent across countries, and consistent with the randomized trial data evidence from the EMPA-REG OUTCOME trial.

So that is striking, and this is consistent across six countries using a very large sample size. But again, the size of the sample is not the most important thing, because in observational studies, you often have very large sample sizes, but if you have bias in your observational study, the bias is just replicated times the size of the study.

The consistency here between the treatment effects across the various countries, the consistency with the efficacy assessed in randomized clinical trials is really a crux in the quality of the data and how believable the results are. Another key aspect that got us really excited is the fact that only a minute fraction of the data is related to use of empagliflozin.

Most of the data was acquired using other SGLT2, and we still only have results now with empagliflozin, we don't have outcome trial data with the other agents. They are pending, but pending the availability of these trials, the fact that this large study sees a consistent benefit, in terms of heart failure and mortality, of the other agents in the class suggests that this is a class effect.

And likewise, the fact that we're seeing these benefits in a population that is much, much broader than the population of EMPA-REG OUTCOMES is also very, very intriguing, and exciting, and makes us really want to see more data not only from the randomized trials that are upcoming, but also from this study.

Because now, what we would like to see is, see the detailed cardiovascular outcomes in these cohorts, and I know that Mikhail and his colleagues are working very, very actively on preparing these analyses. I think this is going to be exciting. This is the first of a series of landmark papers from a model observational study.

There are many issues with observational studies. This is almost as good as it can ever get, and I want to compliment Mikhail and the consortium that's with him, because this is a tremendous effort, across several countries, on achieving this. I think it's very exciting for our readership and for clinicians around the world.

Dr. Carolyn Lam: I couldn't agree more, and I share your compliments for Mikhail. Perhaps, Mikhail, could you give us a sneak peek at the future and the ongoing work?

Dr. Mikhail Kosiborod: We frequently think of, and I think perhaps mistakenly at times, think of clinical trials and observational real-world data as competing with one another. In many cases, they're really complementary, and I think if you really, kind of, think of interventions that we consider as those gold standards enshrined in clinical guidelines, or something we absolutely should be doing for our patients.

Just to pick one example, statins for secondary prevention after a cardiovascular event, for example, there is data from both sources suggesting that these drugs are highly beneficial, right? So it is very important to have data from both sides, and I think, as Gabriel mentioned, I look at CVD-REAL as a model, in many ways, of how compelling the data from non-randomized, large, real-world observational studies can be when done well.

In terms of a sneak peek for the future, there are many, many things going on. We are carefully examining the outcomes that we are reporting in circulation, including heart failure and all-cause mortality in various subgroups. We are, of course, as Gabriel mentioned, intently looking at other outcomes, including myocardial infarction, stroke, cardiovascular death, and a composite of major adverse cardiac events.

We're also examining some of the diabetes, one could argue, maybe, diabetes-specific outcomes, such as hypoglycemia rates. We, of course, as cardiologists tend to concentrate on cardiovascular outcomes, but it's also important to remember that there are other important outcomes that could be associated benefits.

So these medications may be associated with marked reduction of cardiovascular events, such as death and heart failure, but they may also reduce hypoglycemia rates and, of course, that's important from a quality-of-life standpoint for patients with diabetes, so some of that work is ongoing.

And I would say, importantly, one of the other things that we're hoping to be able to do in the future is to go beyond cardiovascular outcomes, and perhaps blood glucose-specific outcomes, such as hypoglycemia, and start looking at events such as renal disease events, which I think are very important, of course. Interact quite a bit with, I suspect, in many ways, with some of the cardiovascular benefits that we're observing with those agents, both in the clinical trials and, now, in large observational studies.

And that's just the beginning. I mean, I think it's fair to say that, as Gabriel mentioned, a huge amount of work went into putting this together, right? And we're actually not only expanding things from a standpoint of outcomes. We're also expanding things from a standpoint of countries that will be participating in CVD-REAL consortium.

So we're actually planning to add at least two or three more countries from Europe, Middle East, and Asia in the coming months, and more so in the future. And of course, once you have a resource like this, there are additional questions that can be addressed, actually, both with SGLT2 inhibitors as a class, but also with other classes of type 2 diabetes medication. So that's, I think, as much of a sneak peek as I can give you right now. Just definitely promise you that there is a lot more coming.

In addition to ADA, we're going to have abstracts being presented at ESC in August, and also the European Association for the Study of Diabetes meeting in Lisbon, in September, and there's going to be a lot more afterwards as well. So just stay tuned, I would say. This is definitely just the beginning. There's going to be a lot more coming.

Dr. Carolyn Lam: You took the words right out of my mouth. Listeners, stay tuned, and don't forget to tune in next week as well.

Circulation July 11, 2017 Issue

10 juli 2017 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Youth National University of Singapore. Coming right up, we will be discussing fascinating new data on the prevalence of subclinical coronary artery disease in masters endurance athletes but first, here's your summary of this week's journal. The first paper provides insight into ischemic cellular post conditioning. Now, we know that cardiosphere derived cell therapy has been utilized as a strategy to treat ischemic heart disease and reduce chronic scar burden when administered months after myocardial infarction. In the current study, by first author Dr. de Couto, corresponding authors Dr. Marban and Berman from Cedars-Sinai Heart Institute in Los Angeles, California, the authors used rat and pig models of myocardial infarction to show that exosomes, which are nanosize lipid bi-layer vesicles, actually mediate the cardio protective effects of cardiosphere derived cells when administered after reperfusion of myocardial infarction.

They further show that treatment with either cardiosphere-derived cells or their secreted exosomes reduce infarct size and improved functional recovery. Using RNA sequencing to determine exosome content and alterations in gene expression profiles on macrophages from cardiac tissue or bone marrow, they found that a specific micro RNA species miR 181-B within the exosomes, acted on macrophages and was implicated as a key mediator of the cardio-protective benefits. Thus, this study gives new reason to test the idea that allogeneic cardiosphere-derived cells may be efficacious in preventing scar formation and improving cardiac function, when given in the earlier reperfusion period. The data further support that exosomal transfer of miR 181-B from these cardiospheric-derived cells into macrophages underlie the cardio-protective effects after reperfusion.

The next study describes a potential new therapeutic strategy for vasoproliferative retinopathy which can underlie age-related macular degeneration, the leading cause of blindness in industrialized nations. First author, Dr. Bucher, corresponding authors Dr. Yea and Friedlander, from the Scripps Research Institute in La Jolla, California used rodent models of retinal neo-vascular disease to show that Tspan-12, beta-catenin signaling plays an important role in the development of vasoproliferative retinopathy. As background, Tspan-12 belongs to the Tetraspanin family, which mainly includes cell surface proteins characterized by four transmembrane domains and two extra cellular domains.

Members of the Tspan family participate in a diverse cellular processes and act as signaling platforms by forming Tspan-enriched micro domains in plasma membranes. The authors went further to use a novel phage display combinatorial antibody library to specifically design a Tspan-12 blocking antibody which is capable of interacting with human and mouse Tspan-12 antigen. They then provided strong evidence that the Tspan-12 blocking antibody prevents developmental pathological neovascularization in murine models of vasoproliferative retinopathy. Combination therapy with a known anti-VEGF agent demonstrated significant synergy supporting the potential clinical use of the anti-Tspan-12 antibody as a novel angiomodulatory agent.

The next study addresses the paradox that blacks have higher coronary heart disease mortality compared with whites, but non-fatal coronary heart disease risks may be lower for black versus white men. To address this paradox, first author Dr. Colantonio, corresponding author, Dr. Safford and colleagues from Weill Cornell Medical College in New York, compared fatal and non-fatal coronary heart disease incidents and case fatality among blacks and whites in three studies. The Atherosclerosis Risk in Communities or ARIC study, cardiovascular health study, and reasons for geographic and racial differences in stroke or regards study, all stratified by gender.

They found that the incidents of non-fatal coronary heart disease was consistently lower among black versus white men, although black men have a higher burden of unfavorable social determinants of health and cardiovascular risk factors and a higher fatal coronary heart disease incidents. Following adjustment for social determinants of health and cardiovascular risk factors, black men and women had a similar risk of fatal coronary heart disease, but a lower risk of non-fatal coronary heart disease compared with white men and women respectively. Finally, blacks with incident coronary heart disease had a higher case fatality compared with whites and the difference remained similar after adjustment for social determinants of health and risk factors. Thus, there is an apparent lower risk for non-fatal coronary heart disease among black versus white men and women, which needs to be further studied. Blacks have a higher risk of their initial coronary heart disease event being fatal compared with whites, highlighting the need for reinforcing primary prevention in this population.

The next study provides important information on the burden of re-admissions after hospitalization for critical limb ischemia. First author, Dr. Kolte, corresponding Dr. Aronow and colleagues from Brown University in Providence, Rhode Island, used the 2013/2014 nationwide re-admissions databases to identify almost 61,0000 hospitalizations for primary diagnosis of critical limb ischemia during which patients underwent endovascular or surgical therapy. They found a 30-day re-admission rate of 20.4%. Independent predictors of 30-day re-admission included presentation with an ulcer or gangrene, age above 65 years, females, large hospital size teaching hospital status, known coronary artery disease, heart failure, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis. Interestingly, mode of revascularization was not independently associated with re-admissions.

The most common reasons for re-admissions included infections, persistent or recurrent manifestations of peripheral artery disease, cardiac conditions, procedural complications, and endocrine issues. Finally, the costs of 30-day re-admissions for critical limb ischemia during the study period were 624 million U.S. dollars. Thus, this study provide knowledge of independent predictors and reasons for re-admissions that will help clinicians and hospitals to identify, develop, and implement strategies to reduce re-hospitalizations and healthcare costs associated with critical limb ischemia.

The final study tells us that there may be a direct relationship between life-long exercise volume, and coronary atherosclerosis in athletes. Dr. Aengevaeren and colleagues from Radboud University Medical Center in the Netherlands, studied 284 middle-aged men engaged in competitive or recreational leisure supports, using contrast enhanced CT to assess coronary artery calcification and plaque characteristics.

Participants also reported life-long exercise history patterns and exercise volumes were quantified as metabolic equivalent of task or met minutes per week. They found that participants in the more than 2,000 met minutes per week group had a higher prevalence of coronary artery calcification and atherosclerotic plaques. The most active group did, however, have a more benign composition of plaques with fewer mixed plaques and more often, only calcified plaques. These observations may explain the increased longevity typical of endurance athletes, despite the presence of more coronary atherosclerotic plaques in the most active participants. Well, that wraps it up for your summaries. Now for our featured discussion.

Our current physical activity guidelines recommend 150 minutes of moderate exercise and that's supposed to protect against cardiovascular disease and increase longevity. However, what do we really know about the dose response relationships and the effects of exercises doses that exceed current recommendations. Well, recent data, including a paper in this week's issue, suggests that long-term, high volume endurance exercise may actually accelerate, rather than reduce coronary atherosclerosis. To discuss this exciting paper, we have the corresponding author, Dr. Sanjay Sharma, from Saint George's University of London, as well as editor of digital strategies and associate editor at UT Southwestern who handled this paper, Dr. Amit Khera. Welcome, gentleman.

Dr. Amit Khera: Good morning.

Dr. Sanjay Sharma: Thanks for having us.

Dr. Carolyn Lam: First, Sanjay, oh yikes! As a runner and as a person who strongly advocates regular exercise, please, please, put us out of our misery. Tell us what you've found and what you think are the possible explanations.

Dr. Sanjay Sharma: I'm a runner too, and I don't think anyone would argue that the benefits of exercise on the cardiovascular system are unrivaled. People who exercise regularly do reduce their risk of an adverse event from a heart attack by 50% when they're in their 5th and 6th decade and they live around three years longer than people who don't exercise at all. Now as you rightly point out, the current recommendation suggests 2 1/2 hours of moderate physical activity per week and by that I would mean, at maximum, a 15-minute mile pace. Clearly, our endurance athletes exercise much, much more than that. They exercise 10 to 20 times greater than that volume and in parallel with this has been the emergence of a large number of people participating in marathon runs. For example, in Europe, there were two million marathon runs per annum and that figure's going up by about 5%.

Coinciding with this burgeoning increase in endurance exercise, is the development of several reports that show that exercise may cause release of biomarkers of cardiac damage. Animal experiments have shown that exercise may cause scaring in the heart and human studies have shown that some marathon runners have more calcium in their coronary arteries compared to relatively sedentary individuals. One of the problems with these studies is firstly, the biomarker release is very transient, it goes away after about two days. Animal experiments cannot really reflect what goes on in human beings because they're artificial and animals are forced to exercise with electrical shocks, et cetera. The studies in human beings have been conducted in runners who have been former smokers.

In fact, the most commonly reported study or cited study, contained individuals of whom 50% had risk factors for coronary artery disease. What we decided to do was to do a clean study, where we took 150 individuals who had none of the risk factors for coronary artery disease and 92 relatively sedentary controls who exercise within the normal limits. We have to exclude a lot of people because we have to exclude anyone that had ever smoked, anyone that had high blood pressure, high cholesterol, or a family history of permanent cardiac disease. We actually subjected them to all sorts of investigations and we found that a small number of male runners had more calcium in their arteries compared to sedentary individuals.

Dr. Carolyn Lam: Wow! Please tell us that there's something good that you can say about that. First of all, I really want to congratulate you on this most elegant study and Amit, I'm sure you put in what the editor's thought but we're just so proud to be publishing such a high quality study here. Amit, is there anything you might want to add of what the editors thought?

Dr. Amit Khera: Sure, I first want to congratulate Dr. Sharma and his colleagues. This was a carefully done study and we've talked a bit about the coronary calcium but there was extensive investigation and I really think this advanced the field. Sounds like all three of us are runners, so this hit home to all of us and as he mentioned, this has been a very hot area and one that's been very controversial. I think here what we have is a manuscript that really helped move the field forward, helped us better understand the biology. The one thing I'll comment on that we found very interesting was the observation that those that were the masters athletes actually had more of a calcific phenotype, where as those that were not looked like a soft plaque phenotype, if you will. Actually, if you look, we have a companion article in circulation looking at sort of dose dependent finding a similar finding. My question, now turned back to Dr. Sharma is, what do you counsel your patients now with these findings? Has it changed now how you recommend exercise or your thoughts on how you counsel them?

Dr. Sanjay Sharma: Well, we examined 152 different athletes, or masters athletes in 92 controls. These athletes were aged 56 years old, who'd been training for 36 years and had immediate marathon number of 13. Now, what we've found in these individuals is that a small number of males, that's 11%, had a coronary artery calcium score of more than 300. Some men had more plaques than sedentary individuals and these plaques were distributed throughout all three coronary arteries. When we looked at the pathology of the plaques very carefully, we found that the plaques in the athletes were calcified. Indeed, 72% of athletes had very calcified plaques. We know that such calcified plaques are stable, they're less likely to fissure and are less likely to cause coronary thrombosis and therefore, acute myocardial infarction.

This led us to propose that although exercise may be causing some atherosclerosis through the sheering and stressful source during exercise of the bending and kicking of vessels, we believe that the repair mechanism here is different to that seen in people who smoke or who have high cholesterol or high blood pressure. The repair mechanism results in very calcified and stable plaques in athletes and this may actually mitigate the risk of acute myocardial infarction and may explain why the number of people who actually suffer an acute myocardial infarction during a marathon run is very small, around 1 in 50,000, and no different to the number of people who suffer a sudden cardiac arrest playing football or basketball, due to congenital or inherited abnormalities of the heart.

Dr. Carolyn Lam: Sanjay, those are just such important points to keep in mind as we read your paper. It did strike me as a significant minority, actually, of these long term endurance athletes who develop significant coronary artery calcification and it could potentially be a clinically benign phenotype. At the end of the day, this is a cross-sectional study, isn't it? We can't, I suppose, extrapolate into the clinical events. What are your postulations there and what could be future work that you're planning?

Dr. Sanjay Sharma: Well, you make a good point. This is a cross-sectional study and the demonstration of an increased cardiopathy calcium does not necessarily reflect future cardiac events. We have followed these individuals up for the last 18 months. These masters athletes and have not demonstrated a single one to develop an acute event that would last 18 months. We really don't know what the meaning of these plaques is. I think the only thing to do now, being we've got the liberty of having so many people that do marathon runs and so many people who've been exercising for three or four decades, we can actually do a prolonged follow up study, so the answers will be a while coming. To follow these people up with high calcium, just to see whether they do go on to develop adverse events in the future. All our study has shown is that some male athletes who've exercised lifelong get an increasing number of plaques. These plaques appear to be calcified and stable and the long term effects of such plaques is unknown.

Dr. Carolyn Lam: Sanjay, just circling back to Amit's question earlier and maybe Amit, you could take it to after this. What do we recommend to our athletes who come in and have a high coronary artery calcium score? Do we tell them to stop?

Dr. Sanjay Sharma: I certainly wouldn't and I'm much less worried about an increase coronary calcium score in a lifelong runner or cyclist than I was 10 years ago. It appears that these plaques are there in some individuals, they are calcified, they appear stable. Given the fact that we know that coronary events during marathon running in experienced runners are very, very low indeed. I don't think I would be keen to do anything about it, not even consider stacking therapy based on our findings at present. As I said before, we do need longitudinal follow up to really identify all ascertain the precise implications of these plaques in masters athletes.

Dr. Carolyn Lam: Right, and this is again recognizing that your particular population was free of traditional cardiovascular disease. Of course, if we were to find these risk factors in our athletes, we would most certainly treat the traditional risk factors. Amit, anything to add there?

Dr. Amit Khera: I think that was an excellent point about his approach to counseling patients. I will mention on the editorial staff, we felt like this was such an interesting area with emerging data and fast moving, that it was warranting of an editorial. I recommend people to look at the one by Aaron Baggish and Ben Levine. I think they had a very similar conclusion and that was that they don't necessarily proscribe exercise in patients with high coronary calcium but rather, focus on risk mitigation strategy, focusing on risk factors as we normally would do. I think the conclusions are similar and the thoughts in that editorial were insightful, pairing both of these papers and helping us make sense out of this really evolving field.

Dr. Carolyn Lam: Well, thank you Sanjay and Amit for this wonderful discussion. I learned so much as I'm sure our listeners did. You've been listening to Circulation On The Run. Tune in next week.

Circulation July 4, 2017 Issue

3 juli 2017 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. What is the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy? We will be discussing new data in this area in just a moment, following these summaries.

The first paper describes the effect of long-term metformin and lifestyle measures on coronary artery calcium. This is a paper from Dr. Goldberg of George Washington University Biostatistics Center and colleagues of the Diabetes Prevention Program Research Group. The Diabetes Prevention Program and its outcome study is a long-term intervention study in subjects with prediabetes, which showed reduced diabetes risk with lifestyle and metformin compared to placebo.

In the current study, the authors looked at subclinical atherosclerosis, which was assessed in 2,029 participants using coronary artery calcium measurements after 14 years of average follow-up. They found that men but not women with prediabetes treated with metformin for an average duration of 14 years had lower coronary calcium scores than their placebo counterparts. No difference in coronary calcium scores was observed in the group receiving a lifestyle intervention as compared to the placebo group.

These findings provide the first evidence that metformin may protect against coronary atherosclerosis in men with prediabetes, although demonstration that metformin reduces cardiovascular disease events in these subjects is still needed before firm therapeutic implications of these findings can be made. The reason for an absence of an effect in women is unclear and deserves further study.

The next study provides insights on the physiology of angina from invasive catheter laboratory measurements during exercise. Dr. Asrress of Royal North Shore Hospital in Sydney, Australia, and colleagues, studied 40 patients with exertional angina and coronary artery disease who underwent cardiac catheterization via radial axis and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual GTN was administered to half the patients and all patients continued to exercise for two minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity, and central aortic pressure were recorded using sensor wires.

Using this novel invasive approach, the authors showed that administration of GTN ameliorated angina by reducing myocardial oxygen demand as well as increasing supply with a key component being the reversal of exercise-induced coronary lesion vasoconstriction. This was evidenced by the fact that there was a relationship between the diastolic velocity pressure gradient with significant increase in relative stenosis severity. In keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilation of normal segments, with trends towards reversal with GTN.

Thus, this study describes the development of a paradigm where patients with coronary artery disease can exercise while simultaneously having coronary and central aortic hemodynamics measured invasively, and has shown that this provides a unique opportunity to study mechanisms underlying the physiology of angina. In treating patients with exercise-induced angina, the results highlight the importance of after-load reduction and the use of agents that reduce arterial wave reflection and promote coronary artery vasodilation.

The next study provides mechanistic insights into reverse cholesterol transport, where excess cholesterol is removed from macrophage-derived foam cells in atherosclerotic plaques. It suggests that melanocortin receptor-1, or MC1-R, may play a role. As background, the melanocortin system, consisting of melanocyte-stimulating hormones and their receptors, regulate a variety of physiological functions, ranging from skin pigmentation to centrally-mediated energy balance control. At the cellular level, the biological actions are mediated by G protein-coupled melanocortin receptors, such as MC1-R. MC1-R not only affects melanogenesis in the skin but also has immunomodulatory effects through its wide expression in the cells of the immune system.

In the current study from Dr. Rinne of University of Turku in Finland, and colleagues, human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was further assessed in apolipoprotein E deficient mice. Their findings identified a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R conferred protection against macrophage foam cell formation through a dual mechanism. It prevented cholesterol uptake while it concomitantly promoted reverse cholesterol transport by increasing the expression of ATP-binding cassette transporters, ABCA1 and ABCG1.

Thus, the identification of MC1-R in lesional macrophages, demonstration of its role in regulating reverse cholesterol transport, combined with its established anti-inflammatory effects, suggests that MC1-R could be a novel new therapeutic target for preventing atherosclerosis.

The next study suggests that obesity-related heart failure with preserved ejection fraction, or HFpEF, is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments. First author, Dr. Obokata, corresponding author, Dr. Borlaug, and colleagues from Mayo Clinic Rochester and Minnesota studied 99 patients with obese HFpEF with a BMI above 35, with 96 non-obese HFpEF with a BMI less than 30, and 71 non-obese controls without heart failure. All subjects underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.

The authors found that, compared to non-obese HFpEF, obese HFpEF patients displayed greater volume overload, more biventricular remodeling, greater right ventricular dysfunction, worse exercise capacity, more impaired pulmonary vasodilation, and more profound hemodynamic arrangements, despite a lower NT-proBNP level. Obese HFpEF patients displayed other important contributors to high left ventricular filling pressures, including greater dependence on plasma volume expansion, increased pericardial restraint, and enhanced ventricular interaction, which was exaggerated as pulmonary pressure load increased.

These data provide compelling evidence that patients with the obese HFpEF phenotype have real heart failure and display several pathophysiological mechanisms that differ from non-obese patients with HFpEF. These and other issues are discussed in an accompanying editorial by Dr. Dalane Kitzman and myself. We hope you enjoy it.

The final study identifies a novel long noncoding RNA that regulates angiogenesis. As background, although we know that the mammalian genome is pervasively transcribed, a large proportion of the transcripts do not encode a protein, and are thus regarded as noncoding RNAs. Based on their length, they can be divided into small or long noncoding RNAs, long being described as more than 200 nucleotides. Although their function is not fully understood, long noncoding RNAs have been increasingly reported to mediate the expression of other genes, affect the organization of the nucleus, and modify other RNAs.

In the current study by first author, Dr. Leisegang, corresponding author, Dr. Brandes, and colleagues of Goethe University in Frankfurt, Germany, epigenetically controlled long noncoding RNAs in human umbilical vein endothelial cells were searched by axon array analysis following knockdown of the histone demethylase JARID1B. The authors discovered a novel noncoding RNA named MANTIS to be strongly upregulated. MANTIS is located in the antisense strand of an intronic region of the gene for annexin A4, calcium- and phospholipid-binding protein. MANTIS is a nuclear long noncoding RNA that is enriched in endothelial cells but also expressed in other cell types. Reducing MANTIS levels led to impaired endothelial sprouting, tube formation, attenuated endothelial migration, and inhibition of the alignment of endothelial cells in response to shear stress.

Brahma-like gene 1, or BRG-1, was identified as a direct interaction partner of MANTIS, implying a role of MANTIS in the formation of the switch/sucrose non-fermentable chromatin remodeling complex. MANTIS binding to BRG-1 was shown to stabilize the BRG-1 interaction, hence by inducing an open chromatin conformation, MANTIS was proposed to maintain the endothelial angiogenic potential. The implications of these findings are discussed in an accompanying editorial by Dr. Zampetaki and Mayr from Kings College London.

That brings us to the end of our summaries. Now for our feature discussion.

Today, we are going to be discussing the association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. To discuss this, I have the first and corresponding author of our feature paper, Dr. Heather Boyd, from Statens Serum Institut in Copenhagen, and our familiar Dr. Sharon Reimold, content editor for special populations from UT Southwestern. Welcome, Heather and Sharon.

Dr. Heather Boyd: Thank you.

Dr. Sharon Reimold: Thank you.

Dr. Carolyn Lam: Heather, it's a topic that I can't say I'm very familiar with, association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy. Could you start by sharing why would we think there would be a link? What was the hypothesis you were testing?

Dr. Heather Boyd: A couple years ago, there was a paper published in the European Heart Journal that reported evidence of angiogenic imbalance in women with fetuses with major congenital heart defects, so women who were pregnant with babies that had heart defects, and then in fetuses that were terminated because of this kind of defect. My research group focuses a lot of attention on preeclampsia. In the last decade or so, angiogenic imbalance in preeclampsia has been a really hot topic. Women with preeclampsia, particularly women with early-onset preeclampsia, have big angiogenic imbalances. When we saw the European Heart Journal paper, we immediately thought, "What's the connection between preeclampsia and heart defects in the offspring?"

Dr. Carolyn Lam: Oh!

Dr. Heather Boyd: Exactly. That was our entry point to it, was the term "angiogenic imbalance" in that paper sort of was a flag for us. It wasn't a completely new idea, but we in Denmark have one big advantage when considering research questions that involve either rare exposures and/or rare outcomes, and that's our National Health Registry. We have the ability to assemble these huge cohorts and study conditions like heart defects with good power, so we decided just to go for it.

Dr. Carolyn Lam: That makes a lot of sense now. Please, tell us what you did and what you found.

Dr. Heather Boyd: The first thing we did was look at the association between carrying a baby with a heart defect and then whether the mom had preeclampsia later in the same pregnancy. We had information on almost 2 million pregnancies for this part of the study. We found that women carrying a baby with a heart defect were seven times as likely as women with structurally normal babies to develop early preterm preeclampsia. We defined that as preeclampsia where the baby has to be delivered before 34 weeks, so the really severe form of preeclampsia. Then, women carrying a baby with a heart defect were almost three times as likely to develop late preterm preeclampsia as well. That's where they managed to carry it until 34 weeks but it has to be delivered some time before 37 weeks.

These findings were similar to those of other studies, but we were able to go a step further and look at individual heart defect subtypes. What we found there waws that these strong associations were similar across defect categories. Then we decided to see if we could shed any light on the origin of the problem, whether it was coming from the mom's side or the baby's side. To do this, we looked at women with at least two pregnancies in our study period to see whether preeclampsia in one pregnancy had any bearing on the chance of having a baby with a heart defect in another pregnancy or vice versa.

This part of the study included 700,000 women. We found very similar findings. We found that women with early preterm preeclampsia in one pregnancy had eight times the risk of having a baby with a heart defect in a subsequent pregnancy. Late-term preeclampsia in one pregnancy was associated with almost three times the risk of offspring heart defects in later pregnancies. Then, we found that it worked the other way around too. Women who had a baby with a heart defect were twice as likely to have preterm preeclampsia in subsequent pregnancies.

Those results were really, really exciting, because whatever mechanisms underlie the associations between preterm preeclampsia in moms and heart defects in the babies, they operate across pregnancies. Therefore, that pointed towards something maternal in origin.

Dr. Carolyn Lam: That is so fascinating. Sharon, please, share some of the thoughts, your own as well as those of the editors when we saw this paper.

Dr. Sharon Reimold: I think that there's a growing data about the links between hypertensive disorders of pregnancy and preeclampsia with subsequent abnormal maternal outcome. But this paper, I think, has implications for how we look at moms who are going to have offspring with congenital heart defects as well as those with preeclampsia. For instance, I would look at a patient now that has preeclampsia, especially in more than one pregnancy, to identify that they may be at risk to have offspring with congenital defects in the future if they have additional children. But the mom is also at risk based on other data for developing other cardiovascular risk factors and disease as she gets older. It was really the link going back and forth with the hypertensive disorders and the congenital defects that we found the most interesting.

Dr. Carolyn Lam: That struck me too, especially when you can look at multiple pregnancies and outcomes. That's amazing. You know what, Heather, could you share a little bit about what it's like working with these huge Danish databases? I think there must be a lot more than meets the eye.

Dr. Heather Boyd: It's an interesting question, because I'm a Canadian and I was trained in the US. I did my PhD in epidemiology at Emery, and then I moved to Copenhagen. When I first got here, I was absolutely floored at the possibility of doing studies with millions of women in them. It opens some amazing possibilities, like I said earlier, for certain outcomes and certain exposures. You just need to have a question where the information you want is registered.

Dr. Carolyn Lam: Yeah. But I think what I also want to put across is, having worked with big databases, and certainly not as big as that one, it's actually a lot of work. People might think, "Oh, it's just all sitting there." But, for example, how long did it take you to come to these observations and conclusions?

Dr. Heather Boyd: I have a fabulous statistician. I think she's the second author there, Saima Basit. She spends a lot of her time pulling together data from different registers. But yes, you're right. The data don't always just mesh nicely. The statisticians we have working with us are real pros at this sort of data slinging.

Dr. Carolyn Lam: Could I just pose one last question to both of you. What do you think are the remaining gaps?

Dr. Sharon Reimold: I think that this is a clinical link. Then, going back to figure more about what's going on biologically to set up this difference? Because right now there's really no intervention that's going to make a difference, it's just a risk going forward. This is sort of like medicine done backwards, that there's this association and now we need to figure out exactly why.

Dr. Heather Boyd: I can piggyback on what Sharon said a little bit, because I think one of the things we need to remember is that not all women with preeclampsia have babies with heart defects. Not by a long shot. What we need to do now is to figure out what distinguishes the women who do get this double whammy from the vast majority who don't.

One of the things that Denmark does really nicely is that there are large bio banks. One of the things we want to do is go back to bank first trimester maternal blood samples and see if we can identify biomarkers that are unique to the women with both preterm preeclampsia and babies with heart defects. That's one of the things we're thinking about to address this gap. Because, as Sharon says, we've got to figure out what the mechanism is.

The other thing we want to do is to see whether the association between preeclampsia and heart defects extends, for example, to other things, to cardiac functional deficits, for example, because it's probably not just severe structural defects. If there's an association, it's probably on a continuum. Are babies born to preeclamptic moms, do their cardiac outputs differ? Do their electrical parameters differ? Do they just have different hearts?

We're really lucky because right now the Copenhagen Baby Heart Study is offering to scan the hearts of all infants born at one of the three major university hospitals in the Copenhagen area. We're about to have echocardiography data on 30,000 newborn hearts to help us look at this. I'm really excited about that possibility.

Dr. Carolyn Lam: I've learnt so much from this conversation. I'm sure the listeners will agree with me. Thank you both very, very much.

Fellows-in-Training Podcast

26 juni 2017 | 26 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore, and I'm just so thrilled to be joined by a co-host today and that's Dr. Amit Khera. He's the Editor of Digital Strategies for Circulation from UT Southwestern. Welcome, Amit.

Dr. Amit Khera: Hi, Carolyn. Thank you for letting me participate today and we're excited about this Fit featured podcast.

Dr. Carolyn Lam: We have a very special episode today. First of all, because we don't have a print issue that follows this week and so, there's no usual summaries, but we do have special guests and these are the Fellows-in-Training.

Now, we sent out a call online to all the fellows to tell us a bit about themselves as well as which articles in Circulation stood out to them, and we had an overwhelming response from all over the world, of which these two fellows really stood out.

So, join me in welcoming Dr. Punag Divanji from United States and Dr. Mayooran Namasivayam from Australia. Welcome.

Dr. Punag Divanji: Hi, thank you so much for having us.

Dr. Mayooran Namasivayam: Thank you very much.

Dr. Carolyn Lam: So, Punag, could you start us off by telling us a little bit about yourself, your training, your dreams, and why you chose that particular paper from this month's Circulation that spoke to you?

Dr. Punag Divanji: I'm currently a second year Cardiology Fellow, completing my General Fellowship and beginning a research year at the University of California in San Francisco. I will be pursuing research in women's health and subsequently pursuing an Interventional Cardiology Fellowship. Subsequently, this, hopefully, will lead to a career in academic Interventional Cardiology.

Dr. Carolyn Lam: Now, we asked you to pick an article from Circulation. I really wonder which was your pick?

Dr. Punag Divanji: I think one of the most important ones that spoke to me recently was the CVD-REAL Study, the comparative effectiveness of cardiovascular outcomes in new users of SGLT2 inhibitors. The CVD-REAL Study from Dr. Kosiborod of the Saint Luke's Mid America Heart Institute and an international group of colleagues was the first multinational retrospective observational study to compare CVD outcomes in patients with type 2 diabetes, who were prescribed sodium-glucose co-transporter 2 inhibitors or SGLT2 inhibitors. The primary objective of this study was to compare the risk of hospitalization for heart failure in patients with established type 2 diabetes that were newly initiated on SGLT2 inhibitors.

Patients who were newly initiated on an SGLT2 inhibitor had a 39% lower risk of hospitalization for heart failure compared with those newly initiated on other glucose lowering drugs. There was significant geographic variation in the use of SGLT2 inhibitors, with the predominance of canagliflozin in the United States, dapagliflozin in European countries, and no more than 7% penetration of empagliflozin in any of these six countries.

Despite this, there was no signs of significant heterogeneity across the countries, suggesting the cardiovascular benefits observed may be class related. In addition, the reduced risk of hospitalization for heart failure was stable across sensitivity analyses, including sequential occlusion of other glucose-lowering drugs like insulin, metformin, or even the GLP-1 receptor agonists, the only other class of drug with benefits in CVOTs.

Dr. Carolyn Lam: Punag, give us an idea why this paper stand out to you. I mean, we had the EMPA-REG Outcome Trial, and I'd love to know how much you use this medication in your practice, and did it change after this?

Dr. Punag Divanji: This is, I think, a profoundly important study for a number of reasons. Type 2 diabetes carries a significant burden of cardiovascular risk. It's associated with complications like heart failure, myocardial infarction, and all caused death, of course. We have for many years been treating cardiovascular disease in diabetes with an aim towards reduction in hemoglobin A1c. However, we know that reduction in hemoglobin A1c has not necessarily resulted in improvement in cardiovascular outcomes. The EMPA-REG Outcome Study and the recent CANVAS Study seem to suggest that these medications may have a benefit, these SGLT2 inhibitors may have a benefit in cardiovascular outcomes.

In practicing clinical cardiology, we often refer our patients with diabetes to endocrinologists or to their Primary Care physicians to initiate diabetes medications, and aren't directly involved in that decision making. The result of trials like these though, seems to indicate that medications that can have a cardiovascular outcome in this high-risk patient population, may indeed benefit from the input of cardiologists.

With the high penetrance of medications like insulin and metformin in this population, there may indeed be room for initiation of SGLT2 inhibitors, and if it is indeed a class effect, as this seems to indicate, there is considerable room for addition of this medication into our [inaudible 00:05:13]. And potentially a pretty significant benefit, in terms of cardiovascular outcomes.

Dr. Carolyn Lam: I agree. I took that with me as well, especially because, you know, it's as the name says, CVD-REAL was supposed to be a real world setting, and it included diabetic patients, like you nicely emphasized that didn't have established cardiovascular disease, so maybe addressing a wider population than that was seen in EMPA-REG Outcomes. Thank you so much, Punag.

Could I turn to you now, Mayooran? So, all the way from Australia, could you tell us a little bit about yourself and your training?

Dr. Mayooran Namasivayam: I'm in my third year of Cardiology Fellowship at St. Vincent's Hospital in Sydney, Australia. I'm also involved with post-graduate research doing my PhD through the University of New South Wales and the Victor Chang Cardiac Research Institute doing clinical work here at St. Vincent's. And my particular areas of interest are cardiac imaging and heart failure, and I'll be looking to do an advance Fellowship in imaging and/or heart failure in the near future.

Dr. Carolyn Lam: Brilliant! So, which paper did you pick over the last month? Which spoke to you?

Dr. Mayooran Namasivayam: I picked two papers. But the first one I was going to discuss was the paper by Nickenig and colleagues, which looked at trans-catheter treatment of severe tricuspid regurgitation using edge-to-edge MitraClip technique, which I found very interesting. So this was an observational feasibility study, which primarily looked at safety outcomes at 30 days, but also the technical feasibility of performing this procedure for tricuspid regurgitation therapy. Essentially the authors demonstrated that there was a reduction in tricuspid regurgitation severity or TR grade in 91% of their cohort. There are also improvement in soft surrogate endpoints such as New York Heart Association class and six-minute walk test distance, and importantly there were no intraprocedural major adverse events; however, there were three in-hospital deaths.

I found the study particularly interesting because it's a very emerging technology using the MitraClip in the tricuspid position and to date, this is the largest study on this subject. It recruited patients from 10 centers. I think, interestingly, the 22 patients in that cohort, had both mitral and tricuspid valve disease treated with the MitraClip technique. I think it really bodes well for the future of transcatheter valve interventions and I think shows that this is A, technically possible, but in the early stages at least safe and possibly efficacious, but certainly we would need longer term data to confirm that this is making a difference for people and that it is safer in the long term. I think it raised a lot of important issues going forward using transcatheter interventions in the tricuspid position.

Dr. Carolyn Lam: You said that you're interested in heart failure and training in heart failure. Do you see that a lot, because I certainly do?

Dr. Mayooran Namasivayam: Yes, we see it quite a lot at our center. Our center is a [inaudible 00:08:10] transplant center and so a lot of our patients with cardiomyopathy have quite bad tricuspid regurgitation. Many of them in the setting of left heart failure, some in the setting of pulmonary hypertension, and then some in our post transplant population we see some tricuspid regurgitation as well.

I think we're following on from the surgical literature, which shows that if you have some degree of mitral regurgitation that requires surgical intervention and there's at least moderate tricuspid regurgitation, then correction of that may be of some benefit. If we follow that on using transcatheter methodology, then certainly this may be an option going forward for patients that have transcatheter mitral valve repairs or replacements. One of the benefits of using a transcatheter method is you're not limited to the one opportunity you have with cardiopulmonary bypass where a decision's made to seek either both mitral and tricuspid together or potentially do it as staged procedure if we were to use the transcatheter approach.

So, yeah, we certainly see severe tricuspid regurgitation a lot and I think options such as this really do give us therapeutic opportunities for our patients who may not have the surgical robustness to have a general anesthetic and a big tricuspid valve replacement or repair surgically. I think the other key population where this may be relevant is tricuspid valve intervention in the post transplant setting where re-operation in the setting of immunosuppression may be problematic and fraught with adverse events. I think it's quite promising going forward and I'd love to see more data on this in the near future.

Dr. Carolyn Lam: Indeed, and it's just so nice to hear about how the articles in our journal have, well, if I may say, inspired both of you.

Amit, I know that we want to get our fellows talking a little bit more about Circulation On The Run. Can I hand it over to you now?

Dr. Amit Khera: Sure, absolutely, and thank you Carolyn for handing the baton.

I first want to give my full disclosure. I'm a Fellowship Program Director and of all the hats I wear, I find that to be one of the most important ones. You know, at Circulation, we certainly appreciate that Fellows-in-Training are the future of cardiovascular medicine and cardiovascular science. We are actively looking for ways to better engage the Fellows-in-Training and to make sure we're meeting their needs and enhancing their career trajectory. So, I appreciate both of you being on the call today and for this inaugural Fit podcast series, and this will not be the last of this series. So, we look forward to doing more.

Maybe I will ask each of you individually, and I'll start with you Mayooran, can you tell me a little bit about how you consume the medical literature. I appreciate that it's generational and back in the day, everybody would get their print copy in the mail and now there's many different ways to consume it. Tell me a little bit about how you go through the medical literature and your way around that.

Dr. Mayooran Namasivayam: I tend to do a regular periodic browsing of the online journals. I tend to have a few journals, one of which is Circulation that I read sort of on a weekly or at most, fortnightly basis. Just to dig out the key articles of interest and the major updates. At our hospital the fellows have a weekly journal club meeting, which I actually chair. It's quite refreshing to get everyone's different opinions in their own areas of interest from the fellows to discuss topics of interest from various journals.

So, for me personally, it's a combination of browsing online journals with combining a more formal setting as our journal club. But from a research perspective, I use things like the RSS feeds and Journal Alerts, so journal articles that come up in key topics of research interest for myself. With regards to clinical practice, I tend to browse. Speaking to colleagues of mine, they use various things like social media or apps which will highlight major developments or summarize key articles. I think increasingly, that will be the way forward. But that's the way I go about it.

Dr. Amit Khera: What I really like what you said were a few things. Obviously there's an overwhelming amount of literature and by using tools like RSS feeds and table of contents, you can sort of keep up. I like that you're complementing that at your institution with this deep dive of journal club; this thing that many institutions including ours do, where you're really vetting articles in detail and hearing different perspectives. So, a nice blend of ways to consume it.

Punag, I'm going to ask you a little bit about social media. When I looked, turns out CVD REAL, the one that you chose, had an altmetric score of 487, so we think of impact factor, but altmetric's a whole other way to look at impact of our articles.

I'm curious about your thoughts on social media and the place of social media with disseminating scientific literature. I know many fellows are actively involved on Facebook and Twitter and other pathways. Tell us a little bit about your thoughts on that.

Dr. Punag Divanji: You know, very similar to the practice described in Australia, it's very similar to what we do here. We have weekly journal clubs, we discuss these articles with the faculty and really try to integrate it into our practice. A big part of that at, I think, many institutions across the country is the use of social media.

It is particularly robust, I think, in the cardiovascular field, especially at national or international meetings wherein late breaking clinical data is rapidly disseminated. The outcomes and a few important trials that will impact clinical practice are rapidly disseminated, such that we are able to, I think, quite quickly access information, but beyond that, learn for example, the description is such that medical literature is doubling every two to three years. It's difficult to keep pace with that, but when thought leaders in the field present data that they find most interesting, most useful, or most relevant to patient care on a platform like social media, it's, I think, a wonderful way for Fellows-in-Training to quickly aggregate high quality data. It's something that I rely on heavily.

Dr. Amit Khera: I think that's a great point, and where things have changed now is not only can you get information quickly through social media, but as you pointed out, the ability to interact with luminaries in the field to get their opinion on it and even engage in a conversation. That certainly wasn't available several years back and I think it's a great advance for Fellows-in-Training.

I'm going to stick with you for a second and hear your thoughts a little bit on how Circulation may better engage Fellows-in-Training or meet their needs.

How can Circulation or other journals for that matter help in the pathway for Fellows-in-Training?

Dr. Punag Divanji: I think the concerns of Fellows-in-Training are unique in comparison to those already in practice. We are at a point in our careers where we're trying to learn the basic important groundwork of cardiology, but at the same time, given the rapid evolution of data, it's imperative that we have the ability to learn new things on top of that foundation.

Engaging fellows in that way, I think, involves a strategy that looks at a couple of different things. One is obviously social media, which is, let's be honest one of the core ways that trainees interact, and let's be honest, one of the most common things you see a trainee doing is looking at their phone.

Dr. Amit Khera: And faculty.

Dr. Punag Divanji: And faculty for that matter, fair enough. But if you're able to provide information via Twitter or via this Circulation app and be able to alert someone of a new update in the field or a new guideline document or a way to better risk stratify patients that come in with myocardial infarction, this type of rapidly accessible data I think plays well to the [ethos 00:15:32] of the fellow wherein we like to be able to do things quickly and effectively, but also expand our knowledge in the most efficient way possible.

Dr. Amit Khera: That's very insightful. So, if I hear you correctly, it's sort of continuing to make sure that we disseminate information quickly and rapidly to Fellows-in-Training in a way that is easy for them to consume.

This brings to the point about when we look at our metrics, the podcast and other digital media strategies we have really hit broadly in an international audience, which we're very excited about.

Certainly, Mayooran, I'm going to ask you as well your views on how can Circulation or other journals for that matter help engage Fellows-in-Training or enhance their training and career trajectories?

Dr. Mayooran Namasivayam: I guess today is a wonderful opportunity for fellows to participate in Circulation's online activities and engage with fellows from around the world, so this is one such example. I think echoing some of the thoughts of Dr. Divanji, as a fellow, you're doing many things and you're wearing many hats. You're learning new procedures, you're learning core cardiology, you're involved in research, you're doing on-call activities and clinical duties, and sort of amassing the latest evidence and putting that together and working out how that's going to change your practice now and in the future is important, but is not always easy to do.

I think features such as Circulation's podcast, which summarize key developments sort of state-of-the-art review articles, guideline summaries, which come out in Circulation, and even the simple things like the summaries that come out on the print journals which say what is new and what are the clinical implications, which allow us to read that in a minute or two, and then read on if we're so interested, but at least get a summary or a snapshot of a major article. I think those features are really key in sort of summarizing key developments in a short and accessible way. I think as been discussed already, engaging with the newer media, social media, online media in the way that other publishing modalities such as newspapers are sort of engaging with their audience I think, is certainly important in the future to an increasingly time-poor audience.

Dr. Amit Khera: Well, glad to hear that these features are resonating well with you both and it's certainly helping you in terms of accessing and understanding the relevance of these articles in your daily practice.

The final question, I'll finish with you and then come back to Punag, is, as Carolyn says every week, this is your backstage pass to the editorial process, so a way to look behind the curtain or Oz if you will on how journals work and we certainly strive for transparency at Circulation.

So, I'm going to maybe ask you if you have any questions for us on how the journal works or any questions regarding the editorial process?

Dr. Mayooran Namasivayam: I guess one of the things that I was wondering was you must, particularly at Circulation, just be inundated with a huge array of papers, which I'm sure all are of excellent quality.

When you're looking at a paper quickly to make a decision about whether it's something you'd pursue further or look into, what gives you that instinct that you know this is probably a good paper? Is it the abstract? Is it the cover letter? Is it the title? What gives you that first impression that we should really look into this a bit further?

Dr. Amit Khera: Well that's a fantastic question. I'll answer and I'll see if Carolyn wants to add anything as an associate editor as well.

First you have to realize that yes, there's enormous volume of papers, but the most important thing is to assemble an expert team. I think Dr. Hill, our editor-in-chief, Joe Hill has certainly done that. He's established an international group of associate editors that are well-accomplished across the breadth of cardiovascular spectrum, so your interest is in heart failure, you have a couple of imaging type articles, Punag has talked about women's cardiovascular health and also diabetes and cardiovascular disease. We have editors that really have expertise on each of these areas.

The first level is our editorial, editor-in-chief, and deputy editors, et cetera who'll take the first pass at which articles seem to be well done and would meet priority for Circulation. Then distribute them to editors that are content experts, that really understand those areas well. I take that responsibility very seriously when I get a paper. I know I've been on the other end of that. It's a tremendous amount of work. All the authors have contributed, patients have contributed their data. So, we take that responsibility incredibly seriously.

We try to be thoughtful, that if it's a paper that really will not meet priority, we should turn it around quickly and let the authors know that so that they can then move onto another journal and not waste time. The flip is, if something seems that in our field, in our expertise would meet priority to our readers and could advance the field, we send it out for expert review, then have a very thoughtful discussion, even in advance online, through a web portal and then as a group with all of our editors across the world, to really think critically about each paper, it's merits and ways to strengthen it. We always try to do that, which is to not only say yes or no on a paper, but what can we tell an author to make a paper better, because we want the very best products coming out on Circulation.

I hope that gives you an idea of how we think about it. It's sort of a tiered approach, starting with our editor-in-chief and deputy editors and then down to associate editors. Again, we try to turn it around, how would we want our papers treated if we were submitting to a journal?

Carolyn, do you have anything to add to that.

Dr. Carolyn Lam: Yeah.

So, Mayooran, that's great question. I think I can guess where it's coming from, sort of if one were to submit a paper to Circulation, is there any particular part that you would want to focus on, because that's the part that immediately catches our attention, right? I think that's what you're asking.

Well, I would say without a doubt it's the science. So, you talked about the cover letter, you talked about abstract and things, the most important bar that the paper has to cross is validity. Then, right next to that would be novelty. So, for us, you know, once we can see that the science is well done and the results look robust, that has to be there before anything even happens beyond. Then, that's when the process kicks in like Amit said. Then we look at it from our specialty points of view and make sure that it's something novel and something that would be of interest to our Circulation audience.

Does that answer your question?

Dr. Mayooran Namasivayam: It does. It does, thank you both very much. Thank you.

Dr. Amit Khera: All right, I'm going to now pitch the same question to you, Punag.

What are your thoughts? What sort of questions you have for us behind the curtain of Oz and the editorial process?

Dr. Punag Divanji: You know it's quite interesting, one of the most compelling components of the Circulation on the Run podcast is at the end when Dr. Lam has a wonderful discussion with the associate editor that was responsible for the article and the authors and gives us an idea not only of what drove their process of scientific discovery, but also what drove the editors to really believe in that article to warrant publication; to say that this is something that our readers need to see. I think that really quite remarkable to gain that point of view.

My question is, you seemed to strike this balance between basic translation and clinical research when publishing each week. There are often a variety of topics that come from all three fields. Each week in the publication, there seems to be this balance between basic translational and clinical research wherein the readers really are able to gain perspective into the entire field of cardiology from articles that range from clinical outcomes from blood sugar management to the [pathophysiology 00:22:57] of takotsubo syndrome.

How do you, as editors, strike that balance in each issue? How do you decide which articles are going to be published in concert with others?

Dr. Amit Khera: That's a great question. Sort of looking at the spectrum of types of articles and types of science and how do you decide sort of what goes together. Kind of like a meal, you know, what components go together.

Dr. Carolyn Lam: I'd like to call it wine paring.

Dr. Amit Khera: Wine pairing. I like that. So, if it's a roast, what sort of red wine and so forth. I think that's an excellent question.

I think first, we do strive for balance and that, as you know, Dr. Hill has a ... his lab is a basic science lab, and Circulation has always been a journal which does the hightest quality science including both basic science and clinical and translational research. I also say we have other offerings as you know, which are thought pieces on my mind, and perspective pieces. So we really try to have the full spectrum. As we talk about, there are many people that enjoy their vegetables, the hard core original research articles, but a lot of people also like the deserts and the appetizers, these other types of articles that I mentioned.

I think it's trying to find that right balance. We always like to have a balance of all of those together, because we appreciate there's a spectrum of readers and at the same time, we also appreciate that I'm more of a clinical researcher, I can gain insight and value from reading basic science research and similarly the basic scientist could gain value from the types of clinical articles we try to place in Circulation.

So I think maybe as was mentioned, a little bit of a menu and a wine pairing we include this whole spectrum of different types of offerings, but I think the one bar is they all have to be articles that have some clinical implications, be it clinical, translational, or basic science, even the epidemiologic studies research that I do, they all have to, in the end, have some sort of clinical importance or relevance. I think that's the benchmark for all of the articles.

Carolyn, do you want to add anything?

Dr. Carolyn Lam: No, I think you got it all. In fact, Amit, I'm going to turn it back to you for the last question.

As Editor of Digital Strategies for Circulation, tell us, what's in store?

Dr. Amit Khera: Well, you know, it's been a great first year and I think many would say one of the highlights has been the podcast for sure. I think we've developed a platform of social media engagement, of learning how to work though our digital strategies platforms and setting a high bar for our podcast.

Now it's time to go to level two, or next level. How do we enhance what we're offering? How do we get creative about new types of podcasts, like this one we're doing today? How do we think about more interactive social media engagement? How do we further enhance the way we distribute science across the world? So, we have a big appetite and big ambition, but I think that is what we should be doing when we have such good science and making sure we disseminate it broadly.

So, I think you'll see building on the platform we've already established, and apropos to today, I hope we really bring the Fits along with us on this ride to further expand our offering of our science.

Dr. Carolyn Lam: Thank you so much for joining us on this special episode. Don't forget to tune in next week.

Circulation June 20/27, 2017 Issue

19 juni 2017 | 20 min

Dr. Carolyn Lam: Welcome to Circulation on the Run your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Is it time to end our debates on short versus long duration of dual anti-platelet therapy? Well I will be discussing this with two very special guests in just a moment. But first here is your summary of this week's journal.

The first paper tells us that HDL particle number may serve as a biomarker of residual risk when assessed on statin therapy. First author Dr. Khera, corresponding author Dr. Mora from Brigham and Women's Hospital and colleagues of the JUPITER trial assessed HDL cholesterol levels, apolipoprotein A-1, cholesterol efflux capacity and HDL particle number at baseline and 12 month in a nested case control study of the JUPITER trial. That was a randomized primary prevention trial that compared rosuvastatin to placebo in individuals with normal LDL but increased CRP levels.

In the current study the authors found that cholesterol efflux capacity was moderately correlated with HDL cholesterol, apoA-I, and HDL particle number. Baseline HDL particle number was inversely associated with incident cardiovascular disease, while there was no significant association for baseline cholesterol efflux capacity, HDL or apoA-I levels. On-statin cholesterol efflux capacity was inversely associated with incident cardiovascular disease but HDL particle number again emerged as the strongest predictor.

Thus for both baseline and on-statin analyses, HDL particle number was the strongest of four HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. Whether therapies designed to enhance cholesterol efflux capacity or an increased HDL particle number can also reduce cardiovascular risk however remains uncertain.

The next study sheds light on mechanisms underlying the de-differentiation and lineage conversion of adult human fibroblast into functional endothelial cells. First author Dr. Zhang, corresponding authors Dr. Rehman and Malik from University of Illinois College of Medicine first generated CD34+ progenitors by de-differentiating adult human skin fibroblasts and showed that these intermediate progenitors could give rise to endothelial cells as well as erythrocytes. They then showed that lineage conversion of fibroblasts via partial de-differentiation recapitulated in part the embryonic development of the vasculature as evidenced by up regulation of anti-aging enzyme telomerase and the bi-lineage potential of the generated progenitors.

Importantly they showed that transcription factor SOX17 functioned as a switch which regulated the cell fate of CD34+ progenitors towards an endothelial versus erythroid lineage. Finally implanted fibroblast derived CD34+ progenitors stably engrafted to form functional human blood cells in mice that improved cardiac function after myocardial infarction. Thus the molecular switch SOX17 provides a means to optimize the generation of endothelial cells for vascular tissue regeneration or disease modeling.

What do drones have to do with out of hospital cardiac arrest? Well in this next study by first author Dr. Boutilier corresponding author Dr. Chan and colleagues from University of Toronto, the authors hypothesized that a drone network designed with the aid of a mathematical model combining both optimization and queuing could reduce the time to AED arrival.

Using data from over 50,000 historical out of hospital cardiac arrests covering over 26,000 square kilometers in Ontario, Canada, they found that a drone network designed to reduce the median AED arrival time by three minutes relative to the historical 911 response could also reduce the 90th percentile of the AED arrival time by between 6 minutes and 43 seconds in most urban regions and 10 minutes and 34 seconds in most rural regions.

Thus this study tells us that drone delivered AEDs have the potential to be a transformative innovation in the provision of emergency care to cardiac arrest patients especially those who arrest in a private or rural setting.

The next study provides thresholds for ambulatory blood pressure among African Americans. Dr. Ravenall and colleagues from New York University School of Medicine analyzed data from the Jackson Heart Study, a population-based cohort comprised exclusively of African-American adults and of whom more than 1000 participants completed ambulatory blood pressure monitoring at baseline.

Based on the outcome derived approach for systolic blood pressure and a regression derived approach for diastolic blood pressure, the following definitions corresponded to clinic blood pressure of 140/90 and were proposed as ambulatory blood pressure definitions for African Americans. Daytime blood pressure above 140/85, 24 hour blood pressure above 135/80 and nighttime blood pressure above 130/75 mmHg. Note that these ambulatory blood pressure thresholds identified for African Americans were higher than those from published recommendations mainly derived in European, Asian and South American populations. The use of these ambulatory blood pressure thresholds for African Americans will lead to a lower prevalence of daytime, 24 hour and nighttime hypertension compared with the current published recommendations.

The next paper provides pre-clinical evidence of a novel target in plaque information in atherosclerosis. Dr. Stachon and colleagues from Heart Center Friburg University in Germany hypothesized a functional role of the signal axis ATP binding to purinogenic receptor P2X7 in inflammasone activation and chronic inflammation driving atherosclerosis.

In an elegant series of experiments they showed that P2X7 receptor activation was crucial for inflammasone assembly and interleukin-1-beta secretion. The lack of P2X7 in mice abolished inflammasone activation in atherosclerotic lesions. P2X7 was expressed in murine and human atherosclerotic lesions. LDL receptor deficient mice lacking P2X7 receptor had reduced plaque inflammation and were less prone to develop atherosclerosis.

Thus this study shows that P2X7 inhibition could be a treatment strategy against plaque inflammation in atherosclerosis.

The next paper describes the first prospective clinical study of adenosine use in pediatric and young adult patients after heart transplantation. Now prior to this study adenosine was relatively contraindicated post-transplant due to a presumed risk of prolonged atrioventricular block in denervated hearts.

In the current study first author Dr. Flyer corresponding author Dr. Silver and colleagues from Columbia University performed a single center prospective clinical study testing whether adenosine caused prolonged asystole after transplant and if it was effective in blocking AV nodal conduction in healthy heart transplant recipients aged 6 months to 25 years presenting for routine cardiac catheterization. Following catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose escalation protocol until AV block was achieved.

Eighty patients completed adenosine testing. And no patient required rescue ventricular pacing. AV block was observed in 77 patients with the median longest AV block of 1.9 seconds and the mean duration of adenosine effect of 4.3 seconds.

Thus, this study suggests that adenosine may be safe and effective in patients post transplantation and establishes both a safe and effective starting dose of 25mcg/kg or 1.5mg for patients weighing 60kg and more. It also establishes a stepwise therapy escalation plan to avoid prolonged bradycardia. Although patients after heart transplantation may require less adenosine to achieve AV block it appears to be safe and effective as therapy for evaluation and or treatment of tachycardia in this population.

Well those were your summaries, now for our feature discussion.

Today for our feature discussion we are talking about a very familiar situation, dual anti-platelet therapy following coronary intervention and the decision of long versus short duration of therapy. A debate we've heard many times but according to the perspective piece in today's journal, maybe a debate we should end. And I am so pleased to have the author, Dr. Glenn Levine from Baylor College of Medicine as well Dr. Laura Mauri associate editor from Brigham and Women's Hospital.

Welcome both.

Dr. Laura Mauri: Thank you Carolyn.

Dr. Glenn Levine: Thank you.

Dr. Carolyn Lam: Glenn would you like to start by presenting your case. It's time to end a dualistic short versus long duration of DAPT debate. I really like that title, tell us more.

Dr. Glenn Levine: Thank you Carolyn.

The point we make in our editorial is that over the last five or six years there have been studies comparing what I term standard, which is usually about 12 months DAPT versus shorter duration DAPT and there are other studies comparing standard DAPT versus longer duration DAPT. Those generated important information in different people interpret them in different ways. What though has happened over the last several years is certainly for both educational and entertainment value at meetings as well in editorials, the idea of how long people should be treated with DAPT has been oversimplified to whether all patients should be treated with short duration or long duration. And Laura herself knows that as she has been in many of these debates.

While I think that initially that was educational and entertaining, I think these days people understand those points and a greater issue is in that we should treat some people with short duration, some with what I call standard and some with long duration. And rather than debating whether everyone should treated with short or everyone should be treated with long, I think what we need to focus on now is which patients should be treated with short duration, which are probably best treated with a standard duration and which are best treated with prolonged or extended duration DAPT.

And that in a nutshell is the main point that we make in this perspective editorial.

Dr. Carolyn Lam: Laura, so do you agree?

Dr. Laura Mauri: I couldn't agree more. I think clinicians really are looking for guidance and what happens at these debates is you see these polarizing opinions that debaters are asked to defend when in actuality there's such a wide spectrum of what individual patients need. And the real question I think going forward is how to end these debates and how to provide really more tailored information so clinicians and patients can make better decisions together. And I think that's really where the piece that Glenn has written really helps direct us.

Dr. Carolyn Lam: Yeah, Glenn, I mean are we talking about the usual risk versus benefits and precision metsan or individualized risk assessment here?

Dr. Glenn Levine: Yeah, what we're talking about is looking at the ischemic risks which are primarily leg stent thrombosis or spontaneous MI versus the bleeding risks which is obviously bleeding and balancing them. And there clearly are decision tools available to clinicians. Laura has pioneered the DAPT score which is an incredibly user friendly and easy tool to use to assess which patients should be continued with prolonged DAPT or not. And there are also some other tools out there including the Paris registry score perhaps a little more complex and then there's also now the precise DAPT score which one can at least assess bleeding risk and indirectly assess the ischemic and bleeding risk.

But really I think that is the focus now on balancing bleeding and ischemic risks and having pools to allow clinicians to easily do that.

Dr. Carolyn Lam: That's true. Now do you think guidelines have to catch up or have they caught up?

Dr. Glenn Levine: Our DAPT duration guideline was coming out just as Laura's DAPT score was about to be published, several months after it had been presented. And we did mention the DAPT score in our paper, it was too early to formally incorporate it into the guidelines. Nevertheless, the way our guidelines are written, they clearly give practitioners the option for individualizing therapy based on ischemic and bleeding risk and Laura's DAPT score fits perfectly into what we aim to do, namely to encourage practitioners to assess patients on an individual level and assess what duration of DAPT is best.

Dr. Carolyn Lam: I do have a question for Laura here though. I see Asian patients, I'm talking to you here from Singapore. And sometimes you wonder the trial situations and what you derive there. How does it differ from real world and how is it impacting your practice for example Laura?

Dr. Laura Mauri: That's a great question. I think you have a number of points there. One is the generalized ability or results from one trial across the world where you might have many different patient populations. And while the DAPT score was an international trial it would be interesting to see more data coming out from other different countries. And as you know there are trials in Asia that have looked at randomized DAPT duration as well.

I think now that we have better access to information especially in cardiology globally, we can get that information and better tailor therapy. When we look at any one randomized trial the results might seem kind of black and white and to certain extent so do guideline recommendations but we are getting better at using the results from randomized trials to really identify risk factors. I think that with time we'll be able to either validate the DAPT score in other patient populations or develop tailored scores from unique data sets. I think the challenge really is making sure that we still get good randomized evidence for our treatment decisions but then when we have treatments that have both benefit and risk that we identify which sub-populations of patients really do achieve most of the benefit. And then the other populations that might be harmed. And that's really what we try to do with this score.

And I think what you'll see, you asked about precision medicine which usually we think about using genetics but I think there's so much just really basic information that we have about patient lesion characteristics and other specific factors that we record routinely in their medical records that we can use and you'll see this, I think more and more frequently across different areas of investigation and in cardiovascular medicine.

One really interesting example recently was this French trial. Data was used to be able to predict, very similar to what we did, but to predict which patients would benefit from lower blood pressure without the risk of more aggressive treatment.

Dr. Carolyn Lam: Yeah, I love the way you put that. Those are really words of wisdom, I do think that that is the way cardiovascular medicine is gonna move. Glenn, how do you put all this into practice for yourself?

Dr. Glenn Levine: I think whether or not I formally calculate a DAPT score or Paris registry score, I think clearly we integrate the factors in those scores into our everyday practice. And clearly there are patients who are at high bleeding and low ischemic risk and vice versa. I would also encourage listeners to in addition to all the scores, one has to think about the consequences of a recurrent MI or stent thrombosis. Obviously someone who has stent thrombosis of a proximal LED lesion, if they already have a depressed EF or occluded RCA, those consequences are likely much more dire then someone who occludes say at a distal OM3 stent who has the normal ejection fraction. It also encourages them to think about the consequences of stent thrombosis as well as the consequences of a recurring MI.

Dr. Laura Mauri: Just to make it clear, we know that clinicians have always tried to balance these different risks of ischemia and bleeding when faced with this decisions. I think the challenge really has been the limited amount of information that we've had to be able to do that. And so we've really just used kind of our gut until recently when we've had several large randomized data sets to be able to look to. And what that's done is it's given us the ability to construct these new tools to be able to make practice more data driven. Now still individualized but based on data that's tailored to our patients.

And so I think we can use that to be able to improve outcomes. That being said, we don't want to rely on a statistic or a score alone and things like the DAPT score are based on patients like the ones that were enrolled into the randomized trial. Those were patients who could take longer anti-platelet therapy. It helps to identify who can take it for longer. But there are patients who get anti-coagulation or have other serious bleeding risks who really are going to benefit from new technologies to be able to shorten anti-platelet therapy.

Dr. Carolyn Lam: Well thank you Glenn once again for a wonderful perspective piece that has really got us thinking about situations even beyond dual anti-platelet therapy. Thank you Laura for your insights and thank you listeners for joining us today. Join us again next week.

Circulation June 13, 2017 Issue

12 juni 2017 | 20 min

In our feature discussion today, we will be talking about insights from the PROMISE Trial regarding the prognostic value of non-invasive cardiovascular testing in patients with stable chest pain. First, here's your summary of this week's journal.

The first paper reports novel findings on gene smoking interactions in coronary heart disease. Co-corresponding authors Dr. Salahin from the University of Pennsylvania and Dr. Riley from Columbia University and colleagues used data on almost 61,000 coronary heart disease cases and more than 80,000 controls to investigate effect modification by smoking behavior at established coronary heart disease and smoking-related genetic loci.

They found that the cardio-protective effects associated with allelic variation at the A-D-A-M-T-S seven, or ADAMTS7 locus, were attenuated by 60% in patients who smoked tobacco, compared to those who did not smoke. Allelic variation in ADAMTS7 associated with reduced coronary heart disease risk, was associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines.

Furthermore, exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. These human genomic data therefore provide new insights into potential mechanisms of coronary heart disease in cigarette smokers and suggests that inhibition of ADAMTS7 may be a novel potential therapeutic strategy for coronary heart disease that may have particular benefits in individuals who smoke cigarettes. This is discussed in an editorial entitled Holy Smokes, an Interaction, by Dr. Braxton Mitchell.

The next paper provides first evidence that genetic over-expression of CD39 may offer ischemic cerebral protection. CD39 is an ectoenzyme with a PYRase activity, which cleaves ATP and ADP. CD39 is expressed on the surface of myeloid and vascular endothelial cells where it dissipates the high local concentrations of ATP and ADP, which would otherwise serve as potent pro-inflammatory and pro-thrombotic signals.

In the current study from first author Dr. Bick, corresponding author Dr. Pinsky from University of Michigan Medical Center and colleagues, authors used a model of permanent middle cerebral artery occlusion to show that CD39 expression reduced edema, infarct volume, and inflammation with corresponding improvements in neurological outcomes, compared to control mice. Over-expression of CD39 in only the myeloid cells also reduced cerebral infarct volume. Thus, amplification of endogenous CD39 expression, or even administration of exogenous circulating CD39, may be of future interest as a therapeutic target to minimize ischemic injury caused by cerebral ischemia.

The next paper provides pre-clinical data to show that MicroRNA93 may have a therapeutic role in peripheral artery disease. First author Dr. Ganta, corresponding author Dr. Annicks and colleagues from University of Virginia, used MicroRNA-106b-93-25 cluster knockout mice and showed that MicroRNA93 over-expression alone was sufficient to enhance angiogenesis, arteriogenesis, and perfusion in ischemic muscle via increased M2-like macrophages.

MicroRNA93 targeted interferon regulatory factor 9 to inhibit immune response gene 1, and itaconic acid generation in macrophages to induce M2-like macrophage polarization. Furthermore, MicroRNA93 over-expression produced a paracrine effect on macrophages that induced angiogenesis and skeletal muscle recovery under hypoxic conditions in vitro.

Thus, these data demonstrate that MicroRNA93 induces beneficial effects in multiple cells that can enhance perfusion in ischemic limb and thus identifies MicroRNA93 as a putative therapeutic target in clinical peripheral artery disease.

The next study is a large scale genetic analysis that represents the most comprehensive causal assessment of adiposity with cardiometabolic diseases to date. Co-corresponding authors Dr. Cassis and Dale from University College London used 97 snips for BMI, and 49 snips for waist-hip ratio adjusted for BMI, to conduct mendelian randomization analysis in 14 prospective studies supplemented with coronary heart disease data from CADRIoGRAM+C4D, stroke data from METASTROKE, Type II Diabetes data from DIAGRAM and lipids data from GLGC Consortium.

They found that both waist-hip ratio adjusted for BMI, and BMI had causal effects on coronary heart disease and Type II Diabetes, and were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6 and circulating lipids. However, only waist-hip ratio adjusted for BMI increased the risk of ischemic stroke. Thus, both the amount of adiposity and its distribution play important roles in influencing multiple cardiometabolic traits and the development of cardiometabolic disease.

Furthermore, the findings indicate that body fat distribution has multiple roles in disease that are independent of general adiposity. This suggests that physicians should pay attention to measures of adiposity beyond BMI.

The next study addresses the conundrum that clinical trials show benefit of lowering systolic blood pressure in people aged 80 years and above, but yet, non-randomized epidemiologic studies suggest lower systolic blood pressure is associated with higher mortality. In the current study by Dr. Ravindrarajah and colleagues of King's College London, a population based cohort study was conducted using electronic health records of 144,403 participants aged 80 years and older, registered with family practices in the United Kingdom, and followed for five years.

Mortality rates increased with frailty level, and were highest at a systolic blood pressure of less than 110 millimeters mercury. Furthermore, systolic blood pressure trajectories showed an accelerated decline in the last two years of life, without evidence of intensification of anti-hypertensive therapy.

Thus, a terminal decline of systolic blood pressure in the final two years of life suggests that non-randomized epidemiological associations of systolic blood pressure with higher mortality may be accounted for by reverse causation. That is, participants with lower blood pressure values were closer on average to the end of life. This is discussed in an accompanying editorial by Dr. Naveed Sattar.

Well, that wraps it up for our summaries. Now for our feature discussion.

The evaluation of stable patients presenting with suspected coronary artery disease is by far one of the most common diagnostic evaluation strategies that we need to undertake in cardiovascular medicine. There's a whole host of evidence supporting prognostication based on various non-invasive tests, such as anatomic imaging with coronary computed tomography angiography, but also with stress testing, or functional testing, such as stress nuclear or echocardiography, or exercise electrocardiography.

However, our paper today really sheds light on the comparison of these two strategies. And I'm just delighted to have starts with me. First, the primary author of the paper, from the PROMISE Trial, Dr. Udo Hoffmann, from Massachusetts General Hospital, Harvard Medical School, and the editorialist of a beautiful accompanying editorial, Dr. Leslee Shaw from Emory University School of Medicine, Atlanta, Georgia.

Welcome both.

Dr. Udo Hoffmann: Hi, Carolyn. Hi, Leslee.

Dr. Leslee Shaw: Hi, Udo, how are you?

Dr. Carolyn Lam: So, Udo, could you start by just sharing what you did in this PROMISE Trial?

Dr. Udo Hoffmann: The Promise Trial is a large comparative effectiveness trial that was done between 2009 and 2012, with follow-up ending 2013, at [inaudible 00:10:13] sites across the U.S. and Canada. And what it did was compare two strategies for testing patients with suspicion of coronary disease, symptomatic patients. These patients were randomized to either receive a functional test first, or an atomic test first, and the idea was to see whether providing the functional information or the anatomic information leads to differences in outcomes of these patients.

As you know, the primary paper showed that the health outcomes of these two strategies were similar and not different. Now in this paper here, we took the slightly different approach and we really wanted to see how the results of the tests as they were seen by the [inside 00:11:02] so it was all based on the sight interpretations of these tests. How the results of these tests actually were associated, or were associated with the health outcomes. And so we directly compared categories of CT results, and categories of functional testing results, and how they are related to outcomes. The good news I think is that sight interpretations in real life do actually have prognostic value for both the anatomic or the CT, and also the functional testing, and so findings as significant disease [inaudible 00:11:36] ischemia have in fact similar prognostic value. And we also saw that on the lower end of the findings, so mildly abnormal findings for example, that the ability to see nonobstructive CAD, perhaps if you're a difference maker and identify from additional patients or group of patients that is at risk for [inaudible 00:12:01].

Dr. Leslee Shaw: I think that often times we struggle with negative trial results, if I can put PROMISE in that negative trial results. And here we have a paper that I think really applies clinically. I think it's going to have far-reaching clinical implications. I think if you look at the CTA findings, this is a real world practice. I think there's a simplicity to CTA interpretations that really is amplified in the nice ability to risk stratify. Whereas the functional interpretation, as you both know, is complex. It integrates a lot of factors, wall motion, perfusion imaging, ST segment changes, exertional symptoms, all of that, and I think we see a lot of sight variability in that image interpretation on the ischemia-side of the functional testing arm.

But there's and important finding from this paper, which I think we have seen in bits and pieces prior to this report, and that is that on the CTA side, you had about a third of the patients having pure normal coronaries. So you see that very low risk in that population. But what you see on the functional testing arm is that the event rate in patients with normal studies and in patients with a mildly abnormal study, the event rates were identical, which is fascinating.

And importantly, two thirds of the population on the functional testing arm were in those normal and mildly abnormal subgroups, something like that. And that has important implications for what is in that one third on a CTA side with normal findings versus three quarters? Well I think from this randomized trial, I think we can infer that you're going to have some non-obstructive disease in that population, but you're also going to have non-ischemic obstructive disease.

We know from FFR and all of the angiographic literature that not every obstructive lesion is ischemic. And so on the stress testing side, we have a lot of obstructive disease that potentially is missed. And I think this study really clearly illustrates that limitation of stress testing and it reflects sight variability in imaging and the interpretation. It reflects the patient populations and the struggles with doing stress testing, but also just flat out reflects the ischemic cascade, and what we can expect from an obstructive lesion, or a non-obstructive lesion, that may not elicit ischemia.

So to that extent, I think Udo's paper is just, just far-reaching and really clearly one of the most advanced papers that we have seen in such a long time. From really providing an important message for those imagers and for folks doing stress testing in this country.

Dr. Carolyn Lam: should we then always do anatomic testing first before selective stress testing?

Dr. Udo Hoffmann: The choice of testing is very much I think tied to the population of the patient you're talking about. I think when you follow the literature, 30 years ago when all the classic studies out of [experienced centers 00:18:53] such as Cedar Sinai, were published, the ischemia burden was much higher in the tested population. Back then you had probably a third or 40% of patients who in fact had some abnormality or ischemia on stress testing. One of the findings here in this study, and that is true for both tests, is that the prevalence of severe findings, severe abnormalities, whether ischemia or obstructive disease, is what I found testing is pretty similar, so it's both around 12%, but it is relatively infrequent. And I think that has changed.

And you cannot expect, as Leslee pointed out nicely, it is not expected from a stress test to detect non-obstructive disease that has prognostic value, but doesn't necessarily explain these symptoms that the patient is presenting. So we should not forget that these patients do not come for primarily for prognostic assessment, they come because they're symptomatic. And the primary question is do we find an equivalent that could explain the symptoms of the patient? And only once we are convinced that there's no such equivalent that would for example lead us to further assess the patient for potential reverse [inaudible 00:20:19] therapy, then the second question that can be answered is for the prognostic implication of the test. And I think in this relatively low risk population, this prognostic aspect gains more importance irrelative to the diagnostic aspect.

Dr. Carolyn Lam: I think Leslee made it very clear in her editorial as well, not to forget in essence at the extremes of disease, that both tests, both strategies conveyed similar prognostic information, and it was more for the fine grain teasing apart that perhaps we need to consider very, very carefully what your paper is saying. But at the end of the day, it's about treating the patients for their cardiovascular risk management, isn't it? Recognizing that even if you don't have ischemia, if you've got the risk factors, like you nicely showed, that we should be treating them for the risk factors.

Leslee, want to share some of your thoughts there? You covered that so nicely in your editorial.

Dr. Leslee Shaw: Well I think that's one thing we've seen from PROMISE, SCOT-HEART, and many, many other recent trials as of late, over the last three or four years, is that the stress test is an opportunity not only to assess ischemic burden, or that CTA's not only a test to assess the extent and severity of coronary disease as well as plaque, but it's an opportunity to identify clear, preventive strategies for the patients.

And this is really something that I don't think at least historically within the stress testing community, that we have taken upon ourselves in order to say, "Okay, here we have a symptomatic patient. We not only are going to assess ischemia, but we're going to look at what else they need to do in order for us to guide prevention." I think this is a clear reminder that this is a great opportunity for us to have a bit of a paradigm shift on the diagnostic testing, to take that whole picture if you will of the patient, and really to focus in on prevention because that is a great opportunity, as Udo talked about just a few minutes ago, it's a great opportunity for us to set the patient on the correct course.

The guidelines, as both of you know, focus in on having that diagnostic evaluation and to implement guideline directed medical therapy as a front line examination. This is a great opportunity for us to just use that diagnostic evaluation ad the initiation of appropriate care for the patient, and then to look at symptom burden, recurrent symptoms, the need for additional interventions. But that first step is guideline directed medical therapy for the patient.

Dr. Udo Hoffmann: Continuing on Leslee's excellent point, I think the paper I think is hopefully a starting point to think about randomized trial, because we assume some maybe come to the conclusion, okay, if you have non-obstructive disease, you should be treated with [inaudible 00:23:13] and aspirin. But we don't know that. I think this is really a call for randomized trial. PROMISE was the one, and it was a good trial. It looked at the association of strategy with an outcome. I think one trial that is needed is to look what specific therapeutic decisions based on imaging or based on test diagnostic test findings, would be justified and would potentially lead to improved outcomes. And that is true for both the stress testing and the CT side. So I think this paper shows the opportunities, but I don't think we have the randomized data to exactly define what are the management options for each of these details of the information that these test results deliver us.

Dr. Carolyn Lam:

Circulation June 6, 2017 Issue

5 juni 2017 | 16 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. Our featured paper today provides important trial evidence that will guide interventional management of symptomatic femoral artery disease, but first, here's your summary of this week's journal.

The first paper sheds light on the interaction between left ventricular dysfunction and mesenchymal stromal cell activation. First author, Dr. Naftali-Shani. Corresponding author, Dr. Leor and colleagues from Neufeld Cardiac Research Institute in Israel isolated mesenchymal stromal cells from cardiac and subcutaneous fat tissues of mice with left ventricular dysfunction, 28 days after myocardial infarction or sham operation. They further injected mesenchymal stromal cells or saline into the infracted myocardium of mice and evaluated left ventricular remodeling 28 days after myocardial infarction. They found that left ventricular dysfunction switched cardiac mesenchymal stromal cells towards an inflammatory phenotype and that these pro-inflammatory mesenchymal stromal cells contributed to adverse left ventricular remodeling and dysfunction. The inflammatory polarization of cardiac mesenchymal stromal cells by left ventricular dysfunction was mediated by toll-like receptor four. Finally, toll-like receptor four deficiency in mesenchymal stromal cells attenuated their pro-inflammatory activation, improved their reparative properties, graft survival, infarct repair and left ventricular remodeling.

In summary, the environment of the failing and infarcted myocardium drove resident and transplanted mesenchymal stromal cells towards a pro-inflammatory phenotype that restricted their survival and reparative effects in a mechanism mediated by toll-like receptor four. Targeting toll-like receptor four in mesenchymal stromal cells could improve the safety and efficacy of cell therapy in heart failure.

The next study provides evidence that fractional flow reserve or FFR is a useful index for decision-making in real life daily cath lab practice. First author, Dr. Ahn, corresponding author, Dr. Park and colleagues from Heart Institute Asan Medical Center in South Korea, evaluated the prognosis of deferred and revascularized coronary stenosis after FFR measurement in the IRIS-FFR registry of 5,848 prospectively enrolled patients. This large prospective registry showed that the FFR was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR of less than 0.75 was associated with better outcomes than deferral, while for a stenosis with a high FFR of greater than 0.76, medical treatment would be a reasonable and safe strategy. Thus, the authors concluded that FFR may be considered a clinical prognostic index in addition to a physiological quantification for flow-limiting stenosis. These and other issues are discussed in an accompanying editorial by Doctors De Bruyne, Fournier and Barbato.

The next study sheds important insights into a potential disease modifier in pulmonary arterial hypertenstion, and that is vascular endothelial growth factor receptor three, or VEGF receptor three. First author, Dr. Hwangbo, Co-corresponding authors Dr. Chun and Dr. Jin from Yale Cardiovascular Research Center in Connecticut, used a combination of experimental animal models, human patient cells and detailed signaling studies to demonstrate the importance of a novel interaction between bone morphogenetic protein type two receptors, or BMPR2 and VEGF receptor three in regulating the robustness of endothelial bone morphogenic protein signaling response. They demonstrated that the interaction was critical for promoting BMPR2 internalization in response to bone morphogenic protein stimulation. They further showed that genetic deletion of endothelial VEGF receptor three in mice resulted in exacerbation of chronic hypoxia-induced pulmonary hypertension and impaired bone morphogenic protein signaling. Thus, these findings identify VEGF receptor three as a key regulator of endothelial BMPR2 signaling and a potential determinant of pulmonary arterial hypertension penetrance in humans.

The next study tells us that a low-dose drug-coated balloon may be a promising treatment option in symptomatic superficial femoral or popliteal artery disease. Dr. Schroeder and colleagues of the Jewish Hospital in Berlin, Germany, reported results of the ILLUMENATE European Randomized Clinical Trial, which was a prospective randomized multi-center, single-blinded trial, where patients were randomized 3:1 to treatment with a low-dose drug-coated balloon or an uncoated percutaneous transluminal angioplasty balloon. The primary safety endpoint was a composite of freedom from device and procedure-related death through 30 days, and freedom from target limb major amputation and clinically-driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency at 12 months. The main results were that in symptomatic patients, with superficial femoral and/or proximal popliteal artery disease, low-dose, drug-coated balloon was safer and more effective than uncoated percutaneous transluminal angioplasty balloons through follow-up of 12 months. This is discussed as a novel strategy to reduce femoral popliteal restenosis in an accompanying editorial by Doctors Goldsweig and Aronow.

The final study provides important genotype-phenotype correlations of SCN5A mutations in probands with Brugada syndrome. First author, Dr. Yamagata, corresponding author, Dr. Shimizu and colleagues of Nippon Medical School in Tokyo, Japan, studied 415 Japanese Brugada syndrome probands to assess the association between SCN5A mutations and clinical outcomes. During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5% per year. Compared to probands without mutations, probands with SCN5A mutations experienced their first cardiac event at a younger age, had a higher positive rate of late potentials and exhibited longer P-wave, PQ and QRS durations, and had a higher rate of cardiac events, especially when the mutations were located in the pore region of the encoded protein. The conclusion was therefore, that genetic screening for SCN5A mutations among Brugada syndrome probands may be useful for stratifying such patients according to their risk of subsequent cardiac events. Well, that wraps it up for your summaries. Now for our feature discussion.

Our feature paper today is the stuff that really could change guidelines. Now, we're talking about superficial femoral artery disease and its treatment. Unlike most other vascular beds, where stenting is the preferred modality of endovascular revascularization, the optimal therapy for superficial femoral artery disease remain controversial. However, today's paper really adds to our insight and I am so pleased to have the first and corresponding author Dr. Ilka Ott, from German Heart Center in Munich, as well as Dr. Manos Brilakis, Associate Editor, from UT Southwestern. Welcome both.

Dr. Ilka Ott: Welcome.

Dr. Manos Brilakis: Morning.

Dr. Carolyn Lam: Wonderful. So Ilka could you please share what you found?

Dr. Ilka Ott: We already know from previous studies there has been a lot of studies showing the drug-eluting balloon is superior to plain angioplasty in superficial artery disease. So then, in our study, we found that the treatment with the drug-eluting balloon plus stenting was very superior to the balloon angioplasty plus stenting and the directional atherectomy. The primary endpoint we used in the study was an angiographic endpoint. It was diameter of stenosis and this was significantly lower in the patients treated by drug-eluting balloon angioplasty, as compared to the balloon angioplasty and atherectomy group. Moreover, we had a clinical follow-up of 24 months and we found that also the target lesion revascularization was 70% in the group of drug-eluting balloon plus stent as compared to 37% in the balloon angioplasty and stent group, and 53% in the atherectomy group. We found a significant reduction also in the clinical endpoint of TLR at three years.

Dr. Carolyn Lam: Wow Ilka, congratulations, but may I just ask, was there any reason to think that a drug-eluting balloon would not be similarly beneficial as in other vascular beds?

Dr. Ilka Ott: Well, I think is not a novelty of the study. We already know from previous studies that drug-eluting balloon is superior to plain balloon angioplasty so that's not a surprising result. However, in disease of the femoral superficial artery we often have the problems, in particular when we treat complex lesions like along occlusions or along calcified stenosis, that drug-eluting balloon is not sufficient, so you need to also stabilize the lesion to stabilize dissections. You also need to do a stent implantation. Our study now shows that the combination of drug-eluting balloon plus stent is superior than plain balloon angioplasty plus stent. The nice approach is most of the time if you need a stent, if you use drug-eluting balloon and the lesion is stable and you don't need a stent you are glad. This has shown previous studies, however, if you need further treatment and you need to place a stent, we now show that the pretreatment with a drug-eluting balloon is a superior option than just the plain balloon angioplasty.

Dr. Carolyn Lam: Manos, what is your take on these results? Do you think it will impact guidelines?

Dr. Manos Brilakis: First of all, I would like to congratulate Dr. Ott for an excellent study. I think what is particularly important here, is the comparative effectiveness component. We have several studies circulating already about drug-coated balloons, have studies on stents, but we don't have studies addressing the other modalities like atherectomy. Why I was particularly impressed, is I think the study will have a finally an assessment of atherectomy as a primary strategy for calcified lesions and it's interesting that that was not as good efficacy. It was actually tents for worse TLR as compared to plain old balloon angioplasty and stent. Would like to ask Dr. Ott what is your kind thoughts about the alone atherectomy give the results of the study? Are they still doing it or is it falling out of favor?

Dr. Ilka Ott: Yes, I think this is a very important point. I think atherectomy alone is not an appropriate treatment but there are some data that atherectomy in combination with drug-eluting balloon gives much better results, or you may even think about a combination of atherectomy and drug-eluting stent, so it often is the case. This study also raises a lot of questions and gives some thought into further studies. I think in the combination atherectomy might still have its place.

Dr. Carolyn Lam: Could you tell us some of those plans for future studies?

Dr. Ilka Ott: Well, we are just in the initiation phase but I think one also very interesting concept is to compare drug-eluting balloon plus stent to the drug-eluting stents that have been on the market. However, as I said before, there's again the concept if you combine the drug-eluting balloon plus a stent it might be also, from the commercial aspect, better because sometimes you don't need the stent. And then moreover, the drug-eluting stents are much more expensive. It would be interested to see a study like that.

Dr. Carolyn Lam: What about the concern that the superficial femoral artery is subject to a lot of stretching and external compression and it's long and ... Maybe I'm out of date here about the concern of stent fractures and so on. It looks like your study has disproven this, or do you think the follow-up's long enough?

Dr. Ilka Ott: I think the follow-up of two years is quite good, but you're right, it seems like in the superficial femoral artery the restenosis process is much longer and more prolonged. Of course, you would like not to place a stent in the SSA but from the interventional aspect, it's often not possible because if you have a dissection with a limiting the flow, you have to fix that by putting in a stent. Nitinol stents are pretty good these days. Moreover, we have another generation of the woven stents the Supera stents that might also be an interesting point to investigate in comparison to the strategy we now have shown to be superior.

Dr. Manos Brilakis: I think what we need is more studies like this, that they take the other modalities like atherectomy, laser and combine them with what is currently the standard of care, which is drug-coated balloons or drug-coated balloons plus stent, as shared in the study. I just want to congratulate Dr. Ott on her study and encourage future studies from the group. I know the ISAR group is been a phenomenally productive group in coronary intervention and I'm delighted to see they're expanding on the peripheral world.

Dr. Carolyn Lam: I couldn't agree more. Congratulations, once again, for a study that really will impact practice and that we're so proud to be publishing in Circulation.

Listeners, I'm sure you learned as much as me, so please don't forget to tune in next week as well. Thanks.

Circulation May 30, 2017 Issue

30 maj 2017 | 21 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Our featured paper this week confirms the clinical utility of a polygenic risk score of common variants of cardiovascular disease. More soon after this week’s summary of articles.

The first original article describes distinct cell-specific roles for NADPH oxidase, or Nox2, in blood pressure regulation. This paper from first author, Dr. Sag, corresponding author, Dr. Shah, colleagues from King's College London British Heart Foundation Center of Excellence in the United Kingdom. The authors used novel gene modified mouse models to show that Nox2 in myeloid cells modulates basal blood pressure whereas endothelial cell Nox2 is involved in angiotensin II-dependent hypertension. The finding that Nox2 in different cell types has distinct effects on blood pressure, suggest that different diseases conditions may alter blood pressure through effects on Nox2 in different cell types. For example, it is conceivable that the effects on myeloid cells on basal blood pressure may be enhanced in inflammatory settings, whereas endothelial cell Nox2 activation may be more relevant to renin-angiotensin system-dependent hypertension. The current results are therefore relevant to the design of novel therapeutic approaches for hypertension by targeting NADPH oxidases.

The next paper provides a new, more accurate atherosclerotic cardiovascular disease risk prediction tool in familial hypercholesterolemia that may increase the efficiency of care and use of newer lipid lowering therapies. Co-corresponding authors, Dr. Mata and Pérez de Isla, from Hospital Clinicals San Carlos in Madrid, Spain, use data from SAFEHEART, a multicenter, nationwide, long-term prospective cohort study of 2,404 adult patients with molecularly-defined familial hypercholesterolemia and who have followed up for a mean of 5.5 years. They developed a robust risk prediction equation for incident atherosclerotic cardiovascular disease based on the following independent predictors; age, male gender, history of previous atherosclerotic cardiovascular disease, high blood pressure, increased body mass index, active smoking, LDL cholesterol and LPA levels. The new SAFEHEART risk equation performed better with a Harrell C index of 0.81 compared to 0.78 for the modified Framingham's risk equation and 0.8 for the ACC/AHA Pooled Cohort risk Equations. The authors therefore concluded that the risk of incident atherosclerotic cardiovascular disease may be estimated in familiar hypercholesterolemia patients, using simple clinical predictors, and that these findings may improve re-stratification and could be utilized to guide therapy in patients with familiar hypercholesterolemia.

The next study tells us that late gadolinium enhancement cardiovascular magnetic residents identifies patients with dilated cardiomyopathy but without severe left ventricular systolic dysfunction, who are still at high risk of sudden cardiac death. In this study, by first author Dr. Halliday, corresponding author Dr. Pennell, from Royal Brompton Hospital in London, United Kingdom, the authors prospectively investigated the association between mid-wall late gadolinium enhancement and the primary composite outcome of sudden cardiac death or aborted sudden cardiac death, among 399 consecutive referrals with dilated cardiomyopathy and a left ventricular ejection fraction above 40% seen at their center between 2000 and 2011. These patients were followed for a median of 4.6 years. 17.8% of patients with late gadolinium enhancement reached the pre-specified end point, compared to only 2.3% without late gadolinium enhancement.

Furthermore, following adjustment, late gadolinium enhancement predicted the composite end point, with a hazards ratio of 9.3. Thus, patients with dilated cardiomyopathy and mid-wall late gadolinium enhancement, and mild or moderate reductions of left ventricular ejection fraction should still be recognized as having a high risk of sudden cardiac death. This is important because these patients are not currently offered ICDs for the primary prevention of sudden cardiac death, based on current guidelines. Due to the low competing risk of death from non-sudden causes, it is possible that these patients will benefit from ICD implantation, but randomized trials are now required. These issues are discussed in an accompanying editorial from Dr. Markman of Johns Hopkins University, and Dr. Nazarian, Hospital of University of Pennsylvania.

The next study enhances our understanding of the role of immunity in hypertension. Now, the innate antigen-presenting cells and adaptive immune T-cells have long been implicated in the development of hypertension, however, the T-lymphocytes subsets involved in the pathophysiology of hypertension remain unclear. A small subset of innate-like T-cells expressing the gamma-delta T-cell receptor, rather than the more commonly expressed alpha-beta T-cell receptor, could play a role, and these were the focus in today's paper by first author Dr. Caillon, corresponding author Dr. Schiffrin, and colleagues from Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Canada. In experimental models, the authors showed than angiotensin-2 infusion increased gamma-delta T-cell numbers and activation in the spleen of wall tite mice, as well as in increased the systolic blood pressure, and decreased mesentric artery endothelial function in wild type mice, but not in mice devoid of gamma-delta T-cells, or in mice depleted of gamma-delta T-cells by depleting antibody injections.

Furthermore, angiotensin-2 induced T-cell activation in the spleen and peri-vascular adipose tissue was blunted in null mice. In humans, there was an association between systolic blood pressure and gamma-delta T-cells. In summary, this is the first in-vivo demonstration that gamma-delta T-cells, a subpopulation of T-cells, play a fundamental role in the development of hypertension and vascular damage. These results will help design novel treatments to limit the progression of hypertension and vascular damage.

The final paper describes a novel multi-modality strategy for cardiovascular risk assessment. Dr. de Lemos and colleagues from UT Southwestern Medical Center in Dallas, Texas, hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic cardiovascular disease risk assessments among individuals without known cardiovascular disease. These modalities included: left ventricular hypertrophy by electrocardiogram, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high sensitivity cardiac troponin-T, and high sensitivity C-reactive protein.

Using data from 6,621 individuals of the multi-ethnic study of atherosclerosis, or MESA, as well as 2,202 individuals from the Dallas heart study, the authors evaluated the association of test results with the global composite cardiovascular disease outcome, and that would include cardiovascular death, myocardial infarction, stroke, coronary or periphery revascularization, incident heart failure or atrial fibrillation, as well as atherosclerotic cardiovascular disease outcomes, which included fatal or non-fatal myocardial infarction or stroke. Over more than 10 years of follow-up, the authors found that each test result was independently associated with the global composite cardiovascular disease events in MESA. When the 5 tests were added to a base model, the C statistic improved, that was significant integrated discrimination improvement, and net reclassification improvement, and the model was well-calibrated. Using a simple integer score counting the number of abnormal tests, they showed that global cardiovascular disease risk increased with increasing score in a graded fashion. These findings were replicated in the Dallas heart study, and were similar for the atherosclerotic cardiovascular disease outcome.

This study therefore supports the potential value of a multi-modality testing strategy in selected individuals, in whom additional risk stratification is desired, beyond measurement of traditional atherosclerosis risk factors. The authors do highlight that additional studies are needed to validate the present findings, determine the optimal approach to implementation, and address direct and indirect cost implications of the additional testing.

Well, that wraps it up for your summaries. Now for our feature discussion.

Our feature paper today tells us that a polygenic risk score identifies a group of individuals with a higher burden of atherosclerosis, and greater relative benefit from statin therapy in the primary prevention setting. But perhaps even more significant, is that it addresses the fact that even relatively small effect sizes of common snips gathered together in a genetic risk score may have clinical utility in the prediction of cardiovascular disease, and to discuss this I'm so pleased to have the first author, Dr. Pradeep Natarajan from Massachusetts General Hospital, and Dr. Anand Rohatgi, associate editor from UT Southwestern. Welcome, gentlemen.

Dr. Pradeep Natarajan: Thank you very much, Carolyn.

Dr. Anand Rohatgi: Thank you, Carolyn.

Dr. Carolyn Lam: Pradeep, could you start by telling us what you did? This was a tour de force, please.

Dr. Pradeep Natarajan: Yeah, thanks so much for the invitation and the enthusiasm. So, briefly, large-scale, genome-wide association studies have discovered genetic risk variants in the population that individually associate with coronary disease risk. Many others have shown that an aggregate of these genetic risk variants predisposes to an increased risk for coronary disease by about 60%. But we sought to, with this study, understand how primary preventive statins could influence that risk, and whether these insights could be helpful in refining statin eligibility. So, among the individual variants that had been associated with coronary disease, we developed a risk score. This encapsulated 57 individual genetic variants. This risk score is independent of traditional cardiovascular risk factors, and identified individuals with a greater burden of sub-clinical atherosclerosis, defined as coronary artery calcium and carotid plaque, and two observational cohorts in individuals with a greater absolute and relative benefit from statin therapy from a subgroup analysis within the WOSCOPS clinical trial.

What we were surprised by is that the conventional wisdom, that all previously described subgroups within statin trials had the same relative benefit, and statins per unit of alveol cholesterol lowering. So, about 20 to 25% lowering of risk per 40mg per deciliter of alveol cholesterol. So we clinically identify individuals who just start out at high absolute risk, assume that the relative benefit will be the same across everyone, and optimize the number needed to treat simply by just finding individuals at high risk. But, here we didn't see the expected 20 to 25% lowering in the high genetic risk group, we saw actually a 44% relative risk reduction for the same lowering of alveol cholesterol. And we have now observed that across three different clinical trials, and these individuals are at high baseline risk, so this translates into an even more optimized number needed to treat, and really the opportunity to identify individuals earlier with an age independent biomarker.

Dr. Carolyn Lam: That's really cool, in fact, the number needed to treat in the high-risk score group was impressively low at 13.

Dr. Pradeep Natarajan: That's correct. Now, overall in the WOSCOPS trial, if you look at all individuals, it's about 38, so it is a high risk primary preventive group of men with, you know, substantial hyperlipidemia, but if you look at at least a relative difference between the two, going from 38 to 13, that's about a three-fold improvement of the number needed to treat.

Dr. Carolyn Lam: You know, what you said about it not correlating with exactly what you expected with the drop in LDL and so on, does that mean that this genetic risk score, that a lot of the snips are probably associated with LDL levels, but that a lot of them may be giving more information beyond LDL? Is that what it means?

Dr. Pradeep Natarajan: Yeah, you know, it's interesting. Most of the genetic variants that are associated with coronary disease actually do not seem to clearly influence traditional cardiovascular risk factors. The latest best estimate of that is about 39% of them associate with traditional cardiovascular risk factors, and then a subset with LDL cholesterol. So the aggregate score actually does not associate with traditional risk factors, and including with LDL cholesterol.

Dr. Carolyn Lam: Wow, and Anand, I'm sure we had so many discussions with the editors about the paper. Could you share some thoughts?

Dr. Anand Rohatgi: Yes, Carolyn. Circulation as a journal represents the best in cardiovascular science, and we're always interested in the highest-level articles related to atherosclerotic cardiovascular disease. So, when we received this manuscript from Pradeep and Sekar’s group, really leaders in the field, we were really excited, and as we went through the review process we got even more excited because it, as you said, Carolyn, it really was a tour de force, it was a high-quality article and it combined multiple things, and that's what we're really interested in seeing at Circulation, is combining several aspects, in this case genetics, sub-clinical atherosclerotic imaging, and also treatment effect.

And, you know, it's interesting because several recent manuscripts looking at genetic risk scores, they were associated with coronary disease but it wasn't clear that they were improving what we call risk prediction performance indices, at least enough to meet the bar of incorporating them into guideline-type recommendations. So I think the field wasn't sure how to move forwards with this type of information, but now I think this study really demonstrates that this type of risk score, this genetic risk score, really can inform treatment decisions in a big way. And so we were really excited to talk about that and then see it move forward.

Dr. Carolyn Lam: So a question for both of you now. Can these data be extrapolated to other cohorts of patients? I mean, WOSCOPS was predominantly white, and all were males, right? So, Pradeep, would you like to take that first?

Dr. Pradeep Natarajan: That's an excellent observation, and I think ... A clear limitation in the field, but an outstanding question that I think can be addressed going forwards. So, the main challenge is that the epidemiological cohorts that were used for genetic analysis largely have been of European ancestry, and we know that genetic background and a variety of non-genetic factors influence cardiovascular disease risk, so in genetic analysis of European individuals the influencers of coronary disease risk may not influence cardiovascular disease the same in non-European ethnicities. And, you know, we've done some work of this specifically in African-Americans, and there are some differences. You know, African-Americans are largely mixed of both African and European ancestry, some of that seems to also influence how you interpret the cardiovascular genetic risk score.

Ideally you would have a risk score that is not influenced by the genetic background, and so the next step going forward are one to look to see how well this risk score predicts in non-European ancestry, because, obviously, not as much statin clinical trial information in non-European cohorts, but I think looking at the treatment effect in non-Europeans will be important. And then, you know, the third step is we and others are participating in several now large ongoing efforts to really define what the genetic influences are in non-European ancestries, and I think that will be a very important next step that's really critical before the clinical implementation.

Dr. Carolyn Lam: Yeah, talking to you from Asia, that's music to my ears, obviously. Anand, did you have any questions for Pradeep or anything else to add about the paper?

Dr. Anand Rohatgi: Yeah, I wanted to add one or two comments. One thing that this study demonstrates is that the genetic risk scores, whether they relate to traditional risk factors or lipids, that doesn't necessarily translate to what it might mean in terms of treatment benefit, and so I think that concept is generalizable and now it needs to be tested in other ethnicities, other types of subgroups, but I think you can disentangle a relationship with risk factors and lipids to its treatment effect and this study really nicely shows that.

And I think just to take a step back, we know statins work in intermediate-risk patients, maybe even low-risk patients with the most recent studies, but at a public policy level, and just as a cognition, we really want to narrow the focus, it's something called precision medicine that the American Heart Association is promoting as a concept, and I think that this study really demonstrates that here we have now another tool that can reduce this number needed to treat, make this choice for statins more precise, maximizing the benefits and limiting cost. So, I think that concept is very generalizable, it needs to be tested now in multiple populations, like Pradeep said, and I guess one of the questions I had had for the authors is: how do we incorporate this finding that they saw with sub-clinical atherosclerosis, which we thought was very fascinating among the editors at Circulation, that now they're also linking with sub-clinical atherosclerosis, is that something that the investigators think needs to be pursued further? Would that be something that would be used clinically as well?

Dr. Pradeep Natarajan: I think there are lots of opportunities for this going forward, you know, in prior work we've done the genetic architecture for clinical coronary disease is actually very similar to sub-clinical coronary disease, and there are many influences for sub-clinical coronary disease, and clinical coronary-disease, that are both genetic and environmental, and the aggregate effect from the polygenic risk on sub-clinical atherosclerosis suggests that it's obviously not absolute and there are other factors that influence sub-clinical atherosclerosis.

Dr. Carolyn Lam: Well, listeners, you heard it right here. Thank you for joining us this week, tell all your friends about it, and don't forget to tune in again next week.

Circulation May 23, 2017 Issue

22 maj 2017 | 23 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment we'll take a deep dive into hemo-compatibility-related outcomes in the MOMENTUM 3 trial of a fully magnetically levitated pump in advanced heart failure. But first, here's your summary of this week's journal.

The first paper sheds light on the biological mechanisms underlying cardioprotective effects of the Mediterranean diet. First author, Dr. Wang, corresponding author Dr. Hu and colleagues of Harvard, TH Chan, School of Public Health in Boston, Massachusetts studied 980 participants from the PREDIMED Trial including 230 incident cases of cardiovascular disease and 787 randomly selected participants at baseline followed up for 7.4 years.

Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a controlled diet. Plasma ceramide concentrations were measured and the primary outcome was a composition of non-fatal acute myocardial infarction, non-fatal stroke or cardiovascular death.

The authors found a novel positive association between baseline plasma ceramide levels and incident cardiovascular disease. In addition, the association between baseline ceramides and incident cardiovascular disease varied significantly by treatment groups where a Mediterranean dietary intervention appeared to mitigate the potential deleterious effects of elevated plasma ceramide concentrations on cardiovascular disease.

These findings, therefore, strengthen the evidence base for recommending the Mediterranean diet for cardiovascular disease prevention and suggest that plasma ceramides have the potential to serve as markers of future cardiovascular disease risk.

The next paper describes a novel therapeutic approach against hypertensive cardiac remodeling and provides the first evidence of the cardio protective effect of cardiofibroblast-specific activating transcription factor 3 or ATF3. In this study from first author Dr. Li, co-corresponding authors, Dr. Du from Beijing Anzhen Hospital in China, and Dr. Ma from Thomas Jefferson University in Philadelphia and colleagues, the authors used a discovery-driven unbiased approach to identify increased ATF3 expression in mirroring hypertensive hearts and the human hypertrophic heart, expressed primarily by cardiac fibroblast cells. ATF3 knockout markedly exaggerated the hypertensive ventricular remodeling, a state rescued by lentivirus mediated microRNA aided cardiac fibroblast selective ATF3 over-expression.

Conversely, cardiac fibroblast specific ATF3 over-expression significantly ameliorated ventricular remodeling and heart failure. The authors further identified MAP2K3 as a novel ATF3 target, and that p38 was the downstream molecule of MAP2K3, mediating the profibrotic hypertrophic effects in ATF3 knockout animals.

In summary, this study provides the first evidence that ATF3 up-regulation in cardiac fibroblasts in response to hypertensive stimuli, protects the heart by suppressing MAP2K3 expression, and subsequently p38 TGF-beta signaling. Thus, identifying molecules mimicking endogenous ligands or inhibiting microRNA that down-regulate ATF3 expression, may represent novel therapeutic approaches against hypertensive cardiac remodeling. These, and other issues, are discussed in an accompanying editorial by Dr. Jennifer Davis of University of Washington.

The next paper tells us that clinical frailty score may need to be part of the pre-operative assessment of patients undergoing transcatheter aortic valve replacement, or TAVR. First author, Dr. Shimura, corresponding author, Dr. Yamamoto and colleagues of Toyohashi Heart Center in Japan, utilized the optimized catheter valvular intervention or OCEAN Japanese Multicenter Registry of 1215 patients undergoing TAVR and found that clinical frailty score correlated with other markers of frailty, such as body mass index, albumin, gait speed and grip strength. Furthermore, the clinical frailty score was an independent predictive factor of increased late-cumulative mortality risk. Thus, in addition to reflecting the degree of frailty, the clinical implications of these findings are discussed in an accompanying editorial by Dr. Jonathan Afilalo from McGill University in Montreal.

In the final study, we learned that long-term anabolic androgenic steroid use may be associated with myocardial dysfunction and accelerated coronary atherosclerosis. Dr. Baggish and colleagues from Massachusetts General Hospital in Boston, used a cross-sectional cohort design of 140 experienced male weight lifters, age 34-54 years, comprising 86 men reporting at least two years of cumulative lifetime anabolic androgenic steroid use, and 54 non-using men. Compared to non-users, steroid users demonstrated relatively reduced left ventricular systolic function and diastolic function on transthoracic echocardiography. Furthermore, steroid users demonstrated higher coronary artery plaque volume on coronary CT angiography compared to non-users. In summary, this is the first large controlled study of its type to demonstrate that long-term anabolic androgenic steroid use is associated with both systolic and diastolic myocardial dysfunction, as well as coronary atherosclerosis. Thus, when clinicians encounter young or middle-aged men who exhibit evidence of unexplained left ventricular dysfunction or premature coronary artery disease, the possibility of cardiotoxicity due to long-term anabolic androgenic steroid use should be considered in the differential diagnosis.

Well, those were your summaries. Now, let's move on to our featured discussion.

For our featured discussion today, we are actually reviewing a secondary analysis of the MOMENTUM 3 Trial, which is a multicenter study of the mag lev technology in patients undergoing mechanical circulatory support, with the HeartMate 3. And to discuss today's findings I'm so pleased to have the corresponding author, Dr. Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as Dr. Biykem Bozkurt, Associate Editor from Houston, Texas.

Welcome Mandeep and Biykem.

Dr. Mandeep Mehra: Thank you. It's a pleasure to be with you all.

Dr. Biykem Bozkurt: Thank you.

Dr. Carolyn Lam: Let's start by getting a few definitions right, shall we, just for our audience. This specific article, and congratulations Mandeep, it's just so great, it speaks of hemo-compatibility-related outcomes. Could you start by telling us what that is, and maybe reminding us what the original MOMENTUM 3 short-term results showed.

Dr. Mandeep Mehra: Sure. As our listeners are aware, left ventricular assist devices have really transformed the management of refractory advanced heart failure, by the introduction of a form of flow, called continuous flow, in the devices, which tend to render patients, relatively low pulsatiles to non-pulsatile. Now what we've seen is that the interface between this very unnatural physiology from continuous flow in concert with the patient's biology tends to create a constellation of problems that we sort of refer to as hemo-compatibility-related adverse events.

For example, we have seen a very curious development of recurrent gastrointestinal bleeds that tend to occur in a manner similar to what was observed with critical aortic stenosis, the so-called Heyde's Syndrome. Similarly we see stroke-related problems and we also see evidence of thrombosis that can sometimes develop within the pump. So we refer to the conglomeration of these unique complications that arise from the abnormal interface between the device and the patient as hemo-compatibility-related adverse events.

Dr. Carolyn Lam: And this is a secondary analysis, a six-month secondary analysis, right? So could you give a little bit of background of why you would hypothesize that these events might be different with the HeartMate 3 versus 2? I mean, it's quite unique that we're going back to creating a pulse.

Dr. Mandeep Mehra: Yes. Let me fist define for our audience what the MOMENTUM 3 Trial was designed to initially do, and is still doing. MOMENTUM 3 is a randomized controlled trial of two devices: one, a conventionally available continuous flow device called the HeartMate 2, and the second device, the novel pump called the HeartMate 3. The HeartMate 3 is a pump that took two decades to engineer. And it took that long because it is very unique, based on the following principles.

First, it's a small profile, so the entire pump can be placed intrathoracically. Second is that the way in which it moves blood, its rotor, is fully magnetically levitated, which means that it has no friction when it rotates. The third is that despite its small profile, this device has wide blood flow gaps, meaning that as blood is moving in this centrifugal flow pump, it does not expose the blood elements to as much of sheer stress as one sees with other conventionally available devices. And then finally, what this device has uniquely is a intrinsic pulse, and what that means is that we program this device in a fixed program to actually ramp its speed up and ramp it down so that it creates an intrinsic pulse of about 30 beats per minute, which is engineering-wise designed to improve pump wash out; that's the intention.

So the MOMENTUM 3 Trial was constructed to really compare these two devices and we recently reported, on the primary end point of the six-month outcomes of this trial. And the trial primary end point was set at survival free of a disabling stroke, or the need for re-operation because of pump malfunction. And what we found was that this pump, the HeartMate 3, clearly met its non-inferiority end point, versus the HeartMate 2, but also demonstrated superiority on the primary end point at six months. We were certainly not expecting to see superiority at this early time point, but we were very fortunate to see that.

Now what is unique about this is that for the first time ever, we saw no cases of suspected or manifest established pump thrombosis, as a result of de novo pump thrombosis requiring re-operations with the HeartMate 3 device. And this is a frequency of about 10% that we normally observe with pumps. That is one in 10 pumps will clot off within about six months, and require re-operation. So we were very gratified to see this observation in the short-term data of the primary MOMENTUM 3 database.

Now as a result of that observation, Carolyn, we thought that the hard end points, as are typically adjudicated for the primary basis of these clinical trials, missed the entire constellation of hemo-compatibility-related outcomes because these are patients who develop both bleeding and clotting complications. And the net burden of hemo-compatibility is not entirely available for review, which is the basis of this important secondary analysis that was published in Circulation.

Dr. Carolyn Lam: What striking findings. So tell us the bottom line.

Dr. Mandeep Mehra: What we found in the secondary analysis was evidence that the burden of hemo-compatibility-related adverse events is lower in patients with the HeartMate 3, compared to the HeartMate 2 device. And that was the basis of the bottom line that we found.

In particular, we knew that there were no episodes of de novo pump thrombosis with the HeartMate 3, but we also found that there was evidence of a reduction in non-disabling strokes with the HeartMate 3 device. So we now have evidence that thrombotic complications, minor strokes, as well as pump thrombosis, seem to be abrogated by this new pump.

What we should keep in mind, however, is that this is still early data from the ongoing MOMENTUM 3 Trial, and the trial is actually designed to enroll and observe over a thousand patients, over two years. And we are basically showing in this a very early look at six months of about 300 of these patients. And so that needs to be kept in mind. But we are extremely encouraged by these early trends suggesting that we may have started to break the issues related to the barriers of implementation of such therapy in the hemo-compatibility domain.

Dr. Carolyn Lam: Yeah, and as a heart failure doc, I can tell you that I share that excitement and I know that Biykem does too, as did the editors.

Biykem, tell us a little bit about what we talked about as editors about this paper.

Dr. Biykem Bozkurt: Indeed. Mandeep, the hemo-compatibility concept which is being addressed in this new publication is quite novel and is exciting, and addresses the continual spectrum of the pathology, ranging from the GI bleed, to the stroke spectrum. The question I have, in this study, the overall scores were not different in the absolute number that we saw as a score from the hemo-compatibility ranking.

Do you think we would continue to use this approach as a quantitative score, given the fact that there may be bidirectional impact from different devices on the different spectrum, especially with the recognition that HeartMate 3 seemed to be protective against the thrombotic, perhaps events, or should we use it more of a qualitative score card looking at which perhaps spectrum the device tends to be a little bit more risky or beneficial. So shall we color code this score and try to perhaps focus on the spectrum of thrombosis versus bleeding and then try to strategize?

Dr. Mandeep Mehra: Thank you for that very erudite question, Biykem. You hit right at the heart of the matter. So let me make a few comments about that. The first issue is that so far, the field has not had a clear definition of hemo-compatibility. Hemo-compatibility has been more of a engineering term. When someone said hemo-compatibility, they thought of biomaterials, rather than a clinical definition of hemo-compatibility. So for the first time, we have actually introduced the term hemo-compatibility into the lexicon of definition, managing patients with LVAD, so that's one important point.

The second important point is that we, until this day, until this analysis, have not had the ability to really provide people with a full picture of the entire burden of experience of hemo-compatibility-related complications that an individual patient experiences as they are on this device, because you know that patient's going to have a GI bleed, and then they may have a stroke, because we may change, dynamically we may change anticoagulation for instance if someone has one event then the other, and the traditional way in which studies are done, hey do not give you a clear picture into the burden of hemo-compatibility. So the most innovative thing about this clinical hemo-compatibility definition, is that we've not introduced a score that reflects the burden of disease, and we have also created tiers of severity of the burden of disease experience into three quantitative tiers that include various subsets which are hierarchal.

So for example, is one gastrointestinal bleeding the same as non-disabling stroke? Well, no. One gastrointestinal bleeding may be a milder form a hemo-compatibility-related problem. So our early look at this clearly shows that survival free of a hemo-compatibility-related event is clearly lower in the patients with a HeartMate 3. However, as you astutely pointed out, when you examine purely the burden of hemo-compatibility-related complications experienced by the survivors, one actually sees a trend in favor of the HeartMate 3, but not a statistically significant difference, largely because we have not yet abrogated problems related to bleeding complications on the side of the hemo-compatibility.

Why is that? Well, it's because we still treat all patients in both groups with the HeartMate 2 or the HeartMate 3 with the same intensity of anticoagulation. What this sort of data points out to us in the future, first of all, is that it allows us to compare apples to apples, as we are looking at different device platforms, that's number one. Second is it gives a much more robust look into the total patient experience. And third, it actually gives us insight into whether altering one component of the equation, so let's say there's a bleeder, if you actually react to that clinically, will you start to see problems on the clotting side.

Dr. Biykem Bozkurt: This is a very, very important study that addresses the whole spectrum of hemo-compatibility in a more comprehensive fashion, and also points out perhaps the differences that we see in overall others, centrifugal flow, left ventricular assists, support systems such as the Heartware HVAD study that showed increase in hemorrhagic stroke, especially hemorrhagic stroke in the first six months in the ENDURANCE Trial, whereas the HeartMate 3 has shown in the MOMENTUM 3 publication, as well as the Circulation secondary end point study demonstrates a reduction in disabling strokes and absence of any pump thrombosis.

So there are differences, despite both of the pumps are centrifugal, there are differences in the profile, and the spectrum of the risk and hemo-compatibility. And one other interesting finding from this study is that the predictors for hemo-compatibility outcomes are complementary to what has been known in the sense that lower antiplatelet and anticoagulation management strategies are associated with increased risk of hemo-compatibility adverse events.

And surprisingly, the control of blood pressure did not appear to correlate with the hemo-compatibility outcomes. So from that perspective, it differs from the ENDURANCE Trial where the uncontrolled blood pressure or hypertension was associated with hemorrhagic strokes, in the ENDURANCE Trial, whereas in the MOMENTUM 3, the blood pressure did not appear to correlate with the hemo-compatibility outcomes or pump thrombosis.

So these are very interesting findings and I think are complementary to the evolving field of the risk benefit ratios in patients with LVAD support. And from that perspective, we in Circulation felt that this will be a very valuable publication for our readership as well as for the whole heart failure and transplant community.

Dr. Carolyn Lam: Thank you, so much for joining us today, don't forget to tune in next week.

Circulation May 16, 2017 Issue

15 maj 2017 | 20 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carlolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. What's the link between DPP4 and aortic valve calcification? Well, to find out, keep listening because we'll be discussing this and an important new paper right after these summaries.

The first original paper in this issue tells us that high sensitivity Troponin I, may have a role in personalizing preventive strategies in patients with Type II Diabetes. Dr. Cavender and colleagues from University of North Carolina, Chapel Hill, sought to describe the relationship between changes in high sensitivity Troponin I and cardiovascular outcomes in the EXAMINE phase 3B trial, which was designed to evaluate the cardiovascular safety of alogliptin. The current analysis was restricted to patients, randomized 30 days or more after the qualifying acute coronary syndrome event, and high sensitivity Troponin I was measured using the Abbot Architect Assay at baseline and six months.

The authors found that high sensitivity Troponin I was detectable in the vast majority - 93% of patients with Type II Diabetes, stabilized within 30 days after acute coronary syndrome. One in six of these patients had high sensitivity Troponin I levels above the 99th percentile upper reference limit. High sensitivity Troponin I had a strong graded relationship with the incidence of subsequent major cardiovascular events.

Changes in high sensitivity Troponin I as small as two to six nanograms per liter over six months, were associated with a heightened risk of adverse outcomes. Particularly cardiovascular death and heart failure. Alogliptin neither increased nor decreased the risk of cardiovascular events in a high risk cohort of patients with elevated high sensitivity Troponin I levels. These findings therefore imply that serial measurements of high sensitivity Troponin may have a role in preventive strategies, either by intensifying or prolonging therapies in patients at high risk or reducing or shortening therapies in patients at low risk of cardiovascular events.

The next paper describes the effects of Pioglitazone on cardiac outcomes after ischemic stroke or transient ischemic attack in patients with insulin resistance without diabetes in the IRIS trial, which stands for Insulin Resistance Intervention after Stroke. As a reminder, the IRIS trial compared the effects of Pioglitazone with placebo on major cardiovascular events after stroke or transient ischemic attack, in patients without diabetes but who had evidence of insulin resistance. And it showed that Pioglitazone improved insulin resistance, prevented diabetes, improved CRP and reduced fatal and non-fatal stroke or myocardial infarction.

In the current paper, by Dr. Young and colleagues from Yale Cardiovascular Research Center in New Haven, Connecticut, the authors performed a secondary analysis of IRIS and examined the effect of Pioglitazone on acute coronary syndromes, mainly myocardial infarction or unstable angina. They found that Pioglitazone reduced the risk of these events by 29%, with benefit emerging after two years of treatment. Furthermore, Pioglitazone reduced the incidence of Type I myocardial infarction with a neutral effect on Type II myocardial infarction. In summary, among patients with insulin resistance without diabetes, Pioglitazone reduced the risk of acute coronary syndromes after a recent cerebrovascular event, and may serve as a useful secondary prevention therapy in addition to statins, aspirin, and other established treatments.

The next study tells us that immune complexes may be an important biomarker in the risk stratification of Antiphospholipid Syndrome. Now recall that Antiphospholipid Syndrome is characterized by recurrent thrombosis in patients with Antiphospholipid predictive antibodies. However, the predictive value of the presence of Antiphospholipid auto antibodies is low. And new markers are needed to identify carriers at higher risk.

In the current study by Dr. Serrano and colleagues from Madrid, Spain, the authors performed a historical cohort follow up study based on the Magnum 12 plus 12 cohort, that included all patients who had received a kidney transplant in their hospital in a 12 year period from 2000 to 2011. Sera used for the analysis were collected in the 24 hours before the kidney transplant surgery, and used to measure circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I.

The authors then investigated the possible association of these immune complexes with thrombosis, graft thrombosis and graft loss in the six months following kidney transplant. They found that in patients with the immunoglobulin A isotope antiphospholipid antibodies, the presence of circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I, pre transplant, was associated with acute thrombotic events. Patients positive for the immune complexes had a much higher risk of developing post transplant thrombotic events, and higher risk of graft thrombosis mediated graft loss. On the other hand, complex negative patients had the same thrombosis risk as the control population. These findings imply that treatment to prevent thrombosis should focus mainly on the immune complex positive patients in this setting.

The final paper addresses the issue that public reporting of PCI Outcomes may create disincentives for physicians to provide care for critically ill patients, particularly at institutions with worse clinical outcomes. In this study from first author, Dr. Waldo from the VA Eastern Colorado Health Care System in Denver, Colorado, corresponding author, Dr. Yeh from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. The authors used state reports to identify 31 out of 86 hospitals that were recognized as negative PCI outliers in two states: Massachusetts and New York, from 2002 to 2012.

They sought to evaluate the procedural management and in hospital outcomes of patients treated for acute myocardial infarction before and after a hospital had been publicly identified as the negative outlier. They found that outlier facilities were larger, treating more acute myocardial infarction patients, and performed more PCI's than non outlier hospital. The rates of percutaneous revascularization increased similarly at outlier and non outlier institutions after report of the outlier status. After outlier designation, the in hospital mortality declined at the outlier institutions to a greater extent than was observed at the non outlier facilities. Thus, public reporting of outlier status may prompt outlier facilities to improve case selection, and employ systems improvements that optimize patient care, and improve in hospital mortality among patients with myocardial infarctions.

We are going to have such a fun discussion in today's feature paper. Have you ever wondered what does dipeptidyl peptidase-4, or DPP4 have to do with aortic valve calcification? Well, you're about to learn, because in today's paper we actually learn that DPP4 inhibitors, which you might recognize from diabetes, you know drugs such as sitagliptin, could serve a potential therapeutic target in aortic valve disease. To tell us about it and discuss it, we have corresponding author, Dr. Jae-Kwan Song] from Asan Medical Center in Seoul, South Korea, as well as Dr. Thomas Eschenhagen, Associate Editor from University Hospital Hamburg Eppendorf in Germany. Welcome, gentlemen.

Dr. Jae-Kwan Song: Hi.

Dr. Thomas Eschenhagen: Hi.

Dr. Carolyn Lam: Fascinating paper. I have to congratulate you first and foremost, but please tell us, what inspired you to look at DPP4 in aortic valve disease.

Dr. Jae-Kwan Song: Yeah, actually as a clinician, I think there is two issues. One is the prevalence of calcific aortic valve disease is increasing rapidly in the developed and also developing countries. The second important issue is that we do not have effective medical treatment option. So I will say that the medical treatment of calcific aortic valve disease is a typical example of unmet clinical needs to serve this kind of troubled scientific issues, our team have focused on the reciprocal interaction between endothelial cells and interstitial cells. Because this potential mechanism was well reported by other investigators that the interaction between two cells are very critical for maintaining aortic valve tissues. So first we started with Enos knockout mouse, to go over what's going on in the aortic valve in the models. In the human tissues in patient with calcific aortic valve disease, we have found that DPP4 is specifically activated. That's the beginning of our study.

Dr. Carolyn Lam: Could you please explain to those of us who don't do basic science research everyday, I mean, your study involves tissues both from humans and mirroring models. Could you explain it very simply what you did and what you found?

Dr. Jae-Kwan Song: Yes, in the Enos Knockout mouse, we have found that those mouse showed very strong calcification process compared to the live animals. What is the mechanism of this enhanced calcification in this mouse? And we found that the loss of endothelial function is critical, and then we found that DPP4 is actively involved in the calcification process. The first test we have done is the isolation of developed interstitial cells. And then we focused on osteogenic transformation over this valvular interstitial cell both in the Enos Knockout mouse, and the human developing interstitial cells. So we have found that the endothelial dysfunction activates the DPP4 activity in these tissues, which resulted in the increase osteogenic transformation of developed interstitial cell. So that's the beginning of our observation.

Dr. Carolyn Lam: And could you describe what you did subsequently to prove the whole mechanism?

Dr. Jae-Kwan Song: As you know the DPP4 has many substrates including many peptides involved in glucose metabolism, so the hardest part of our study is what is the molecule target, or associated with DPP4 in the pathologic process of calcification in developing interstitial cells. We tested many different substrates known to the potential targets of DPP4, and we have found specifically insulin-like growth factor-1 (IGF-1) is the key proponent of all this process. With further study, we found that the DPP4 cleaves or inactivates or decrease IGF1 activity in the valvular interstitial cell, and in the normal status IGF1 is a very critical to protect osteoblastic transformation of valvular interstitial cell. We have found that the DP4 and IGF1 exercises key therapeutic target, and the key molecules involved in valvular calcification. As you know we do have a DP4 inhibitors, which were successfully clinically to reduce the diabetes control. So it's very easy to test the DP4 inhibitors in animal models. Both in the Enos Knockout mouse, and we also developed in the calcific aortic valve disease using some treatment, including Vitamin D and hypercholesterol and diet the in vivo experiment showed that [inaudible 00:13:58] inhibitors effectively prevented the development of calcification and prevented the development of calcification and prevented the developement of calcific aortic disease. This the main finding of our study.

Dr. Carolyn Lam: That is so fascinating, and really especially what you just said, that sitagliptin in this rabbit model prevented calcific aortic valve disease with the concurrent increase in plasma IGF1 levels in line with the DPP4 inhibition. That is just such a beautiful piece of work, congratulations. And congratulations Thomas on managing such a nice paper. Take us under the hood about the discussions that happened with the editors. Surely you recognized the translational impact. What do you think? Is it time to reposition DPP4 inhibitors?

Dr. Thomas Eschenhagen: We and the reviewers like the paper because first of all it describes a new, interesting biological mechanism. If we are done, and we like that it uses human samples, but also this treatment in two different animal models. This together, really makes it a strong paper, we've found perfectly suitable for Circulation. As you said Carolyn, the translation perspective is fascinating. Obviously it's very early days. There is no specific evidence yet from patients. But that could, in patients, take actually very very long. Even the big studies already been done with sitagliptin and other DPP4 inhibitors, that don't show a signal in this direction yet, but I would say that could still happen, and maybe in the long term, all of the cardiologists putting all this stuff in German it's call TAVS, in America it's called TAVR does not work anymore, obviously. That's just the speculation.

But it gives a very interesting signal, and this study certainly should stimulate research in humans and do some prospective studies in patients.

Dr. Carolyn Lam: Yes indeed. If I may ask, Jae-Kwan, do you have plans for further steps?

Dr. Jae-Kwan Song: Yeah, we are expecting some [inaudible 00:16:06]. The first process with proof of concept study as you know is DP4 inhibitors have been actually been used for the diabetic controls, so we may have a patient cohort who also underwent [inaudible 00:16:22] echocardiogram [inaudible 00:16:23] while without medication. The analysis of those later can be used for proof of concept study. But we are challenging issues that although many drugs are classified as a DP4 inhibitors, we should really focus on the tissue distribution on these drugs, specifically on the cardiac issues. It may be possible that the different drugs have a different tissue distribution even after all our medication. The second critical issue is what is the actual dose of these drugs to prevent calcific aortic valve disease. Usually these drugs are used for diabetes control. We may need different lab results of these drugs for different critical indications. So that's the two important issues to be solved.

Dr. Carolyn Lam: That's wonderfully put, and I couldn't agree more. Thomas, could we switch tracks a little bit. Because now that I have you online, and you're the first time joining us on the show too, tell us a little bit more about what it's like as an associate editor really looking at these pre clinical data, being able to parse out what you think has translational value, and especially for circulation. We have a very strong emphasis now on clinical translation. Share some of your thoughts there on how it's been for us.

Dr. Thomas Eschenhagen: It's been a great experience. I do have some experience with other journals as an associate editor, or being on an editorial board. But I have to say circulation is really quite unique. I think it's a very strong group of people. I'm amazed by the level of knowledge and also the level of engagement of the other editors and associate editors, in every single paper. What's also really rewarding is the overall quality of papers being submitted to circulation, it's really great. A lot of papers are not only presenting some beautiful, basic science, but also this translational perspective, that's actually what we are looking for. So very solid, exciting scientific work in cells, animals, but always some link, either some materials from humans or a good link to a translation perspective. That's the perfect paper for circulation and I have to say we get quite a bit of them, and it's sometimes even difficult to pick the ones we really like. But it's great, it's really been a lot of fun.

Dr. Carolyn Lam: This is actually one of the purposes of this podcast. It's hoping to share with our readers, with our listeners, what happens at these editor discussions because it's so interesting, I just wish everyone could listen to all the science and the clinical translation that we discuss. Thank you very much for sharing your thoughts today, both Thomas, and Jake Won, beautiful work. We're very proud to be publishing this work in circulation.

Thank you listeners for joining us this week. Don't forget, tell all your friends about this podcast, and tune in again next week.

Circulation May 8, 2017 Issue

9 maj 2017 | 17 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. In just a moment, we will be discussing the sources of sodium in the US diet, results that may surprise you, and that carry profound public health importance. But first, here's your summary of this week's issue.

The first original paper advances the field of cardiac tissue engineering by establishing a defined serum-free protocol to generate functional human myocardium from pluripotent stem cells. In this paper by first author, Dr. Tiburcy, corresponding author Dr. Zimmermann and colleagues from the University Medical Center Goettingen in Germany, the authors systematically investigated cell composition, matrix and media conditions to generate engineered human myocardium from embryonic and induced pluripotent stem cells and fiberglass, under serum-free conditions. The engineered human myocardium demonstrated important structural and functional properties of post-natal myocardium, including rod-shaped cardiomyocytes with M-bands, systolic twitch forces, a positive force-frequency response, inotropic responses to beta adrenergic stimulation, evidence of advanced molecular maturation by transcriptome profiling and the engineered human myocardium even responded to chronic cholinomimetic toxicity with contractile dysfunction, cardiomyocyte hypertrophy, cardiomyocyte death, and anti-pro BNP release, which are all classical hallmarks of heart failure.

Finally, the authors demonstrated scalability of engineered human myocardium according to anticipated clinical demands for cardiac repair. In summary, this paper provides proof of concept for a universally applicable technology for maturation and scalable production of engineered human myocardium, something that is termed a stride forward in an accompanying editorial by Doctors Yang and Murray, from University of Washington in Seattle.

The next paper describes a new frontier for interventional cardiology, the percutaneous therapy for tricuspid regurgitation. Here, Dr. Nickenig and colleagues, from University Hospital Bonn in Germany, recruited 64 consecutive patients deemed unsuitable for surgery who underwent mitroclip treatment for chronic, severe tricuspid regurgitation for compassionate use. Twenty-two patients were also concurrently treated with a mitroclip system for mitral regurgitation as a combined procedure. The degree of tricuspid regurgitation was severe or massive in 88% of patients before the procedure. The mitroclip device was successfully implanted in the tricuspid valve in 97% of cases.

After the procedure, tricuspid regurgitation was reduced by at least one grade in 91% of patients. 13% of patients with tricuspid regurgitation remained severe after the procedure. There were significant reductions in effective regurgitant orifice area, vena contracta width, and regurgitant volume. There were no intra-procedural deaths, cardiac tamponade, emergency surgeries, stroke, myocardial infarction or major vascular complications.

There were three in-hospital deaths. New York Heart Association class was significantly improved and six minute walk distance increased significantly. In summary, this study demonstrates that trans-catheter treatment of tricuspid regurgitation with the mitroclip system seems to be safe and feasible in this cohort of pre-selected patients.

The next paper describes the pooled safety analysis of evolocumab, a fully human monoclonal antibody to PSK-9. Dr. Toth of Johns Hopkins University School of Medicine and the PROFICIO investigators perform this pooled analysis from the PROFICIO program, which included over 6,000 patients from 12 Phase 2 and 3 trials, and the corresponding open-label extension trials, and they showed that treatment with evolocumab, up to one year, was not associated with discernible differences in adverse events, serious adverse events, or key laboratory assessments, compared to control or standard of care.

In addition, adverse events rates did not increase among patients attaining very low levels of LDL cholesterol, of less than 25 milligrams per deciliter, compared to patients attaining LDL cholesterol levels above 40 milligrams per deciliter. In summary, the present analysis confirms a favorable benefit risk profile for evolocumab treatment for up to one year.

Does aggressive blood pressure lowering prevent recurrent atrial fibrillation after catheter ablation? Well, this question is addressed in a randomized, open-label clinical trial known as the Substrate Modification With Aggressive Blood Pressure Control or SMAC-AF Trial. In this trial, Dr. Parkash of Halifax, Canada and colleagues, randomly assigned 184 patients with atrial fibrillation and a blood pressure of greater than 130 over 80 to aggressive blood pressure lowering, with a target of less than 120 over 80, or to standard blood pressure treatment, to a target of less 140 over 90, prior to their scheduled atrial fibrillation catheter ablation.

The primary outcome was symptomatic recurrence of atrial fibrillation, atrial tachycardia, or atrial flutter lasting greater than 30 seconds, determined 3 months beyond catheter ablation. The authors found no additional benefit to the addition of aggressive blood pressure lowering over a median of 3.5 months, over standard blood pressure therapy, in patients undergoing catheter ablation for atrial fibrillation to prevent recurring atrial arrhythmia.

In subgroup analysis, a signal of benefit was observed in groups whose blood pressure were lower at the point of entry into the study, and in those patients who were older. The duration of blood pressure lowering in the study did not result in reduction of recurrent atrial fibrillation after catheter ablation, however there was a higher rate of hypotension requiring medication adjustment in the aggressive blood pressure group.

Thus, this trial showed that neither aggressive blood pressure lowering compared to standard blood pressure lowering, nor the duration of aggressive blood pressure treatment reduced atrial arrhythmia occurrence after catheter ablation for atrial fibrillation, but resulted in more hypotension.

Well, that wraps it up for our summaries! Now, for our feature discussion ...

Our topic today is so universal and so important. It's about sodium intake and the sources of sodium, at least in the US, and I have with me two lovely ladies, the corresponding author of our paper, Dr. Lisa Harnack, from School of Public Health, University of Minnesota, and a regular on the show, shall I say, Dr. Wendy Post, Associate Editor from Johns Hopkins. Welcome, ladies!

Dr. Wendy Post: Thanks you, Carolyn! It's a pleasure to be here.

Dr. Lisa Harnack: Thanks, thanks.

Dr. Carolyn Lam: Lisa, let's dig right into your paper. Let's start by discussing that there was a prior paper that looked at sources of sodium in the US population. So please tell us, what inspired you to do your paper, and were you surprised by your findings?

Dr. Lisa Harnack: Right, well the previous study was over 25 years old, and it involved just 69 people from one geographic area, and, you know, it was informative, but it didn't tell us about America today, and how much sodium we're getting from different sources, and it didn't tell us much about a variety of ethnic groups ... we're a diverse country. So the CDC actually funded this study, and really they saw the need for it and laid out that this study needed to be done, as it was done, in three geographic areas, representing different ethnic groups.

Dr. Carolyn Lam: Tell us what you did.

Dr. Lisa Harnack: So, we recruited 450 people from 3 different areas, from Minneapolis/St. Paul metropolitan area ... Stanford was a partner in this study and they recruited people from that area of California, and then, finally, Birmingham, Alabama was a partner was a partner, and we got participants from there.

So the racial groups we had represented were white Americans, African Americans, Asian Americans and Hispanics.

Dr. Carolyn Lam: Yeah, I was really struck ... you had almost equal representation of women as well, didn't you?

Dr. Lisa Harnack: Right, so we made sure we had half of the participants were women, so we could really see how things stood with a variety of groups.

Dr. Carolyn Lam: That's excellent. What I was really impressed, as I'm sure, Wendy, you were, too, was the detail of the methodology. Could you tell us a little bit about that?

Dr. Wendy Post: Right, so we wanted to know all the sources of sodium. Part studies have tended to not ask about salt added to food at the table, and in home food preparation, because it's really hard to actually know ... you know, if you ask somebody, "Oh, did you add salt at the table? How much did you add?" They don't know. They just say, "Oh, well, I shook some salt on." So, we had people collect duplicate samples of the salt they added to food at the table and home food preparation. We gave them little baggies ... collection bags ... you know, after they added salt at the table, shake some into the baggy. So, we knew exactly how much because people do add salt in the home, so they have some control over how much sodium is in their diet. But the question is in how much under people's control in their home versus what's coming from the food supply.

Dr. Carolyn Lam: Right. And what I loved about the results is ... I think that it would challenge a lot of what people expect. Because when we talk about sodium restriction, everyone thinks, "Oh, it's the additional salt we add." And your study actually had surprising results. So, could you tell us?

Dr. Wendy Post: Yes, so it really was clear that the salt that people add at the table is just 5% of their total sodium intake, on average, across people in our study, and the salt added in home food preparation, like maybe the salt you add to your pasta when you're boiling it or to your eggs ... that was just 6%. So, 11% of the sodium in our study participants' diets was sort of that under-your-control in-the-home, and the rest was from other sources. So, the other things we looked at was, "Will water contribute some sodium?" So, we wanted to see how much comes from your home tap water. There's sodium that's just naturally occurring in food, like milk just naturally contains some sodium. So we wanted to look and see how much came from just naturally occurring in the food, and then the other question was how much is added by food manufacturers as part of making the food product, and that included the salt that might be added in making potato chips, as well as in restaurants ... the salt that might be added in making French fries or a pasta dish at a restaurant.

Dr. Carolyn Lam: And the biggest culprit?

Dr. Lisa Harnack: Yes, the biggest culprit was that latter source ... food added in processing.

Dr. Carolyn Lam: I thought that was amazing. Wendy, what do you think the public health message is? I mean, 70% almost of the salt's coming from processed foods from outside. What do we do? Stop eating it? What do we do?

Dr. Wendy Post: Right, so, on the editorial board for Circulation, we really liked this paper because of its very high impact for a public health message. So, as was stated, the sodium that we're getting in our diet is largely coming from processed foods and from foods we eat in a restaurant. So there are a number of ways that that can be modified and one is for our patients to read food labels and to make smart choices when they are shopping for processed foods in the supermarket.

But the other is for food manufacturers to decrease the amount of sodium in the products that they are making and there are voluntary suggestions by the FDA that food manufacturers reduce the sodium content of the food, and especially bread is incredibly high in sodium, and I suspect that most of our patients don't know that. So, if we were able to reduce the amount of sodium in the food supply by just a small fraction, it could have a large public health impact because we all eat.

So, it would affect everybody, and then I think the other really important public health message is about eating in restaurants and, of course, some people eat out more than others, and some people eat out in fast food restaurants, which, of course, are very high in sodium, but even in some of the nice restaurants that we go to, even expensive restaurants, the food is very heavily salted and I, for one, when I go out to eat, and sometimes don't like the taste of the food because it has so much salt in it, when I'm used to eating a low sodium diet.

So, there are a number of changes that occur on that level. One is for our patients to understand what foods tend to have a lot of sodium at a restaurant, but also for restaurants to notify their clientele of what foods are potentially lower in sodium and calories and generally provide the nutrient value so that we can make smart choices when we eat out.

Dr. Carolyn Lam: Yeah, indeed, congratulations, Lisa - what an important paper. Quick question, so that was the overall main message, but did you find any differences by different racial groups, by sex, by different socioeconomic status?

Dr. Lisa Harnack: We did find some differences. We found one difference was it looked like African Americans tend to add more salt at the table than some of the other groups, and, actually, Asians add less in our study. But still for all groups, that sodium added to food in processing was still the main source by a long shot, so, although there were some small differences by groups, it was clear that for all groups, the issue was the sodium added in processing.

Dr. Carolyn Lam: And for both Lisa and for Wendy, do you think these results are generalizable even beyond the US?

Dr. Wendy Post: I'd imagine that there would be quite a lot of variability, based on the habits of the various populations. So, here we're talking about eating outside the home, or food that's processed outside of the home, so there may be countries where most people are producing their own food and not necessarily buying processed foods or eating in restaurants, and then this would definitely be less applicable. And, of course, there are differences in foods that we eat based on our different ethnic groups.

Dr. Lisa Harnack: No, I would agree with what's just said. It really could be variable, but it does seem that a lot of countries are concerned about processed foods. Some countries implemented mandatory limits on the sodium in the foods in their food supply, so that would indicate to me that they know there's ... for some countries, there's serious concern about this source of sodium.

Dr. Carolyn Lam: Yeah, and I think this is really a wake-up message for us to examine where these sources of sodium ... I mean, even that simple message that it could be coming from bread, from drinking water, I think that would be surprising to a lot of us, even those of us practicing in medicine. Wendy, finally, you thought this was important enough to invite an editorial. I'd really like your thoughts there.

Dr. Wendy Post: You'll be able to read the editorial when it comes out in print, but the editorial also congratulates the authors on a really important paper, and the important public health messages, and, especially, compliments the authors on having a diverse group of participants, including ethnic minorities and men and women, and different geographic locations, so overall, it's a very important paper that I'm sure will have an important impact on the public health of our country and others.

Dr. Carolyn Lam: Listeners, you heard it right here. Remember, you're listening to Circulation on the Run. Please share this episode, and tune again next week!

Circulation May 2, 2017 Issue

1 maj 2017 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Doctor Carolyn Lam, associate editor for the National Heart Center and Duke National University of Singapore. Our feature paper today presents the first information on the impact of cardiovascular health in middle age and the burden of mobility in older age. This exciting data is from the Chicago Heart Association study. First, let me give you your summary of this week's journal.

The first study tells us that patients with long QT syndrome type II are at increased risk of hypoglycemia. First author, Doctor Hilton Cavallius, co-corresponding authors Doctor Tarakov and Hanson from University of Copenhagen, Denmark, noticed that loss of function mutations in HERG, which encodes the voltage gate at potassium channel 11.1, causes long QT syndrome II, but that the specific voltage gate at potassium channels are also present in pancreatic alpha and beta cells and intestinal L and K cells, which secrete glucagon, insulin, and the incretins, glucagon-like peptide one or GLP1, and glucose-dependent insulinotropic polypeptide, or GIP.

All these hormones are crucial for glucose regulation. The authors therefore hypothesize that patients with long QT syndrome II may have increased incretin and beta cell, but decreased alpha cell function and thus, lower glucose levels. To test this hypothesis, they measured secretion of these hormones and cardiac repolarization in response to a six-hour, 75 gram oral glucose tolerance test in 11 patients with long QT syndrome II with functional mutations in HERG with 22 matched healthy participants.

They found that following glucose ingestion, patients with long QT syndrome II displayed exaggerated incretin and endocrine pancreatic function with more than 50% increased levelsq of circulating insulin, GLP1 , and GIP and defective glucagon secretion, causing low plasma glucose levels and thus, increased risk of symptomatic reactive hypoglycemia following the glucose load.

Furthermore, in rats, pharmacological blockade of these voltage gate at potassium channel 11.1 with [inaudible 00:02:43] had similar effects and inhibition of HERG in beta and L cells increased insulin and GLP1 secretion up to 50%. Finally, glucose ingestion aggravated cardiac repolarization disturbances in patients with long QT syndrome II with a 122% greater increase in QT interval in these patients compared to controls. The take home message is that clinicians should be more aware of the risk of hypoglycemia with glucose ingestion in patients with long QT II syndrome and also recognize that this reactive hypoglycemia can further increase the risk of malignant arrhythmia in these patients.

The next paper is the first study to describe the risk of myocardial infarction after discontinuation of thienopyridine therapy in the DAPT study, or dual antiplatelet therapy study. As a reminder, in this trial, after PCI and 12 months of clopidogrel or prasugrel plus aspirin, eligible patients remained on aspirin and were randomized to continue thienopyridine versus placebo for 18 months. At 30 months, patients stopped the study drug and were observed for three months. In the current study by first author Doctor Schmidt, corresponding author Doctor Mauri, and colleagues from Brigham and Women's Hospital in Boston, Massachusetts. The authors looked at cumulative incidents of myocardial infarction assessed over three months after randomization and three months after study drug discontinuation. They found that discontinuing thienopyridine after either 12 or 30 months was associated with an early increase in myocardial infarction risk, mainly unrelated though to stent thrombosis. The magnitude of risk was highest in the early time frame and lower in patients not treated with the [inaudible 00:04:47] eluting stents.

The authors further compared pateints with DAPT scores above or below 2, and showed that both groups had lower rates of myocardial infarction with continued thienopyridine . Thus, while higher DAPT scores identify patients with a greater absolute ischemic benefit relative to bleeding with continued thienopyridine therapy, discontinuation at 12 months increases the myocardial infarction hazard regardless of DAPT score group.

The next paper describes the impact of depression treatment on one year mortality following acute myocardial infarction. Doctor [inaudible 00:05:28] and colleagues from the University of Missouri School of Medicine in Kansas City looked at the TRIUMPH study, which is an observational multicenter cohort study that enrolled more than 4000 patients with acute myocardial infarction between 2005 and 2008 from 24 US hospitals.

Patients were administered the patient health questionnaire 9 during the index myocardial infarction admission and depression was defined by a score of 10 or above. This was categorized as treated if there was a documentation of a discharged diagnosis, medication prescribed for depression, or referral for counseling, and is untreated if none of these three criteria were documented. Overall, 18.7% of patients met criteria for depression and 30.4% were treated. Compared without depression, patients with treated depression had one year mortality rates that were not different. However, patients with untreated depression had a higher one year mortality when compared to patients without depression. In summary, this study really shows that the association between depression following myocardial infarction and increased mortality differs by depression treatment status at the time of the index myocardial infarction. Patients with untreated depression have a 70 to 90% higher risk of dying at one year after the myocardial infarction than patients without depression or patients with treated depression. These findings should therefore encourage further research to examine the impact of depression recognition and treatment at the time of an acute myocardial infarction.

The final study provides insight into the paradox that folate deficiency is an independent risk factor for congenital heart disease, yet the maternal plasma folate level is paradoxically not a good diagnostic marker of this risk. In the current study by first author Doctor Wang, co corresponding authors Doctors Chow and Wang, from Fudan University, Shanghai, China. The authors examined six folate related polymorphisms in three independent case control groups comprising 1489 patients with congenital heart disease and 1745 healthy individuals from the Han Chinese population. They found that a specific fidgetin intronic 4 variant was associated with decreased circulating folate levels and increased protection against congenital heart disease. They further showed that increased fidgetin expression inhibited proteasomal degradation of reduced folate carrier 1 and dihydrofolate reductase, thus facilitating [inaudible 00:08:29] uptake and metabolism of folate. Their results therefore demonstrated that folate utilization, rather than the circulating folate levels, determined the preventive effects of folate against congenital heart disease. These findings provide new insights into the relationship of circulating folate levels with congenital heart disease and potentially other folate associated diseases.

Well, that wraps it up for your summaries. Now, for our feature discussion.

Today's feature paper really represents the first data we have that tells us what our cardiovascular health in middle age is doing to us in older age, in terms of both morbidity and longevity. To discuss this paper today, I'm so happy to have the first and corresponding author, Doctor Norrina Allen from Northwestern University in Chicago and Doctor Jarett Berry, associate editor from UT Southwestern. Welcome, both.

Dr Norrina Allen: Thank you very much.

Dr Jarett Berry: Thanks, Carolyn.

Dr Carolyn Lam: Norrina, could I start with you? This represents the 40 year follow up of the Chicago Heart Association detection project and industry. Could you maybe start by telling us a little bit about the Chicago Heart Association study?

Dr Norrina Allen: The Chicago Heart Association study was a large study that recruited almost 40,000 individuals who were employed in Chicago. They did a baseline exam between 1967 and 1973. After that baseline exam, we followed those individuals for over 40 years using their Medicare records, so we've been able to monitor their healthcare utilization and the incidence of disease across their lifetime up through 2010.

Dr Carolyn Lam: Then you measured their cardiovascular health by specific measurements, right? Could you tell us how that was defined and then also how was morbidity burden defined?

Dr Norrina Allen: Of course. We really think the overall burden of cardiovascular health tells us something more than looking at individual risk factors, so we classified each of the CHA participants into one of four groups, and each of those groups was defined by the level of main cardiovascular risk factors, including blood pressure, BMI, diabetes, smoking, and cholesterol level. We identified people who had favorable levels of all of those risk factors, individuals who had one elevated but not clinically of those high risk factors, individuals who had one high level, or individuals who had two or more high levels. That was based on their baseline exam. Overall we found that about 6% of the CHA participants had favorable levels of all of the risk factors at baseline, 19% had one or more that was elevated, 40% had one high, and 35% had two or more high risk factors, and again this was at the baseline exam when they were young to middle aged.

We then followed them, as I mentioned, using Medicare data and we identified the burden of whole morbidity based on the ICD9 codes in their Medicare record, and we identified the level of morbidity for each year of age, from entry into Medicare, [inaudible 00:11:54] all the way to their death.

Dr Carolyn Lam: And now, drum roll, your findings, they were pretty stunning.

Dr Norrina Allen: Yeah. As you mentioned when you introduced the study, this study is really the first to look at the whole of an individual's later life, meaning not just looking at the incidence of disease or longevity but taking those both into account. What we were particularly interested in was looking at the cumulative burden of morbidity in older age and the relative proportion of life that people live with cardiovascular or all cause morbidity. What we found was that individuals, who at baseline in young and middle age and favorable levels of all major cardiovascular risk factors, lived longer by almost four years but they also delayed the onset of all cause and cardiovascular morbidity by 4 and a half and almost 7 years respectively. What that means is that the proportion of their life that they live with morbidity was much shorter, they lived longer and healthier as compared to individuals who had one or two more high risk factors.

Dr Carolyn Lam: What an important public health message. Jarett, this concept of morbidity compression, tell us your thoughts.

Dr Jarett Berry: This is a really important paper. We've known for a long time, of course, that low risk individuals live longer, but the question of whether or not low risk individuals lived better throughout their life has been incompletely understood. The problem is that because low risk individuals live longer, the question that many have asked is that when we live longer is there a so-called expansion of misery, which some have talked about? That we live longer, but we have the same burden of disease or is that extended time horizon with the extended life span ... is the burden of morbidity compressed into a shorter period of time? In order to do that you need a couple things. You need a very large study that's followed for a very long time. Importantly, not just follow them for a long period of time, but follow enough individuals all the way until death so you know not just the first part of the story but we know the end of the story.

It really wasn't until [inaudible 00:15:18] paper, with not only the very large sample side but the very long term follow up until death, that we've been able to understand that actually low risk status in middle age does actually compress morbidity. This question of morbidity compression is not just an academic question but it actually has potential implications for cost savings and how we think about health care costs in our health care system. It'd be nice to hear [inaudible 00:15:18] thoughts about that as well, what else she found in regard to the Medicare costs.

Dr Norrina Allen: Right. As Jarett mentioned, not only from an individual perspective but at a societal level, what we're interested in is whether being in favorable cardiovascular health actually lowers healthcare costs at the same time as increasing an individual's health and longevity. What we found was that not only do the individuals in favorable health live longer and healthier, but they also have lower cumulative and annual healthcare costs, meaning that from a societal standpoint the compression of morbidity results in healthcare savings. We really think this is a strong method that provides support for earlier prevention efforts not only to improve an individual's quality of life but to reduce the healthcare costs associated with later life morbidity.

Dr Carolyn Lam: Indeed, what an important message to live longer and better and to save societal cost we need to get healthier cardiovascularly in middle age. Now, what really scares me though, is the statistic you told us a bit earlier. Only 6% of the individuals that you studied had a favorable level of all factors. What do you think this implies? What do you think needs to be done?

Dr Norrina Allen: Unfortunately, at this point, it's relatively rare in our population to reach middle age, 40 to 50 years of age, with favorable levels of all major cardiovascular risk factors. I think ... my research is really focused on trying to identify ways and times to intervene, to really help promote cardiovascular health early in life. I really think that we need to work hard to prevent the occurrence of these risk factors and the elevation of these risk factors much earlier in life. That means, even before the age of 40 and much earlier than that, we really need to be focusing on preserving cardiovascular health so that by the time individuals reach later life they can have a good quality of life and a longer, healthier life.

Dr Jarett Berry: I think the issue of the fact that low risk status is rare is that's a challenge that we continue to wrestle with as a society and as investagators interested in this are and how to improve that. When you look at your data, Norrina, I guess one silver lining here is we do see that ... when you look across the strata of risk groups ... it wasn't just the low risk individuals that seemed to benefit. It seemed that there was a little bit of a dose response. The goal obviously is to promote low risk status, but if we could limit the prevalence of those at the highest risk and shift them down a little bit, that could also have potential implications. I'd be interested to hear your thoughts about that.

Dr Norrina Allen: I think that's very accurate. There really is kind of a dose response level, so that every risk factor that's favorable adds a benefit and the more we can do to reduce the high risk factors over time, the better the long term outcomes are likely to be. I do really think prevention doesn't only have to exist before the development of the risk factors, but also there's a benefit to reducing risk factors that may have already developed or are elevated, and to try and reduce their level. I would say that I think that's an interesting next step that we really want to look at and try and think about how best to intervene even at middle age and help improve outcomes much later in life.

Dr Carolyn Lam: Thank you, listeners, for joining us today. I'm sure you agree, it's such an important message. Share it with your friends and tune in next week.

Circulation April 25, 2017 Issue

24 april 2017 | 19 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week really adds to our understanding of the cause/effect relationship between obesity and heart failure, this time by comparing the effects of gastric bypass surgery versus intensive lifetime treatment on heart failure risk. Before we talk about that, though, let me give you your summary of this week's journal.

The first paper brings us one step closer to understanding cardiac recovery in response to mechanical unloading by left ventricular assist devices and it does this by showing that this process may involve the transverse tubular system, which is a micro structural feature of ventricular cardiomyocytes important for contractility and consisting of tubular invaginations of the sarcolemma predominantly located at the Z-lines of sarcomeres. This transverse tubular system is crucial for efficient excitation contraction coupling by bringing L-type calcium channels in the sarcolemma in proximity to clusters of ryanodine receptors in the sarcoplasmic reticulum.

In the current study by co-corresponding authors, Dr. Seidel and Drakos and Sachse from University of Utah, the authors studied left ventricular biopsies obtained from five donors and 26 patients with chronic heart failure undergoing implantation of left ventricular assist devices or LVAD's. They used three dimensional confocal microscopy and computational image analysis to assess the transverse tubular system's structure, density, and distance of ryanodine receptor clusters to the sarcolemma.

They found that the majority of heart failure myocytes showed remarkable transverse tubular system remodeling, particular sheet-like invaginations of the sarcolemma, which is previously unknown phenotype. This sheet-like transverse tubular system remodeling led to increased distances of ryanodine receptors to the sarcolemma causing heterogeneous intracellular calcium release and consequently inefficient excitation contraction coupling. High degrees of transverse tubular remodeling at the time of LVAD implantation was associated with absence of functional cardiac recovery during mechanical unloading, whereas preserved transverse tubular systems structure was associated with recovery.

In summary, cardiac recovery during unloading may require an intact transverse tubular system at the time of LVAD implantation. And characterizing this system may help to identify patients with a high probability of functional cardiac recovery in response to mechanical unloading.

There have been a proliferation of algorithms based in high sensitivity assays for cardiac troponins for the diagnosis or exclusion of myocardial infarction. All these algorithms have the potential to overwhelm clinicians with options. Well, there is help in this week's issue with two observational studies directly comparing the diagnostic performances of multiple high-sensitivity troponin testing strategies.

Now, before I describe these two studies in detail, here are some important reminders. Remember that as of early 2017, although high-sensitivity troponin assays are routinely used in many regions of the world, they are not available in the United States. Thus, the specific algorithms discussed here are not applicable with the contemporary sensitive assays that are presently used in the United States. Next, let's remind ourselves that both the United States and European professional guidelines recommend serial measurement of cardiac troponins at presentation or zero hours and three to six hours later with additional testing beyond six hours in patients who have electrocardiographic changes, or intermediate or high clinical risk features.

The 2015 European Society of Cardiology Guidelines also included an alternative strategy reducing the sampling interval to one hour when using a high sensitivity troponin assay with a validated zero and one hour algorithm based on the 99 percentile cutoff of these high sensitivity troponin assays. Now to the two studies in the current issue, which tie together the expanding evidence with direct comparisons of several of the strategies using the same high sensitivity cardiac troponin assay by Abbott.

Dr. Chapman and colleagues from the royal infirmary of Edinburgh, United Kingdom, compared the standard ECS zero and three hour strategy based on the 99th percentile upper reference limit at both time points with the high sensitivity troponin in the evaluation of patients with acute coronary syndrome, or high stakes algorithm, and that would be a zero, three, and six hour algorithm that incorporates a zero hour criteria and at a very low cutoff of five nanogram per liter and a three hour criterion that directs patients with either a rising concentration or with an absolute concentration above the upper reference limit to additional testing.

Among 1,218 patients with suspected myocardial infarction, the high stakes algorithm delivered both a higher proportion ruled out for myocardial infarction at zero hours and a higher negative predictive value of 99.5% versus 97.9%. The ESC pathway missed 18 index and two recurrent myocardial infarction events, whereas the high stakes pathway missed two index and two recurrent myocardial infarction events. These findings demonstrate the value of adding a very low zero hour cutoff to facilitate earlier rule out as well as the value of a delta criterion to exclude increasing values among patients that progress to three hour sampling.

In the next study, first author, Dr. Boeddinghaus, corresponding author Dr. Mueller and colleagues from University Hospital of Basel, Switzerland compared the ESC alternative zero and one hour strategy with three other approaches using either a single cutoff at zero hours, or the one hour strategy. Among 2,828 patients with symptoms suspicious for myocardial infarction and no ST elevation, each of these four approaches delivered a negative predicted value above 99% comparing favorably to the ESC zero and three hour algorithm that had a negative predictive value of 98.4%.

Now, although each of the strategies performed similarly among patients presenting more than two hours after symptom onset, among the early presenters, the negative predictive value and sensitivity were diminished using the single zero hour cutoff of five nanograms per liter. The authors concluded that the single cutoff strategy, the one hour algorithm, and the zero and one hour algorithm, allow the triage towards rule out of myocardial infarction in more than half of consecutive patients presenting with suspected MI to the emergency department. However, the single cutoff strategy should not be used in patients presenting early after chest pain onset.

These papers are discussed in an excellent editorial, which also puts everything in perspective by Dr. David Morrow from Brigham and Women’s Hospital in Boston, Massachusetts. I particularity want to refer all of you to the figure that's found in its editorial which really helps you to understand the different strategies involved.

The final study tells us about potential death averted and serious adverse events occurred from the adoption of the SPRINT intensive blood pressure regimen in the United States. As a reminder, the systolic blood pressure intervention trial, or SPRINT demonstrated a 27% reduction in all caused mortality with a systolic blood pressure goal of less than 120 versus less than 140 mm Hg among American adults at high cardiovascular risk, but without diabetes, stroke, or heart failure.

In the current study, Dr. Bress and colleagues from the University of Utah School of Medicine applied the SPRINT eligibility criteria to the 1999 to 2006 National Health and Nutrition Examination Survey or NHANES and linked this with the national death index through December, 2011. They found that if fully implemented in eligible US adults, intensive blood pressure treatment was projected to prevent about 107,500 deaths and 46,100 of heart failure per year. But, you also give rise to about 56,100 episodes of hypertension. 34,400 episodes of syncope, 43,400 serious electrolyte disorders, and 88,700 of acute kidney injury per year compared to standard blood pressure treatment. Thus, they take home message is careful patients selection and implementation are important because intensive treatment while preventing deaths is associated with increased risks of hypertension, syncope, electrolyte abnormalities and acute kidney injury.

Well, that brings us to a close for the summaries, now for our feature discussion.

We are discussing obesity and heart failure. Now, we've heard of the obesity paradox, but we also know that obesity may be a risk factor for heart failure and the study today really puts perspective on this and is really one of the largest most convincing studies I've read on this topic. I am so pleased to have the person corresponding author, Dr. Johan Sundstrom from Uppsala University Hospital in Sweden. Welcome, Johan.

Dr Johan Sundstrom: Thank you, lovely to talk to you.

Dr Carolyn Lam: And especially pleased to have back on the show again, Dr. Torbjorn Omland from University of Oslo, Norway. Hi, welcome back, Torbjorn.

Dr Torbjorn Omland: Thank you very much. It's a great pleasure being here.

Dr Carolyn Lam: Johan, you know what? Could you just start by telling us about your study?

Dr Johan Sundstrom: So, we were fortunate enough to have two great databases here in Sweden. One was the obesity surgery registry called SOREG in which all people have a gastric bypass surgery, for people who are registered. And we also have a company called Itrim who provide intensive lifestyle program, which takes people down on average about 11 kilos, and they have a very structured database as well. So, we were able to pull this data in order to try and understand the effects of intentional weight loss to two different levels of weight loss, what that does to the heart failure incidence.

This is a bit of a comparative effectiveness study, so it's of course necessary to make the examples as similar as possible to apply exclusion criteria. We took away everyone who had a body mass index of less than 30 and above 50 and then we applied propensity scores to those two data sets and we had to trim the data sets a little bit further in order to get so called region of common support, which means that we were left with two samples who could have either had surgery or a lifestyle intervention. And then we applied an inverse probability weighting scheme to that. It's statistically complicated but what that does, is it's a matching, but it's not as complicated as matching. With matching, you just give people a weight of 1 or 0, but this gives people other weights as well.

So, we end up with characteristics that were very similar at baseline. So, we tried to mimic as close as possible what a randomized clinical trial looks like, but of course we did it posthoc and it’s observational. So, we get our table one, sort of, in this paper that shows very similar characteristics of the two groups. So, what we did then is we noted what happened to the people in these two groups in terms of heart failure incidence and we followed them in our national inpatient registry. So, all the Swedish citizens get a personal identification number so we can use that to follow people in our patient registry. So, we know exactly what drugs people will collect from pharmacies, and we know what they died from, and we know all of their hospitalizations. And we previously validated their heart failure diagnosis in the Swedish Inpatient Registry and we noted that you were in a pretty good position if you were hospitalized with heart failure as the main cause of hospitalization and we noted that people who had agreed to do surgery, had about half the incidence of heart failure than people who were in the intensive lifestyle program.

We also noted, if you looked at the achieved weight loss one year after baseline, we noted that a ten kilo weight loss after one year was related to about a 23% lower risk of heart failure. So we noted a litany of association between the achieved weight loss and heart failure incidence. It should said, though, that heart failure in this age group, they are only 41 on average, 41 years old. Heart failure's still very unusual at this age, even in many of these people. We only had 73 cases of heart failure. So, the exact numbers need to be taken with a pinch of salt and have wide confidence intervals around them.

Dr Carolyn Lam: Johan, this is exactly why I'm so impressed with your data. First you showed a dose response relationship between the weight loss and risk of heart failure. You also show that it's not an event that occurs very often and so, it would be very difficult to imagine doing a randomized controlled trial for example in this setting and having to wait very long for these events. So, it really goes to show your observational data are extremely important. And I really like the way you took the pains to describe how you tried to overcome the differences that exist between the groups and try to make it as much resembling a randomized trial setting as you could. So, maybe I could turn it over to you, Torbjorn. Could you tell us what you think the implications of this paper are?

Dr Torbjorn Omland: First, I will say that that this paper has all the characteristics of a very high quality study. It's a very timely topic that interests a lot of people. The paper's very well written. It's a large sample size as you said and it was very clinically meaningful difference between the groups and that translated into very clear and robust answers. So, I think that this has every mark of high quality paper.

But, of course, the very important question is how will this translate into actions? How can we use this information to prevent problems? We know heart failure is a very prevalent disease, especially in the elderly and although the incidence was lower here, I think my question for Johan at least is what would be the next step? What changes can we implement to reduce heart failure among the obese?

Dr Johan Sundstrom: That's a great question. I think in this study puts a little piece of the puzzle on the table and that's trying to add a little more evidence towards a causal association between obesity and heart failure. I'm not sure about what we can offer these patients and what will be the translation to lower heart failure incidence in the long run. Of course, we need to follow this sample for longer to have more heart failure cases, because I don't think we've seen the full impact of weight loss in these two samples. We might need to follow them into older age where they would have a higher heart failure incidence.

But, how to tackle obesity, I think we'll need accommodate population strategies and high risk strategies. I think if the general consensus in the scientific community after reading this and other important papers, is that there's causal link between obesity and heart failure, then we might need to understand that people who are obese and who have shortness of breath and perhaps swelling or what not, may not just be having low fitness, they might actually behaving signs of heart failure.

So, I think as a sort of increased diligence on heart failure, these people might be one thing. But, we didn't really study that. So, I wouldn't draw conclusion. But, otherwise I think it's more of a causal inference piece of the puzzle that we've laid rather than a clinical care piece of the puzzle.

Dr Torbjorn Omland: No, I agree, and here you won't to make any recommendations in regards to what interventions you should recommend particularly based on this particular study.

Dr Johan Sundstrom: No, because I think there are so many other things that need to be taken into account when it comes to treatment of obesity. Heart failure is actually one of the uncommon outcomes in this age group. We're looking at other outcomes after they present. Myocardial infarction, ventral fibrillation and mortality are actually much more common. So, I think a lot of other data should go into decisions on how to treat patients, not just for heart failure, which is still fairly uncommon at this age.

Dr Carolyn Lam: Going back to the other question that Torbjorn asked, do you think that this question still needs to be answered in any way? You've got the Mendelian randomization data. Now, you've got your data. Do you think it's still a question of whether obesity is a risk factor for heart failure? And just in case there's any confusion out there, would you put that together with the so called obesity paradox in heart failure?

Dr Johan Sundstrom: To answer the first one, I think we're not going to have any randomized evidence. Treatment of heart failure with intensive programs and prevention of heart failure ... It needs for huge samples that I don't think we're going to have any much better observational evidence anytime soon either. So, we can probably set that question aside a little bit. But, when it comes to the obesity paradox, first of all that's not what we studied here. We didn't have anyone with heart failure in this sample. We included all those people. We can only speculate. I'm a clinical epidemiologist myself, but I'm envious of people who have animal and other models because I think there's a lot more work to do in terms of ppars and and lipid metabolism in obesity and in heart failure. So, I think there'll be more interesting experimental research to come that can help us answer the obesity paradox.

Dr Carolyn Lam: Please don't forget to tell your friends about this podcast, and tune in again next week.

Circulation April 18, 2017 Issue

17 april 2017 | 18 min

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Our feature paper this week discusses the very important patient group with myocardial infarction and non-obstructive coronary artery disease, a paper that we will be digging deep into right after these summaries.

The first paper identifies a novel therapeutic target in pulmonary arterial hypertension, and that is nicotinamide phosphoribosyltransferase, a cytozyme which regulates intracellular NAD levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis.

This is a paper from first author Dr. Chen and co-corresponding authors Dr. Machado from University of Illinois Chicago and Dr. Garcia from the University of Arizona. The authors found that plasma and mRNA and protein levels of nicotinamide phosphoribosyltransferase were all increased in the lungs and the isolated pulmonary arterial endothelial cells from patients with pulmonary arterial hypertension.

They were also increased in the lungs of rodent models of pulmonary hypertension. Nicotinamide phosphoribosyltransferase deficient mice were protected from hypoxia mediated pulmonary hypertension; whereas, enhanced activity promoted human arterial smooth muscle cell proliferation via paracrine effect and inhibition of activity attenuated pulmonary hypertension in rats.

This paper, therefore, provides evidence that nicotinamide phosphoribosyltransferase plays a role in pulmonary vascular remodeling and its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.

The next study suggests that high sensitivity cardiac troponin T may be an early biochemical signature for clinical and subclinical heart failure. In this study from first author Dr. Seliger, corresponding author Dr. deFilippi, and colleagues from Inova Heart and Vascular Institute, the authors measured high sensitivity cardiac troponin T at baseline among almost five thousand participants in the multi-ethnic study of atherosclerosis MESA cohort, who were initially free of overt cardiovascular disease.

Cardiac magnetic resonance imaging was performed at baseline and repeated 10 years later among 2,831 participants who remain free of interim cardiovascular disease events, among whom 1,723 also received gadolinium enhanced cardiac magnetic resonance for characterization of replacement fibrosis by late gadolinium enhancement. Results showed that a mild elevation of high sensitivity cardiac troponin T identified subjects at highest risk for an increase in left ventricular mass and end diastolic volume over the next 10 years.

Higher levels also associated with an increased incidence of replacement fibrosis, but with no differentiation between ischemic or non-ischemic fibrosis patterns. For the more high levels remained an independent predictor for incident heart failure, coronary heart disease events and cardiovascular events, independent of underlying left ventricular hypertrophy or ejection faction.

The implications are that myocyte injury, measured with a highly sensitive cardiac specific troponin assay may ultimately be an important early signal used to target therapy to prevent or delay left ventricular remodeling and progression to heart failure.

Does maintenance of cardiovascular risk factors at target eliminate the excess risk of mortality in cardiovascular diseases associated with type 1 diabetes? Well, this question was addressed in the next paper by Dr. Rawshani and colleagues of the Swedish National Diabetes Register in Gothenburg Sweden. The authors compared more than 33,300 patients with type 1 diabetes to more than 166,500 match controls without diabetes from the Swedish National Diabetes Register. They found that patients with type 1 diabetes, with five selected cardiovascular risk factors at target, demonstrated a non-significant access risk of death compared to controls.

These five risk factors included glycated hemoglobin, blood pressure, albuminuria, smoking, and LDL cholesterol. Nonetheless, despite having all risk factors at target, persons with type 1 diabetes still had 82% to 97% elevated risk of myocardial infarction and heart failure respectively. For every incremental risk factor not at target, the excess risk of death in cardiovascular outcomes increased in a graded fashion.

In conclusion, there was a steep graded association between decreasing number of cardiovascular risk factors at target and major adverse cardiovascular outcomes with patients with type 1 diabetes. While achievement of current evidence based target levels of five cardiovascular risk factors markedly reduced or even potentially eliminated the excess mortality risk, these patients remained at higher risk of myocardial infarction and heart failure compared with controls.

The final paper suggests that hemodynamic guided heart failure management may be beneficial in general clinical practice and not just in the context of controlled trials. In this study by Dr. Heywood and colleagues from Scripps Clinic Torrey Pines in La Jolla, California, the authors examined the first 2,000 patients implanted with the novel Pulmonary Artery Pressure Sensor, CardioMEMS, in the general cardiology practice setting.

They found that patients uploaded information an average of every 1.2 days, and that pressures were significantly reduced by remote monitoring using the Pulmonary Artery Sensor where patients with the highest mean pulmonary artery pressures had the highest reduction in pressures. Furthermore, they found that these general use patients experienced a greater reduction in pulmonary artery pressure over time compared to those in the pivotal CHAMPION clinical trial.

The results from this large observational study, therefore, demonstrates hemodynamic heart failure management may be effective in U.S. clinical practice with high rates of patient adherence and effective pressure management.

This paper is accompanied by an excellent editorial by Drs. Gorter, Rienstra, and van Veldhuisen from University Medical Center, Groningen, Netherlands, which really places this paper in the clinical context of heart failure and particularly patients with heart failure and preserved ejection faction

Well that wraps it up for your summaries. Now for our feature discussion.

We're discussing a hugely important emerging issue today. And it's MINOCA, a myocardial infarction with non-obstructive coronary arteries, and a very important paper in today's issue, which really provides the first insight into potential long-term medical therapy in the management of MINOCA.

However, now this issue of MINOCA is quite new and I'm sure new to many of those listening on the line. So, I am with the first and corresponding author of the paper, Dr. Bertil Lindahl from Uppsala Clinical Research Center in Sweden. Welcome.

Dr Bertil Lindahl: Thank You.

Dr Carolyn Lam: And also the associate editor who managed this paper, Dr. Gabriel Steg from Hospital Bichat in Paris, France. Welcome back.

Dr Gabriel Steg: Hello.

Dr Carolyn Lam: Now, we need to start by first understanding what we're talking about. MINOCA ... give us a good definition of what you mean by MINOCA. And does it include the non-coronary causes of AMI, or non-obstructive disease? Does it include myocarditis? Does it include the non-cardiac causes, like pulmonary embolism?

Dr Bertil Lindahl: Our definition of MINOCA used in this paper is that you received the ICD code for acute myocardial infarction. If you have a clinically clear case of myocarditis or Takotsubo and were not included in this analysis. But we know if we look into patients that have got the diagnosis of myocardial infarction ... if you performed, for instance, MRI afterward, you can see that a portion of the patients experience ... between 10 and 30 percent of the MINOCA patients, have evidence of myocarditis, although it was not clinically expected.

So this is a heterogeneous population ... initial diagnosis was myocardial infarction.

Dr Carolyn Lam: Thank you for clarifying what you used in your study. Gabriel, could I just, you know, bring you in on this because you invited an excellent editorial that accompanies this paper. And, basically, it helps to get us past all this terminology you know, MINOCA now. Could you maybe just clarify the overall perspective of what it means?

Dr Gabriel Steg: Yeah. This area is fairly new and we still have a major nomenclature problem. Clearly it's been recognized for many years that patients who have a clinical syndrome of myocardial infarction do not necessarily have obstructive coronary artery disease. At least severe obstructive coronary artery disease. Many patients have mild lesions and some patients apparently have no lesion at all.

Now, over the last few years we've understood that this is really a syndrome. And that under that big umbrella, there are patients who have non-cardiac causes of troponin elevation and chest pain. These should be excluded from MINOCA. If you have pulmonary embolism, this is not MINOCA. This is pulmonary embolism.

The second aspect is there are more subtle distinctions to be made with fairly new entities such as Takotsubo. When this study was started, Takotsubo was an emerging disease concept. And so the authors were not able to properly rule out the Takotsubos and probably a few myocarditis from their data set. We now have learned over the past few years that MRI is an excellent tool to screen MINOCA patients and flush out patients who have myocarditis or Takotsubo, which are not rare. Actually it's a substantial portion of that entity.

And then we're left with what I call the true MINOCA. Now what's fascinating in the study here is really that ... first of all I want to say this is another great study from our Swedish colleagues leveraging their data collection tools, which are remarkable. Really an example to the world.

The second thing is they have collected ten years of data on MINOCA. And they're able to tease out which are the agents that should be using secondary prevention in that population. Elegantly demonstrating with sensitivity analysis and positive and negative controls what are the agents associated with improved outcomes and what are the agents that apparently do not impact outcomes.

So even though at the time they were not able to rule out myocarditis and Takotsubo properly, still the sheer size of their study, long term follow up, and the careful statistical analysis that they've done are remarkable.

Dr Carolyn Lam: I couldn't agree more. And more so in an area that is really emerging in importance. And for which we don't have any prospective clinical trials. I'm correct in saying that, right ? So Bertil, this would be a great point for you to let us know what are the main findings from your study please.

Dr Bertil Lindahl: The main findings are that statins are associated with a beneficial effect on the cardiac event. And also, ACE inhibitors or ARBs , while we were not able to show statistically things you can affect with beta blockers and similarly not with dual anti-platelet treatment. So that's basically the main findings of the study.

Dr Carolyn Lam: May I ask how have these findings personally impacted your clinical practice or do you think the next steps are gaps that need to be addressed first?

Dr Bertil Lindahl: I think that's an ongoing discussion in Sweden now and in our hospital on how this should be applied to clinical practice. Nothing. It will have an effect that statins and ACE Inhibitors or ARBs will be used. I'm not sure whether we still can say that we should not use beta blockers or dual antiplatelet treatment. But I think also that we are now discussing we should do a randomized clinical trial to really tease out whether we should use beta blockers or not or also verifying the findings regarding ACE Inhibitors and ARBs.

So, I think there's always a discussion whether we can really use observation studies for treatment decision. But I think since we don't have any better trials so far I think that this is the best that we can get. So I think it will be used and applied in clinical practice.

Dr Carolyn Lam: Indeed. I really agree with what Gabriel said this is the best available evidence we have now. And my personal take home message was to pay more attention to the statins and the ACE Inhibitors. So congratulations on this great study.

Gabriel, what do you think? What are next steps? I mean, MINOCA's not even in the guidelines now. Our guidelines talk about type 1, type 2, AMI ...how does it all fit in?

Dr Gabriel Steg: Well, we've seen a sea change in the concepts regarding myocardial infarction over the last fifteen years with the advent of troponin and the ability to diagnose new patients that previously we wouldn't even label as an MI.

The second aspect is we've recognized over the years that there are some genuine MI's that don't have severe obstructive coronary artery disease. Now what's interesting is that some of them may have apparently mild obstructive disease. Which presumably is related to coronary dissections, embolism, plaque rupture with thrombosis that disappeared in the interim. And some of them may have actually "clean" coronary arteries and have myocardial infarction related to other mechanisms such as micro vascular mechanisms. What's interesting, and I'd like to ask the opinion of Dr. Lindahl is, these three types of diseases; mildly obstructive disease, coronary dissection, and microvascular angina are all more frequent among women. And I wonder whether you have any insights regarding gender differences in your registry.

Dr Bertil Lindahl: In this study, in the sub-group analysis we saw no significant interaction between gender and the effects. But unfortunately we don't have the registry information between , let's say completely "normal coronary arteries" versus "mildly obstructed coronary arteries". And that's a clear limitation of this study. It will be very interesting to see whether these effects are similar in these two sub-groups.

It seems from other studies that approximately fifty percent of the MINOCA patients that have normal coronary arteries and fifty percent that have mild aortic disease. So this is a limitation of this study and I think that's just something we have to look for in the future. And I hope that we will have in the registry onwards, data on whether this normal or mild coronary artery disease.

Dr Carolyn Lam: Really appreciate that and really appreciate the insights you gentlemen have shared. Any final words or concluding remarks, Gabriel?

Dr Gabriel Steg: Well, again congratulations on the great study. I would refer our readers to the excellent editorial of John Beltrame that accompanies this paper, which reviews the concepts of MINOCA, the nomenclature, and some of the remaining and lingering questions that plague the field. And delineates way forward for studies.

I think it's a fascinating area. I'm sure we're going to hear a lot more, both from the Swedish Heart Registry as well as other data sources. I think we all need to stay tuned to this important area. The prognosis of these patients is not so good, so we need to pay attention to that entity.

Dr Carolyn Lam: Wonderfully put. Well, thank you listeners for joining us this week. Please share this episode with all of your friends. So thank you and join us next week.

Circulation April 11, 2017 Issue

10 april 2017 | 21 min

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Today's issue features two exciting papers regarding heart failure in patients with breast cancer. We will be discussing this right after these summaries.

Are we any closer to improving survival in Eisenmenger syndrome? Well, today's first original paper looks at contemporary trends and presents a multivariable mortality risk stratification model based on five simple noninvasive predictors of death in this population. Dr. Kempny and colleagues from Royal Brompton Hospital in London in the United Kingdom preform a large multicenter study in 1098 patients with Eisenmenger syndrome followed up between years 2000 and 2015.

At the end of the study almost two-thirds of patients were on advance therapy for pulmonary arterial hypertension, while only six patients underwent lung or heart and lung transplantation. The study showed that despite advances in management, there was significant mortality amongst contemporary adults with Eisenmenger syndrome and 25.3% of patients died over a median follow up period of 3.1 years. Mortality was higher in older patients, those with a pre-tricuspid shunt, lower oxygen saturation, absence of sinus rhythm, or with a pericardial effusion.

This important study is accompanied by an editorial by Drs. Lange, from Texas Tech University Health Sciences Center El Paso and Dr. Brickner from UT Southwest Medical Center in Dallas, Texas. The editorialists call for a prospective randomized control trials of the effect of current, or future pulmonary vasoactive disease targeting therapies on mortality in Eisenmenger syndrome patients, and say it's time to direct our efforts from improving risk-stratification towards improving survival.

The next study provides experimental evidence of tolerogenic dendritic cell therapy as a novel anti-remodeling therapy in myocardial infarction. Tolerogenic dendritic cells are promising, potent, beneficial regulators of the post-infarct healing process via their control of T-regulatory cells and M1 M2 macrophages. Plus they have the advantage of the ease of administration and feasibility of a heart specific tolero-dendritic cell production.

In the current paper by co-first authors, Drs. Choo and Lee, and co-corresponding authors, Drs. Chang and Lim, from Catholic University Korea and Chai University in Korea, authors generated tolerogenic dendritic cells by treating bone marrow-derived dendritic cells with TNF-alpha and cardiac lysate from mice with myocardial infarction. They then injected myocardial infarction mice twice with tolerogenic dendritic cells within 24 hours and at 7 days after LAD ligation. In treated animals, in vivo cardiac magnetic resonance imaging and ex vivo histology confirm the beneficial effects on post-infarct LV remodeling. Furthermore, subcutaneously administered tolerogenic dendritic cells near the inguinal lymph node migrated to the regional lymph nodes and induced infarct tissue specific T-regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, all of which elicited an inflammatory to reparative macrophage shift. The altered immune environment in the infarcted heart resulted in better wound remodeling, preserved left ventricular systolic function, and an improved survival following myocardial infarction. Thus, this study shows that tolerogenic dendritic cell therapy in a preclinical model of myocardial infarction may be potentially translatable into an anti-remodeling therapy for ischemic repair.

The final paper reports results of cell therapy on exercise performance and limb perfusion in peripheral artery disease from the PACE trial, which is an NHLBI-sponsored randomized double-blind placebo-controlled phase two clinical trial, designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright cells in peripheral artery disease, and to explore associated claudication physiological mechanisms. In this paper from corresponding author Dr. Moye from UT School of Public Health in Houston, Texas and colleagues of the Cardiovascular Cell Therapy Research Network, a total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at nine sites to receive alcohol dehydrogenase bright cells or placebo. All patients underwent bone marrow aspiration and isolation of aldehyde dehydrogenase bright cells followed by 10 injections into the thigh and calf of the index leg. Results showed that there were no significant differences in the change over six months between study groups for the co-primary endpoint of peak walking time, collateral count, peak hyperemic popliteal flow, and capillary profusion measured by magnetic resonance imaging.

Additionally, there were no significant differences for the secondary endpoints including quality of life measures. There were no adverse safety outcomes. Interestingly, a post-hoc exploratory analysis suggested that aldehyde dehydrogenase bright cell administration might be associated with an increase in the number of collateral arteries in participants with completely occluded femoral arteries.

In summary, cell therapy did not improve peak walk time or magnetic resonance outcomes, and the changes in peak walk time were not associated with the anatomic or physiologic MRI endpoints. However, future peripheral artery disease cell therapy trial design may be informed by new anatomic and perfusion insights. These and other issues are discussed in an accompanying editorial by Drs. Breton-Romero and Hamburg from Boston University School of Medicine. Well, that wraps it up for our summaries, now for our feature discussion.

We are really in the grove here in Washington, D.C. and I am borrowing the words of my very special, star associate editor, guest, Dr. Gregory Hundley, and he's from Wakefield University School of Medicine. We're discussing two very important papers and they deal with the risk of heart failure following breast cancer. Why they're so important? Well, first of all, it's about time we looked at this problem in detail, and secondly, they actually represent papers in a new section of the journal called "Bridging Disciplines," and in this case cardio-oncology. Very, very important topics.

We're here with the corresponding authors of both papers, Bonnie Ky from University of Pennsylvania School of Medicine and Dr. Margaret Redfield from Mayo Clinic.

Dr Gregory Hundley: Thank you, Carolyn. I really appreciate that wonderful introduction and also the chance to talk with Bonnie about this exciting topic.

So, Bonnie, you've got a paper here, now, where you did a study in patients with breast cancer, and it sounds like you acquired echocardiograms over a period of time. Can you tell us a little bit about that?

Dr Bonnie Ky: Correct. So this is longitudinal prospective cohort study, it's an NIH-funded R01, whereby we are enrolling patients from the breast cancer clinic who are receiving doxorubicin or trastuzumab or a combination of the two therapies. And we're performing very careful cardiovascular phenotyping, from the time at which they initiate chemotherapy through their chemotherapy and then annually once a year we have them come back, for a total follow up time of 10 years.

We took a subcohort, 277 patients, and from their echocardiograms, we analyze them very carefully for various measures of left ventricular size, function, not only systolic function but also diastolic function. We also looked at measures of contractility such as strain in multiple dimensions, and then also measures of ventricular arterial coupling, as well as arterial loads, so how the ventricle interacts with the arterial system. And what we found was that over a 3.2 period time period, on population average, these modest declines in left ventricular ejection fraction, and even across all three treatment groups, and even at three years there were persistent LVF declines.

Dr Gregory Hundley: So, I understand, Bonnie, that you also collected some information as to whether or not these patients were experiencing symptoms associated with heart failure. How did the imaging markers relate to the symptomatology associated with heart failure?

Dr Bonnie Ky: What we found was that early changes in arterial stiffness or total arterial load, as well as early changes in EF were associated with worse heart failure symptoms at one year. A lot of our other analysis was focused on defining what echo parameters of remodeling, size, function are driving or associated most strongly with LVF decline, as well as LVF recovery.

Dr Gregory Hundley: And then at two years, what happened? Did the echo parameters, were they still associated with heart failure or was there a little discrepancy there?

Dr Bonnie Ky: Interestingly, at two years ... no, there was no significant association with changes in arterial load and heart failure symptoms at two years.

Dr Gregory Hundley: So there might be something transient that's occurring that is associated with heart failure early, and then the patients still had heart failure late, so maybe something else is operative. What do you think we need to do next? What's the next step in your research and then other investigators around the world; what do we need to do to design studies to look at these issues further?

Dr Bonnie Ky: Yeah. What does the field need, the field of cardio-oncology that's really growing and developing at rapid paces. Some of the major findings from the study was that changes in total arterial load were very strongly associated with both LVF decline and LVF recovery. So total arterial load is the measure of blood pressure or total arterial stiffness, it's derived from blood pressure. And to me, that begs the question, or begs the next step is that changes in blood pressure are associated with decline as well as recovery. I think, oh, as cardiologists we've also always recognized the importance of afterload reduction. And to me, this study suggests that we need a study, a randomized clinical trial, looking at blood pressure lowering in this population to help mitigate LVF declines.

Dr Carolyn Lam: I'd actually like to turn it back to you. You are world-renowned for your work in cardio-oncology. Where do you think this fits in, and where do you think we need to address most urgently?

Dr Gregory Hundley: I think where this fits in wonderfully is a lot of individuals around the world are collecting echocardiographic measures, and all different types. And what Bonnie has helped do is clarify what we would expect to see in this particular patient population. How those measures change over time and that feeds into another block of data, when the measurements head south, do we change therapy, do we add protective agents, and things of that nature. So I think Bonnie's work really contributes on that front. What she has also pointed out is that more research needs to be performed, not necessarily because the patients had heart failure symptomatology at two years, but not necessarily associated with the decline in EF; are there other systems in the cardiovascular realm that are being affected? The vascular system-

Dr Carolyn Lam: Yeah.

Dr Gregory Hundley: Skeletal muscle, many other areas. So as cardiologists start to work more with oncologists in this space, and we're all working together to make sure that not only patients survive their cancer, but they have an excellent quality of life, I think we'll see, as we have in other heart failure syndromes, a look toward other aspects of the cardiovascular system, body in general, to reduce the overall morbidity associated with the disease.

I think what we need to recognize as cardiovascular medicine specialists is that now for many forms of cancer, cardiovascular events, and certainly morbidity are becoming the primary issue that folks have to deal with with survivors. It's not necessarily the cancer recurrence, it's not necessarily a new cancer, it's cardiovascular. So we've got to integrate cardiology earlier in working with oncologists to improve overall survival and create an excellent quality of life from our different perspectives.

Dr Carolyn Lam: So, Maggie, let's move on to your paper now. You looked at radiotherapy's effect, whereas Bonnie looked at chemotherapy's effect. Could you tell us what you did and what you found?

Dr Margaret Redfield: The rationale for doing this study was, of course, seeing a lot of patients with HFpEF who had had radiation therapy for breast cancer, and I always just sort of assumed that that was because 12% of women over the age of 40 get breast cancer and 20% of women over the age of 40 get heart failure, but it seemed to be somehow more common than that. The other rationale was that radiation therapy does not actually affect the cardiomyocytes; they are very radiation resistant. And what radiation does is cause microvascular endothelial cells damage and inflammation, and that is felt to be fundamental in the pathophysiology for HFpEF.

So we thought we should look at this. I collaborated with a radiation oncologist and oncologists, and they were interested in looking at this because there's a lot of techniques now to reduce cardiac radiation exposure during radiation therapy, including proton beam therapy, and they're trying to prioritize who they use this new technology on. So what we did was start with a population-based study, all women who lived in Olmsted county who received radiation therapy for breast cancer in the contemporary era, where they're already using these dose reducing techniques. So we wanted to make it relevant to what's going on today. And so we started with a base cohort of all women. We matched patients' cases, it was a case-control study, so we matched cases and controls according to their age at the time of breast cancer, whether they had heart failure risk factors, like hypertension or diabetes, whether they got adjuvant chemotherapy, and tumor size, because we felt it was important that radiation could affect different parts of the heart, depending on whether it was right- or left-sided tumor.

And what we found is that the risk of heart failure increased with the mean cardiac radiation dose. We measured the mean cardiac radiation dose in every case and every control from their CT scans and their radiation plants. And as the radiation dose went up, the risk of heart failure went up, even matching or controlling for chemotherapy, which wasn't used that often in this group, or heart failure risk factors. And the vast majority of these cases were indeed HFpEF.

So we then looked at factors that happened in-between the radiotherapy and the onset of heart failure, making sure that this all wasn't just coronary artery disease, 'cause we know radiation can increase the risk of coronary artery disease. And indeed there were, only in about 18% of cases was there a new episode of coronary disease in the interim between the radiotherapy and the breast cancer. So, basically found that the mean cardiac radiation dose, even in today's era, does increase the risk of heart failure with preserved ejection fractions.

Dr Carolyn Lam: The things that stuck out to me ... it's population based. You did such a comprehensive study to really answer very key questions: dose of radiation, is it really just mediated by age and age-related risk factors, is it just about MI or could it be more microvascular disease? Congratulations, I really appreciated this paper. Some of the take-home messages are directly related to the treatment of breast cancer, isn't it? And about the importance of minimizing radiation dose if possible. I suppose one of the take-homes is, as well, for screening and watching out for heart failure. One thing though: how were these woman diagnosed with HEpEF? I mean, this is always the questions I get. How do you get diagnosed with HEpEF?

Dr Margaret Redfield: Right, well, first we started with looking to see if they had a ICD code for heart failure, and then we looked at each case of heart failure and determined if they either met Framingham criteria at the time of the diagnosis and the majority of them did. If they didn't actually meet the Framingham criteria, we looked to be sure there was a physician diagnosis of heart failure in the record and that they had supportive evidence of heart failure: echocardiographic findings, natriuretic peptide findings, and other clinical characteristics of heart failure.

And importantly, in the large control group from where we, you know, got our controls, people, a very large group of patients who did not get heart failure, we'd use natural language processing to look at all those records to make sure we weren't missing anybody who didn't have an ICD diagnosis or code for heart failure to make sure we weren't missing any cases of heart failure. So, we really tried to use very stringent methods to make sure we had true cases and control groups.

Dr Carolyn Lam: Indeed, and it actually goes back to Bonnie's paper as well, where we have to remind everyone that the diagnosis of HEpEF really starts with the symptomatology of heart failure in particular, that you so rigorously determined. I think just one last thing, Maggie: what do you think this implies now, for HEpEF? What do we do in general so the non-radiation-associated, do we believe more the Walter Paulus-Carsten Tschope hypothesis, and if so, what do we do?

Dr Margaret Redfield: Yes, well I think it really does support that hypothesis. We know that radiation therapy, again, we know what it does to the coronary microvascular endothelial cells and that's been elegantly worked out both in patients and in animal models. I think this really supports the Paulus hypothesis because this microvascular damage was able to produce heart failure, so I think that really supports that hypothesis. And there's been some studies showing decreased coronary flow reserve in HEpEF patients; it's very common. So I think indeed it does support that hypothesis and that the coronary microvasculature is key in the pathophysiology of HEpEF.

However it's a little scary to me because that sort of damage, once it's established, may be very hard to treat. You know, proangiogenic strategies in peripheral vascular disease have not yet yielded the benefits that we hoped for, so I think it's a tough therapeutic challenge that'll be very important to try to address in pre-clinical studies to try and figure out once the microvasculature is so damaged how do we treat that? How do we reverse that process?

Dr Carolyn Lam: Yeah. Words of wisdom. Maggie, thanks so much for inspiring, just all of us in this field. I just had to say that. You know, you are the reason that I am totally in love with HEpEF. (laughter)

Dr Margaret Redfield: (laughter)

Dr Carolyn Lam: So thank you so much for joining me today on the show. In fact, thank you to all my three guests.

You've been listening to Circulation on the Run. You must tell everyone about this episode, it is full of gems.

Thank you, and tune in next week.

Circulation April 4, 2017 Issue

3 april 2017 | 18 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editor's. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our Journal this week features important new data telling us that a common genetic variant risk score is associated with risk of drug induced QT prolongation and torsades de pointes.

First, let's give you your summary of this week's journal. The first paper provides both clinical and experimental data to show that the adipokine, retinal binding protein four promotes atherosclerosis. First author, Dr. Liu, corresponding author, Dr. Xia and colleagues from Sun Yat Sen University in Guangzhou, China first evaluated the association between serum retinal binding four levels and the incidents of adverse cardiovascular events in a community based prospective cohort and then examined the effects of retinal protein four gain or loss of function on macrophage foam cell formation and atherogenesis in an apple lipase protein E deficient mouse model. They found, in the clinical cohort study, that base line serum retinal binding protein four level was an independent predictor of incidents of adverse cardiovascular events after adjustment for traditional risk factors.

In the experimental study's, they showed that retinal binding protein four promoted macrophage derived foam cell formation through the activation of scavenger receptor CD36 mediated cholesterol uptake. In turn dependent on June and terminal kinase and signal transducer and activator of transcription one, as well as upstream regulation by the tracing kinase CSRC. These findings, therefore, support the use of retinal binding protein four as a novel biomarker for the prediction of cardiovascular risk. The data also provide insight into the mechanism of action of retinal binding protein four in the path of physiology of atherosclerosis.

The next paper is the first clinical trial, looking at remote ischemic pre conditioning prior to carotid artery stinting in patients with severe carotid artery stenosis. Remote ischemic pre conditioning is a protective, systemic strategy by which cycles of bilateral limb ischemia are applied briefly to confer protection from subsequent severe ischemia and distant organs. First author, Dr. Zhao, corresponding authors, Dr. Ji, and colleagues from Xuanwu Hospital, Capital Medical University in Beijing, China performed a proof of concept, single center, prospective, randomized control trial to assess whether remote ischemic preconditioning was safe and effective in attenuating ischemic injury related to carotid artery stinting in 189 patients with severe carotid artery stenosis. Results show that daily remote ischemic pre conditioning for two weeks, prior to carotid artery stenting, was feasible, safe, well tolerated, and may effectively attenuate secondary brain injury as evidence by a decreased incidence and reduced volumes of new ischemic legions on magnetic residence imaging performed within 48 hours post operation. The clinical implications are that if results are confirmed by future, larger studies, remote ischemic preconditioning may evolve into a nonpharmacological, neuro protective method for inhibiting carotid artery stenosis related cerebral ischemic events.

This potential for clinical translation in discussed in an accompanying editorial by Doctors Bell and Yellen, from University College, London.

The final paper discusses firefighting and the heart. What's the link? Well, cardiovascular events are the leading cause of death amongst firefighters and the risk is known to be substantially increased during fire suppression duties. In the current study, first author Dr. Hunter, corresponding author, Dr. Mills, and colleagues from University of Edinburgh in United Kingdom sought to understand this link better by assessing the effects of simulated fire suppression on measures of cardiovascular health in an open label, randomized cross over study of 19 healthy firefighters. These firefighters performed a standardized training exercise in a fire simulation facility or like duties for 20 minutes. Following each exposure, ex vivo thrombus formation, fibrinolysis, platelet activation and for armed blood flow in response to intra-arterial infusions of endothelium dependent and independent vasodilators were all measured. The authors found that exposure to extreme heat and physical exertion during fire suppression activated platelets, increased thrombus formation, impaired vascular function, and promoted myocardial ischemia and injury in healthy fire fighters. These finding provided pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction in fire fighters.

The implications of these findings for prevention are discussed in an accompanying editorial from Dr. Kales, of Harvard school of Public Health and Dr. Smith from Skidmore College and University of Illinois fire service institute.

Well, those were your summaries. Let's welcome our guests for our feature discussion.

Today's feature paper describes a pilot study that shows that a common genetic variant risk score, is associated with drug induced QT prolongation and torsades de pointes. This paper is so interesting to me because I found that the learning points, at least for me, really extended well beyond the trial itself. I'm so delighted to have with me the co corresponding authors, Dr. David Strauss from the US FDA, as well as Dr. Christopher Newton-Cheh from Massachusetts General Hospital. Welcome, gentlemen.

David: Thanks very much, glad to be here.

Christopher: Thank you, Carolyn.

Carolyn: So, I've always thought that common genetic variants identified via GWAS, for example, are individually very weak effects on medical traits. For example, systolic blood pressure or in this case, QT interval. But what I'm so impressed with this study is that you show, I think for the first time, that even these small effects can add up to clinically meaningful results that are testable or demonstrable in a trial. David, could you begin by telling us a little bit about this trial and what the primary results were.

David: In the study, we tested the hypothesis that a weighted combination of common genetic variants, contributing to the QT interval at base line, identified through prior GWAS studies, can predict individual response to multiple QT prolonging drugs. We performed a genetic analysis of 22 subjects and a secondary analysis of a randomized, double blind, placebo controlled cross over trial, that included three QT prolonging drugs, with 15 tie matched QT and plasma drug concentration measurements. This allowed us to carefully control for the inter individual differences in pharmacokinetics and just focus on the pharmacodynamics so the direct effect of the drug on the heart.

What we found was, there was a significant correlation between the weighted combination of common genetic variants, which we call the genetic QT score, and drug induced QT prolongation. More specifically, we found that the genetic QT score explained 30 percent of the variability in response to dofetilide, 23 percent in response to quinidine, and 27 in response to ranolazine.

We also investigated how response to one QT prolonging drug predicted the response to other QT prolonging drugs. There were significant correlations between all the drug/drug relationships with response to each drug explaining 24 to 29 percent of the variability in response to each of the other drugs. It's important to note that QT prolongation, by itself, is not harmful. The real concern is torsades de pointes, which can degenerate into ventricular fibrillation and cause sudden death. So, the test, irrelevant to the common genetic variants in predicting drug induced torsades, we then went on to examine a previously published, genome wide association study that included 215 patients with drug induced torsades, compared to 771 ancestry match controls and that prior study that was previously published had found that each individual common genetic variant did not reach genome wide significance, as you suggested, Carolyn. However, when we applied the weighted combination of common genetic variants, we found that the genetic QT risk score was associated with significantly increased risk of drug induced torsade, explaining 12 percent of the variation in risk.

Carolyn: So, my simplistic understanding was more or less there. That these genetic risks of these common variants kind of add up. I'm just curious ... Chris, do you think that this has implications for even other diseases? That's one question. And then secondly, I really appreciated your comment about using an intermediate trait, if you may, of QT interval versus looking at the disease itself of torsade de pointes. Could you give me comments on both these things?

Christopher: The study of intermediate traits, such as, quantitative traits like QT variability on the EKG are, I think very tractable for the study of genetic bases of underlying physiologic processes because we can study so many people. So the original genome wide association study that detected these individually weak genetic effects could only find them because we studied about 75,000 people who had had genome wide genome typing and QT intervals measured. It requires such large sample sizes to reach p values that are able to distinguish true positive associations from false positive associations, due to the multiple testing burden.

I think a challenge of what to do with these genetic effects once they've been reliably detected is that they do have weak effects and they influence intermediate traits. Nobody really cares whether their QT interval is three milliseconds longer, or three milliseconds shorter. What they care about is hard outcomes, or the likelihood that they'll have a toxic drug response. So, it was a natural follow on to that work to try to test these variants, and we knew that based on their weak effects individually on QT interval in the general population, that it was unlikely that they would individually explain a significant portion of either drug response or torsade. Which is why we aggregated the facts into the weighted score.

I think we tried to examine what we thought were the most proximal, clinically relevant outcomes. Specifically, drug response. QT drug response to drugs that are established to cause QT prolongation and arrhythmias. Whether the QT score will have meaningful or detectable impact on drugs that have much weaker effects on re polarization and risk of torsade, I think, would remain to be seen.

Carolyn: That's really remarkable.

David, how about your perspective of the implications of this? It's so unique that you're actually from the FDA so, why is this important to the FDA?

David: As Chris mentioned, the specific application we studied here, a drug induced QT prolongation and torsade have resulted in the withdrawal of several drugs from the market both in the US and worldwide. Many critical drugs remain on the market that are associated with QT prolongation and torsade…over 100 drugs, likely. What some people may not be familiar with is that at FDA we perform research to move new science into the drug review process and close the gap between scientific innovation and drug review. Like practicing clinicians, we seek to understand inter patient variabilities and we conduct research to better evaluate, benefit, and risk of medications. This is in line with the broader initiative ... the precision medicine initiative, which seeks to move away from the traditional “one size fits all” approach for medical therapy and instead, take into account specific characteristics of individual patients.

People are most familiar with this being applied in oncology and advances in pharmacogenomics have been more limited in other areas with the exception of the genetic bases of metabolism and pharmacokinetics where the traits are often controlled by one or a few genetic mechanisms, rather than the many mechanisms responsible for complex traits and diseases, as Chris discussed. As I mentioned earlier, what was relatively unique about this study is that we were able to control for the difference in pharmacokinetics and investigate the inter individual differences in the direct effect of drugs on the heart, the pharmacodynamics. We think it's very exciting that a combination of common genetic variants and aggregate can explain a significant portion of the inter individual variability and, as Chris mentioned, this is also important because the incidence of torsade is quite low. Only a small number of patients will develop drug induced torsade. It's possible that in the future analysis of a large number of common genetic variants that can be identified through genome wide association studies as in this case, may help to better define the personalized benefit risk profiles for individual patients.

Carolyn: You've really articulated that remarkably. That's exactly the excitement I think the entire editorial team shared when we read your paper. Thank you so much for it. Maybe just one last question thrown out to both of you, what's the next step? What's in the future.

Christopher: I think one next step, based on this proof of principle study, will be to try to test the impact of these genetic risk scores in real world clinical settings where individual patients with the diversity of different comorbidities and different drug exposures are also receiving QT prolonging drugs. Because that will have the biggest relevance for our patients who faced increased risk of drug toxicity.

David: The issue of cardiac safety of drugs is something that is very important to us at the FDA and we have some parallel initiatives that, in collaboration with other global drugs ... regulatory agencies and industry and academic collaborators ... we are working to develop new cardiac safety evaluation paradigms for new drugs, or existing drugs, that could even be applied in the preclinical setting and really focus on the mechanistic base, pro arrhythmic risk. So, we should have more exciting work coming forward in the near future for better prediction and individualized prediction of benefit and risk of medication.

Carolyn: Thank you, listeners, for joining us. You've been listening to Circulation on the Run. Join us next week.

Circulation March 28, 2017 Issue

27 mars 2017 | 18 min

Caroline: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Up next, we are discussing the featured paper in this week's journal regarding the increased risk of cerebrovascular events in young cancer survivors, the downside perhaps of surviving cancer, so to speak. But first, here's your summary of this week's journal.

The first paper describes the US national trends in atrial fibrillation hospitalization, readmission, and mortality. This paper from Dr. Freeman and colleagues of Yale University School of Medicine in New Haven, Connecticut used data from all Medicare fee-for-service beneficiaries between 1999 and 2013, and found that the adjusted rates of hospitalization for atrial fibrillation increased by almost 1% per year. Median hospital length of stay remained unchanged at three days, but median Medicare inpatient expenditure per beneficiary increased from $2,932 to $4,719 per stay.

During the same period, the rate of inpatient mortality during hospitalization for atrial fibrillation decreased by 4% per year, and the rate of 30-day readmission also decreased by 1% per year, while the rates of 30-day and one-year mortality decreased more modestly by 0.5% and 0.26% per year, respectively. Thus, between 1999 and 2013, among Medicare fee-for-service beneficiaries, rates of hospitalization for atrial fibrillation and the cost of those inpatient stays increased substantially, but this was associated with improved outcomes, including lower rates of readmission and mortality. These findings suggest that increased hospitalization and more costly contemporary treatments, such as atrial fibrillation catheter ablation, may be associated with improved outcomes.

The next study provides insights into the mechanisms underlying augmentation of muscle blood flow by ultrasound cavitation of microbubbles. Now, this is a promising approach for rapidly correcting tissue profusion in acute ischemic syndromes or for treating chronic ischemic symptoms. In this paper by first author Dr. Belsik, corresponding author Dr. Linder, and colleagues from Night Cardiovascular Institute Oregon Health and Science University in Portland, Oregon, the authors hypothesized that pure endergic signaling may be responsible for sheer dependent increases in muscle profusion during therapeutic ultrasound cavitation.

To test this hypothesis, the authors studied unilateral exposure of the proximal hind limb of mice with and without ischemia produced by iliac ligation, to therapeutic ultrasound after intravenous injection of lipid microbubbles. They further performed a proof of concept study with twelve patients with stable sickle cell disease. They found that therapeutic ultrasound cavitation increased muscle profusion by seven-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle profusion in patients with sickle cell disease.

Augmentation inflow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced a nearly forty-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation. Furthermore, combined indomethacin and inhibition of eNOS abolish the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins. Thus, the authors concluded that therapeutic ultrasounds using microbubble cavitation to increase muscle profusion relies on sheer dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. Cavitation-related release of ATP may further serve to explain ultrasound's role in other therapeutic applications, such as wound and bone healing, and ultrasound facilitated drug or gene uptake.

The final original paper describes the age-specific trends of heart failure in Denmark over the last two decades. Dr. Christiansen and colleagues of University of Copenhagen in Denmark studied more that 210,000 Danish individuals over the age of 18 years, with a first time in-hospital diagnosis of heart failure from three nation-wide Danish registries.

They found that the incidents of ischemic and non-ischemic heart failure in Denmark declined by approximately 50% among older adults more than 50 years old, but increased by about 50% among younger individuals, or individuals less than 50 years old, between 1995 and 2012. Furthermore, they observed a concomitant increasing trend of various treated co-morbid conditions, including hypertension, diabetes, and ischemic heart disease in the population. These findings from Denmark imply a change in the profile of the heart failure community and portend a higher burden of heart failure in the future. The increasing trend of incident heart failure among young individuals especially warrants further investigation.

Well, those were the original papers this week. Now, for our feature discussion.

Our feature paper today discusses a hugely important modern issue that may seem like good news at first sight. We know that survival in cancers has rapidly improved with advances in early detection and treatment, however the improved survival also extends the window for the occurrence of long-term complications such as psycho-social effects, fertility problems, secondary malignancies, and, as highlighted in today's paper, the risk for cerebrovascular events. I'm so pleased to have with us first, author Chloe Bright from University of Birmingham, United Kingdom, as well as associate editor Dr. Graeme Hankey from University of Western Australia. Welcome, Chloe and Grim!

Chloe Bright: Thank you for having me.

Graeme Hankey: Thank you Caroline.

Caroline: Chloe, what an interesting and important focus on cerebrovascular events following survival from cancer. Please, can you share your inspiration for looking at this and what you found?

Chloe Bright: As you've just said, the five year survival rate from teenage and young adult cancer has been increasing and increasing, and it's over 80% now, which means there's such a large population of survivors who are at increased risk, or potentially increased risk, of developing adverse health outcomes. So, as you know, cerebrovascular disease can be potentially fatal so it's really important that we estimate how much teenage and young cancer survivors are at risk of this. So to start of with our group in Birmingham actually set up the teenage and young adult cancer survivor cohort study. And this is a cohort of over 200,000 five year survivors of cancer who were diagnosed between 15 and 39 years of age. And this was set up because there's hardly any literature regarding the adverse health outcomes of teenagers and young adults who have had cancer.

So, as I said, cerebrovascular disease is a really important outcome to look at. So we decided we've got this resource in the UK, which is the Hospital Episode Statistics, and this carries information on all the inpatient hospitalizations in England. So from this we were able to determine how many people with teenage and young adult cancer had been hospitalized for cerebrovascular events and compare this to what we would expect to see in the general population to see if they had an increased risk or not. So from limited previous literature that was out there we did know that TYA cancer survivors had an increased risk of developing a cerebrovascular event. However, we were unsure how this risk varied with certain explanatory factors, such as age of cancer diagnosis or the decade of cancer diagnosis, gender, and attained age, so that's the age at which a stroke event might occur. So the main aim of our study was to quantify this.

Caroline: Yes and to put some numbers to that increased risk. It was a 40% increased risk, wasn't it? That is striking.

Chloe Bright: We observed almost 2,800 cerebrovascular events. That related to a 40% increased risk of being hospitalized compared to what we would expect to see in the general population, which is really quite substantial.

Caroline: Now, were there particular risk factors that were associated with more cerebrovascular complications like certain types of tumors or certain types of therapies and so on?

Chloe Bright: Survivors of central nervous system tumors, head and neck tumors, and leukemia were all at the greatest risk compared to the general population. And this is probably related to radiotherapy that they had for their initial treatment. So radiotherapy to the neck, which could involve damage to the carotid artery, or radiation to the head which again could cause damage to the cerebral arteries in the brain. And then also we found that the risk increased dramatically as people aged for neck tumor survivors and CNS tumor survivors. So specifically cerebral infarctions, the additional number that we saw was a lot greater in, say, survivors over age 60. And this is probably because this is when strokes in the general population are becoming more incident.

And actually an interesting finding, we observed that males actually had a higher number of excess infarctions than females, and this was especially among head and neck tumor survivors. So we can't confirm this, but this could potentially be due to difference in smoking habits because there could be a said etiology between smoking and the risk of head neck cancer and also smoking and the risk of stroke. Unfortunately, we didn't have the information on smoking status to confirm this.

Caroline: This is a huge study. It shows a substantial increased risk of stroke in these young cancer survivors, and also sheds light on the possible underlying mechanisms. What you mention about vasculopathy following radiotherapy really reminds me about what we learn about breast cancer radiotherapy and the risk of myocardial infarction.

Graeme, what are your perspectives on this paper please?

Graeme Hankey: Well as an editor, as everyone knows, what we're really looking for are four main points. Firstly that the study was ethical, which it was. Secondly that the results are valid, internally and also externally. And we're very confident in the validity of the results. This was a very large study of 180,000 people, and more importantly had 2,800 cerebrovascular events so that's a lot of [inaudible 00:12:25] and the followup was pretty rigorous over 11 years, and the outcome events were [inaudible 00:12:32] by a data linkage through the hospitalization for the cerebrovascular events.

The other two key features of course is are the results novel and are they important? And these are novel results. There's only been one previous similar study of a Danish cohort that was only 43,000 but one quarter the size of this study, and one year survivors of teenage and young adult cancer from 1943 to 2009 and followed up. And the results were actually very similar, showing a 1.3 or 30% increased risk of hospitalization for cerebrovascular events. Again supporting the validity of this recent study to obtain similar results, but in a four times greater population and in a more contemporary population whose patients were recruited between 1971 and 2006 and followed up from 1997 to 2012.

And the other thing is it's not just ethical, valid, and novel, but it's important because it really has big implications for stroke prevention in young adult survivors of cancer. And it has implications for once they get the diagnosis and they're through their treatment to really focus on what were their pre-morbid vascular risk factors? Are they actually causal risk factors and not just cancer but also for future stroke like smoking and alcohol, and hypertension and diabetes? Secondly to try and recognize what is their absolute risk? Are they men who are at higher risk? Have they had previous irradiation that probably puts them at higher risk, as well as their current respective profile?

Thirdly for them to then realize what's the impact of their cancer diagnosis on their future behaviors if they become depressed or change their diet or taking other treatments, or abusing drugs, and could that increase their vascular risk? And fourthly, what should be done? Should they just control their vascular risk factors through lifestyle? Or should we actually have a randomized trial of risk factor control, and/or antiplatelet therapy and/or statins and/or blood pressure lowering in these high risk survivors of cancer who are sill in their forties or fifties. Should they actually be taking antiplatelet therapy or statins? We probably need a randomized trial because they're high risk, we would think, or certainly a sub-population.

Caroline: Thanks Graeme for framing that so excellently. You're absolutely right that these are the things we look for in a paper as editors. And for our listeners to hear that is just so important.

Well, I'd like to hand it over to you now Chloe. What are the next steps in your mind? What are the remaining gaps in knowledge you'd like to address?

Chloe Bright: I really think it relates to what Graeme just said. We need to get the information on the specific radiotherapy, the doses that have been used, the potential lifestyle factors of these individuals to see how much of an effect that has on the risk of stroke. So potentially conduct a case control study while we're able to get this information and then use that. And then, as Graeme said, once there is more information potentially a randomized control trial might be useful. But again, I think we need some more information before we can get the go ahead to doing that.

Caroline: Great. Just one more quick question please. You know, Chloe, you found that those who were more recently treated had a higher risk of cerebral hemorrhage than among survivors diagnosed earlier. Now, did you have any postulations on why this was the case?

Chloe Bright: This increase in the hemorrhage with more recent diagnosis was actually restricted to glial tumor survivors. So one explanation that we thought might explain this was that in recent years due to advances in treatments those glial tumor survivors, glial tumors who had more advanced stage at diagnosis, potentially surviving a little bit longer, so reaching five year survival which would enter them into our study. However they potentially might be having another occurrence, which would be causing them to have a hemorrhage, which in the previous decades perhaps they wouldn't have survived that long in the first place. That's just one of many ideas.

Graeme Hankey: I think the recurrence of not just glioma but perhaps also melanoma that the survival is much greater now with new immunomodulating therapies for melanoma, we'll probably see longer survival in melanoma which typically when it metastasizes is hemorrhagic and perhaps also leukemia with thrombocytopenia, with more hemorrhage and other metathesis. The other thing it could be though is a diagnostic ascertainment bias in that I'm 60 now, and when I started neurology 35 years ago we didn't really have much brain imaging and couldn't diagnose intracerebral hemorrhage very well. And clinical diagnosis wasn't very reliable. Now the imaging which can actually distinguish hemorrhagic from ischemic stroke is much more widely available. And I suspect there's a greater increase in the diagnosis of cerebral hemorrhage now because of better imaging. We've seen that in other epidemiologic studies with that diagnostic trend.

Caroline: What excellent points. Thank you so much Chloe and Graeme.

Well you've been listening to Circulation on the Run. Thanks for joining us today and don't forget to tune in next week.

Circulation March 21, 2017 Issue

20 mars 2017 | 18 min

Dr. Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In this week's issue, we are discussing if public placement of defibrillators in the community can be improved. First, here's your summary of this week's Journal.

Stroke incidents, prevalence, and risk factors have been changing over the past 50 years so do we need a more contemporaneous revised Framingham Stroke Risk profile to reflect these trends? Well the first paper in our issue looks at this and this is from first author Dr. Dufouil, corresponding author Dr. Seshadri and colleagues from the Boston University School of Medicine.

Let's first recall that the Framingham Stroke Risk profile was originally described in 1991 and integrates the effect of age, sex, and baseline measurements of various vascular risk factors such as systolic blood pressure, use of anti-hypertensive medications, left ventricular hypertrophy on ECG, prevalent cardiovascular disease, current smoking status, atrial fibrillation and diabetes all to describe the 10-year probability of incident stroke.

In the current paper, the authors updated the Framingham Stroke Risk profile using the means of risk factors that reflect current prevalence, the estimate of incident stroke to reflect current rates, and the hazards ratio that reflect current associations. They used the same risk factors identified in the original stroke risk profile with the exception of left ventricular hypertrophy. The authors compared the accuracy of the standard old risk profile with the revised new risk profile in predicting the risk of [alt 00:01:58] and ischemic stroke and validated the new risk profile in two external cohorts, the three cities and regards or reasons for geographic and ethnic differences in stroke studies.

They found that the new stroke risk profile was a better predictor of current stroke risks in all three samples than the original old Framingham Stroke Risk profile. The new stroke risk profile was also a better predictor among whites compared to blacks in the regard study. The authors therefore concluded that a more contemporaneous revised Framingham Stroke Risk profile could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.

The next study provides preclinical proof of principle that an apelin receptor agonist may be of therapeutic use in pulmonary arterial hypertension. And the agonist in this case is Elabela/Toddler or ELA, first identified as an essential peptide in the development of the heart in Zebrafish, and subsequently proposed as a second endogenous ligand at the G-protien coupled apelin receptor, which works at this receptor despite a lack of sequence similarity to the established ligand, apelin.

In this study from first author Dr. Yang, corresponding author Dr. Davenport and colleagues from University of Cambridge in the United Kingdom, ELA competed for binding of apelin in human hearts with overlap of the two peptides indicated by encyclical modeling. ELA activated G-protein and β-arrestin dependent pathways and as expression was detectable in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output, and elicited vasodilatation in rats in vivo.

ELA expression was reduced in cardiopulmonary tissues from patients with pulmonary arterial hypertension and in rat models. Finally, ELA treatment significantly attenuated the elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in monocrotaline exposed rats. Thus, these results suggest that a selective agonist that mimics the action of indulgence ligand apelin or Elabela/Toddler, ELA, may be a promising therapeutic strategy in the treatment of pulmonary arterial hypertension.

The final paper looks at sudden cardiac death after coronary artery bypass grafting, its incidents, timing, and clinical predictors. First author Dr. Rao, corresponding author Dr. Velazquez and colleagues from Duke Clinical Research Institute in Durham, North Carolina, looked at the patients enrolled in the STICH, or Surgical Treatment of Ischemic Heart Failure Trial who underwent coronary artery bypass grafting with or without surgical ventricular reconstruction. They excluded patients with a prior ICD and those randomized only to medical therapy. Over a median followup of 46 months, 113 out of 1,411 patients who received coronary artery bypass surgery, had sudden cardiac death while 311 died of other causes.

The five-year cumulative incidence of sudden cardiac death was 8.5%. In the first 30 days after bypass surgery, sudden cardiac death accounted for 7% of all the deaths. The numerically greatest monthly rate of sudden cardiac death was in the 31 to 90 day time period. In multivariable analysis end-systolic volume index and BNP were the most strongly associated with sudden cardiac death. Thus, this study shows that the monthly risk of sudden cardiac death shortly after bypass surgery among patients with a low ejection fraction is highest between the first and third months, suggesting that risk stratification for sudden cardiac death should occur early in the post-operative period, particularly in patients with an increased preoperative end-systolic volume index and/or an increased BNP.

Well, that wraps it up for you summaries, let's turn to our feature paper.

I love our feature paper this week. You know why? It actually tells us what Tim Hortons, Starbucks, Second Cup and ATMs may have in common and may have to do with sudden cardiac death. Indeed, our feature paper actually tells us that coffee shops and ATMs may be the best spots to place AEDs at, well at least in Toronto. And to discuss this really interesting paper, I have the corresponding author, Dr. Timothy Chan from University of Toronto as well as Dr. Sana Al-Khatib, welcome again Sana, Associate Editor from Duke University, welcome to you both.

Dr. Al-Khatib: Thank you, my pleasure.

Dr. Chan: Thank you, very nice to be here.

Dr. Lam: So Tim, was that an interesting enough lead up? I mean you have to tell us about your study, it is so fascinating.

Dr. Chan: I'm very pleased that you find it interesting and not just us. So we undertook this study, we started this actually a couple of years ago, and we've been working on this issue of defibrillator location optimization for several years, and we've been talking and we have meetings in coffee shops and we were just wondering one day, what would be the risk or the coverage provided by all these different well-recognized location types around the city, and that was really the motivation that got us started looking at this study.

Dr. Lam: Tell us what you did and also how it differs from the study you did that was published in 2016 where you also reported on the spatial temporal analysis of registered AEDs in Toronto. The current study clearly extends it, but could you clarify to us all how it does?

Dr. Chan: Maybe just give a little bit of a background and context with regards to other literature that's similar. There have been studies in the past that looked at what we would call spatial coverage of cardiac arrest, so they looked at different broad location types and they tried to calculate, they basically calculated how many cardiac arrests happened, let's say within 100 meters of those location types. And what we've done here is we've extended that in a couple of directions. The first direction is looking at spatial temporal coverage and so this is not just in the nearby vicinity, IE, 100 meters, but also that cardiac arrests happen when that nearby location that had the AED was open. So if a cardiac arrest happens, but for example, let's say there's a coffee shop that actually has an AED and that coffee shop is closed, it's almost as if that AED is not even there. So one of the major things we made sure to include was this idea of temporal coverage as well, on top of the spatial.

The second major difference I would say would be the fact that we're really looking at more granular location types, so you mentioned a few businesses in your opening such as Tim Hortons and Starbucks and so on, which are coffee shops, and so one of the things that we find is when we look at very broad location types, we tend to aggregate together lots of different types of businesses. For example, if you think about a restaurant, there are many different types of restaurants that get lumped in to this category, and they do have different cardiac arrest coverage associated with them. So by breaking it up into smaller location types, we wanted to get a better idea of the risk at different locations and if you also think about one of the long term goals of this work would be to try and help policy makers identify promising partners to partner with for, let's say public access defibrillation programs, by identifying specific businesses or municipal locations, it might actually give them better targets to try and pursue rather than let's say a group of different businesses.

Dr. Lam: That makes so much sense and it really just seems like such an important public health message as well. The sensible part being of course, if you have an out of hospital cardiac arrest, you need an AED that's both nearby and available, so that was really clever. Sana, could you give us your take on the public health implications of Tim's findings?

Dr. Al-Khatib: I think the public health implications of this work can be vast and if you look at what he's done in terms of ascending to out of hospital cardiac arrests a lot of initiatives have been launched to try to improve the outcomes of patients who have the out of hospital cardiac arrests. Unfortunately despite all the work that has been done and all the wonderful initiatives that have been launched, we still have a lot of work to do to improve the survival of those victims. So certainly a crucial step is how we deploy AEDs in a strategic way based on data and evidence such as these data that are provided to us by Tim and his colleagues.

I think this is very clever, I do agree that we have to be more strategic in how we deploy AEDs and having the data such as these will only help us improve and get better of course. Everybody has limited resources, and so if we can be more selective in terms of how we deploy AEDs I think that would help everybody. I realize this was done within Toronto and some of these findings may not be generalizable to other cities, but I think this is definitely a great way to make us reshape our thinking in terms of how we do this, and so a question I have for Tim if I may, are you aware of any similar studies that have been done looking at this in other cities and then if not, how do we encourage other groups to do similar work?

Dr. Chan: There have been similar studies done that have focused really on the spatial side of things, so doing this 100 meter radius and counting cardiac arrests that have been nearby, there's actually been fairly little work that's been done on the spatial temporal side. And a couple of exceptions that I will note that I think are important to point out is there was a very nice study that was done out of a group in Copenhagen, and they were looking at actually spatial temporal coverage, particularly the loss in coverage that you experience when you go from looking at spatial to spatial temporal. For example if you count all of the cardiac arrests that happen nearby a registered AED based only on 100 meters, and then you count the same number, but you have to now layer on top of that when the building that the AED is in is open, then you tend to get a big loss. They found quite striking numbers, I think they found a 50% loss, when you look at evenings and weekends I believe, in Copenhagen. So basically all the cardiac arrests that happened where you thought there was an AED nearby, there's actually only one in two is actually nearby and accessible when you looked into hours of operation.

And this actually comes back to the earlier question from Carolyn about how our study relates to our previous study in 2016, so we actually replicated that Copenhagen study in Toronto where we measured spatial coverage and we measured spatial temporal coverage and we measured that loss, and we found a similar loss overall, about 20%, so 1 in 5 cardiac arrests happened where there was an AED nearby, but that AED was not available because that location was closed. So that was one of the impetuses for leading us to do this study where we start to examine specifically the different location types and the specific businesses that were involved.

Dr. Lam: Wow, that's just really inspiring Tim, I mean I'm kind of thinking about the Singapore situation too and I think it's actually applicable and I would love if we had local data similar to yours, so congratulations, I really share what Sana said. Thinking though about the public health and the larger implications of what you're talking about, what do both of you think of the implications for a public commercial partnership in these things if it is coffee stores or banks that seem to be the best locations, perhaps these have implications to how the public and private should collaborate to make these things happen, what do you think?

Dr. Chan: I completely agree. These types of public private partnerships, specifically for AED deployment are not necessarily new, they already happen in some parts of the world. One of the examples I always like to bring out is if you go to Japan and they have vending machines everywhere in Japan and then you'll often run into vending machines that have an AED right in them, so one of the benefits is that first the vending machines are everywhere and second, if you're a citizen there, you probably know where the vending machines are where you travel in your day to day life and so I would say that would be a very similar thing here in North America, whether it be coffee shops or ATMs, if someone were to put me in a random part of the city and ask me, "Hey Tim, do you know where the nearest AED is?" I'd probably have a lot of trouble, but if they said could you figure out where the nearest ATM is for your bank or where the nearest Starbucks is you know, there's pretty much one on every corner. It would be much easier to identify and find, so I think there are significant benefits to partnering with these companies or these businesses that have very broad name recognition and brand recognition, are geographically well spread and located in populated areas.

I should also mention, I feel like there's a few other benefits for these types of locations, so for example for ATMs, I think there's a lot of secondary benefits, so for example, there's a built in security component, there's a video camera there, that might be able to help make sure that no one's vandalizing or stealing an AED. There's perhaps built in weather protection because there's electricity there already, so in a cold climate like Toronto where you might worry about putting an AED outside, you could have potentially a heating cabinet that would be fed by the electricity for the ATM and so on. So I think there's actually a lot of benefits if we could actually operationalize a system like this.

Dr. Lam: Sana, do you think there are some more unanswered questions?

Dr. Al-Khatib: I did want to agree with Tim on what he said, that these public private partnerships have been in place. Unfortunately we haven't been able to make much progress. As I said, I do see the results of this study as being potentially a catalyst to improve the work that we are doing and ensuring stronger partnerships and collaborations to help us achieve what we want to achieve which is basically improve the survival rate of out of hospital cardiac arrests, so I completely agree with that and I loved your idea, Tim, when you talked about now people may not recall where AEDs might be, but if you link them with teller machines or coffee shops, I think that would be much easier to remember.

You know of course there are a lot of questions that remain unanswered unfortunately. Again as was stated by Tim and his colleagues in the paper and on the call, how we can translate these findings to other locations I think is really key and then of course doing the work, meaning let's use these data to deploy more AEDs and then really looking at the impact of that. Ultimately we want to make sure that if we hypothesize that by doing this we can improve outcomes for these victims, we would want to prove that. So I think the next steps would be to see if this can be replicated in other places, but also even within Toronto, if we can accomplish some of this and then examining the impact, I think would be extremely beneficial.

Dr. Lam: Fabulous, thank you so much Sana, thank you so much Tim for sharing your thoughts today.

Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.

Circulation March 14, 2017 Issue

13 mars 2017 | 19 min

Caroline: Welcome to Circulation On The Run! Your weekly podcast, summary, and backstage pass to The Journal and it's editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore. What does the gut microbiome have to do with Cardiovascular Disease? Well to find out you'll just have to stay tuned for our featured discussion debate. First, here's our summary of this week's journal.

The first paper seeks to answer the question "does first trimester screening modify the natural history of Congenital Heart Disease?" To answer this question Doctor Jasinskyl and colleagues from the University Hospital in Masaryk University in the Czech Republic, analyze the spectrum of congenital heart defects and outcomes of 127 fetuses diagnosed with congenital heart defects in the first trimester compared to 344 fetuses diagnosed in the second trimester screening. All of these analyzed between 2007 and 2013.

They found that the spectrum of congenital heart defects diagnosed in the first versus second trimesters differed significantly with a greater number of comorbidities, defects with univentricular outcomes, intrauterine deaths, and terminations of pregnancy in those diagnosed in the first compared to second trimester.

They further analyze 532 fetuses diagnosed with congenital heart defects in the second trimester but in an earlier period of 1996 to 2001, which is the period before first trimester screening was introduced. In this group they found significantly more cases of defects with univentricular outcomes, intrauterine deaths, and early terminations of pregnancy. In comparison to fetuses also diagnosed with congenital defects in the second trimester but in the later period of 2007 to 2013.

Thus, the authors concluded that first trimester screening had a significant impact on the spectrum of congenital heart defects and on the outcomes of pregnancies with defects diagnosed in the second trimester. Early prenatal cardiac ultrasound screening may therefore, in some countries, reduce the number of children born with severe cardiac abnormalities and associated comorbidities.

The next study sheds light on the use of intravenous recombinant tissue plasminogen activator, or "RTPA," in patients with acute ischemic stroke also receiving no wax or the newer oral anticoagulants. Doctor Sienne and colleagues from the Duke Clinical Research Institute in Durham, North Carolina use data from the American Heart Association "Get With The Guidelines" stroke registry in 42,887 ischemic stroke patients treated with RTPA at 1,289 hospitals in the United States between 2012 and 2015. They basically found no statistically significant differences in the risk of symptomatic intracranial hemorrhage between patients who were taking Noac, Warfarin, or not taking any anticoagulant before the stroke.

This largest clinical experience of stroke thrombolysis in patients receiving Noac before the strokes thus suggest that RTPA is reasonably well tolerated without prohibitive risks for adverse events amongst selected Noac treated patients. However, the authors are quick to say that their observations must be considered as preliminary due to the absence of coagulation parameters, timing of the last Noac intake, and whether or not non-specific reversal strategies may have been applied.

The next paper provides experimental evidence of the unique effects of plasminogen activation and Alpha 2 antiplasmin inactivation on the fibrinolytic system in pulmonary embolism. In this paper from Dr Sing, Hong, and Reed from the University of Tennessee Health Sciences Center in Memphis, Tennessee the authors use mouse models of experimental pulmonary emboli to show that monoclonal antibody inactivation of Alpha 2 antiplasmin, which is an endogenous inhibitor of plasmin, effectively dissolved pulmonary emboli with similar potency to high dose RTPA.

Alpha 2 antiplasmin inactivation synergize with low dose RTPA to enhance thrombus dissolution. And like RTPA, Alpha 2 antiplasmin inactivation alone or in combination with low dose RTPA, did not cause fibrinogen degradation or increased bleeding. The authors therefore concluded that Alpha 2 anti plasmin is a dominant regulator that prohibits thrombus dissolution in vivo.

Therapeutic modulation of Alpha 2 antiplasmin activity may therefore prove an effective strategy to enhance fibrinolysis without significantly increasing the bleeding risk. These results are discussed in an accompanied editorial by Doctor Yurano from Hamamatsu University School of Medicine in Japan.

More exciting experimental data in the next paper showing that novel beta arrestin signaling pathways may be viable targets in dilated cardiomyopathy. First author Doctor Reba, corresponding author Dr Solaro, and colleagues from University of Illinois at Chicago treated a dilated cardiomyopathy mouse model expressing a mutant tropomyosin for three months with either a beta-arrestins two biased ligand of the entertance and receptor or losartan and angiotensin receptor blocker as control. Treated mice showed improved cardiac structure and function associated with myofilamins that had significantly improved myofilament calcium responsiveness. Which was depressed in the untreated mice.

These functional changes were mediated through beta arrestin which may have a novel role in increasing MLC2V phosphorylation through a previously unrecognized interaction of beta arrestin localized to the sarcamore. Thus, long term beta arrestin 2 biased agnonism of the angiotensin receptor may be a viable approach to the treatment of dilated cardiomyopathy. Not only by preventing maladaptive signaling but also by improving cardiac function by altering the myofilament calcium response via beta-arrestin signaling pathways. The concept of a two in one angiotensin receptor blocker and calcium sensitizer is discussed in accompanying editorial by Doctors Wu, Ju, and Siao from Peking university in China.

The final paper asks the question "are three arterial graphs better than two coronary artery bypass grafting?" Doctor Galdino and colleagues from Weill Cornell Medicine in New York performed a meta analysis of eight propensity score matched observational studies on more than 10,000 matched patients comparing the long term outcomes coronary artery bypass grafting with the use of two verses three arterial graphs.

They found that the use of a third arterial condo et in bypass grafting is a associated with superia long term survival irrespective of sex and diabetes status and without a higher operative risk. These results therefore support a strategy of the use of a third arterial graph and really deserve confirmation in prospective randomized trials. Well, that's it for the summaries. Let's welcome our guests.

Our topic for discussion today is so exciting. In fact, I am going to read from the paper describing it as an exciting, new, and important field of investigation where we start to understand how nutrition, our gut micro-community composition, and our genetics actually all play a part in Cardiovascular Disease. And to discuss this paper I have the first and corresponding author Doctor Wilson Tang from Cleveland Clinic Foundation as well as Doctor Nikhil Munshi, Associate Editor from UT Southwestern. Welcome Wilson and Nik!

Nik: Thank you.

Wilson: Thank you.

Caroline: Wilson, please set the stage for us! What does our gut microbiome have to do with cardiovascular disease? I agree it's a hot area but, you know, could you just describe what it actually means.

Wilson: This has been somewhat of an accidental discovery from our group when we start encountering different types of metabolites that we measure to kind of associate them with Cardiovascular Disease. And unbeknownst to us, some of them are produced by the bacteria that live inside us to which we convert and try to eliminate. So one such metabolite that we identify is, which in many of the foods that we tell our patients, advise our patients that have high risk of Cardiovascular Disease. So all these connections come together to form a scientific basis to which how one of the biggest environmental exposures that we have which is what we eat every day is filtered by trillions of bacteria that live inside us and many of these metabolites become hormones that effect our every day function and activity.

And, in many ways, can actually lead to diseases that are so remote from the gut but such as Cardiovascular Disease, Atherosclerosis, and we further identify these process and they impact downstream organ function like heart function and kidney function. So these are all very excited areas and this is just one of several metabolites. There are other metabolites that also impact blood pressure and even brain function and so all these areas become kind of a new avenue for us to look at potential therapeutic targets.

Caroline: Yeah I think it's so completely fascinating that we can actually each experience a given meal differently based on the different types of gut microbial communities in our bodies isn't it? And that that actually can effect things all the way from atheroscleroses, to obesity, insulin resistance, and so on. Could you give us a specific example from your research?

Wilson: We actually identified a metabolite, a very small molecule called Trimethylamine N-oxide, we abbreviate it as TMAO. And TMAO is actually formed from the bacteria from a precursor called Trigosamine which is, you know, gas. In other words, the bacteria taken substances of nutrients such as choline and connetine which is actually common in many foods but particularly in red meats, in egg yolks, and many other foods that we know are potential contributors to Cardiovascular Disease.

And actually converted into this gaseous compound that our liver converted into a neutral compound, that we think is neutral for a long time and nitrogenous waste, except that when we have both animal studies and human studies patients with high levels of this TMAO metabolite has been associated with a high risk of Cardiovascular Disease. And in fact in animal studies we have direct evidence that show its contributing to the mechanistic compartment.

Caroline: Now extrapolating from what you just said so vegetarians, for example, or vegans even more so, would have less TMAO levels then?

Wilson: Yeah, obviously there are wide variation in these levels actually change almost by the minute because obviously we eat different times of the day and it comes in and out of our bodies. But in general, yes, in other studies that we actually identified a higher level of in carnivores which are meat eaters verses vegans and vegetarians who do not eat meat.

Wilson: Yeah and we actually use... I sort of labeled choline and connetine to actually directly show that the synthesis of TMA and TMAO by a labeled connetine is higher in meat eaters, carnivores, verses vegetarian or vegans.

Caroline: Oh, I really have to ask both you Wilson and Nik the following question then. What do you think is the, you know, take home message? How do you apply this clinically and even more cheeky, perhaps, how are you applying this in your own life? I mean with this knowledge have you become vegetarian? I'm putting you on the spot here.

Wilson: I think this is basically a very scientific demonstration of how what we eat does impact our every day bodily function. And I think many cultures have this identification. Obviously many Asian cultures have seen the impact of food. In fact, it actually opens entire insight into how different medicinal food may actively be impacting the gut microbiome that actually creates different effects in the body. But in terms of diet and nutrients, yeah I have totally have eaten less meat in my every day dietary habits.

I definitely think it's something that is certainly quite insightful and probably very impactful. That being said, I think different cultures also have different populations of microbiome and I think it's not a one size fits all. In fact I think every individual has his own dynamic ranges and we are still in the very very first early stage of understanding how this impact helps in disease. So there's a lot of excitement and there's a lot of technology that hopefully can help us to unravel this mystery.

Caroline: Exactly, a new and important field just like you said. Nik, what do you think?

Nik: From my standpoint, I'm actually not a big meat-eater so this was very welcomed news when this all came out. But, you know, from another standpoint it really opens up a lot of new questions. You know, it kind of blurs the line between sort of genetics and environmental factors. You know, so the questions of maybe a family who shares certain genetic traits may also share certain environmental traits. In other words, they share certain gut microbial components and maybe this sort of complicates how we're going to disentangle some of these risk factors going forward. I'm interested to get Wilson's take on this.

Wilson: Yeah it gives us a lot of insight to the I guess what happens is the microbiome is isolated in the family lineage because the lifestyle exposure are very similar in each household. So, what we thought is inherent is being inherited from both the genomic but also a microbiome perspective.

Caroline: Nik, you manage this paper. I really love, for example, that figure which I think everyone should get ahold of the journal and have a look at. Could you tell us a little bit more about this category of papers?

Wilson: I'm sort of charged with this task of bringing sort of basic Science across the aisle to clinicians so that we can all sort of talk the same language and perhaps interact on a higher level. And so I was really excited reading some of Wilson's work and you know I really wanted to bring that to some of our broad readership just so that we could sort of appreciate what sort of science was going and I really think that this is a really great example of something that's on the verge of being translated.

You know you can imagine that by either effecting certain metabolite compositions or maybe by treating certain subsets of bacteria we may be able to influence long term cardiovascular risks not to mention obesity, diabetes, and some of these other diseases that Wilson is actively working on. So I really read this with a lot of excitement and I wanted to bring this to a broader audience and you know we have a number of other articles that are in the pipeline that I think will serve to bridge this gap and put us on the same field so that we can kind of speak the same language.

Caroline: Wilson, did you have a good time sort of writing something like this its not long.

Wilson: It's actually very difficult. In fact, its just like writing poetry. You know it's hard to write in simple and short sentences. So it actually was a big challenge for me and I really thank the opportunity to be able to do that but I also want to emphasize I think it was a very insightful experience for me too. Because as a practicing physician and a commissioned scientist don't always merge these too few, these two areas in a way to actually see the importance we like to learn the science and try to explore I think clinicians really need to take charge and learn exciting science that's occurring. I think this is a wonderful avenue and I applaud [inaudible 00:18:10] for setting this radio [inaudible 00:18:11]

Caroline: Well listeners you heard it first here on Circulation On The Run it is poetry by Wilson Tang. So please, please pick up a copy of today's journal and don't forget to tune in again next week!

Circulation March 7, 2017 Issue

6 mars 2017 | 15 min

Dr. Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and [inaudible 00:00:06] of the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In just a moment we will be discussing really fascinating preclinical data to suggest that high fiber diet and acetate supplementation may change the gut microbiota and thereby prevent the development of hypertension and heart failure. But first here's your summary of this week's issue.

The first paper describes the impact of heart transplantation on the functional status of children with end stage heart failure in the United States. First author, Dr. Peng, corresponding author Dr. Almond and colleagues from Stanford University, use the organ procurement and transplantation network to identify 1,633 US children age less than 21 years, and surviving one year or more post-heart transplant, from 2005 to 2014, with a functional status score available at three time points. Namely at listing, at transplant, and one year or more post-heart transplant. They found that at the one year assessment 64% were fully active with no limitations, or a functional status score of 10. 21% had minor limitations with strenuous activity, or a functional status score of 9. And 15% scored a functional status score lower than 9. Compared to the listing functional status, functional status at one year post-transplant increased in 91%, and declined or remain unchanged in 9%. Early rejection, older age, African-American race, chronic steroid use, hemodynamic support at heart transplantation, and being hospitalized at transplantation, were all associated with abnormal functional status post-transplant.

These findings may be helpful to patients, families, and referring providers by providing a contemporary picture of the post-heart transplant life in children as they weigh the risks and benefits of transplantation.

The next paper brings cardiac reprogramming one step closer to clinical translation. In this paper by first author Dr. Mohamed, corresponding author Dr. Srivastava, and colleagues from Gladstone Institute of Cardiovascular Disease in San Francisco, the authors used a high throughput chemical screen in post-natal mouse cardiac fibroblasts, and found that transforming growth factor beta, or TGF beta, and WNT, or wint inhibition, enhanced transcription factor based direct reprogramming of cardiac fibroblasts to induce cardiomyocyte like cells in vitro and in vivo. A combination of TGF beta and wint chemical inhibitors increased the quality, quantity, and speed of direct reprogramming, resulting in improved cardiac function after injury as early as one week after treatment. These chemical inhibitors enhanced human cardiac reprogramming and reduced the number of transcription factors needed for human cardiac reprogramming to just four factors. These findings if validated in large animals could facilitate a combined gene therapy and small molecule approach to heart failure.

The next study is the first report of the risks of cardiac mortality among five year survivors of childhood cancer beyond 50 years of age. First author Dr. Fidler, corresponding author Dr. Hawkins, and colleagues from University of Birmingham in United Kingdom, looked at the British childhood cancer survivors study, a population based cohort of 34,489 five year survivors of childhood cancer that was diagnosed from 1940 to 2006 and followed up until February 28th in 2014. The authors quantify the cardiac mortality access risk. Overall 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were two and half times more at risk of ischemic heart disease, and almost six times more at risk of cardiomyopathy or heart failure at death than expected. Among those aged over 60 years, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, 15% of all deaths. Specifically for cardiomyopathy or heart failure deaths, survivors diagnosed between 1980 and 1989 had 29 times the excess number of deaths observed per survivors diagnosed either before 1970 or from 1990 onwards. Thus the authors concluded that excess cardio mortality among five year survivors of childhood cancer remains increased beyond 50 years of age, and has clear messages in terms of preventative strategies. However, the fact that the risk was greatest in those diagnosed in 1980 to 1989, suggests that initiatives to reduce cardio toxicity among those treated more recently may be have a measurable impact.

The last study describes the 30 day results of the Source 3 Registry, that is the European Post Approval Registry of the latest generation of the Sapien 3 trans-catheter heart valve. Dr. Wendler and colleagues from King's Health Partners in London, describe that these 30 day results of the Source 3 Registry demonstrate that trans-catheter uratic valve implantation, or TAVI, using the Sapien 3 resulted in high procedural success with low procedural complications, and excellent post-implant hemodynamics. Moderate to severe paravalvular leakage appeared to be lower with the Sapien 3 than reported with prior versions of this trans-catheter heart valve. Rates of pacemaker implantation were higher with the Sapien 3 than in earlier generations of the valve. This, in combination with the growing experience of patient selection, procedure planning, execution, and post-operative care has led to one of the best short-term outcomes ever reported after TAVI. These results are discussed in an accompanying editorial by Dr. [Altassi 00:06:58], and Dr. [Urani 00:06:58], from the Emery Midtown Hospital in Atlanta, Georgia, where they say that these early results from Source 3 Registry are a source of encouragement with some caveats.

Well, those were your summaries. Now for our feature discussion.

I am so honored to have two lovely ladies join me today on the show. And they are the first author of a feature paper, Dr. Francine Marques from Baker Heart and Diabetes Institute in Melbourne, Australia, as well as Dr. Peipei Ping, associate editor from the David Geffen UCLA School of Medicine. Welcome ladies.

Dr. Peipei Ping: Hi, hello.

Dr. Francine Marques: Hi, thank you for having us.

Dr. Carolyn Lam: As a clinician, I have very very often advised my hypertensive patients to go on the dash diet. And you know, I have no had any trouble explaining the low salt bit, right? I understand it. But then I realize that I've always advocated as well the high fiber bit, not actually really understanding how high fiber directly impacts blood pressure. And I'm so excited because your paper, Francine, shed some light on this and it actually has something to do with the gut. So could you please explain what you did and what you found?

Dr. Francine Marques: So we fed a mouse model called [adoca 00:08:25] model of habitation, that also developed heart failure, we fed them a high fiber diet for three weeks, and then after that we did a surgery to make them become [habitant 00:08:36] safe and we followed them up for six weeks. And what we observed through that trajectory is that mice that were fed a high fiber diet had significantly lower systolic and diastolic blood pressure, and also an improvement in the heart function, and also a decrease in both heart and brainal fibrosis. And the reason why the fiber is so important is because although we usually don't digest the fiber, the bacteria in our gut absolutely love it. And that allows the bacteria, good bacteria to grow. And with that growth we have release of the fermentation of the fiber, releases in short chain fatty acid. So these specific molecules can then be put back into our body and can help us in our health. So we also fed these mice acetate, which is one of the short chain fatty acids, directly and we also observed very good improvements in blood pressure and cardiovascular health.

Dr. Carolyn Lam: It's just fascinating. So these are studies in mice. What do you think of clinical translational aspects of this?

Dr. Francine Marques: Large epidemialogical studies have shown that there is an inverse correlation between fiber consumption and blood pressure. And they have seen this through very small clinical trials looking into the intake of fiber lowering blood pressure. But our study opens the possibility of new interventions using maybe short chain fatty acids specifically, but are also looking into a different type of fiber. So most studies would look into either soluble or insoluble fiber directly. Our study, the diet that we used, is mostly resistant starches. So these are their preferred type of fiber for bacteria growth in our gut. And maybe they use a [inaudible 00:10:32] type of fibers as well could be a new [inaudible 00:10:36] opportunity.

Dr. Carolyn Lam: Peipei, I remember you discussing this paper at our editorial meetings and you so beautifully highlighted the novelty of this paper. Could you share this with our listeners?

Dr. Peipei Ping: Often within many complex studies trying to understand cellular pathways and mechanisms of cardio protection, it's a very important topic as we have had our research focus on in the pas t 25 years. What's very unique and provocative of this particular study is that it simply identified critical metabolic pathways that actually is underlying the protective effects. Many of us have wondered about with eating, for example vegetables or high fiber diet, it is examined specific molecules that have both a direct as well as an endocryne path that would circulate things back to the cardiac muscles, and having the muscles becoming more protective because of regulation of certain transcriptomic pathways to support cardiac muscle contraction. So we were very impressed by both the new concept as well as the state of the art technologies employed in this investigation.

Dr. Francine Marques: Thank you, that's very nice.

Dr. Carolyn Lam: I couldn't agree more, you put it so beautifully Peipei. I thought that it was really nice also linking pathways as well as linking several organ systems. Is there anything you might want to highlight about the renal effects, not just cardiac?

Dr. Francine Marques: Yes. Many times investigations been focusing on if something went wrong how do we cure it? More precious is when we find novel results telling us the healthy individuals, what are the things we should be doing so our blood pressure would stay at the normal level, or our cardiac function is being protected if there's an insult or injury. And so in this situation, the examination of the entire renal transcriptomic do give us very valuable information on how the blood pressure regulation system that maybe actually protected by the short chain fatty acid acetate.

Dr. Carolyn Lam: So true Francine. Anything else to add?

Dr. Francine Marques: Just to say circulation, for giving the opportunity to submit this paper, and share it with the world. We're very very excited about the data.

Dr. Carolyn Lam: Yeah we should be the ones to thank you. It's a beautiful paper. We're very privileged to publish it in circulation. May I ask what are next steps for you? What do you think needs to be done from here?

Dr. Francine Marques: We're validating this in other models now. And we're also looking into the [inaudible 00:13:57] microbiome and how that's related to habitation. So trying to really pinpoint mechanisms and how we can move this forward into the clinic.

Dr. Carolyn Lam: That's so great. And Peipei, do you think that there's certain gaps that urgently need to be addressed now?

Dr. Peipei Ping: Yes, I think one of the most beautiful thing that ... Concept, illustrated this investigation is we really couldn't be just focusing on one organ, our primary interest organ, heart, alone. What's demonstrated here is a beautiful link of both mechanism as well as governed by transforming parbolytes with endocryne effects. How the gut, the kidney, and the heart are all connected together in this process, achieving a better protective condition in the environment for the cardiac muscle.

Dr. Carolyn Lam: Thank you listeners. You've been listening to Circulation on the Run. Tune in next week for even more news.

Circulation February 28, 2017

27 februari 2017 | min

Dr. Carolyn L.: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. On our podcast today we are discussing the role of diastolic stress testing and the evaluation of heart failure with preserved dejection fraction, a really hot topic indeed, but first here's your summary of this week's issue.

The first study tackles the obesity paradox in cardiac surgery, where morbidity and mortality are lower in obese patients. This study sought to ask the question, "Is this due to reverse epidemiology, bias, or confounding?" To answer this question, Dr. Maris Kelko and colleagues from University Leicester in United Kingdom used two separate analysis. One, registry data from the National Adult Cardiac Surgery Registry and two, a systematic review in meta-analysis of studies. Of more than 400,000 patients in the cohort study and more than 550,000 patients in the systematic review, the authors found a U shape association between mortality and body mass index classes, where lower mortality was observed in overweight and obese class one and two patients, relative to normal weight patients, and mortality was increased in underweight individuals.

Now, the obesity paradox has been attributed to reverse epidemiology where the survival benefit associated with obesity is thought to actually reflect worse outcomes in the underweight patients who also had frailty, cachexia, or severe chronic disease. However, in the current study, counter to the reverse epidemiology hypothesis, the protective effects of obesity were less in patients with chronic renal, lung, or cardiac disease and greater in older patients as well as in those with complications of obesity, such as metabolic syndrome and atherosclerosis. Furthermore, adjustments for important confounders did not alter the results. The authors therefore concluded that obesity is associated with lower risks after cardiac surgery with consistent effects noted in multiple analysis even after attempting to address residual confounding and reverse causation.

The authors even went as far as to suggest that their findings do not support common practice where weight loss is recommended prior to surgery or where very obese patients are refused surgery in the morbidly obese. These provocative findings are discussed in an accompanying editorial by Doctor's Carnethon and Kahn from Northwestern University. While the editorialists agree that this well-designed study highlights an important knowledge gap, they pointed out that the obese class two patients had nearly five times greater risk for deep sternal wound infection and 25% higher likelihood of needing renal replacement therapy.

In such patients additional intervention in the perioperative period may still be indicated and include weight loss recommendations and postoperative surveillance for complications. Thus, a more cautious final recommendation may be for future studies to prospectively assess weight loss interventions prior to elective surgery in the context of overall surgical risk as assessed by the EuroSCORE or STS models.

The next paper describes mechanistic studies showing for the first time that nucleoside diphosphate kinase suppresses cyclic-AMP formation in human heart failure. In this paper by First Authors, Dr. Abu Taha and Hagemann, corresponding authors Dr.'s Tobref and Weilend from the Heidelberg University in Germany, the authors performed biochemical studies of nucleoside diphosphate kinase and G Protein signaling in human and rat tissue samples, assessed the functional impact of nucleoside diphosphate kinase C on cyclic-AMP levels and contractility and isolated red cardiomyocytes and determined that in vitro effects of these nucleoside diphosphate kinases on contractility in zebra, fish and mice.

They identified nucleoside diphosphate kinase as the critical isoform for the regulation of G Protein function and cyclic-AMP levels in the heart with important consequences for cardiac contractility. The increased nucleoside diphosphate kinase membrane content in human heart failure could potentially counteract a fading beta adrenoceptor response in the early stages of heart failure by increasing the amount of G Alpha stimulatory proteins in the plasma membrane. However, by switching from stimulatory to G Alpha inhibitory to activation, nucleoside diphosphate kinase may play a role in heart failure progression by reducing cyclic-AMP levels, typical for end-stage human heart failure.

The study, therefore contributes to a better understanding of the molecular processes, underlying alter G Protein signaling in heart failure, and may help to develop new heart failure therapies.

The next study tested the hypothesis, that high intensity interval training is superior to moderate continuous training in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure and reduced ejection fraction.

Doctor Ellingson and colleagues from the Norwegian University of Science and Technology, performed a multicenter trial, comparing twelve weeks of supervised interventions of high-intensity interval training at 90 to 95% maximal heart rate, moderate continuous training at 60 to 70% maximal heart rate, or a recommendation of regular exercise in 261 patients with heart failure and ejection fraction less than 35%, in New York Heart Association class II or III status.

The primary end point of change in left ventricular end-diastolic diameter from baseline to twelve weeks was not different between the high-intensity and moderate continuous groups. There was also no difference between the high-intensity and moderate groups in peak oxygen uptake, although both were superior to the recommendation for regular exercise. None of these changes were maintained at follow up after 52 weeks. Serious adverse events were not statistically different. However, training records showed that 51% of patients exercised below the prescribed target, during supervised high-intensity interval training, and 80% above the recommended target in those with moderate continuous training. Given that high-intensity interval training was not superior to moderate continuous training, in reversing remodeling or improving secondary end points, and considering that adherence to the prescribed exercise intensity based on heart rate was difficult to achieve even in the supervised setting.

The authors concluded that moderate continuous training remains the standard exercise modality for patients with chronic heart failure.

The final paper tells us, that brain emboli after left ventricular endocardial ablation may be more common than we knew. First author Doctor Whitman, corresponding author Doctor Marcus and colleagues from University of California studied eighteen consecutive patients, scheduled for ventricular tachycardia or premature ventricular contraction ablation, over a nine month period. Twelve patients undergoing left ventricular ablation were compared to a control group of six patients, undergoing right ventricular ablation only. Heparin was administrated with a goal activated clotting time of 300 to 400 seconds for all left ventricular procedures. Pre impulse procedural brain magnetic resonance imaging was performed on each patient within a week of the ablation procedure. The authors found that seven of the twelve patients, or 58% undergoing left ventricular ablation, experienced a total of sixteen cerebral emboli, compared with none among patients undergoing right ventricular ablation. Seven of the eleven patients undergoing a retrograde approach to the left ventricle, developed at least one new brain lesion. Thus, more than half of patients undergoing routine left ventricular ablation procedures, experienced new brain emboli after the procedure, even in the absence of clinically apparent stroke.

Future research is critical to understanding the long-term consequences of these lesions and to determine optimal strategies to avoid them. This is further discussed in an editorial entitled "The Sound of Silence". How much noise should we make about post ablation silence strokes? By Doctor Z and Vora from Stanford University. Well, those were your summaries, now for our featured discussion.

I am so thrilled to have with me two special guests to discuss the topic of the diagnosis of heart failure preserved ejection fraction or HFpEF. As you all know, that's my favorite topic and I have favorite people with me today. First, the corresponding author of our feature paper, Doctor Barry Borlaug from Mayo Clinic, Rochester, Minnesota. And, for the first time on the podcast, Doctor Mark Drazner, Senior Associate Editor from UT Southwestern. So, welcome Barry and Mark.

Barry Borlaug: Thank you Carolyn.

Mark Drazner: Thank you, great to be here.

Dr. Carolyn L.: So, Barry, you talked about the role of stress diastolic testing, shall I call it, in the diagnosis of HFpEF in your paper. Could you tell us why you looked at it and what you found?

Barry Borlaug: Sure, Carolyn. When you have dyspnea and fatigue and you got a low EF, it's pretty easy to make the diagnosis of heart failure reduced EF, but we've been struggling for years with making the diagnosis of dyspnea, whether it's HFpEF or not in people with normal ejection fraction. And that's because physical and laboratory and clinical signs of high filling pressures and congestion, are either difficult to see or only present during stress, like physical exercise, in patients. So that's really what motivated us to pursue this study.

We took patients, that were referred to our cath lab for invasive hemodynamic exercise testing, so we directly measured filling pressures, PA pressures and cardiac output reserve, to get a gold standard assessment, whether people have heart failure or not. And then we performed simultaneous echocardiography and blood testing to measure NT-proBNP levels, and then we just looked at what we could figure out. Can you accurately discern HFpEF patients from patients without cardiac dyspnea, using these non invasive estimates.

We saw that a lot of people, with, for example, NT-proBNP levels that are low enough to be where most would consider HFpEF excluded, actually had HFpEF. And we saw that there were modest correlations between non-invasive echocardiographic estimates of filling pressures, specifically the E to E Prime ratio, and directly measured left heart filling pressures. But when we applied the criteria that had been initially proposed, we saw poor sensitivity to make the diagnosis with exercise. And this was largely related to the difficulty with getting all of the different echocardiographic indices, that are currently examined as part of the diastolic stress testing non-invasively. Next, we looked at just adding the exercise E to E Prime, which is an estimate of filling pressures, and when we used the cut-point, that's already been proposed, according to contemporary data, we found that this substantially improved the sensitivity to identify HFpEF, but there was a bit of a trade-off in that specificity decrease.

Dr. Carolyn L.: That's so cool. So let me summarize some of these take-home messages here. First of all, using just rest echo. I was really impressed to see that rest echo indices alone only identifies a third to maybe up to 60% of the patients you found with invasively proven HFpEF. So, we may be specific, but we're really missing quite a number of patients. And then if you exercise them, what your data is really showing is that it's better to exercise them and use this data for the negative predictive value, isn't that what you're saying?

Barry Borlaug: You know, the exercise is really the gold standard, so it gives you both, the negative and positive. With the echocardiography, relying on the exercise E to E Prime ratio, that was really helping us, as you say, Carolyn, with the higher negative predictive value. So most people, that had HFpEF, in this series, where we could get adequate, highly controlled environments, adequate diagnostic echocardiographic data, most people that ended up having HFpEF fit those criteria, we could see an elevation in this E to E Prime on exercise, so it did provide good negative predictive value.

Dr. Carolyn L.: These are just such important data, because I think we're all still struggling with how to make this diagnosis of HFpEF. Mark, could you just share some thoughts on whether you think this is going to really change practice, even change guidelines?

Mark Drazner: I think, if you read this paper, you would recognize it, that it's certainly a critical question that we're all facing, how to make the diagnosis of HFpEF. And all of their guidelines that have been advocated, there really wasn't much data, and these really are the best data out there. So, certainly, it's [inaudible 00:15:41] me a direction of changing practices. Barry says, certainly, the approach will need to be validated, I think, before it reaches high level guidelines, but certainly I think it's a step in the right direction, and points the way towards the future in terms of improving our ability to diagnose HFpEF. And really, that's why both reviewers and [inaudible 00:15:59] this is such an important paper.

Dr. Carolyn L.: Right. Barry, I have a quick question for you though. Doing exercise echo, not easy. E to E Primes are all over the place usually. How easy was it? How feasible was this test?

Barry Borlaug: So, first I'd like to say that we have outstanding, very well-trained, very highly skilled research scenographers, here at Mayo doing this. In very controlled environment, we're providing plenty of time for them to obtain images and that's going to be a question moving forward, because not everybody in clinical practice has that capability. But with that said, in this very controlled environments, skilled scenographers, we were able to measure the exercise data during low level exercise about 85 to 90% of the time and at peak exercise about 75 to 80% of the time. So, it's fairly feasible, but even in this best case scenario, we can't get it on everybody.

Mark Drazner: Even in the [inaudible 00:19:49] echo lab, the recommended approach by the ASE with the four measures. How many times they were not able to acquire all those images, are necessary for those four techniques and so, here you have a [inaudible 00:20:03] of AS echo lab not being able to do that, and being transparent about that, and [inaudible 00:20:08] to the community, saying that, although these are ideal measures, even the [inaudible 00:20:12] perhaps you can't acquire them. I think that was another important point that came out of this and then lead to the focus on the E to E Prime.

Barry Borlaug: I couldn't agree more. You got one of the world renowned labs, very skilled scenographers doing imaging, and we're still not able to get it all in each patient, and that just points to the difficulty of getting really high quality diagnostic images, and a lot of time you need the next level test, when that happens. And invasive exercise testing is really that test, the gold standard.

Mark Drazner: When you get echos from the outside and you look at the E to E Primes, are you confident that the data, that's generally acquired, is gonna be acceptable for this [inaudible 00:20:50]?

Barry Borlaug: Yes and no, I mean I'm always a little bit concerned, but it's not just being a control freak, you know, wanting to see everything, but I think that if it's a still frame doppler, tissue doppler spectrum, you can see that the sample volume is in the right place, and it's really unequivocally normal or abnormal, I feel pretty good about that. Not as good as when they get a full dedicated study here.

Mark Drazner: Of course, the gold standard is also difficult. The invasive measurement.

Barry Borlaug: Yes it is, I didn't [inaudible 00:21:18] that, but we've been doing a lot of invasive exercise tests for the last ten years now. And we do like 250 a year here, so we're really quite [inaudible 00:21:28] but we have all hands on deck in the lab. We have a couple technicians running gas samples around, all over the place. Somebody is on the medgraphics card, measuring oxygen consumption. We've got a nurse in there, that's helping out, so it's complicated, and of course we're using the micromanometer catheters for the pressure assessments, because you get so much more artifacts from width and under damping and over damping with the pressure tracing, so that's also not easy to do if you say.

Mark Drazner: So maybe for practicing cardiologists it's gonna be hard to duplicate that and perhaps spend the energy in terms of doing the exercise echo techniques off the speed, for example. Perhaps, it's another message.

Barry Borlaug: I would agree completely. And I think that again, when you do that, if you do a really high quality exercise echo and it's still not quite definitive, then you can refer on to a center that does have that capability, because obviously it's just reality, not everybody is going to be able to do this. Not every place has the size and resources to be able to do these really advanced tasks.

Dr. Carolyn L.: And do you apply exercise echo now in making your diagnosis? How do you use this data, for yourself, clinically?

Barry Borlaug: We started to think about this, and I think that the best case scenario where the people, that really have an intermediate pretest probability, based on their clinical characteristics. Somebody has jugular distension and a very high NT-proBNP level, and edema, you really don't need further testing, you know that that's going to be HFpEF. And if somebody has no risk factors, and everything is stone cold normal, they don't.

But in some of these people that have some signals, but they don't quite meet criteria, we are doing this, again, if they have adequate echocardiographic images at rest. And then we're looking really carefully at the exercise echocardiography data, one concern from this data, I want to make sure people are very circumspect and really critically looking at the quality of their data, because we shouldn't over-interpret equivocal findings. And as you said earlier, E to E Primes can be all over the map, they're very difficult to obtain during exercise. But I think that if everything looks very high quality and is definitely abnormal or definitely normal, that can be helpful. More so, if it's normal. We did see more false positive, so if it is abnormal, we did suggest that you may want to perform further confirmatory testing, because of the higher false positive rate with exercise echo.

Mark Drazner:

I would say for the listeners, they should take a look at his figure six, which really is a nice diagnostic algorithm, where Barry shows, or advocates, for taking patients with intermediate probability and then using this to restratify that, using [inaudible 00:19:40] approach. I know that, that figure resonated with the editors and the reviewers dramatically, so I'd encourage listeners to take a look at that.

Dr. Carolyn L.: Listeners, you heard it right. [inaudible 00:22:36] Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.

Circulation February 21, 2017

20 februari 2017 | 20 min

Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. I am so excited to be discussing the diabetic HFpEF or heart failure with a preserved ejection fraction phenotype, with world experts and new insights from the I-PRESERVE Trial. That will just be in a moment and here are your summaries first.

The first paper in this issue is a systematic review and meta-analysis of risk factors for Co-Arctation of the Aorta on pre-natal ultrasound. In this paper by first author Dr. Familiari and corresponding author Dr. D'Antonio and colleagues from Arctic University of Norway, the authors performed a systematic review of 12 studies on 922 fetuses with echo-cardiography, and found that those with a post-natal diagnosis of co arctation had significant differences in several cardiac morphological parameters compared to cases without co arctation. The presence of a co arctation shelf, or hypoplastic arch, was associated with a significantly increased risk of co arctation. Furthermore, they reported multi-parametric diagnostic models that were associated with an increased detection rate. Thus, this paper tells us that assessment of left inflow and outflow tracts prenatally may help in stratifying the risk of co arctation.

The next paper reports pre-clinical data that truly represents a paradigm shift in our understanding of vascular resident endothelial progenitors in tissue regeneration. In this paper by first author Dr. Patel, corresponding author Dr. [Cossroterrani 00:02:00], and authors from Royal Brisbane and Women's Hospital in Australia, the authors studied protein expression levels of common endothelial markers in mice using flow cytometry. They discovered an endovascular progenitor cell in vivo that is present in normal endothelium in the aorta and lungs and activated in vessel walls during various endogenic situations, such as in the placenta, skin wound healing, and tumors. They further define at a molecular level an entirely novel endothelial hierarchy from an endovascular progenitor cell to a mature different-shaded endothelial cell via complete RNA sequencing. They further clarify the linage of endothelial progenitors in their origin by using bone marrow transplantation and vascular-specific, lineage-tracing mouse models, showing that the endovascular progenitor cells were derived neither from bone marrow nor from hematopoietic progenitors. This discovery of an endovascular progenitor cell will have significant implications for the development of endothelial progenitors as a cell therapy.

The next paper addresses the chicken or egg question regarding the association between obesity and atrial fibrillation, and this is done using Mendelian randomization to define a causal association between body mass index and atrial fibrillation. In this study by Dr. Chatterjee and colleagues from Massachusetts General Hospital, the authors looked at more than 50,000 European individuals without atrial fibrillation at baseline and showed that genetic variance associated with increasing body mass index were significantly associated with an increased risk of atrial fibrillation. The association between genetically determined obesity and atrial fibrillation persisted even after adjustment for traditional atrial fibrillation risk factors, such as hypertension, diabetes, coronary artery disease, and heart failure. Taken together, these data are consistent with a causal association between increasing body mass index and incident atrial fibrillation. These findings therefore support the primordial prevention of obesity as a significant public health target to combat the expanding global burden of atrial fibrillation.

The last paper provides contemporary estimates of the stroke burden in China, a country which bears the biggest stroke burden in the world. In this paper by doctors Wang and Fagen from the Capital Medical University in Beijing, China and Auckland University of Technology in New Zealand, and colleagues, the authors reported results of a nationally represented door-to-door survey conducted in 2013 in 155 urban and rural centers in 31 provinces in China, totaling 480,687 adults. They found that the age standardized prevalence was 1,115 per 100,000 people, incidence rate was 247 per 100,000 person years, and mortality rates were 115 per 100,000 person years. The stroke prevalence estimates in 2013 were greater than those reported in China three decades ago, especially among the rural residents. Finally there was a north to south gradient of stroke in China, with the greatest burden observed in the northern and central regions. Well, that wraps it up for our summaries. Now for our discussion.

For our featured discussion today, we are talking about my favorite topic and of course that is HFpEF, or heart failure with preserved ejection fraction, and I am so thrilled to have with us today Dr. John McMurray from University of Glasgow, who's the corresponding author of our featured paper referring to diabetes in patients with HFpEF and really talking about the novel results from the I-PRESERVE Trial. Welcome, John!

John McMurray: Thank you Carolyn, it's always a pleasure to speak to you.

Carolyn Lam: Oh, I have been waiting for this one, and I'm so excited I don't know where to begin, but how about with this? Diabetes and HFpEF, first of all, haven't we spoken to death about co-morbidities in HFpEF? And secondly, what makes this paper special? Because we've heard about diabetes and HFpEF from CHARM, from DIG, from Relax, so tell us: why the interest in diabetes and HFpEF?

John McMurray: Sure, Carolyn. I think you and I have been interested in diabetes and heart failure, that terrible combination, for a long time. But I think there's a lot more interest in it today because, of course, we've had several new clinical trials with interventions to lower blood glucose that have showed both beneficial and potentially harmful effects on the development of heart failure. But really what these trials have highlighted is just how common heart failure is as a complication of diabetes. And we strongly suspect, though we don't know for sure of course, but we strongly suspect that most of that heart failure developing amongst patients with diabetes is probably heart failure with preserved ejection fractions. So, I think the context currently is that what's different about our study compared to the ones that you mentioned is that in I-PRESERVE we measured a number of things that were not available in, particularly, the large clinical trials previously. So, in I-PRESERVE we measured natriuretic peptides, we looked at health-related quality of life, and maybe most importantly of all we had a large echo-cardiographic sub study. So I-PRESERVE is quite different than DIG-Preserved and CHARM-Preserved, and of course a lot larger than the RELAX HFpEF study.

Carolyn Lam: I was the associate editor managing your paper and I was so excited about this that I invited an editorial as well by Brian Lindman, and he's got this beautiful table that summarizes what your study really adds to the literature, and I think it's so critical. Could you start by summarizing? What are the main findings?

John McMurray: Well, I-PRESERVE, as you know, was a trial of just over 4,000 individuals with HFpEF defined clinically and with an ejection fraction of 45% or above. There was actually a trial comparing the angiotensin receptor-blocker [inaudible 00:09:17] placebo, though in fact there is no difference in morbidity and mortality between those two treatment groups. So we've looked, as you said, at the patients who had diabetes and compared those to the patients who didn't have diabetes. I think there was some very interesting novel information; if you look at the two subsets of patients, they actually don't differ in terms of age and sex and, importantly, in left ventricular ejection fraction.

But there are other differences that you would expect; for example, many more of the patients with diabetes were obese. But interestingly, and despite that, the patients with diabetes had higher, significantly higher, NT-proBNP levels. So as you know, obesity tends to be associated with lower rather than higher natriuretic peptide levels, so here we were finding higher natriuretic peptide levels in a subset of patients who were actually, by and large, more obese. And there was no difference in other things that might have accounted for that difference; natriuretic peptides, for example, there was no difference in the proportion of patients who had atrial fibrillation.

So that was important, and that's also important when we come to think of outcomes because of course the previous studies reporting worse outcomes in patients with diabetes had not adjusted for natriuretic peptides because they by and large weren't available in the large prior trials. So that, of course, could have accounted for some of the worse outcome.

Some of the other things, features, maybe to pick out in terms of baseline characteristics ... one was that these patients had many more features of congestion, so patients with diabetes had more edema, more often had a raised jugular venous pressure and so on, and that's interesting given some of the recent clinical trial data that we might come back to. And even though the [inaudible 00:11:22] class distribution was not different between patients with diabetes and those without, what was very different was health-related quality of life, which was much worse in patients with diabetes than those without. Now you could if you chose to, Carolyn, look at that as saying that physicians weren't assessing worse functional status or symptomatic status in the patients with diabetes, but the patients were certainly self-reporting a much worse health-related quality of life.

So those were the, sort of, clinical characteristic differences. We did, as I said, have an echo-cardiographic sub study. There were 745 patients in total in the trial who had a detailed echo study, and there were perhaps more modest differences than I might have expected (and I'd be interested in your opinion about this) in patients with diabetes. So they had a somewhat greater, statistically significantly greater left ventricular mass, they had increased early diastolic mitral inflow velocity through E, they certainly had increased E over E prime increased left atrial areas, so there was some left ventricular remodeling and there was some evidence of increased left ventricular filling pressure, maybe diastolic disfunction. But the differences were not very striking; they were there, and as I said previously, ejection fraction (which most of us regard as perhaps not a very good measure of systolic function) was similar between the two groups. We didn't look at more sophisticated and [inaudible 00:13:09] measures of systolic functions so those could have been different, we just don't know.

So that's the baseline clinical features and baseline echo-cardiographic findings. And then, of course, we followed these patients for a median of just over four years and what we found was that the cardiovascular and all cause mortality was about twice as high in patients with diabetes as in those without. And if you adjust for conventional clinical variables, including NT-proBNP, which is individually the most powerful predictor of outcome, you only very slightly attenuate that greater risk associated with diabetes. The risk of heart failure and hospitalization was also about doubled in an unadjusted analysis, but that was more attenuated in the adjusted analysis. But you've also got to remember that, of course, the patients with diabetes were not surviving as long, so the very fact that they had a substantially higher risk of heart failure and hospitalization despite a shortened longevity is important.

Then lastly, again I think a fairly unique aspect of this study was that we then added the echo-cardiographic findings into the multi-variable model [inaudible 00:14:33] because it was only a subset of patients in which we had echo-cardiographic measurements. The statistical reliability of this is not as robust as in the main model, but what we saw was that there was more attenuation of the risk associated with diabetes when you added in the remodeling and diastolic dysfunction findings that we saw in the echo-cardiographic sub study. So that's a summary, I think, of the key points.

Carolyn Lam: John, I was really impressed and struck by the consistency of the message, which is what I really appreciated. What you added to the field was this consistent message that the diabetic HFpEF just had more signs of fluid overload in general, be it clinical, be it by NT-proBNP, be it by echo. And I thought that was something you said it was a moderate difference by echo; it was enough to be convincing to me, and I really appreciated that. The fact that adding the echo findings attenuated the significance ... you know we went back and forth about that quite a bit together, didn't we?

John McMurray: We did.

Carolyn Lam: I think at the end it is consistent, it is useful information. It tells me that perhaps some of these outcomes are mediated by this access fluid, to me, at least part of it. And I think that is how we ended up expressing it in the final paper.

John McMurray: I think you are absolutely spot on, Carolyn, because I don't think I had anticipated that the features of congestion would be so different. And you are correct in that, of course, correlates very well with natriuretic peptides, with the left atrial enlargement and so on.

And then of course (and this is clearly extrapolation) but then of course it makes one wonder about some of the trials with diabetes drugs that we've seen. The TZDs, glycosomes, which calls a little bit of fluid retention, of course precipitating heart failure, and then the opposite recently with the SGLT2 inhibitors which of course are diuretics, and those drugs preventing the development of heart failure.

And it does make me wonder if the diabetic phenotype maybe was a little bit of renal dysfunction, some subtle renal dysfunction, is a sodium and water avid phenotype state and that it doesn't take very much to tip those patients into frank heart failure and perhaps we need to think (and I think you might have been alluding to it) think about insuring that we adequately diurese these patients given that in this study where people were supposed to be optimally treated, clearly there was still a lot of evidence of residual fluid overload.

Carolyn Lam: I absolutely agree, and yes you read my mind that I was going to allude to the implications for therapies that have a diuretic effect, you know, like the SGLP2 inhibitors and in fact this was discussed in Brian Lindman's editorial, which is a must read.

Just another question though. What do you think of peripheral mechanisms contributing to all this?

John McMurray: Yeah, obviously there is the kidney aspect that we saw a relatively small difference in estimated GFR. Of course that only tells you one aspect of renal function and the nephron in diabetes may well be sodium avid maybe more likely to retain water. So certainly the kidney as a peripheral mechanism might be very important.

And then of course the blood vessels, I mean there's no question that patients with diabetes have more abnormal endothelial function probably have got enhanced vascular stiffness. And of course we know from a long time ago at least in HFrEF (I'm not so sure about HFpEF) but in HFrEF there's evidence that some of the vascular stiffness you see in patients with HFrEF is actually due to sodium in the vessel wall and there's some beautiful old-style clinical physiology experiments showing that if you diurese patients with HFrEF you restore vasodilation you restore basal motor responsiveness. It could also be true in HFpEF though of course patients with HFpEF and many other reasons to have vascular stiffness.

So yes, peripheral mechanisms may well be important. Your humoral abnormalities may be more pronounced in patients with HFpEF and diabetes compared to those without diabetes. We don't know because I'm not sure that's been measured very often. Certainly natriuretic peptides are, but what about things like the angiotensin system and arginine/vasopressin and the sympathetic nervous system. You know, there's still so much to study looking at patients with heart failure with and without diabetes because they're really quite distinct. And whatever's going on it makes a big difference the way those patients feel, what they can do, and what happens to them.

Carolyn Lam: Yeah, and your study really establishes that. Congratulations once again John, it's just been such a delight chatting with you.

John McMurray: Likewise, Carolyn.

Carolyn Lam: Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and turn in next week!

Circulation February 14, 2017 Issue

13 februari 2017 | 19 min

Dr. Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our podcast is taking us to Japan today where we will be talking about aspirin for primary prevention in patients with diabetes. First, here's your summary of this week's issue.

The first study provides insight into the development of neurologic injury in patients with single ventricles undergoing staged surgical reconstruction. In this paper by Dr. Fogel and colleagues from the Children's Hospital of Philadelphia, the authors recognize that single ventricle patients experience greater survival with staged surgical procedures culminating in the Fontan operation, but experience high rates of brain injury and adverse neurodevelopmental outcome. They therefore studied 168 single ventricle patients with MRI scans immediately prior to bi-directional Glenn, prior to the Fontan, and then three to nine months after the Fontan reconstruction. They found that significant brain abnormalities were frequently present in these patients and that the detection of these lesions increased as children progressed through staged surgical reconstruction. In addition, there was an inverse association of various indices of cerebral blood flow with these brain lesions. This study therefore suggests that measurement of cerebral blood flow and identification of brain abnormalities may enhance recognition of single ventricle patients at risk for poor outcomes, and possibly facilitate early intervention.

The next paper uncovers a unique mechanism underlying arrhythmogenesis and suggests that the anti-epileptic drug valproic acid may possibly be repurposed for anti-arrhythmic applications. In this paper by first authors Dr. Chowdhury and Liu and corresponding author Dr. Wang and colleagues from University of Manchester UK. The authors used mouse models and human induced pluripotent stem cells derived cardiomyocytes to discover a new mechanism linking mitogen activated kinase-kinase 7 deficiency with increased arrhythmia vulnerability in pathologically remodeled hearts. Mechanistically, mitogen activated kinase-kinase-7 deficiency in the hypertrophied hearts left histone deacetylase-2 unphosphorylated, and filamin A accumulated in the nucleus, which then formed an association with kruppel-like factor 4 preventing its transcriptional regulation. Diminished potassium channel reserve caused repolarization delays resulting in ventricular arrhythmias, and the histone deacetylase-2 inhibitor, valproic acid restored potassium channel expression abolishing the ventricular arrhythmias. This study therefore provides exciting insights in developing a new class of anti-arrhythmics specifically targeting signal transduction cascades to replenish repolarization reserve, all for the treatment of ventricular arrhythmias.

Does the Mediterranean diet improve HDL function in high risk individuals? Well, the next paper by first author Dr. Hernaiz, corresponding author Dr. Fito and colleagues from Hospital Del Mar Medical Research Institute in Barcelona, Spain addresses this questions. The authors looked at a large sample of 296 volunteers from the PREDIMED study and compared the effects of two traditional Mediterranean diets, one enriched with virgin olive oil, and the other with nuts to a low-fat control diet. They looked at the effects of these diets on the role of HDL particles on reverse cholesterol transport, HDL antioxidant properties, and HDL vasodilatory capacity after one year of dietary intervention. They found that both Mediterranean diets increased cholesterol efflux capacity and improved HDL oxidative status relative to the baseline. In particular, the Mediterranean diet enriched with virgin olive oil decreased cholesterol ester transfer protein activity, and increased HDL ability to esterify cholesterol, paraoxonase-1, arylesterase activity, and HDL vasodilatory capacity. They therefore concluded that adherence to a traditional Mediterranean diet, particularly when enriched with virgin olive oil, improves HDL function in humans.

The final study tells us that among hospitalized medically ill patients, extended duration Betrixaban reduces the risk of stroke compared to standard dose enoxaparin. In this retrospective sub-study of the APEX trial, Dr. Gibson and colleagues from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts randomized 7,513 hospitalized acutely ill patients in a double-dummy, double-blind fashion to either extended duration of the oral Factor Xa inhibitor Betrixaban at 80 mg once daily for 35 to 42 days, or standard dose subcutaneous enoxaparin at 40 mg once daily for 10 days all for venous thromboprophylaxis. They found that the extended duration Betrixaban compared with enoxaparin reduced all cause stroke by almost one half with a relative risk of 0.56 equivalent to an absolute risk reduction of 0.43 percent and number needed to treat of 232. The effect of Betrixaban on stroke was explained by a reduction in ischemic stroke with no difference in hemorrhagic stroke. The reduction in ischemic stroke was confined to patients hospitalized with acute heart failure or non-cardioembolic ischemic stroke.

This paper is accompanied by an editorial by Drs. Quinlan, Eikelboom, and Hart in which they articulate three reasons that they think these results are important. First, the results demonstrated an unexpectedly high rate of new or recurrent ischemic stroke during the first three months in hospitalized medical patients receiving standard enoxaparin prophylaxis, the rate being even higher in patients presenting with heart failure or ischemic stroke. Secondly, the data demonstrated for the first time that a NOAC reduces the risk of ischemic strokes in patients without known atrial fibrillation. Thirdly, the effects of Betrixaban on stroke were dose dependent, all of the benefits were seen in those who received the 80 mg dose, whereas the 40 mg dose did not provide advantages compared with enoxaparin or placebo. While these results are encouraging, the editorialists also warn that these are based on a post-hoc analysis and should be considered hypothesis generating.

Well, that brings it to the end of our summaries. Now for our feature discussion.

Today our feature discussion focuses on the exciting 10-year follow up results of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes, or JPAD trial. I am simply delighted to have with me first and corresponding author Dr. Yoshihiko Saito from Nara Medical University, Japan. As well as a familiar voice on this podcast, Dr. Shinya Goto associate editor of Circulation from Tokai University in Japan. Welcome gentlemen!

Dr. Goto: I am very pleased to have this opportunity. I am always enjoy listening your podcast, and this is very interesting topic of aspirin in prevention cardiovascular event in patients with diabetes, type II diabetes.

Dr. Lam: I couldn't agree more, because the burden of cardiovascular disease globally is actually shifting to Asia, and the burden of diabetes especially, is one of the fastest growing in Asia. So a very, highly relevant topic indeed. Could I start, Yoshi, by asking you: these are the 10 year follow up results, what inspired you to take a re-look at the original JPAD results and to report this 10 year result?

Dr. Saito: The American guidelines said that low-dose aspirin is recommended to the type II diabetes patient for the primary prevention of cardiovascular events who are older than 30 years old, and who are not contraindicated to aspirin. That meant that almost all type II diabetes patients were recommended to low dose aspirin. However, at that time there was no direct [inaudible 00:09:49] evidence for it. So we connected the prospective randomized control trial that examined the effects of the low dose aspirin on primary prevention of cardiovascular events in type II diabetes patients without preexisting cardiovascular disease. The name of this trial, JPAD trial, that stand for the Japanese Primary Prevention of Atherosclerosis with aspirin in Diabetes. We enrolled 2,539 patients who were assigned to the low dose asprin group or the no aspirin group. So we followed them with a median follow up period of 4.4 years.

The results of the original JPAD trial were that low dose aspirin reduced CV events by about 20%, but the reduction could not reach statistical significance. So I don't know the exact reason, but one is the reason is low statistical power, because event rate was about one-third of the anticipated. Another reason is that low dose aspirin really could not reduce cardiovascular events. So we decided the extension of the follow up of the JPAD trial to elucidate the efficacy and safety of long term therapy with low dose aspirin in type II diabetes patients. This extension study was named the JPAD 2 study. We followed them up to the median follow up period of more than 10 years.

In this time the JPAD trial study, we analyzed the patients in a pod protocol method because the randomized control trial was ended after 2008. Finally, we analyzed the 992 patients in the aspirin group, and 1,168 patients in the no aspirin group who retained the original allocations throughout the study period. The primary endpoint were composite endpoint of cardiovascular events including sudden cardiac death, the fatal and the non-fatal coronary artery disease, fatal and non-fatal stroke, peripheral vascular disease, and aortic dissection. This end point is the same as the original JPAD trial. The main results are the primary endpoints, 15.2% of patients occurred primary endpoints in aspirin group, and 14.2% in the no aspirin group occurred in the primary endpoints. So the primary endpoints rate is singular in both groups, with the hazard ratio is 1.14 with a 95% CI is 0.91 to 1.42 with a p value of 0.2 by log-rank test. So the low dose aspirin therapy could not reduce cardiovascular events in the type II diabetes mellitus.

We also analyzed these data by intention to treat analysis, the results is singular. Again, the low dose aspirin therapy could not reduce the cardiovascular event in type II diabetes mellitus. However, I was told the hemorrhagic events, total hemorrhagic events was singular in both groups, but gastrointestinal bleeding of about 2% in the aspirin group but only 0.9% in no aspirin group. That means our gastrointestinal bleeding is doubled in the aspirin group compared with no aspirin group. This is the main outcome of the JPAD and JPAD-2 trials.

Dr. Lam: Thank you so much Yoshi, and really congratulations on such a tremendous effort. I completely applaud the idea of looking at the 10 year follow up trying to address the issue of whether or not it was a lack of power that limited JPAD-1, but what you found really reinforced what you found in JPAD-1, which is low dose aspirin did not reduce cardiovascular events in the diabetic group. They're still huge numbers, I'm so impressed that 85% of the treatment assignment was retained. Then furthermore you even showed increased gastrointestinal bleeding with aspirin. So really remarkable results. Can I just ask, are you surprised by the results, and how do you reconcile it with what was found in the general population studies like the Physician Health Study, or the US Preventive Services Task Force, where they really seem to say that primary prevention aspirin works in the general population when your risk is a certain amount?

Dr. Saito: I think that we studied only the type II diabetes patients, so it is not clear that our results are applied to the general population, but our results is very much similar to the current European guidelines and American guidelines.

Dr. Lam: That's a very interesting point about diabetic versus non-diabetic population and the utility of low dose aspirin. Shinya, you brought this up before. What do you think?

Dr. Goto: For the primary prevention population cohort study, aspirin demonstrated 25% reduction of cardiovascular event. We are not recommending aspirin for primary prevention due to the balance of bleeding and cardiovascular protection, absolute risk. In Yoshi's paper, in patients with type II diabetes aspirin evened that [inaudible 00:16:13], and that is very important message he had shown in this long term outcome randomized trial.

Dr. Lam: Do you think that there are some pathophysiologic differences when you study a diabetic versus non-diabetic population?

Dr. Goto: Yes, that is a very important topic, and we have very nice review paper by Dr. Domenico and Fiorito. In patients with diabetes the platelet time over becomes relatively rapid as compared to general population. New platelets come to blood and COX-1 inhibition by aspirin cannot reach to enough level in diabetes patient. Still, this [inaudible 00:16:57] hypothesis, very interesting hypothesis.

Dr. Saito: I think so, I think so. That review that proposed the same concept, their higher dose of aspirin as possibly effective for diabetic patient.

Dr. Lam: That's interesting. Are you planning any future studies Yoshi?

Dr. Saito: Yeah, maybe two times study.

Dr. Goto: But anyway, the event rate is currently very low than the old [inaudible 00:17:28]. So the sample size should be huge. Huge sample size is needed for the primary prevention setting to analyze the effect of aspirin, so the number needed to treat in the primary prevention setting is more than 1000. If diabetes patient, aspirin is resistant to aspirin so the number needed to treat is getting larger. So the sample size is getting larger and larger. That is not practical to perform that clinical trial.

Dr. Lam: That's a very good point that the contemporary trials like yours are really challenged by the low event rates because of improved preventive treatment across the board like high dose statins, like very, very low LDL targets, and so on. That's a good point. Actually, could I ask both of you gentlemen, and maybe Shinya you can start, can you let us know what is it like to perform such a large rigorous clinical trial in Japan? It must be a lot of effort. Could you give us an idea?

Dr. Goto: In Japan, medical care system is a little bit different from the U.S. Every patient covered by the homogeneous health care system so it means it is rather difficult to conduct a clinical trial. I appreciate the effort by Professor Saito, Yoshi, it is extremely difficult to conduct the study. Japan is relatively small island, patient stick to the clinic so the long term follow up with relatively low follow up can be expected. [inaudible 00:19:15] number of patients is a challenge, and Yoshi did succeed it. We can do that and due to the baseline therapy is quite homogenous, impact of the clinical care like this has very strong impact.

Dr. Lam: Exactly, and I share your congratulations once again to Yoshi for really tremendous effort, important results. Thank you so much Shinya for helping with this paper, and for really highlighting how really important it is. Did anyone have anything else to add?

Dr. Saito: Yes, I have one thinking, in respect to the Japanese clinical trials. I think the Japanese evidence, as derived from Japanese clinical studies is getting better and better in quality. Almost all Japanese clinical trials enrolled only Japanese patients, so the way the Japanese not so good at to organize the international clinical trial because of the, one is the language problem, and the other is funding problem. In Japanese funding agency, the AMED, that is similar to the NIH in United States, but AMED is not so strong as NIH so that they cannot give a bigger budget to the Japanese clinicians. That is another problem to organize a big clinical trial. The funding [inaudible 00:20:49] apprenticeship without holding investigators are very, very important to be better clinical situation in Japan, I think so.

Dr. Lam: Thank you for listening to Circulation on the Run, don't forget to tune in next week.

Circulation February 7, 2017 Issue

2 februari 2017 | 13 min

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from The National Heart Centre and Duke-National University of Singapore.

Today is special, special, special because here with me is the editor of special populations and that is Dr. Sharon Reimold from UT Southwestern, who is the editor handling the special issue for Go Red For Women.

Welcome, Sharon.

Dr Sharon Reimold: Thank you, Carolyn. I'm happy to be here.

Dr Carolyn Lam: This is so cool. Just us ladies chatting about issues that we need to be talking about.

Now first of all, this is the first time that Circulation is doing a focus issue for Go Red for Women. Could you tell us a little bit more about that?

Dr Sharon Reimold: Sure. The Go Red for Issue campaign has been around for many years. The editorial staff realized that we really hadn't had an entire issue devoted to cardiovascular issues in women. We decided several months ago to try to make this a reality and asked for submissions of articles and we’re delighted to see the interest that our cardiologists across the country had, as well as across the world, in submitting their research for consideration in this issue.

Dr Carolyn Lam: I know. There are seven original papers. There are review papers. There are research letters. It's an amazing issue.

Dr Sharon Reimold: We had hoped to focus on a lot of different areas in which heart care in women is influenced. We're really quite delighted that we had papers on pregnancy, papers related to strategies to get women involved in trials. We were able to look at novel risk factors in women, and also, have an excellent review about arrhythmias in women versus men that I think everyone will want to take in.

Dr Carolyn Lam: Yeah. Congratulations once again right off, but let's jump straight into this set of twin papers that deal with post MI outcomes and sex differences. There've been quite a number of publications on this. What makes these two papers special?

Dr Sharon Reimold: I think these papers are special because they're trying to think more deeply into why women tend to get re-hospitalized after a heart attack more often and what are the reasons that they're getting readmitted.

For instance, it seems that women, as we know, may get a variety of different symptoms that are their equivalent or anginal equivalent after they've been in the hospital and also before they were in the hospital. I, personally, suspect that when somebody comes to the hospital with chest discomfort and they've recently had a heart attack, then often times, they get readmitted and re-hospitalized.

These papers are starting to look at mechanisms, why this happens. I think this will be the bridge to the point where we figure out what can we about this, to hopefully, make men and women more equal in this regard.

Dr Carolyn Lam: That's so true and well put. I also found very, very interesting and important that paper that really highlighted the importance of coronary flow reserve and microvascular ischemia, not just obstructive disease. Can you say a few words about that paper?

Dr Sharon Reimold: Sure. It's been known for a long time that if you perform catheterizations on men versus women with similar presentation ... Women may not have as much obstructive disease. This particular manuscript explores coronary flow reserve and identifies this as being part of the difference between men and women in that regard. That, obviously, could have important implications for the clinical care of these patients.

Dr Carolyn Lam: I like that. All these papers really took what we may have known a bit before, but took them to a deeper level and in a very novel way. So important. You mentioned some of the novel aspects that were also explored in the issue, the pregnancy related factors, in fact, novel risk factors that we should be taking note of in women. Do you want to comment on a few highlights?

Dr Sharon Reimold: The relationship of pregnancy complications to long term, both maternal and offspring health has been around for a while, but really, we don't know very much about it. We, certainly, have known previously that women with preeclampsia, or those who have significant hypertension, or diabetes in pregnancy may have later problems when they are in middle age or older.

What we are learning from some of these new entries into the research domain is that women who have premature labor and delivery are also at risk for having complications, and this sort of fits in the middle. It's not just preeclampsia, or hypertension, or diabetes. It's that you delivered earlier. Then moreover, we have a couple of research focused letters that describe arrhythmias in pregnancy and what happens to those women during pregnancy. I think we all have seen young women come in and have symptoms, but we really don't know what their outcome has been because any single physician probably just sees a few of them. This highlights arrhythmias as a issue in that population.

We also looked at other articles that focused on other risk factors for heart disease, ranging from breast arterial calcification to traditional biomarkers that we may be drawing in hospital, BMP, troponin, and such. There's a nice manuscript that focuses on hormone changes in women and how they're associated with development of cardiovascular disease. So a fairly broad look at a variety of different risk factors that we don't think about when we're simply asking, "How old are you? What's your blood pressure? What's your diet? Do you have diabetes, and do you have lipid disorders?"

What I would hope that we would get out of this is to open all of our minds and our approaches to patients to think about asking about their pregnancies, did they have any complications, figuring out if they have any hormonal issues, and then being free to consider whether or not the woman that you have in front of you actually has obstructive disease or perhaps has issues with abnormal flow reserve.

Dr Carolyn Lam: Exactly. I would, actually, add to that, also, looking at our commonly used cardio metabolic biomarkers with the lens of realizing that there are important sex differences in all these biomarkers. That was a very nice paper, corresponding author, Dr. James de Lemos. All these papers are just so practical.

I'm actually going to switch tracks now, Sharon, because I really want to talk about this final paper. All I need to do is read the title of the editorial and it’ll be self-evident. "Women are less likely than men to be full professors in cardiology. Why does this happen and how can we fix it?" I love that you invited this editorial. Could you tell us a bit about the paper that sparked this editorial and your thoughts on this?

Dr Sharon Reimold: Yes. The original article has as its first author, Dr. David Blumenthal. It's an article that's one of a series of manuscripts that looked at academic cardiologists and looked at faculty rank where they were able to gather data on sex differences, clinical productivity, research funding, publications, et cetera. They have looked at other disciplines other than cardiology, but this particular manuscript focuses on cardiologists. What it demonstrates is that we are getting, perhaps, a little bit more women in at the assistant professor level, but there’s still a significant lag at the full professor level.

In fact, in many centers if you query development offices, there's probably at least a seven year lag between women and men in terms of making it through the whole spectrum. While perhaps, this is not new conceptually, I think it does quantitate it for us and it highlights the concept that this is an issue now, similarly to what it was 25 years ago when I was a cardiology fellow.

The interesting compliment to this is the editorial by Dr. Karns and Dr. Bairey Merz which tries to go into why does this happen and how can we fix it. They took a very academic approach to their editorial in terms of looking at data and then talk about implicit bias and how even a very small degree of implicit bias will cause men to be promoted, perhaps more in a faster manner than in women, and also bring up some things we don't even think about. One of the best ones was the concept that you advertise for a new position as a cardiologist. If you advertise for someone and you list the skills you want and what you want to build, then that's a more gender neutral way to approach a job. If you advertise for a dynamic, outgoing, I don’t know, vigorous sort of person, and there are ads out there that read like that, you are, inadvertently, advertising for a man, most of the time.

Dr Carolyn Lam: Male characteristics.

Dr Sharon Reimold: Yeah. They talk about that. Then they obviously end up with how can we fix it? I think that's a real challenge.

There are some data within the field of literature for development that suggest that mentoring and coaching are important, but that they don't necessarily push people up the ladder very rapidly. There are some places, for instance, our University of Texas system now that is very interested in the concept of sponsorship. That someone sponsors another individual, could be male or female, to get involved and pushes them ahead, not pulls them, so that they have opportunities for faster career development and success. In any event, I think this compliment of paper and editorial really highlights an issue that, while not necessarily affecting female patients, certainly affects cardiology as a destination career.

Dr Carolyn Lam: I agree. I think part of the how to fix it is simply by being aware and acknowledge the issue. That is exactly what we’re doing in these papers. I love that they are academically written. Like you said, you read a lot about these gender biases in the popular press, but it's so refreshing to see it addressed in an editorial, in a beautiful paper, in circulation.

Sharon, congratulations on just this excellent, excellent issue. Is there anything else you may want to highlight about the issue?

Dr Sharon Reimold: I think that's the major thing. I think we moved a long way from the beginning of Go Red For Women as a campaign where we really wanted patients to be aware that hypertension or elevated cholesterol levels were an important issue. I think now is a time where we move forward. We’ll learn more about differences between men and women and we figure out how we can treat or account for these differences as we strive to make health care for all and cardiovascular care for all improve over time.

Dr Carolyn Lam: Thanks Sharon. Everyone of you listening to this, go pick up this issue. I'm sure we've peaked your interest.

Thank you for listening to Circulation On The Run. Don't forget to tune in next week.

Circulation January 31, 2017 Issue

30 januari 2017 | 17 min

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke-National University of Singapore. Our featured discussion today relates to 20 year outcomes after mitral valve repair versus replacement for severe degenerative mitral regurgitation.

But first, here's your summary of this week's issue. The first paper suggests that agonistic angiotensin receptor autoantibodies may be biomarkers of adverse outcomes. In this study from first author Dr. Abadir, corresponding author Dr. Fedarko, and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, authors developed a quantitative immunoassay for measuring agonistic angiotensin AT1 receptor autoantibodies in the serum.

They then assessed its operating characteristics in a discovery group of 255 community dwelling adults from Baltimore and validated these findings in a second group of 60 individuals from Chicago. They found that AT1 receptor autoantibody levels were significantly associated with higher levels of inflammatory cytokines, weaker grip strength, slower walking speed, higher risk for frailty, more falls and increased mortality.

Furthermore, chronic treatment with angiotensin receptor blockers, it attenuated the AT1 receptor autoantibody association with decline in grip strength and increased mortality. These results therefore suggest that followup studies and intervention trials in chronic inflammatory diseases should test whether AT1 receptor autoantibody levels can be used to stratify patient risk and whether they can be used to identify patients who may benefit from angiotensin receptor blocker treatment.

The next paper suggests that baseline target mismatch on CT perfusion imaging may predict the response to tenecteplase in ischemic stroke. Dr. Bivard and colleagues from John Hunter Hospital University of Newcastle in Australia pooled two clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke.

Baseline CT perfusion was analyzed to assess if patients met the diffused two target mismatch criteria. These criteria are absolute mismatch volume of more than 15 mL, mismatch ratio of more than 1.8, baseline ischemic core less than 70 mL and volume of severely hypoperfused tissue less than 100 mL.

Among 146 pooled patients, 71 received received alteplase and 75 received tenecteplase. Overall tenecteplase treated patients had greater early clinical improvement by NIH Stroke Scale change and less parenchymal hematoma, but did not show a significant difference in three month patient outcome by the Modified Rankin Scale.

74 of the 146 patients met target mismatch criteria. It was only among these patients with target mismatch that treatment with tenecteplase result in greater early clinical improvement and better late independent recovery than those treated with alteplase. In summary, tenecteplase may offer an improved efficacy and safety profile versus alteplase, benefits that are possibly exaggerated in patients with baseline CT perfusion defined target mismatch.

The next study is the first to provide a comprehensive analysis of circulating metabolite levels and relate these to clinical outcomes in patients with pulmonary arterial hypertension. First author Dr. Rhodes, corresponding author Dr. Wilkins and colleagues from Imperial College London conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry in 365 patients with idiopathic or heritable pulmonary arterial hypertension and 121 healthy controls.

They found that increases in circulating modified nucleosides originating from transfer RNAs, energy metabolism intermediates, tryptophan and polyamine metabolites and decreased steroids, sphingomyelins and phosphatidylcholines independently discriminated pulmonary arterial hypertension from controls and predicted survival. Furthermore, correction of metabolite levels overtime was linked to better clinical outcomes and patients who responded well to calcium channel blocker therapy had metabolic profiles comparable with healthy controls, thus these findings suggest that monitoring plasma metabolites overtime could be useful to assess disease progression and response to therapy in pulmonary arterial hypertension. Therapeutic strategies targeted against metabolic disturbances, particularly translational regulation and energy metabolism, may merit further investigation in pulmonary arterial hypertension.

The final study takes a contemporary look at age associated changes in left ventricular diastolic function. Dr. Shah and colleagues from Brigham and Women's Hospital in Boston, Massachusetts related diastolic measures including tissue Doppler E prime, E to e prime and left atrial size, to the risk of heart failure hospitalization or death in 5801 elderly participants in the ARIC study. They further defined sex-specific 10th percentile limits in 401 participants free of cardiovascular disease or risk factors. They found that each diastolic measure was robustly associated with incident heart failure hospitalization or death. Reference limits for E to e prime and LA size were generally in agreement with existing guidelines, whereas limits for tissue Doppler E prime were substantially lower at 4.6 for septal E prime and 5.2 for lateral E prime in the ARIC study compared to 7 and 10 respectively in international guidelines. Compared to the guideline cut points, the ARIC base limits improved risk discrimination and reclassified over one-third of the study population as having normal diastolic function. These findings were further replicated in the Copenhagen City Heart Study.

In summary, this study suggests that a decline in left ventricular longitudinal relaxation velocity occurs maybe as part of healthy aging and is largely prognostically benign. This supports the use of age-based normative values when considering an elderly population.

Well, that wraps it up for the summaries, now for our featured discussion.

Today we are discussing the very important result of the mitral regurgitation international database and we have with us today no other than the corresponding author Dr. Jean-Louis Vanoverschelde, and he is from University of Louvain in Brussels. Welcome Jean-Louis, I made it.

Dr Jean-Louis Vanoverschelde: Hey, how are you?

Dr Carolyn Lam: Thank you so much for joining us. Also joining us today is Dr. Victoria Delgado, associate editor from Leiden University Medical Center in the Netherlands. Welcome Victoria.

Dr Victoria Delgado: Hello. Thank you very much for having me in this podcast.

Dr Carolyn Lam: So, severe degenerative mitral regurgitation with flail leaflets, a very important condition and your study, Jean-Louis, really provides important clinically applicable information. Could you please address our clinicians out there with a take home message from your paper.

Dr Jean-Louis Vanoverschelde: Well, the take home message is very easy, once this condition needs to be operated on, there are really two options, one which is to repair the valve and keep the native tissue and the other is to replace the valve and trash the native tissue if I can say so. The results of the study are really clear. There is a major survival advantage by repairing the valve as opposed to replacing it. So for everyone of those who have degenerative mitral regurgitation with flail leaflets, the best treatment option is mitral repair.

Dr Carolyn Lam: Now these results came from a multi-center registry of thousands of patients. I was really struck with the duration of the study. I think that's something that's really novel. You had a 20 year follow up but also patients were recruited from 1980 all the way to 2005, am I right? So could you expand a little bit about the possibility of techniques changing during that period?

Dr Jean-Louis Vanoverschelde: Although there has been subtle changes in the practice, the basic principle have remained the same. So we have not really accounted for these changes in the practice over time, with regard to what happened to mitral valve replacement, clearly the prostheses that were there 30 years ago are not the same as the ones that are currently implanted to the patients, but none the less when we performed an analysis, a sensitivity analysis to look at whether the results were different from 20 years ago compared to those that were more recent, we found exactly the same result.

Dr Carolyn Lam: Yes, I thought that was a very important sensitivity analysis. Tell us a bit more about the propensity score matching as well because another thing people will be thinking is, you know, this is a registry, huge numbers very important but obviously there would be differences in indication for repair versus surgery.

Dr Jean-Louis Vanoverschelde: For sure, the fact is that there are statistical means that allow you to mimic not to be the exactly the same as, but to mimic randomization and it is the propensity score matching. That means that you perform a prior analysis that will identify similar patients in the two cohorts and match them so that you are basically having the same kind of patients that are treated with two different ways. So it's not randomization but it’s getting close to randomization when you use cohorts like the one from the MIDA registry.

Dr Carolyn Lam: Perfect. Victoria, did you take the same take home messages and are you applying this clinically? I noticed that you invited an editorial, a lovely editorial on this paper as well, so please share your thoughts.

Dr Victoria Delgado: Yeah, I share the same take home message that Dr. Vanoverschelde has outlined. I think that this is very important article, it's a landmark article highlighting one of the most important things that mitral valve repair should be probably the standard of care for patients with severe mitral regurgitation without degenerative cause with a flail and the article basically what it does is also endorsing the recommendations of current guidelines highlighting the value of mitral valve repair. Of course that mitral valve repair should be performed in centers with experience and with good durability of these repairs, so the centers need to have a good heart team where they can analyze their results in such a way like the MIDA registry has done demonstrating a good durability of the repair.

Dr Carolyn Lam: And do you have anything to add to that Jean-Louis?

Dr Jean-Louis Vanoverschelde: No, I think basically Victoria very well summarized the basic features not only of the paper itself but also of the condition and what currently is in the guidelines. In fact, the guidelines have already said that we should be preferring mitral valve repair over replacement, but the data on which this was based were probably not as conclusive as the one that are provided by this analysis of our registry, so I think it's really reinforcing the idea that we should go ahead and try to perform repair as much as possible, now with a caveat of course that the surgeons need to be skilled enough to perform that. But with the type of differences that we see in survival between the two cohorts I think that if a surgeon does not feel comfortable with repairing the valve and would rather replace it, he might refer the patient to another surgeon that is capable of repairing the valve. The impact and outcome is such that I think this really supports the idea that the patient should be referred to high volume and skilled centers.

Dr Carolyn Lam: Could you give us an idea of what kind of impact you're talking about, what kind of numbers that you see?

Dr Jean-Louis Vanoverschelde: It's the same in all the analysis, whether it's in the overall population or in the matched cohorts by 20 years, we have something like 20 to 25% survival difference, absolute survival difference between the two groups. So it's a reduction of mortality approximately by half if you perform repair compared to replacement, and it is increasing with time, so it's not something that is only present in the first years but is increasing with time, so it's about 20 to 25% absolute difference between the two cohorts.

Dr Carolyn Lam: That truly is remarkable. Congratulations again on such a landmark paper like Victoria said. Now to either of you, question that's a bit left field maybe, but what do you think the role is now for percutaneous techniques of mitral valve repair or replacement then?

Dr Jean-Louis Vanoverschelde: That's an interesting question. I think that if you really look far away into the future probably everything at some point in time will be percutaneous. At this stage I’m not sure that the percutaneous technique able to mimic what we can do with surgery in terms of mitral valve repair. So, it's an alternative to surgery in patients who are inoperable. In those who can undergo a surgical mitral repair, my first choice will certainly be to go surgically rather than percutaneously, at least right now.

Dr Carolyn Lam: Victoria?

Dr Victoria Delgado: I also agree with those comments. I think that now we have a lot of possibilities to treat these patients but the most important thing is to have the entire clinical picture of the patient, to see the pros and cons of preparing the patient for surgery or for percutaneous valve. There should be also an integration of imaging to know which is the cause of the valve dysfunction and to see whether the anatomy could be easily repaired by surgery or instead if the patient has contraindication for surgery, if it could be repairable as well with transcatheter therapy. But then for that I think that is really important and this is what the editorial also highlights, the role of the heart team, where there are different specialist surgeons, clinical cardiologists, heart failure specialists, imaging specialists that can integrate the entire information of the patient in order to select the most appropriate therapy. But still for patients who do not have contraindications for surgery who have repairable valve and as you can see from this registry, the percentage of repairability is quite high, I would still refer the patient as well for surgical valve repair.

Dr Carolyn Lam: You heard it right here. Thank you so much for joining us today and please don't forget to tune in next week.

Circulation January 24, 2017 Issue

23 januari 2017 | 17 min

Dr Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke-National University of Singapore. In just a moment, we're going to be discussing new results of the pioneer trial, and the patient with atrial fibrillation who undergoes intracoronary stenting, a familiar conundrum. What's the role of NOACs? Is there still a role for full-dose triple therapy with warfarin? First, here's your summary of this week's journal.

The first paper tells us about the clinical impact of left atrial appendage closure. Dr. Melduni and colleagues from the Mayo Clinic in Rochester, Minnesota, studied 9,792 patients undergoing bypass or valve surgery between 2000 and 2005. They used propensity score matching to estimate the association of left atrial appendage closure with early post-operative atrial fibrillation- defined as atrial fibrillation within 30 days of surgery- ischemic stroke, and mortality. They found that after adjustment for treatment allocation bias, left atrial appendage closure during routine cardiac surgery was significantly associated with an increased risk of early post-operative atrial fibrillation, and did not influence the risk of stroke or mortality.

They therefore concluded that it remains uncertain whether prophylactic exclusion of the left atrial appendage is warranted for stroke prevention during non-atrial-fibrillation-related cardiac surgery.

The next study provides pre-clinical evidence that genes on sex chromosomes may contribute to the sexual dimorphism of abdominal aortic aneurysms. That is, we well know that abdominal aortic aneurysm is a male-predominant disease. Now, in this paper, by first author Dr. Alsiraj, corresponding author Dr. Cassis and colleagues from the University of Kentucky, female LDL-receptor-deficient mice, with an XX or XY sex chromosome complement, were infused with angiotensin II for 28 days to induce abdominal aortic aneurysms. DNA microarrays were performed on the abdominal aortas, and to mimic the males, the female mice were administered a single dose of testosterone.

They found that an XY sex chromosome complement, in phenotypic females, profoundly influenced aortic gene expression profiles and promoted abdominal aortic aneurysm severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. The mechanisms for augmented abdominal aortic aneurysm severity in XY females included increased inflammation, augmented matrix metalloproteinases, and oxidative stress. These results, therefore, demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of aortic abdominal aneurysms. Sex chromosome genes may therefore serve as novel targets for sex-specific abdominal aortic aneurysm therapeutics.

The next two studies shed light on the mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism. In the first study, Dr. Watts and colleagues from University of Western Australia carried out a two-by-two factorial trial, of high-dose atorvastatin versus evolocumab on stable isotope tracer kinetics in 81 healthy, normal lipidemic, non-obese men.

They found that both atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL apoB, IDL apoB, and LDL apoB. On the other hand, evolocumab, but not atorvastatin, also decreased the production rate of IDL apoB and LDL apoB. The reduction of LDL apoB and LDL cholesterol was significantly greater with a combination versus either mono-therapy. In summary, they found that in healthy, normal lipidemic men, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism, and by reducing IDL and LDL production. The latter effects are incremental to statins.

The second paper to deal with this topic comes from Dr. Ginsberg and colleagues from Columbia University in New York, who studied 18 participants, this time 10 of whom were women, who completed a placebo-controlled two-period study, receiving two doses of placebo followed by five doses of alirocumab. These authors found that alirocumab decreased LDL cholesterol and LDL apoB by increasing IDL and LDL apoB fractional clearance rates, and by decreasing LDL apoB production rates. These results were consistent with increases in LDL receptors available to clear IDL and LDL from the blood during PCSK9 inhibition. These two papers are discussed in a beautiful accompanying editorial by Dr. Chris Packard from University of Glasgow. In his editorial entitled "Unpacking and Understanding the Impact of PCSK9 Inhibitors on Apolipoprotein B Metabolism." Those were your highlights! Now for our feature discussion.

Today we are going to be discussing one of the most common conundrums in all of cardiovascular medicine, and that is the care of patients with atrial fibrillation who also need percutaneous coronary intervention. Of course, both dual antiplatelet therapy and oral anticoagulation therapy would be indicated to reduce the risk of stent thrombosis and thromboembolism in atrial fibrillation, respectively. However, with the intensification of the anti-thrombotic regimen, there is the inevitable trade-off with more bleeding. Now, to discuss this, we have the first and corresponding author on a very novel study of the pioneer trial, and that is Dr. Michael Gibson, from Harvard Medical School and Beth Israel Deaconess Medical Center. We also have the editorialist for this very exciting paper, Dr. Deepak Bhatt from Brigham and Women's Hospital, and finally, we have Dr. Dharam Kumbhani, associate editor from UT Southwestern. Welcome, gentlemen!

Dr Deepak Bhatt: Thank you.

Dr Michael Gibson: Thanks.

Dr Dharam Kumbhani: Thank you.

Dr Carolyn Lam: So, Michael, could I start with you? This is a sub-study of the pioneer study. Could you tell us how this is different from the primary results, what were you looking for, and what you found?

Dr Michael Gibson: As you know, as [inaudible 00:07:40] said, we have a lot of bleeding with conventional triple therapy, and we used two regimens to try and reduce that bleeding. One was a reduced dose of rivaroxaban, 15 milligrams, plus thienopyridine. The other strategy was baby dose rivaroxaban, 2.5 milligrams twice a day, plus DAPT. What we found in the overall study was a significant reduction in bleeding- from, say, 26.7% down to 18% for riva plus DAPT- that's the baby dose plus DAPT- and down to 16.8% for the 15 milligrams of riva plus the thienopyridine.

You'd have to treat about 11 to 12 patients to prevent one significant bleeding event. That's the mainstay. What we found in this very, very important sub-study is that that was associated with reduction in hospitalization. All-cause hospitalization was reduced, and cardiovascular hospitalization went down from 28.4% to about 20% for the two regimens. Bleeding with hospitalization went down, from 10.5% to about 6%. At the end of the day, you'd only have to treat 10 to 15 people to prevent one hospitalization, so from a health economic perspective, and from a patient viewpoint and hassle perspective, this was very important.

Dr Carolyn Lam: In fact, Michael, I would say from a clinician-cardiologist perspective, these results are really very applicable. In fact, I really like, in the accompanying editorial, what Deepak wrote, that it may be one of those rare occasions where a sub-study provides very clinically meaningful information compared to the primary study. Deepak, would you like to elaborate a little bit more about that?

Dr Deepak Bhatt: Sure. A really great point that you've raised. It wasn't, in fact, a sub-study we're talking about in Circulation. It was an analysis from the overall trial, looking at a different endpoint than the primary endpoint, the hospitalization, and the composite of hospitalization and mortality. I think that's a very important endpoint. If it were a heart failure trial, for example, that's the endpoint everyone would hone in on- mortality and hospitalization. The fact that that was significantly reduced, I think, is very clinically meaningful. Mike mentioned the economic implications, which for sure are there, by reducing hospitalizations and re-hospitalizations.

The impact on cardiovascular hospitalizations- the reduction there- I find particularly remarkable. The reduction in bleeding, of course, is good, and in its own right has a great deal of value, but the additional reduction in cardiovascular hospitalizations, I think, is quite reassuring for those that are worried about the efficacy of the two experimental regimens that he and his colleagues studied. Sure, the trial's not powered in each individual sub-group for rare events like stroke, but the fact that CV hospitalizations are not increased, and in fact reduced, tells me that this is a winning strategy or strategies.

Dr Carolyn Lam: Right. Michael, another issue, though- this is open label, and I suppose one of the criticisms could be that there is a bias for clinicians managing patients on the traditional Vitamin K antagonist to maybe hospitalize patients more for some reason. What is your response to that?

Dr Michael Gibson: That is always the criticism of an open label trial, but again, the events were adjudicated, and for the heart events, that's done in a blinded fashion, so it's reassuring that there was a blinded assessment of the heart events.

Dr Carolyn Lam: True. How about comments on generalizability? I mean, what do you think? Trial setting, real world ...

Dr Michael Gibson: Yeah, I think that's one of the advantages. This was very much a real-world kind of study. It was truly done throughout the world. We had a very broad entry criteria. Anyone who was getting a stent put in- you didn't have to have ACS, although about half the patients did. The only real exclusive criteria was you couldn't have any bleeding or be profoundly anemic. You couldn't have a stroke or [TIA 00:11:58] in the past. Other than that, it made real-world practice in a lot of ways.

Dr Dharam Kumbhani: This is Dharam. If I may ask both the other people on the call, is ... Rivaroxaban is not FDA approved, in these doses, for use. I'm wondering if they might provide some comment, given the benefit that we see in this trial, overall, what their thoughts are and what the next steps might be.

Dr Carolyn Lam: Sure. Maybe Michael, then Deepak?

Dr Michael Gibson: Yeah, that's a good point. It is important to point out that you'd need to check the prescribing information in your country. In some countries- I think it's about 54 countries- the 2.5 milligram dose is available. It is approved for ACS, but is not approved for a-fib. Then, you have a dose of 20 milligrams that's approved worldwide for a-fib, but there are some countries- it's important to note, in some countries, 15 milligrams is the full dose that's approved- say, in Japan and Taiwan. There are Japanese studies showing that 15 milligrams was not only safer than warfarin, but more efficacious than warfarin in a trial like J-ROCKET. You're right, the 15 milligram dose is available in the US- it's approved for renal insufficiency, but at this time, it's not labelled for the ACS or stented patient.

But again, physicians are at liberty to look at this data, which is the first real data that we have to guide decision-making in this setting, and they're at liberty to make their own choices.

Dr Deepak Bhatt: Yeah, I would agree with that assessment, and emphasize ... Like Mike said, it's an international audience for Circulation, so I would say, look in your own country, and in many parts of Europe, the 2.5 milligram rivaroxaban dose is available and approved for ACS, and could therefore be used for this purpose, though not strictly falling within the label indications. In the US, there's the 15.

I think, if I just answer the previous question, the results are very generalizable, and for doctors that critique that point, I'd say, "Why didn't you enroll your patients in the trial?" There's the RE-DUAL as well, that's ongoing, with dabigatran, AUGUSTUS with apixaban, and I'm missing one that's also ongoing as well, I think, but there are four different trials that are out there. The Pioneer was the first to report ...

Dr Carolyn Lam: I think you're thinking of the Entrust AF-PCI with Edoxaban.

Dr Deepak Bhatt: The most recent one, yes. I forgot the acronym, there. If people are really thinking that the results don't apply to their patients, well, there are trials that are ongoing. Enroll your patients. But to say, "Oh, my patients, I'm not going to enroll them in the trial," and then say, "The results aren't generalizable," I always find that an odd thing. I think the results are very generalizable. The one word of caution I would say, though, is to make sure to renally dose, as was done in the trial. That is, there was a downward adjustment in dose from the 15 milligrams to the 10. In real life, we've seen in registries with NOAC use, whether it's rivaroxaban or any of the others, a lot of times, the renal function is not carefully monitored in those patients that are on the fringe in terms of their renal function, and that's the one situation NOACs can backfire, where the dose isn't corrected for their degree of renal dysfunction. Other than that one caveat, I think the results are quite generalizable.

Dr Carolyn Lam: Excellent comments. We should wrap up soon, but not before I want to ask Dharam. Thank you for managing this beautiful paper. What, to you, is the take-home message for clinicians out there?

Dr Dharam Kumbhani: Yeah, it was an absolute honor and delight to manage this, and I think the paper's great. The editorial's great. It's gotten a great response. I think the take-home message is that this is a very clinically relevant question, and a very clinically relevant trial, and it shows that the needle will be moving towards using non-VKA-based agents, especially in patients such as this, who have both a-fib and PCI. I think this is very exciting space, a very important space. This trial suggests that if you use the strategy rivaroxaban low dose, with or without a DAPT, that it is safer, both in terms of mortality and bleeding, compared with what is traditionally being used with warfarin plus DAPT. I think this was a very, very exciting trial.

Dr Carolyn Lam: Indeed, and congratulations to all three of you. Thank you so much for joining me on Circulation On The Run. Thank you, listeners, for joining us too, and don't forget to tune in next week.

Circulation January 17, 2017 Issue

16 januari 2017 | 26 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.

The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.

They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.

On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence.

In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.

The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.

This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.

All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.

They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.

In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.

In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.

The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.

They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.

Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.

Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.

The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.

The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.

These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.

After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.

These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.

The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.

As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.

The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.

Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.

Those were your highlights. Now, for our featured discussion.

On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.

This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.

Welcome Daniel.

Dr. Daniel Singer: Thank you for having me.

Dr. Carolyn Lam: Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana.

Dr. Sana Al-Khatib : Thank you Dr. Carolyn, I'm happy to be here.

Dr. Carolyn Lam: Daniel, could we start by you letting us know what you sought to do in your study and what you found?

Dr. Daniel Singer: We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.

There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.

While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.

What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper.

Dr. Carolyn Lam: Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation.

Dr. Daniel Singer: We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.

Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.

Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.

If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"

We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores.

Dr. Carolyn Lam: The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static.

Dr. Daniel Singer: Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.

We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.

One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation.

Dr. Carolyn Lam: Daniel, congratulations again for that fascinating and really very sobering findings.

Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts?

Dr. Sana Al-Khatib : Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.

A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.

I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well.

Dr. Daniel Singer: Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.

The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.

We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.

This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.

I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror.

Dr. Sana Al-Khatib : That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.

As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.

If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.

In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that?

Dr. Daniel Singer: I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.

At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.

We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke.

Dr. Sana Al-Khatib : I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.

I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.

One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients.

Dr. Carolyn Lam: Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.

Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings.

Dr. Daniel Singer: I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.

The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.

I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid.

Dr. Carolyn Lam: Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.

Circulation January 10, 2017 Issue

9 januari 2017 | 23 min

Dr. Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This episode marks the six month milestone of our run together, a run that has taken us around the world from the United States to Europe, South Africa, and Asia, and one that is shared by listeners all over the world.

On behalf of the editors, and from the bottom of my heart, I want to thank you for your support and request that you please subscribe to our podcast and share it with your friends and colleagues. We commit to bringing you the best of cardiovascular science in the most accurate and digestible way possible, thus suiting the busy cardiologist on the run.

Dr. Lam: All right, here are your highlights of this week's issue.

The first paper looks at tissue plasminogen activator, or TPA treatment in ischemic stroke, addressing two aspects that are still unclear. Number one, the degree of additional benefit accrued with treatment in the first 60 minutes after onset of ischemic stroke; and number two, the shape of the time-benefit curve through 4.5 hours. First author, Dr. Kim, corresponding author Dr. Saver and colleagues from UCLA stroke center analyzed more than sixty-five thousand acute ischemic stroke patients treated with intravenous TPA within 4.5 hours of onset from the "Get With the Guidelines" Stroke U.S. National Program.

They found that 878 of these over sixty-five thousand patients were treated within the first 60 minutes after onset, a ten-fold increase over previously available data. Thrombolytic treatment within the first 60 minutes was associated with the highest rates of favorable discharge outcomes. The shape of the time-benefit curve throughout the first 4.5 hours was non-linear for some outcomes. Discharge to home and discharge free of disability decayed more rapidly in the first hundred to a hundred and seventy minutes after onset than later. While independent ambulation at discharge and in-hospital mortality declined in a steady fashion through the time window.

These findings reinforce the importance of quality improvement programs to accelerate door to needle time for thrombolytic therapy in acute ischemic stroke.

Dr. Lam: The next study sheds light on mechanisms underlying red blood cell mediated hypoxic vasodilation. A highly conserved response coupling oxygen delivery to metabolic demands of the tissues, and very clinically relevant in states of systemic hypoxemia and impairment in oxygen delivery, such as in patients suffering from cardiovascular, pulmonary, or hemolytic diseases.

In this paper, Dr. Bailey and colleagues from University of British Columbia Okanagan in Canada studied ten healthy participants who were randomly assigned to a normoxic, or 21% oxygen, and hypoxic, or 10% oxygen trial with measurements performed at rest and following 30 minutes of cycling at 70% of maximal power output. Blood was sampled simultaneously from the brachial artery, internal jugular, and femoral veins with plasma and red blood cell nitric oxide metabolites measured. Cerebral and femoral venous blood flow were determined by transcranial doppler ultrasound and constant infusion thermodilution respectively.

The authors found that hypoxia was associated with a mild increase in both cerebral and femoral blood flow, with further more pronounced increases observed in femoral blood flow during exercise. Plasma nitrite gradients reflecting consumption were accompanied by red blood cell iron nitrosyl hemoglobin formation at rest in normoxia, during hypoxia and especially during exercise, with the most pronounced gradients observed across the femoral circulation. In contrast, there were no gradients consistent with S-nitrosohemoglobin consumption.

Collectively, these findings suggest hypoxia, and to a far greater extent exercise, independently promote arteriovenous delivery gradients of intravascular nitric oxide with deoxyhemoglobin mediated nitrite reduction, identified as the dominant mechanism underlying hypoxic vasodilation. This is as opposed to the competing hypothesis of S-nitrosohemoglobin formation.

In summary, by distinguishing between the two competing mechanisms that underpinned endocrine nitric oxide vasoregulation, that is, the S-nitrosohemoglobin hypothesis versus the nitrite reductase hypothesis, these data help us to understand the dynamic interplay that takes place between nitric oxide metabolites as a function of oxygen demand in vivo, and will help to establish the most specific and sensitive prognostic markers of vascular health and therapeutic interventions that optimize tissue oxygenation.

Dr. Lam: The next study addresses the controversial issues of thrombus aspiration during percutaneous coronary intervention, or PCI, for the treatment of ST elevation myocardial infarction, or STEMI.

Dr. Jolly and colleagues from Hamilton General Hospital in Ontario, Canada performed an individual patient meta-analysis of three eligible large randomized trials that is the TAPAS, TASTE and TOTAL trials including more than eighteen thousand patients who underwent PCI for STEMI. They found that as a routine strategy thrombus aspiration did not reduce cardiovascular mortality for STEMI patients undergoing primary PCI, and that exploratory analysis of patients with high thrombus burden suggested that thrombus aspiration may improve cardiovascular mortality but at the price of an increased risk of stroke or transient ischemic attack.

In summary, these data suggest that thrombus aspiration should not be used as a routine strategy in patients with STEMI, however in patients with high thrombus burden, further large randomized trials are needed to determine if improved forms of thrombus aspiration can reduce cardiovascular mortality and to determine its safety with regards to stroke.

Dr. Lam: The next paper is the first study to look at coronary artery calcium imaging as a tool to personalize systolic blood pressure treatment goals.

Dr. McEvoy and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland studied 3,733 participants from the multi-ethnic study of atherosclerosis with systolic blood pressure between 120 to 179 millimeters of mercury. Within subgroups categorized by both systolic blood pressure and estimated ten year atherosclerotic cardiovascular disease risk, they compared multi-variable adjusted hazards ratios for the composite outcome of incident atherosclerotic cardiovascular disease or heart failure after further stratifying by coronary artery calcium.

The authors found that combining coronary artery calcium imaging and assessment of global atherosclerotic cardiovascular disease risk had potential to guide personalized systolic blood pressure goals, particularly among adults with an estimated risk between five to fifteen percent, and pre-hypertension, or mild hypertension.

For example, among those with an atherosclerotic cardiovascular disease risk of less than fifteen percent and who had systolic blood pressure between 140 and 159, those with a coronary artery calcium score up to 100 were at two times the risk, while those with a coronary artery calcium score more than 100 were at 5.7 times the risk of events, all compared to a coronary artery calcium score of zero. Thus, information on coronary artery calcium burden may be considered when making personalized treatment decisions about blood pressure targets, particularly among patients with an estimated cardiovascular risk between five and fifteen percent, and who have either pre-hypertension or mild hypertension.

In summary, information on coronary calcium burden may be considered when making personalized treatment decisions about blood pressure targets, for example, choosing a traditional goal of 140 or a more intensive goal of 120 millimeters of mercury. The authors ended by calling for a precision medicine clinical trial evaluating risk-based blood pressure treatment goals, preferably incorporating coronary artery calcium.

Well, those were your highlights, now for your feature discussion.

Dr. Lam: On today's episode we are going to be discussing the very important issue of type-two myocardial infarction, very important yet usually neglected compared to type-one myocardial infarction. As a reminder to our listeners, type-two MIs are the ones where there is myocardial demand-supply mismatch whereas type one is the usual acute coronary artery plaque rupture and thrombosis. To discuss this I am really honored to have two James' on the podcast. The first is Dr. James Januzzi from Massachusetts General Hospital, the second is Dr. James de Lemos, executive editor of Circulation from UT Southwestern.

Welcome to you both.

Dr. Januzzi: Thank you very much Carolyn, really great to be speaking with you.

Dr. de Lemos: Thanks Carolyn, it's great to be on.

Dr. Lam: Dr. Januzzi, could you please let us know what you found in this paper, it's really extraordinary. Just give us a top line of the results.

Dr. Januzzi: Basically we set out to examine the question of how frequent type-two myocardial infarction is in a population of patients followed longitudinally after they have taken a trip to the cath lab for one reason or another. Really with the goal to better understand the type-two MI syndrome. It was our hypothesis that type-two MI was perhaps more common than people may have recognized, and that type-two MI would be higher risk in terms of the likelihood for ischemic complications than what people had previously recognized. As you point out, type-two MI is often neglected from a management perspective.

What we found, basically, was among a cohort of patients, 1,250 patients coming through the cath lab at the Massachusetts General Hospital Heart Center, in follow up over a several year follow up period with a maximum of eight years of follow up, with a mean of about 3.4, a median of 3.4 years follow up. Out of the 1,251 patients that we enrolled and followed, 152 actually had an incident type-two myocardial infarction during follow up. Additionally, type-two MI was actually quite recurrent in many patients, and in each of the cases whether individual or in most patients with recurrent type-two MI, the mortality risk was really quite striking. Patients that had a type-two MI, partially because they were more complicated medically speaking, as one might have expected, they were older and had lower blood pressure, more coronary disease, heart failure and other medical comorbidities. The likelihood for a major adverse cardiovascular event was more than doubled in patients that suffered an incident type-two MI, the risk for mortality was actually remarkably almost ten-fold higher with a cardiovascular death rate that was around nine-fold higher, heart failure was tripled.

Really just illustrates the very morbid nature of the type-two myocardial infarction, and illustrates the fact that studies are urgently needed to better understand how we should manage these patients.

Dr. Lam: Dr. Januzzi when I manage patients I find this diagnosis of type two-MI to be a very dirty one to make, if you know what I mean. It's hard to really be sure what's happening, and what to attribute rises in troponin to, and so on. Could you tell us a little bit more about how difficult it was to adjudicate the events, and what's the risk of misclassification in your study?

Dr. Januzzi: It's a challenge, and that's something that came up during the peer-review process. We really wanted to make sure that we got this right, so in fact we went back and did a cross-sectional re-review of cases to make sure that our adjudication process was accurate. It's not a very straightforward thing to judge, obviously. A rise and/or fall in troponin may be from a type-one myocardial infarction. There's increasing interest in a syndrome of myocardial injury in the absence of a classical myocardial infarction. Then lastly, we recognized that troponin may rise and fall, for example, in patients with heart failure, possibly due to non-coronary mechanisms. You are correct, it may be a challenge to classify these patients solely on the basis of the presence of a rise or fall of troponin.

What we did was classify them utilizing the Universal Definition of MI Task Force criteria, which includes symptoms and signs, as well as a rise and/or fall of troponin, plus evidence for loss of myocardial function on non-invasive testing. We were pretty strict, actually, in terms of how we judged them, and when we went back and re-reviewed ten percent of the cases, we actually found that all of the fifteen cases that we went back and re-reviewed met the criteria that we had articulated in the front end. We feel pretty confident that we got the diagnosis correct, but obviously it's a challenge in every day practices, as you rightfully point out.

Dr. Lam: It does certainly sound very rigorous, indeed. Dr. de Lemos, you managed this. He mentioned reviewers giving him a hard time, what was it like managing this paper?

Dr. de Lemos: It was fascinating because the Universal Definition that introduced type-two MI into the classification scheme is only a decade old. It's remarkable how little we know about the problem, and how much we struggle in clinical practice. We thought this paper was one of the first and most comprehensive evaluations to put some construct around the problem. As you pointed out, Carolyn, it is a messy diagnosis. Even when you do it in an organized, researched fashion this reflects what we all deal with in clinical practice where it's not so easy to define myocardial infarction even when given the criteria of the Universal Definition. The challenge really is that only a minority of the troponin elevations that are the classic type-one MIs that we know what to do with. The rest of them are either these troponin elevations NOS, type-two MI, or something on a continuum on this spectrum that's really hard to differentiate.

This paper's important because it really highlights that these non-type-one MIs whatever they are, are common and associated with really high risk, and it's sort of a call to arm that we better start to understand and sub-classify these if we're going to be able to reduce risk in this very high risk population. That's really why we were so interested in the paper, and why we worked so closely with Jim and his team to address some of the issues that you just raised.

Dr. Lam: I completely agree, in fact it's beginning to remind me of the world of HFpEF when we first started realizing that people with heart failure, even though ejection fraction's normal are definitely not doing well. James Januzzi, if you don't mind, what do you think are the implications for treatment, what are the things that you think need to be examined going forward?

Dr. Januzzi: Carolyn I laughed when you mentioned HFpEF because at one of the recent Universal Definition of MI Task Force meetings, I actually said that type-two MI is the HFpEF of the myocardial infarction world. To answer your question, I have approached this question very much the way we do in the heart failure space relative to heart failure with preserved EF. In order to develop a strategy for treatment for type-two MI, we need considerable advances still in our understanding of just what exactly is a type-two MI, what types of patients have type-two MI, and on an individual level, the treatment strategies may follow.

The problem here is if you look just at all comers who suffered a type-two MI in our study, the majority were actually taking statins, they were taking aspirin, they were more likely to be taking beta-blockers. So the patients themselves were actually on the very treatments that we might think about prescribing in those folks that have a type -wo MI, and yet they still suffered the MI, and they had worse outcomes. One might think about coronary disease and revascularization, and indeed one of the nice things about our study is we enrolled patients at the time of coronary angiography, and then followed them subsequently, so we actually had detailed coronary angiograms on every one. Those suffering an incident type-two MI certainly had more coronary disease, so one might argue revascularization might either be protective if done prior to the onset of type-two MI, or at the time of type-two MI a revascularization-driven strategy might be a logical approach.

I think more fundamentally, bringing it back to heart failure and to the HFpEF analogy, I think that in order to better understand treatment we need to better understand just who these patients really are. So much like has been done in the heart failure space we're now doing cluster phenotype analyses where we're looking at the various phenotypes of patients with type-two MI using network analyses, which is one way to approach a problem when you've got a mix of various diseases that fall under the same title. So in those patients with preserved ejection fraction heart failure, there are patients that are younger obese patients, there are the patients with advanced diabetes, et cetera.

Our hypothesis for our present research is to examine this question within the type-two MI diagnosis to see if we can identify specific clusters of phenotypes that might be treated in specific ways. The coronary patients might deserve revascularization, the heart failure patients might deserve a different approach for their care. That, I think, might be the way forward, exactly taking a page from the playbook that you just mentioned with respect to preserved ejection fraction heart failure.

Dr. Lam: Wow, how terribly exciting. Congratulations again for this paper, I really think it's a landmark and will open the door to many more important papers. I would like to switch tracks a little bit at the moment. We are coming to six months into the new Circulation editors that have been under the leadership of Joe Hill and James de Lemos, and I'd actually like to start by asking you, Dr. Januzzi, what was it like working with our new Circulation team? Then handing the mic over to Dr. de Lemos to tell us a little bit more about what the journey has been so far in the last six months.

Dr. Januzzi: Thanks for asking, it was an absolute pleasure. I trained with Dr. Hill and with Dr. de Lemos in one degree or another during all of our respective residency and/or fellowship training, so I've known these guys for a long long time. I think that the most important aspect in the peer review process is a collaborative and collegial process where the division between author and editor can allow for communication. In this experience with this manuscript, it was a very easy-going and collaborative process where the paper from beginning to end grew in its quality, and ultimately landed in the journal, and the way that it did was, I think, a substantial likelihood for heavy citation. That says a lot about the editors who really help us to bring it to this final product.

Dr. Lam: Dr. de Lemos?

Dr. de Lemos: We're now six months in to the new Circulation editor team's tenure, and I think all of us are having a blast. I think we've put together this team of diverse international experts that build off each other and thrive off each other, so from the team perspective, we're just having great fun, working hard, learning a great deal. We hope that those of you out there that are listening and reading, and submitting papers, and using our journal for your own research, are noticing the changes that we've made and think we're headed in the right direction. We'd love to hear from you about the things you like, and those things you don't like. We do think we've, in many ways, modestly changed the focus of the journal. There's so many new content categories that are designed to speak to the global burden of cardiovascular disease, the international aspect of cardiovascular research, and new clinically relevant problems, translating basic science so that clinicians can understand it. We hope that clinically active, as well as basic investigators are finding these changes useful in their own daily lives.

Dr. Lam: Thank you both so much for spending time with me on Circulation on the Run. Thank you everyone, don't forget to tune in next week.

Circulation January 3, 2017 Issue

27 december 2016 | 23 min

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Caroline Lam, associate editor from The National Heart Center and Duke National University of Singapore. Today we will be discussing the results of an individual level meta-analysis regarding venous thromboembolism and its risk factors, but first, here's your summary of this week's issue.

The first paper provides insights into paracrine signalling pathways that regulate epicardial adipose tissue formation. That is, referring to the adipose tissue located between the epicardium and underlying myocardium that is known to be strongly associated with coronary artery disease. In the current study from Dr. Lira of Icahn School of Medicine at Mount Sinai, New York, Dr. Pu from Boston Children's Hospital, Dr. [Chien 00:00:56] from Karolinska Institute and colleagues, the authors used a novel modified mRNA screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the heart. Using two independent lineage tracing strategies in murine models, they showed that cells originating from the WT1-positive mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue following myocardial infarction. This differentiation process required WT1 expression and was stimulated by insulin-like growth factor 1 receptor activation. Insulin-like growth factor 1 receptor inhibition significantly reduced its adipogenic differentiation and reduced WT1 lineage cell differentiation into adipocytes following myocardial infarction.

These results thus establish insulin-like growth factor 1 receptor signalling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury. And it does this by redirecting the fate of WT1-positive lineage cells. The study also demonstrates the utility of a modified RNA based paracrine library screening to dissect signalling pathways in homeostasis and disease.

The next study brings us closer to understanding the mechanisms underlying diabetes-associated heart failure. In this study by first author, Dr. Wang, corresponding authors, Dr. Abel and Xiang from University of California, Davis and colleagues. High-fat diet feeding was used to induce obesity and diabetes in wild-type mice or mice lacking the beta-2 adrenergic receptor or beta-arrestin 2. High-fat diet feeding was found to selectively increase the expression of phosphodiesterase 4D in the mouse hearts in concert with the reduced phosphokinase A phosphorylation of phospholamban which contributed to systolic and diastolic dysfunction. The expression of phosphodiesterase 4D was also elevated in human hearts with diabetes. The induction of phosphodiesterase 4D expression was mediated by an insulin receptor and substrate as well as by beta-arrestin-2 dependent activation of a beta adrenergic receptor, ERK signalling cascade.

Genetic deletion of beta-2 adrenergic receptor or beta-arrestin-2 or pharmacological inhibition of beta-2 adrenergic receptor with carvedilol or G-protein receptor kinase 2 with paroxetine all significantly attenuated insulin-induced phosphorylation of ERK and phosphodiesterase 4D induction thus preventing diabetes-related systolic dysfunction. Thus, targeting the insulin beta-2 adrenergic receptor pathway may be a novel way to prevent diabetes-associated heart failure.

The next study addresses the gap in care pertaining to implantable cardioverter-defibrillator or ICD use among Medicare patients with low ejection fraction following myocardial infarction. Dr. Pokorny and colleagues from Duke University Medical Center examined rates of post-discharge ejection fraction assessment and ICD implantation among more than 10,280 Medicare-insured patients age 65 years above with an ejection fraction 35% and below during an index myocardial infarction admission in the ACTION Registry Get With the Guidelines. They found that the cumulative incidence of ejection fraction reassessment within one year of myocardial infarction was 66.8%. Within the first year of post-myocardial infarction, 11% of patients who had an ejection fraction reassessment underwent ICD implantation which was significantly higher than patients without an ejection fraction reassessment. After multivariable adjustment, ejection fraction reassessment remained significantly associated with a higher likelihood of ICD implantation within one year in both revascularized and non-revascularized patients. Based on these findings, the authors recommend that all patients who are potential candidates for ICD therapy be scheduled for follow-up outpatient ejection fraction assessment prior to hospital discharge to bridge these currently observed gaps in care.

The next study is the first multi-institutional study in Asia describing current treatment strategies for total anomalous pulmonary venous connection. This retrospective study of 768 patients with total anomalous pulmonary venous connection operated on between 2005 and 2014 is from first authors Dr. Shi, Zhu, and Chen, corresponding authors, Dr. Chen and Zhuang and colleagues from the Shanghai Children's Medical Center and Guangdong General Hospital in China. While most patients underwent conventional repair, a sutureless patient was technique was employed in 10% of patients. Over a median follow-up of 23 months, there were 38 intraoperative deaths and 13 late deaths. A younger age at the time of repair, next an infracardiac total anomalous venous connections, pre-operative pulmonary venous obstruction, prolonged cardiopulmonary bypass time and longer duration of ventilation were all factors associated with increased mortality. Among these 717 survivors, recurrent pulmonary venous obstruction was found in 15% or 111 patients. Risk factors for recurrent pulmonary venous obstruction included pre-operative pulmonary venous obstruction, infracardiac total anomalous pulmonary connection, mixed venous connections and prolonged cardiopulmonary bypass time, a sutureless technique was associated with a lower restenosis rate compared to conventional repair in patients with pre-operative pulmonary venous obstruction but not in newborn patients. Thus, this study provides an important data on the outcomes following surgical correction and risk factors for poor prognosis in total anomalous pulmonary venous connection in Asia.

The final study is the first systematic review and meta-analysis on the association of genetic polymorphisms and outcome of clopidogrel-treated patients with ischemic stroke or transient ischemic attacks. In this paper from first author, Dr. Pan, corresponding author, Dr. Wang and colleagues from Beijing Tiantan Hospital, Capital Medical University in Beijing, China. Authors looked at 15 studies of 4,762 patients with stroke or transient ischemic attack treated with clopidogrel and this included 3 studies from Europe and 12 studies from East Asia. They found that carriers of the CYP2C19 loss-of-function alleles were at increased risk of stroke compared to noncarriers. Composite vascular events were also more frequent in carriers compared to noncarriers while bleeding rates were similar. There was no evidence of statistical heterogeneity among the included studies for stroke but there was for composite vascular events suggesting that publication bias cannot be ruled out. Genetic variance other than CYP2C19 were not associated with clinical outcomes. The author suggested that their findings may justify genetic testing when clopidogrel is otherwise considered the preferred treatment modality, especially in East Asian patient populations in whom the prevalence of CYP2C19 loss-of-function allele is high.

In an accompanying editorial, Dr. Simon and [inaudible 00:10:11] suggest it maybe time to consider a prospective trial of personalized medicine using CYP2C19 genotyping in acute ischemic stroke and perhaps considering alternative medications in poor or intermediate metabolizers such as in the popular ongoing genetics trial in STEMI patients undergoing PCI. That wraps it up for the summaries this week. Now for our feature discussion.

Today's feature paper talks about the association of traditional cardiovascular risk factors with venous thromboembolism. And it is the first individual level meta-analysis of prospective studies. I am so delighted to have the first and corresponding author here with us, Dr. Bhaktawar Khan Mahmoodie from San Antonio's Hospital in the Netherlands. Hi Khan, thanks for being here.

Dr. Bhaktawar Khan Mahmoodie:

Thank you for inviting me. Thanks a lot.

Dr. Carolyn Lam:

And I am particularly delighted to have associate editor, Dr. Josh Beckman from Vanderbilt University joining us today as well. Welcome Josh.

Dr. Josh Beckman:

Caroline, it is such a pleasure to be here with you. I've been listening to these podcasts and they have been incredible. I've been waiting to be able to jump in and today's paper is an awesome place to start.

Dr. Carolyn Lam:

It certainly is. Congratulations on managing such an important paper. Khan, maybe I could start with you. Venous thromboembolism versus arterial thromboembolism. We're very familiar with the latter. We know it comprises coronary heart disease, stroke, peripheral artery disease. We're very familiar with the risk factors such as hypertension, hyperlipidemia, diabetes, smoking. But here you're asking, are these same risk factors applicable in venous thromboembolism. That would include deep venous thrombosis, pulmonary embolism, where we traditionally classify it into provoked events that is triggered by things we know well like immobilization, surgery and so on. And then there are the unprovoked events that don't have any risk factors. So could you, first of all, point out ... you were looking at venous thromboembolism. What was your hypothesis with regards to the traditional cardiovascular risk factors?

Dr. Bhaktawar Khan Mahmoodie:

Many researchers in the last 10, 15 years, they go questions whether there is connection between venous and arterial thromboembolism. Since then, several studies published on that with controversial results. So our hypothesis for this paper was to see whether there is real associations or are we looking at some kind of associations due to confounding factors such as age and overweight which are risk factors for both.

Dr. Carolyn Lam:

Yeah. And yours is actually the first individual level meta-analyses of prospective studies dealing with this. Tell us what you found in ... Were you surprised by your findings?

Dr. Bhaktawar Khan Mahmoodie:

What we found that actually traditional, modifiable, cardiovascular risk factors like hypertension, diabetes and hyperlipidemia were not risk factors for venous thromboembolism. The exception was smoking, current smoking, which was particularly associated with provoked venous thromboembolism which is probably pro its association with cancer. And cancer itself is a strong risk factor for venous thromboembolism. About whether I was surprised, I was not surprised at all. We saw in several cohort studies and well-defined cohort studies that the association disappeared after adjustment for age and body mass index which are important confounders in these [inaudible 00:14:06]. That's what I expected and we found it and it is confirmed with this large individual level meta-analysis.

Dr. Carolyn Lam:

Great. But what did you think of the association of higher systolic blood pressure not with higher but with lower risk of venous thromboembolism?

Dr. Bhaktawar Khan Mahmoodie:

That was a bit surprising for us too but I think the best explanation we can give at the moment is probably that we have some kind of competing risk. And one suggestion that we gave in the paper as well is that maybe what we already know is that higher blood pressure is a strong risk factor for atrial fibrillation. Most of these people they receive oral anticoagulants. That is subsequently probably a protective factor for venous thromboembolism. We probably deal with some kind of competing risk from another condition like the atrial fibrillation and use of anticoagulants which we could not unfortunately adjust for in this analysis.

Dr. Carolyn Lam:

Sure. That makes sense. Josh, can I bring you into this? I mean I remember well our multiple and long discussions at the editors meetings. This is one of those papers that is extremely important for its negative, neutral associations isn't it?

Dr. Josh Beckman:

I think this is one of the more important papers in this field in a long time. I am one of those people who has followed this literature and believed, based on the best previous publications, that there was a link between many of the arterial thrombosis or atherothrombotic risk factors and venous thromboembolism. In fact, Circulation published one of these meta-analyses, and I'm going to say only because this little paper is so large with only 21,000 patients demonstrating a clear association. So the first question I would have, we published that back at 2008, the first question I would have is can you describe for the general readership what such a large series of patients allows you to do that was not permitted by the other meta-analyses of say twenty to thirty thousand patients that have been previously in the literature.

Dr. Bhaktawar Khan Mahmoodie:

Thank you Dr. Beckman and thank you also for managing this paper. This is an important question and I think what we were able to do compared to the previous analysis in 2008, we were able to adjust for confounding risk factors. In the course, we included were all with validated venous thromboembolism events and also the events are temporal character, like all the risk factors were measured and then followed-up for event. While in that paper, there were many case-controlled studies added and the results were not adjusted for age and also not adjusted for body mass index. And if we do the same with what's done there, then we have the same results like in our [inaudible 00:17:14] associations, all of these risk factors were indeed positively associated with risk for venous thromboembolism.

Dr. Carolyn Lam:

Let me just state, I mean, there were almost 245,000 participants in your study. With 4,910 thromboembolism events, so this is really huge and gives you a lot of power to look at this thing very carefully.

Dr. Josh Beckman:

It was a 10-fold increase from any of the major publications in this area. It was almost geometrically larger in size which is why, I think its conclusion will be accepted differently than all the previous analyses. Now, let me ask one question about what you already identified in your discussion as a possible limitation. Is this study applicable to all populations around the globe or do you think it is a bit more focused?

Dr. Bhaktawar Khan Mahmoodie:

I think it is focused at least. We don't have Asian population in these analyses and also the proportion of African-Americans were limited which was only limited to some U.S. cohorts so I think that there is a limitation which is results are probably only applicable for Caucasian population.

Dr. Josh Beckman:

I guess my other question is, one of the reasons that people, I think, advance the argument that there may be overlap between the two kinds thrombosis is that there was evidence that the medication, statin, may ... to a much smaller degree, reduce venous thrombosis as well as reducing arterial thrombosis. Do you think that this is evidence of some common pathophysiology? Or is it like smoking, it's truly working separately from arterial disease?

Dr. Bhaktawar Khan Mahmoodie:

Personally, I think that this association or the finding of statins reduce the risk of thromboembolism could be due to some pleiotropic effects of statins. Like even for stroke, we know that the association of cholesterol with stroke is not so clear-cut as it is with myocardial infarction but still it reduces risk of stroke. And also for venous thromboembolism, the risk reduction of venous thrombosis in the JUPITER trial was like 50%, which is very high, even better than aspirin. But I think that may not be directly related cholesterol levels but more to another pleiotropic effects of statins. It could influence levels of various coagulation [inaudible 00:19:56] in the endothelial stabilization which may be also important risk factors for venous thrombosis.

Dr. Josh Beckman:

One of the reasons that this paper is very important is that we begin to look for therapies and risk factors based on what the disease is caused by. And so the fact that you guys were able to establish, in my opinion, quite clearly what does and what does not contribute to venous thrombosis allows us to begin to think about the disease differently and approach it differently. I would like to provide congratulations. My one little ask of you is that one of the things that I think this podcast is great for is to explain to the readership what goes into this kind of work. Everybody thinks that someone else's research is easier to do than their own, which of course is a ridiculous thing. But can you describe for us what it's like and how long it took from the study initiation to when you completed it? How much work went into trying to get all these studies together to create this individual patient level data?

Dr. Bhaktawar Khan Mahmoodie:

Yeah. That was a great amount of work. Actually, I did a systematic review of the only PubMed publications back in 2014 and it took almost 2 years at least. I was not always active the whole 2 years but still I had to visit several PIs of the studies to get them so far to share their data. Eventually, I had to develop a code that will make it possible without sharing the individual level data by using the same definitions and the same categorization of variables so we call it a two-stage meta-analysis similar to one-stage if the definitions are similar. And eventually, I think that the real part of the analysis and inclusion of studies took like half a year or so. There was a lot of work.

Dr. Josh Beckman:

I think this is a tremendous amount of work and for those members of our readership who do basic research, or translational work, or practice in the clinics, it really needs to be made clear that this is a heroic effort of hundreds and hundreds of hours. And that getting together all of these studies is just an enormous undertaking. And that even though, we can read the paper in 10 minutes and gleam the most important part. It is an incredible amount of work for which you guys are to be congratulated.

Dr. Bhaktawar Khan Mahmoodie:

Thank you for acknowledging this. Thanks a lot.

Dr. Carolyn Lam:

Josh, I couldn't agree with you more and I truly couldn't have said it any better. Thank you both of you for making this just one of the best discussions we've had on this podcast. I'm sure the listeners all agree what a wonderful time we've had.

You've been listening to Circulation on the Run. Please remember to tune in next week.

Circulation December 20/27, 2016 Issue

19 december 2016 | 18 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. We have such a special issue today. You see, it's entirely focused on resuscitation and I am delighted to have with me today, Associate Editor, Dr. Mark Lane from Puffs Medical Center, who really put this issue together. Welcome, Mark.

Dr. Mark Lane: Thank you Carolyn.

Dr. Carolyn Lam: Mark, maybe you could start by telling us why the focus on resuscitation? I do believe this is the first time we've done this at Circulation.

Dr. Mark Lane: Yes, this is the first time we've done this at Circulation. It really was a confluence of a couple things coming together. Once is that over the spring and summer, we had a very high volume of high quality resuscitation papers come to Circ. This was not something that we actually asked for but we noted that there were a number of these. Also, it's an important time in resuscitation because a number of the resuscitation counsels across the world have called for improvements in the survival rate, noting that we already have the tools that we need to increase survival and we have to better apply these tools. The HA has provided a goal of doubling resuscitation and resuscitation counsels in Europe, New Zealand and Australia have also echoed that call.

Dr. Carolyn Lam: That's great, so this is a really important issue. I just echo your words about their being a remarkable number of original papers. We have seven and they're just such high quality. Let's chat through them, shall we? I'm going to go by pre-hospital setting to the out of hospital setting and finally end up in the in-hospital setting. Shall we do that?

Dr. Mark Lane: That sounds great.

Dr. Carolyn Lam: The first paper is really about identifying patients at risk for pre-hospital sudden cardiac death at the early phase of myocardial infarction. You want to tell us a bit about that one?

Dr. Mark Lane: This is a study coming from the emergency medical services in the greater Paris area, where they looked at their cardiac arrest and STEMIs over the last seven or eight years. What they were specifically looking at is, can you identify STEMI patients who are at risk for having a cardiac arrest, because if you could identify those patients, you'd want to get there very quickly because if you know they're going to arrest or they're going to have a cardiac arrest, then having a defibrillator there would be very important.

What they found, is that you can actually identify STEMI patients who are higher likelihood of arrest and those STEMI patients are those with younger age, they're not obese, they don't have diabetes. They have shortness of breath in addition to their chest pain and they have a very short delay from the time of chest pain to their call EMS. That is they're very concerned about their chest pain. You could use these characteristics to predict which STEMI patients, which chest pain patients were at highly likelihood of having a cardiac arrest. There was as much as a 19-fold difference between individuals without any of these factors and individuals with several of these factors.

Dr. Carolyn Lam: What I like about this, is that simplicity of that score. Age, symptoms and kind of the absence of diabetes, absence of obesity and that short time frame. It's something that could be asked on a routine questionnaire by EMS dispatchers, for example.

Dr. Mark Lane: Right. It highlights the importance of the dispatch system. That simple questions, you can really stratify risk and it's not just getting an ambulance out there. Truly stratifying risk in order to get there quicker.

Dr. Carolyn Lam: There are two papers that deal with out of hospital cardiac arrest. One of them interestingly focusing on the neuro-protective effects of Glucagon-Like Peptide-1 analog Exenatide. Thoughts about that one?

Dr. Mark Lane: This is a randomized study from Denmark. Notable that there are very low number of randomized trials in resuscitation so the fact that they did this is remarkable. What they did, is this glucagon-like peptide analog is a type II diabetic medicine and there is some reason to believe that that may protect the brain after resuscitation and ROSP. They had two goals in this trial. One was to see if it was feasible to administer a drug within six hours of a cardiac arrest and the other was to get any sort of outcome measure of whether this could provide some benefit. They randomly assigned 120 comatose patients and half of them got the peptide analog and the other half did not. What they showed, it is feasible to give IV administration of a drug within six hours of a cardiac arrest. Unfortunately, the drug they used did not appear to have any clinical benefit and this was both a composite end-point of death in neurologic function but also an evaluation of a brain neuron specific amylase, which was actually brain damage so they didn't see any biological or clinical neuro-protective effects of this drug.

Dr. Carolyn Lam: I didn't realize it until you said it, it is very difficult to do a randomized control trial. This is very significant just for that. The next study about the out of hospital arrest, really talks about bystander CPR and I think seeks to answer to what degree bystander CPR remains positively associated with survival with increasing time to potential defibrillation. Important question, what do you think of that?

Dr. Mark Lane: It's an important question that surprisingly has not been evaluated that closely. Most either studies either look at bystander CPR or EMS arrival times but don't look at the interaction between the two. This study looks at the interaction between bystander CPR and EMS response time and that's the critical thing in this paper that's very interesting.

What they did is, they split bystander CPR with or without and then EMS response times five minutes, 10 minutes and longer. If EMS responds within five minutes and you had bystander CPR, the survival rates with good neurological outcome were 14.5%, which is really a remarkable number. If there was no bystander CPR and the EMS arrived within five minutes, it dropped to 6.3%. There was 2.3-fold higher likelihood of good neurologic survival with bystander CPR with EMS within five minutes.

They also looked at the 10 minute response time of EMS and if you had bystander CPR and EMS arrived within 10 minutes, the survival rate was 6.7% and without bystander CPR, it was 2.2%. With bystander CPR and EMS arrival within 10 minutes, there was a three-fold higher likelihood of survival with bystander CPR. It's interesting that by 13 minutes, there really was essentially no difference in those individuals who had bystander CPR or not, suggesting that at that point it's taken so long for EMS to arrive, it really doesn't make really much difference between whether you have bystander CPR.

A really important paper showing that bystander CPR is critical, but so is EMS arrival within five minutes especially, but even 10 minutes.

Dr. Carolyn Lam: I like that paper and I really like the way you crystallized the findings so clearly like that. What I'm also liking is the way, even though these papers weren't invited or anything, there is this nice flow because from bystander CPR we now talk about duration of resuscitation. There's one regarding adults and followed by one in pediatric population so very nice set of papers. Could we start by maybe talking about the adult one? The one looking at the association between duration of resuscitation and favorable outcomes after out of hospital cardiac arrest from North America.

Dr. Mark Lane: The reason that these two papers are important is really the futility issue. When is it futile to continue a CPR and that's a very important question. This adult paper is from the ROC Consortium. The ROC is a North American Seer NIH Sponsored consortium that's been going on over the last 10 or so years. What they looked at was outpatients and they had a very large number of greater than 11,000 subjects and of those 8% survived with a good outcome. That's 8% of those 11,000. If you looked at those 8% that survived, 90% of those had return of spontaneous circulation with 20 minutes. You really wanted to get their blood pressure back within 20 minutes.

If you went beyond 20 minutes to the return of spontaneous circulation, you still could get good outcome. It was less likely but it was more likely if you had initial shockable rhythm, you had a witnessed cardiac arrest or you had bystander CPR. If you had some of those features, then you would argue to continue CPR for a longer time period. Actually a very nice important paper that if you had those other three features, you could still get good neurologic functioning, even with resuscitation attempts up to 40 minutes.

Dr. Carolyn Lam: Exactly. I thought I saw 47 minutes somewhere, but it gives us a bit of a guidance when we're making these really tough decisions and talking about tough decisions and futility, I think it's even more amplified in the pediatric population, isn't it? This next paper from Japan talks about the duration of pre-hospital CPR in the pediatric population. What are your thoughts on that one?

Dr. Mark Lane: This was a study from Japan, using their nation-wide Japanese data base. Actually, in many ways mirrored the adult experience. The number of patients analyzed with roughly the same. This was nearly 13,000. They looked at 30 day survival both overall and 30 day survival with good neurologic function and 30 day survival overall were 9% so similar to the 8% in adults and good neurologic function were 2.5%, which wasn't quite as good as in the adults and that the duration of CPR also was very important. Once CPR went out to 42 minutes there was less than 1% chance that that individual was going to survive with any significant neurologic outcome. If you had bystander CPR you could increase that time by four to five minutes but again showing very similar numbers to the adult population that once you start hitting that 40 to 45 minute time frame, if there's no return of spontaneous circulation then the odds of survival are really quite low.

The time frame may be extended a bit by CPR, maybe be extended by a bit if you had a shockable rhythm. Again, very similar features to what were found in the adult study.

Dr. Carolyn Lam: What a nice pair of papers. You know, the pediatric paper was paired by yet another, wasn't it? This one now addresses very importantly conventional versus compression only CPR in the pediatric population. Again, from Japan. I know both the pediatric papers were of great interest because you invited an editorial on this as well. You want to comment on those?

Dr. Mark Lane: This issue of compression only CPR versus standard CPR, which includes compression and ventilation is a very hot one because we know that if you can do compression only CPR, the individuals willing to do that type of CPR are much greater than the individuals willing to do mouth to mouth. In the adult population, there's been a number of very good retrospective registries and also randomized trials that showed that compression only CPR may be very similar ... In fact some studies better, some studies a little worse than compression-ventilation CPR.

Whether this applies to the pediatric population is not clear. There is more asphyxial arrest in the pediatric population whereas in the adult it's more cardiac so there is concern that compression only CPR will not be as good in children. This group of investigators used the same registry. A little shorter time-frame. They looked at it for two years and thus only had 2,000 patients in this registry. Of these 2,000 patients 400 received conventional CPR, 700 received compression only CPR and 1,000 did not receive any CPR. The important findings in this study was that any CPR increases survival so if you did not get any CPR, your survival was 3.7%. If you got conventional CPR your survival was 25.9% and if you got compression only CPR your survival was 9.3%.

When you compared unadjusted survival with compression only versus the standard CPR, the odds ratio were 3.42 that standard CPR was better than compression only CPR. However when you did multi-variable adjustment, that big difference decreased and was no longer statistically significant between conventional CPR and compression only CPR. The same was true when you did propensity score matching which is an attempt to randomize to match groups. There was really no difference between conventional CPR and and compression only CPR.

From this study, it's clear that any CPR is better than no CPR. There was a hint here that standard CPR was better than compression only CPR but because that improvement disappeared with multi-variable adjustment and propensity score matching both the authors and the editorialists have called that it's time for a randomized trial of compression CPR in kids.

Dr. Carolyn Lam: Very nice. That brings us already, to the last original paper. Into the in-hospital setting and it talks about time to epinephrine. That's nice. We've got time to balloon and time to door and and now we've got time to epinephrine. Tell us about this one.

Dr. Mark Lane: This was a very nice study from the guidelines database. This is a data base that the HA is using to evaluate resuscitation in hospitals. In this database, the investigators looked at times to the epinephrine administration and then overall patient survival for the hospitals. What they found is that there was wide variability in the time to first epinephrine dose. The HA and other counsels have recommended that it be given as soon as possible or early-on in resuscitation and in this database 12.7% of patients had delays greater than five minutes to epinephrine.

What importantly they showed, when you looked at the hospital's overall time to epinephrine administration and the hospital's overall resuscitation survival rates, they were inversely proportional. That is, the longer that hospitals took to give the first dose of epinephrine, the lower their survival rate. This really leads to a very important question, is it the delay in epinephrine administration that makes the difference between these good functioning hospitals and poor functioning hospitals, or is it that the delay to epinephrine administration is really a surrogate for poor CPR performance. I suspect that both of them could be true, although I suspect the second one is probably a higher likelihood.

Dr. Carolyn Lam: Congratulations again on this amazing issue with extremely important take-home messages just from the original papers. Were there other papers you wanted to highlight in this issue?

Dr. Mark Lane: Yeah, there were three research letters and this is a newer type thing for SERP. These are original manuscripts but in a very succinct fashion in that they're making a single point. I actually thought these three research papers were very interesting also. One was on the mechanical CPR in the cares database and in this paper they actually showed that mechanical CPR was associated with poor outcomes in resuscitation so a paper well worth reading. In another paper from France looked at pulmonary embolism related to sudden cardiac death and what they found is that PEs were present in a significant percentage of people who had sudden cardiac arrest and again if you had a non-shockable rhythm, female, prior thromboembolism or absence of heart disease you were more likely to have a pulmonary embolism.

The final research letter looked at ticagrelor versus clopidogrel in comatose patients undergoing PCI, a randomized study. Succinct paper well worth reading. In addition to those three research letters, there were four frames of reference. These are more a personal perspective on resuscitation and resuscitation signs over time and interesting reading, all four of them.

Dr. Carolyn Lam: Mark, that was a beautiful summary and I am sure you've whet the appetites of all the listeners to just grab hold of this issue. Thank you so much for joining me today. Thank you listeners for tuning in and don't forget to tune in next week.

Circulation December 13, 2016 Issue

12 december 2016 | 23 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal.

The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms.

Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo.

In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases.

The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking.

First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders.

The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers.

Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers.

The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation.

These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways.

The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States.

Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model.

In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman.

The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction.

The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial.

Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level.

Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level?

We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims.

Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events?

Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard.

Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find?

Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25.

Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions?

Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example.

Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses?

Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here.

I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50?

One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you.

We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies.

Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred.

Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall.

As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs?

That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial.

Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help.

Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.

Circulation December 6, 2016 Issue

5 december 2016 | 24 min

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion is regarding the exciting results of the masked hypertension study showing that clinical blood pressure underestimates ambulatory blood pressure, but first here's your summary of this week's issue.

The first study reviews the largest clinical experience so far with pulmonary vein stenosis following ablation for atrial fibrillation. First author Dr. Fender, corresponding author Dr. Packer and colleagues from Mayo Clinic Rochester, Minnesota evaluated the presentation of 124 patients with severe pulmonary stenosis between 2000 and 2014 and examined the risk for re-stenosis after intervention utilizing either balloon angioplasty alone or balloon angioplasty with stenting. All 124 patients were identified as having severe pulmonary vein stenosis by CT in 219 veins. 82% were symptomatic at diagnosis with the most common symptoms being dyspnea, cough, fatigue and decreased exercise tolerance. 92 veins were treated with balloon angioplasty, 86 with stenting and 41 veins were not intervened on. The acute procedural success rate was 94% and did not differ by initial management. Overall, 42% of veins developed re-stenosis, including 27% of veins treated with stenting and 57% of veins treated with balloon angioplasty.

The three-year overall rate of re-stenosis was 37% with 49% of balloon angioplasty treated veins compared to 25% of stented veins developing re-stenosis. This was a difference that remained significant even after adjusting for age, CHADS2 VASC score, hypertension and time period of the study with an adjusted [inaudible 00:02:30] ratio of 2.46 for risk of re-stenosis with balloon angioplasty versus stenting. In summary, this study shows that the risk for pulmonary vein re-stenosis is significant following atrial fibrillation ablation. The diagnosis is challenging due to non-specific symptoms and while there is no difference in acute success by type of initial intervention, stenting significantly reduces the risk of subsequent pulmonary vein re-stenosis compared to balloon angioplasty.

The next paper shows that the index of microvascular resistance, which is a novel invasive mreasure of coronary microvascular function, has emerging clinical utility as a test for the efficacy of myocardial re-perfusion in invasively managed patients with acute ST elevation myocardial infarction. In this study by first author Dr. [Carrick 00:03:30], corresponding author Dr. Barry and colleagues from the University of Glasgow in Scotland, index of microvascular resistance and coronary flow reserve were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST elevation myocardial infarction. Authors found that compared with standard clinical measures of the efficacy of myocardial re-perfusion, such as ischemic time, ST segment elevation and angiographic blush grade, the index of microvascular resistance was more consistently and strongly associated with myocardial hemorrhage, microvascular obstruction, changes in left ventricular ejection fraction and left ventricular end diastolic volume at six months as well as all caused death of heart failure during the median follow up of 845 days.

In fact, compared with an index of microvascular resistance greater than 40, the combination of this index and coronary flow reserve less than two did not have incremental prognostic value. The take-home message is therefore that an index of microvascular resistance above 40 represents a prognostically validated reference test for failed myocardial re-perfusion at the end of primary percutaneous coronary intervention. This study supports further research into microvascular resistance based therapeutic strategies in these patients.

The next study provides experimental data regarding molecular mechanisms underlying calcific aortic valve disease. First author, Dr. Haji, and corresponding authors Dr. Matthew and [Bose 00:05:24] from the Quebec Heart and Lung Institute in Canada performed genomic profiling and in-depth functional assays in human aortic valves. They demonstrated for the first time that the promotor region of the long non-coding RNA H19 is hypomethylated in patients with calcific aortic valve disease. This hypomethylation in turn increases H19 expression in the valve interstitial cells where it prevents Notch 1 transcription by blocking or out-competing P53’s recruitment to the Notch 1 promotor. Thus, H19 appears to be the missing link connecting Notch 1 to idiopathic calcific aortic valve disease. It may therefore represent a novel target in calcific aortic valve disease to decrease osteogenic activity in the aortic valve.

The next paper describes the largest cohort of mycotic abdominal aortic aneurysms to date and is from Dr. [Sorelias 00:06:37] and colleagues of Uppsala University in Sweden. These authors identified all patients treated for mycotic abdominal aortic aneurysms in Sweden between 1994 and 2014. Among the 132 patients, they noted that the preferred operative technique shifted from open repair to endovascular repair after 2001 with the proportion treated with endovascular repair increasing from 0% in 1994 to 2000 to 60% in the 2008 to 2014 period. Survival at three months was lower for open repair compared to endovascular repair at 74% versus 96% respectively with a similar trend present at one year. A propensity score adjusted analysis confirmed the early better survival associated with endovascular repair. During a median follow up of 36 months for open repair and 41 months for endovascular repair. There was no difference in long-term survival, infection-related complications or re-operation. The take-home message is that endovascular repair appears to be a durable surgical option for treatment of mycotic abdominal aortic aneurysms.

The final study provides insights into the molecular mechanisms by which aldosterone triggers inflammation and highlights the particular role of NLRP3 inflammasome, which is a pivotal immune sensor that recognizes endogenous danger signals and triggers sterile inflammation. Authors Dr. Bruden [Esimento 00:08:32], Dr. [Tostes 00:08:33] and colleagues from the University of Sao Paulo in Brazil analyzed vascular function and inflammatory profiles of wild-type NLRP3 knockout, caspase-1 knockout and interleukin-1 receptor knockout mice, all treated with vehicle or aldosterone while receiving 1% saline. They found that mice lacking the interleukin-1 beta receptor or lacking inflammasome components such as NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In-vitro, aldosterone stimulated NLRP3-dependent interleukin-1 beta secretion by bone marrow derived macrophages. Chimeric mice reconstituted with NLRP3 deficient hematopoietic cells showed that NLRP3 in immune cells mediated the aldosterone-induced vascular damage.

In addition, aldosterone increased the expressions of NLRP3, caspase-1 and mature interleukin-1 beta in human peripheral blood mononuclear cells. Finally, hypertensive patients exhibited increased activity of NLRP3 inflammasome. Together these data demonstrate that NLRP3 inflammasome via activation of interleukin-1 receptor is critically involved in the deleterious vascular effects of aldosterone, thus NLRP3 is a potential target for therapeutic interventions in conditions with high aldosterone levels.

That wraps it up for our summaries. Now for our feature discussion.

On today’s podcast we are going to be discussing the very important issue of masked hypertension. This is an issue that gets a lot less attention than I think compared to white coat hypertension. I’m so pleased to have the first and corresponding author of the masked hypertension study, Dr. Joseph Schwartz, from Stony Brook University and Columbia University in New York. Welcome to the show, Joe.

Dr. J. Schwartz: My pleasure. I’m delighted to join you.

Dr. Carolyn Lam: We have a regular on the show today as well, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back Wanpen.

Dr. Wanpen V.: Thank you so much. Happy to be here.

Dr. Carolyn Lam: Joe, I want to start by addressing the common misperception that ambulatory blood pressure is usually lower than clinical blood pressure. That seems to make a lot of sense to us clinically because, for example, I always use ambulatory blood pressure to diagnose white coat hypertension and so the assumption there is that my clinically measured blood pressure is higher than what I’m going to be finding if this patient measures the blood pressure on an ambulatory 24-hour basis. It’s also from the cutoffs that we use. For example, ambulatory blood pressure we use a 24-hour cutoff of 130/80 to make the diagnosis whereas with clinical blood pressure we use a cutoff of 140/90 so all of this kind of reinforces that ambulatory blood pressure is usually lower. Your study, though, tells us otherwise so please fill us in here.

Dr. J. Schwartz: You're right that in the doctor's office there are a certain set of people who probably get anxious when they're around a doctor and with that anxiety may cause a temporary increase in their blood pressure, a temporary elevation, and that's the basis of where we think white coat hypertension comes from. That's a very widespread belief among doctors and it's even been in previous guidelines, there have been statements to that effect. When I talk to people out in the general public and tell them I'm doing a study comparing blood pressure out in the real world compared to blood pressure in the doctor's office, all of them tell me, "Well, usually when I'm in a doctor's office that's a relatively calm period for me unless there's really something wrong with me and out in the everyday world I have to face a variety of stressors. I have deadlines. I have places I need to get to. Sometimes I have people yelling at me. Sometimes I'm just in a hurry."

All these things elevate your blood pressure out in the real world and so when we were trying to recruit people for the study, and we were very agnostic in recruiting them, telling them that we were interested in the differences in blood pressures between the doctor's office and the ambulatory blood pressure and they might go in either direction. When I told them about the fact that their ambulatory blood pressure or real world blood pressure might be higher than in the doctor's office, the vast majority of people nodded affirmatively and said, "It wouldn't surprise me at all."

Dr. Carolyn Lam: Could you define masked hypertension compared to white coat hypertension and tell us a little bit about the population you studied.

Dr. J. Schwartz: Sure. First with the definition. I'm going to say something a little bit different from something you said before. You mentioned cutoffs that we typically used for ambulatory blood pressure of 130/80 and those are the cutoffs that are used if you compute an average blood pressure over the entire 24 hours. What many people do, and what we did for this study, was compare the average blood pressure when people were awake to their blood pressure in the doctor's office because obviously in the doctor's office everybody is awake. The typical cutoffs there are 135/85, recommended by numerous guidelines in this country and with our international collaborators. The definition of masked hypertension is having a blood pressure in the clinic setting that's below 140/90 but having an ambulatory blood pressure where either the systolic blood pressure is above 135 or the diastolic is above 85 millimeters of mercury.

In terms of the sample, for years I've had a particular strategy for trying to recruit participants. I do worksite-based studies and so I identify large organizations that will allow me to recruit their employees and then what we did for this study is go to individual departments, both here at Stony Brook University, at Columbia University, at a residential veterans' home that's affiliated with Stony Brook University and then also at a local private hedge fund management company. We would go to these sites, I talk to the head of a department and tell them a little bit about masked hypertension and what the study was about and ask them if they would be willing to have their employees participate in the study. Once I had the okay from the department head then we would conduct public health screenings, blood pressure screenings. My staff and I would go into the department for multiple days and invite anybody who was interested to have their blood pressure taken on site and while we were taking those blood pressures carefully.

The proper way to take those is to take three readings and leave a minute or two interval between them and rather than just have silence then between the readings we would tell them a little bit about our study. At the end of the study if they didn't have extremely high blood pressure and were not taking blood pressure medication we would ask them if they might be interested in participating in the study that we just described. That's how we identified potential participants and about 2/3 of the people that we talked to who looked eligible indeed chose to participate.

Dr. J. Schwartz: The one other thing I might mention that I think we mentioned, I hope we mentioned as a limitation of the study, is that everybody in the study had health insurance and at least until recently there were very large portions of the population that didn't have health insurance, everybody by virtue of their employment by the organizations that participated in the study, did have employer-based health insurance.

Dr. Carolyn Lam: Thanks for clarifying the population so well. Could you just give us the top line of your findings. How big a difference did you find, which direction and that intriguing effect of age?

Dr. J. Schwartz: Sure. The first thing we found is that on average the systolic blood pressure is seven millimeters mercury higher out in everyday life than it is in the clinic setting where we take our clinic readings. I should mention that unlike most studies, and all studies at the time that we began our study, we brought people in three separate times to take the clinic blood pressure. Up until that, almost all of the studies of ambulatory blood pressure monitoring only had clinic blood pressures from a single visit. I think we have a very reliable measure of the clinic blood pressure as well as reliable measure of ambulatory blood pressure. We see a seven millimeter difference in the systolic blood pressure and a 2 millimeter difference, again the ambulatory being higher for diastolic blood pressure.

What's more remarkable is if you think about what's a sizable difference. If you think if we perhaps somewhat arbitrarily say 10 millimeters of systolic blood pressure is a large difference. More than 35% of the population has an ambulatory blood pressure that is more than 10 millimeters higher than their clinic blood pressure whereas only 3% of our sample had that large a difference in the opposite direction, what many people would call a white coat effect. It's more than a 10 to 1 difference in numbers of people who have elevated ambulatory versus elevated clinic.

You asked me to mention something about the age difference. When you look at how that difference in systolic blood pressure varies by age, it's quite a bit larger for people who are younger. If you're under 30 the difference is, on average, 10 millimeters rather than seven millimeters and if you go up as you approach 60 years of age or so the difference becomes relatively small, perhaps in the neighborhood of two millimeters. We don't have enough people because it's a working population over 65 to say very much about what would happen. In fairness to prior research, which often is on older populations and particularly hypertensive populations, the studies that have historically shown that ambulatory blood pressure tends to be lower than clinic blood pressure are in these older populations and populations that have elevated blood pressure to start with.

My speculation there, and you haven't asked me to mention it but I will, is that older people and those with hypertension have a reason to be more nervous or more anxious when they go to the doctor than people who are not taking medication and probably don't even know that they have hypertension. People who are just being screened perhaps during a routine physical for the possibility of hypertension, because the doctors take a blood pressure reading every time you go in, they're doing that in order to see whether you might have hypertension, but most people who are going in for what we call a well patient visit are not nervous about their blood pressure being high.

Dr. Carolyn Lam: I have to say, the take-home message for me when I read this was, I am not paying enough attention to masked hypertension and then another thing was, maybe I need to think about more white coat hypertension in the older and masked hypertension in the younger. Wanpen, do you think it's as simple as that? What were your take-home messages?

Dr. Wanpen V.: I think this is a very important study that examines this in a systematic way. I'm not surprised that Joe found as much masked hypertension here. I think that he's absolutely right. We looked at this in Dallas Heart Study as well recently and we found that in the population-based sample in Dallas almost 20% of people have masked hypertension and white coat we found only like 3% and the average in the Dallas Heart Study was very close to those samples, about mid-40s. I think that's a very important finding in that the people with masked hypertension would not be suspected otherwise to have problems. Also, in the Dallas Heart Study they used home readings but Dr. Schwartz used ambulatory blood pressure monitoring. Unless extra out of office monitoring is being done we will totally miss these people who are more likely to have target organ damage from high blood pressure. I think that's absolutely important.

Dr. Carolyn Lam: Actually, Wanpen you brought up something I was going to bring up as well. Where does home blood pressure fit in with this? Do you think it's home blood pressure versus ambulatory blood pressure?

Dr. Wanpen V.: The US Preventive Services Task Force has issued a little bit of recommendations recently that we need to either use ambulatory blood pressure monitoring or home blood pressure monitoring to confirm diagnosis of hypertension in the office. If someone shows up with elevated blood pressure in the office either home blood pressure or ambulatory blood pressure needs to be done. If we just followed that guidelines we're still going to miss people with masked hypertension because by definition they don't have elevated blood pressure in the office. I think that from these findings and Dr. Schwartz' study I think to catch these people we really need to pay attention to people with pre-hypertension type of blood pressure because it seems like those are the group that has the most probability to have elevated ambulatory blood pressure so anyone with borderline blood pressure in the clinic, those are the ones who the doctor needs to tell the patient to monitor blood pressure at home or order ambulatory blood pressure themselves if that's available in their facility.

Dr. Carolyn Lam: Wanpen, I fully agree. What an important message. Joe, I'd like to give you the final word but I'd love to hear how you have maybe taken this into your own practice.

Dr. J. Schwartz: I think we mostly focused on and indeed the paper mostly focuses on the difference between clinic blood pressure and ambulatory blood pressure. When we talk about the young people, the young people have a bigger difference but those differences are for the most part all in the normal range. You might see a 10- or a 12-point difference but it might be that the ambulatory is 124 and the clinic is 112 and no doctor is going to worry about that very much. There are really always two things that we're trying to look at simultaneously: The first is what is that difference between the ambulatory and the clinic, but the second is for whom does the clinic stay under the threshold for diagnosis of hypertension but the ambulatory is over? That's the diagnosis of masked hypertension.

We haven't said it today so I'll say it: Of those people who had normal clinic blood pressures averaged across three repeated visits, 15.7% of them had elevated ambulatory blood pressure and would have been diagnosed as having hypertension based on their average daytime ambulatory blood pressure reading. That's one message.

The last message is unfortunately there is almost no research yet telling us what we should do in terms of treating people with masked hypertension. We are now at the point where we can identify these people and we're also at the point where we now know that there are a lot of such people and we don't even have any research to base guidelines on for deciding what we should do with them. The most obvious thing is to recommend lifestyle changes. If they're overweight we could suggest that they lose weight. We could suggest that they exercise more. We might think about treating some of those people, especially if their ambulatory blood pressure is well above 140/90. There are no statements out in the literature by any of the organizations, and in fact there's no research examining whether there's a benefit or not a benefit to perhaps putting some of those people on medications. I think that's a big question that future research needs to address.

Dr. Carolyn Lam: Joe, thank you so much. I think your last statements just really emphasize how important this paper is. It increases awareness and it's going to open the door to much more needed research in this area. Thank you so much. Thank you Joe and Wanpen for being on the show today.

Thank you listeners for joining us. Don't forget to join us next week for even more news and exciting discussions.

Circulation November 29, 2016 Issue

28 november 2016 | 19 min

Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.

The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.

Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.

The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.

However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.

In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.

The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.

A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.

The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.

Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.

Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.

Speaker 2: Thank you very much.

Carolyn Lam: We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.

Speaker 3: Hi Carolyn, thanks for having me.

Carolyn Lam: So Jonas, could you start off by telling us why you did this study and what you found?

Speaker 2: We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.

Carolyn Lam: Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.

Speaker 2: It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.

Carolyn Lam: Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?

Speaker 2: We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.

Carolyn Lam: Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?

Speaker 3: I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.

But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.

Carolyn Lam: Actually, Jonas could you let us know is there any sex differences in the performance of the score?

[00:14:46]

Speaker 2:

There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.

Carolyn Lam: That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.

Speaker 3: We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.

Speaker 2: We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.

Carolyn Lam: It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.

Speaker 3: Yeah, no absolutely. And I think that's great.

Carolyn Lam: Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?

Speaker 2: We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.

Carolyn Lam: That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.

Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.

Circulation November 22, 2016 Issue

21 november 2016 | 20 min

Carolyn: Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...

In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...

The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.

The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...

The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.

They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.

The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...

The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.

They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...

The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.

In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.

Those were the highlights from this week's issues. And now for our feature paper ...

We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.

Zuzana: Thank you for having me.

Carolyn: We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.

Gabriel: Yes, hello Carolyn, hello Zuzana.

Carolyn: So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?

Zuzana: The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.

Carolyn: Could you, maybe now, clearly describe what you did in this study and what were your findings?

Zuzana: The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.

So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.

So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]

Carolyn: That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.

Zuzana: Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.

Carolyn: Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?

Gabriel: First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.

Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.

The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.

In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?

Zuzana: Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.

Gabriel: The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.

It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.

Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...

Carolyn: Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...

Circulation November 15, 2016 Issue

14 november 2016 | 25 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In today's podcast interview we will be discussing the ruling in and ruling out of myocardial infarction with the European Society of Cardiology 1-hour algorithm. Stay tuned for a discussion of new data and controversies on this hot topic. Now, here's a summary of this weeks issue.

The first paper brings us one step closer to the ultimate goal of cardiac tissue engineering. That is to replicate functional human myocardium in vitro. In this study, by first author Dr. Ruan, corresponding authors Dr. Murry and Regnier from the Institute for Stem Cell and Regenerative Medicine and University of Washington, authors recognize that human-induced pluripotant stem cells, or iPSC-derived cardiomyocytes, really provide a cell source for cardiac tissue engineering. However, their immaturity limits their potential applications. Hence, they sought to study the effect of mechanical conditioning and electrical pacing on the maturation of iPSC-derived cardiac tissues.

They found that after two weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility, tensile strength, construct alignment, cell size, and SERCA2 expression. When electrical pacing was combined with static stress conditioning the tissue showed an additional increase in force production and further increases in expression of RyR2 and SERCA2. These studies really demonstrate that electrical pacing and mechanical stimulation promote the maturation of the structural, mechanical, and force generation properties of iPSC-derived cardiac tissues and constitute a really important contribution to cardiac tissue engineering.

The next study is the first large-scale, nationwide, population-based investigation of the association between congenital heart defects and any placental measure. This study by Dr. [Matheson 00:02:27] and colleagues from Aarhus University Hospital in Denmark, included all 924,422 live-born Danish singletons from 1997 to 2011. Congenital heart defects was present in 7,569 newborns. The authors compared the mean differences in placental weight between newborns with and without congenital heart defects and found that only three specific subgroups of congenital heart defects were associated with measures of impaired placental growth. These included Tetralogy of Fallot, double outlet right ventricle, and major ventricular septal defects. In these subgroups, the mean deviations from the population mean head circumference and birth weights were reduced by up to 66%, with adjustment for placental weight. In other words, up to two thirds of the deviations in fetal growth, including fetal cerebral growth, may be related to the impaired placental growth. The present work provides an important contribution to the existing knowledge on the association between congenital heart defects and placental anomalies as well as the possible importance for fetal growth in this population.

The next study provides an up-to-date evaluation of the cost effectiveness of antibiotic prophylaxis in the prevention of infective endocarditis. In this study by first author Dr. Franklin, corresponding author Dr. Thornhill, and colleagues from the University of Sheffield, the cost effectiveness of antibiotic prophylaxis, namely single dose amoxicillin or clindamycin, in patients at risk of infective endocarditis. They did this using, firstly, recent estimates of the effect of antibiotic prophylaxis on infective endocarditis in the English population; secondly, rates of antibiotic adverse drug reactions; and thirdly, estimates of the probability of developing infective endocarditis following dental procedures derived from French data. All this as foundation for analysis of cost and health benefits.

A decision analytic cost effectiveness model was used based on the decision model by the National Institute for Health and Care Excellence, or NICE, that was used to inform the 2008 guidelines. The authors found that antibiotic prophylaxis was less costly and more effective than no antibiotic prophylaxis for all patients at risk for infective endocarditis. In fact, if antibiotic prophylaxis was reinstated in England for those at moderate or high risk of infective endocarditis, it could save 5.5 to 8.2 million pounds and result in health gains of more than 2,600 quality-adjusted life years. Antibiotic prophylaxis was even more cost effective for those at high risk of infective endocarditis, being cost effective even if only on 1.44 cases of infective endocarditis was prevented per year. In summary, these updated findings really support the cost effectiveness of guidelines recommending antibiotic prophylaxis use, particularly in high risk individuals.

The last study provides data on long term cardiac mortality among survivors of cancer diagnosed in teenagers and young adults in the largest population-based cohort to date. Furthermore, the study provided, for the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 to 39 years. For example, survivors of Hodgkin lymphoma, lung cancer, acute myeloid leukemia, non-Hodgkin lymphoma, and CNS tumors experience 1.3 to 3.8 times the population-based mortality rates. This study provides important insight into the cardiotoxicity of the treatments given in the past to teenagers and young adults with each individual type of cancer and importantly, provides an initial basis for developing evidence-based follow up guidelines.

Those were you summaries. Now for our feature interview.

Our feature paper today discusses the hot and controversial topic of ruling in and ruling out myocardial infarction with the European Society of Cardiology 1-hour algorithm. I'm so excited to have with us the corresponding author of the paper that really represents the first multi-center external validation of these ESC guidelines for MI and the first multi-centered direct comparison of the performance of the algorithm with high-sensitivity troponin I and high-sensitivity troponin T assays. This would be Dr. Martin Than from Christ Church Hospital in New Zealand. Welcome Martin.

Martin: Thank you very much. It's a great pleasure for me to be able to join everybody and talk here.

Carolyn: It's great to have you. We also have with us the editorialist on this paper, Dr. Allan Jaffe from Mayo Clinic, Rochester, Minnesota. Allen, it's so good to hear your voice again.

Allan: Good to talk to you again too, Carolyn.

Carolyn: Finally, we have Dr. Deborah Diercks, Associate Editor from UT Southwestern. Welcome Deb.

Deborah: Oh, it's good to be here and I'm looking forward to the conversation and what we're going to learn from these two gentlemen.

Carolyn: Absolutely. You know what? I'm going to start with Martin. I love the way to set up your paper. You very correctly pointed out that there's a tension in that ED physicians require really high sensitivity to confidently rule out MI and send patients home, whereas cardiologists do not want high proportion of false positives because we don't want false high risk to lead to invasive testing. I just love, if you could start by telling us how the ESC 1-hour algorithm fits into all this and what you were trying to do in your study.

Martin: I heard Deb Diercks on the phone as well, who's a very respected emergency physician in this area, and I think we would both say that we have a certain bias in our perspective on this, which is of course we are the people at the end of the day that have to send people home when they present with chest pain and possible myocardial infarction. We are also, of course, the people that take the fall if there are any mistakes made. Historically, people have not been very kind to emergency physicians who miss such a diagnosis. It's an extremely high source of medical legal action in the United States and, in fact, worldwide. So we're somewhat paranoid as a speciality about missing cases of myocardial infarction because at the end of the day, the worst thing that can possibly happen is for you to send someone home who comes to harm from the very clinical complaint for which they came to you for help. We want to avoid that at all costs and that was the basis behind us trying to put together this paper.

Soon after the ESC guidelines come back and I returned from London, where they were announced at the conference, to New Zealand, I received quite a lot of phone calls and correspondence saying, "Okay, we see these new ESC guidelines are out. When are we going to start introducing them?". I immediately wanted to say, "Well, the key thing is to understand how they would work, how they would be implemented, and whether they'd work in my own setting" because if we want to implement them in New Zealand or Australasia, we would want to double-check on that first. That's the basis and the philosophy behind the manuscript.

Carolyn: Tell us what you found.

Martin: As Allan will be the first to point out, I think there are a number of flaws in the data we had available to us that allowed us to do this analysis, but based on the concept that when we've surveyed emergency medicine physicians, the sensitivity that was wanted was at least 99% if not higher. We found that neither of the algorithms produced that level of sensitivity, although the algorithm based on hsTnI was very close. I think it's 98.8%, so that was very good. Reasonably wide confidence intervals on that. The hsTnT algorithm performed slightly less well with a sensitivity around 97%. I guess, if I was to start with an a priori question, which is did we reach a standard of 99%, then our answer to this was, in one case, not quite, and the other case, no, we probably didn't. We said that if you wanted to use a metric of negative predictive value, which I know a lot of people do, then there was actually very good negative predictive value in the high 99 percentage range for both pathways.

Carolyn: Do you mind if I stretch you a little bit and ask you to describe exactly what you did in the cohorts? You were saying that there were some imperfections. Maybe you'd like to tell us a little bit about that.

Martin: Absolutely. As always, when you're writing a paper, you look back and you always feel there are far too many imperfections, but I guess the principle one I would say that's been noted is that we had samples done on arrival and the algorithm itself specifies a [inaudible 00:11:43] one-hour second sample. We didn't have those specimens, so we had to base our data analysis on samples done either at 90 minutes afterwards or two hours afterward. It's clearly not being tested exactly as it was written, although one could argue that that slightly delayed sampling is potentially reflective of real life, where it's very hard to hit a one hour mark in a busy emergency department, and two, where the slight delay in getting the samples would actually allow more time for a troponin to rise and therefore give a chance of providing a better sensitivity.

I think the other I guess key flaw is that of course, the people present to emergency departments at different time frames following the onset of their symptoms. There's been some valid concern raised that algorithms may not necessarily perform as well in very early presenters. In fact, that is something that's being emphasized now in the ESC guidelines.

Carolyn: Right. Allan, I loved your editorial. You did mention a couple of these points. Would you like to maybe clarify your view of this?

Allan: I think that there are two or three terribly important issues. We all would like to have very facile algorithms. Particularly given removing the high sensitivity, the idea would be gee, wouldn't it be nice to have something really simple that works perfectly? If you look at the validation and the way the algorithm has been put together, immediately there are some concerns that people ought to have and that at least we tried to point out, that were important. One of them Martin has already discussed a little bit, which is one looks at most of the validation studies. There are very few patients who are evaluated very early after the onset of their symptoms. That's a potential problem because the overlap, since they use very low values or very small change, that there could be, with people who have real disease, is in those very early presenters. The initial algorithm from the ESC used both a very low level troponin and a set of change criteria. Actually when they published those criteria, they changed that and eliminated, at least for the first three hours, the very low values. If one looks at Martin's study, it was again, the very early patients who potentially may have been missed. I think we need more data before we go ahead and acknowledge that this will be working for those early presenters.

There are two other problems with the population that we need to be careful about. It's been well known that when you have a negative troponin at six hours all the way back to [Chrisann's 00:14:26] original article in the '90s, that you're pretty safe. The population that you'd like to look at really are the patients who, after two hours in Martin's study, since he took a little bit longer given the logistics that were there in New Zealand and Australia, is the patient who came in at four hours because by six, they're actually meeting that six-hour criteria. When you have a large number of other such patients, you simply add noise and it makes you sensitivity look better, but it's not necessarily the case that that give you that same degree of reassurance that ED physicians would like.

The third population-related issue is that you'd like to do this in all-comers. The protocol was developed for chest pain patients, but there are a variety of patients in whom we evaluate myocardial infarction in, who may not qualify for that. The patients who are critically ill, for example, who may have Type 2 infarctions. The individuals who may come in who are very elderly, who often don't have chest pain so we don't identify them necessarily as a rule out. Interestingly, if you start thinking about those groups, they tend to have much higher troponin, so they may well skew the cut-offs that are used and change the algorithm.

In truth, we don't want more than one way of defining myocardial infarction. We only want one algorithm for ruling in and ruling out. Having an all-comers study, in my way of thinking, would be important. In that same regard, let me point out that you can rule out myocardial infarction because you don't have an acutely changing pattern of troponin elevations, but what we really rule in myocardial infarction? You rule in acute cardiac injury. Could be myocarditis, could a apical ballooning. There are a whole variety of other types of disease entities that could be involved and the arbitrary value of 52 that was put in the algorithm really, I think, is much too low for two reasons. One reason, because it didn't include all-comers. A second reason is because of the way in which the comparison between troponin T and I were done. I'll talk about that in just a moment. I would point out that using a different assay, the troponin I assay, in another set of studies, another group from Hamburg has suggested that very different metrics would be much better.

The final thing to say about extrapolation between the assays, and then I have some suggestions about what would make this better if you want to go there now or we can wait, is the comparison and the way in which the metrics for troponin I were developed really weren't by using troponin I as a gold standard. It was by taking and using troponin T as the gold standard for the diagnosis, then thawing samples many years later, running troponin I, and then extrapolating from the gold standard of troponin T to troponin I. Well, there's several problems with that. Number one is that appropriate comparisons should be fresh samples. Fresh samples. In addition, we believe, from the way in which we think about high sensitivity, which may not be correct, that the troponin I assay should be more sensitive and in [inaudible 00:18:05] fact, in the papers that were done validating this approach or attempting to describe the approach, troponin T was wildly more sensitive than was troponin T. We're extrapolating some data that doesn't sort of fit the way in which the information we have, it would mean all of the troponin I validation studies are incorrect.

That's where those numbers came from and even more problematic are the change numbers, which are very low. For the troponin T assay, they're three in five between ruling in and ruling out, which if you look at the assay imprecision, is something the assay can't do. Now you're extrapolating them in a very, very loose manor to troponin I and making them even lower. Those are not doable sorts of things. There's a real problem with the way in which the metrics for troponin I, even though it performed well in this circumstance, ended up being developed. I think all of those things need to be taken into account when we look at the results of the study. The results that Martin and his group got are very similar to the other validation studies that have been done because they've all done it pretty much that same way. There's not a surprise that their validation is similar, but I think unfortunately, we didn't have an opportunity to unmask, in a data-driven way, the problems that I just described.

Carolyn: Thank you Allan. Deborah, if you could share your thoughts on this.

Deborah: Martin raises some valid issues. That if something goes out as an algorithm, people want to use it. That use needs to be predicated on does it work in their patient population and is it feasible in the time frame and can it be adopted safely and what the indications are. In the emergency department, the value really is the negative predictive value because we want to be able to safely send people home. That's where rapidity of an evaluation is very important.

The other issue raised was exactly what Dr. Jaffe talked about. Does the algorithm itself reflect what we really need? Can you validate something that was created by the scientific way, but really a combination of a lot of information? Are the thresholds really valid themselves? That's the challenge with it. I think what you heard here are kind of two issues we struggle with it. We have a very respectable organization putting out an algorithm that is scientifically based and we want to adopt early, but there are questions on both sides of the issue on whether it can be adapted into real-world clinical practice on a global nature where prevalence of disease is different and the patients it'll be applied to vary, whether it's been on time of presentation or overall demographics.

Also on the scientific side, on the assays itself, are we using the right cutoff? Especially when we're looking at deltas and looking at such a rapid change. It's very nice to hear both of those points so eloquently described today during the discussion.

Carolyn: Thanks Deb. I fully agree. Hence, again, the importance of this paper. Martin, I'd love to hear your responses to Allan's comments and then also share with us, what's the take-home message for you as a clinician? How are you applying what you just found?

Martin: The guidelines are good on the right line, it's just as I said, they may not necessarily translate to all other environments. I guess that's my take-home message to myself, which was if I were to look at my own data from my own center, in Christ Church, and the way it's applied here, if I had applied the ESC guidelines and it had met the metrics which I was satisfied with, which I guess would be a very high sensitivity for me in terms of rule out, then I would actually seriously consider implementing it in my own center. It didn't reach that threshold so now I want to try and refine or explore further how I could allow the guidelines to do that. For example, one way that, and this is in the guidelines, but not necessarily in the flow chart, is the importance of applying clinical judgment and clinical findings with the results of the algorithm. I think that's a very important step in it. For example, if I was going to apply this in my own center, I'd want to be setting out clearly for the doctors concerned, how one would incorporate clinical judgment rather than it being a very subjective thing, which might vary significantly between a junior doctor or a far more experienced one.

I guess the take home message for me is this. The ESC guidelines are a very important piece of work. They've been robustly developed. For people who want to implement them, I'm no saying don't use them at all. I'm just saying that, you know, just think about carefully how you would use them and check whether you think they're appropriate for your setting.

Carolyn: That's great. Allan, what about you? What are your thoughts on how this may be applied in clinical practice and what more needs to be done?

Allan: I think we need to have a real trial where patients are managed based on the results of these approaches rather than more observational studies. I would argue that those management trials that involve an all-comers sort of population, so we are comprehensive, and should also interrogate whether or not the protocol itself is adequate or whether or not it requires follow-up to meet the metrics that have been proposed. I would point out that in the past, in the studies from the group from New Zealand and Martin Than particularly, have had very, very good follow-up. One at least needs to ask the question whether or not the algorithms that are proposed work perfectly without any follow-up or whether or not follow-up is an important component. We don't know that yet.

Carolyn: Thanks Allan. I'd love to give the final words to Deb. Take home messages?

Deborah: You know, I think that we need to look at this as a positive in that we're looking at time frames that provide a rapid evaluation and the discussion is around safety. As long as we keep focused on appropriate evaluations for the patients and applying the right algorithm to the right patient, we're going to benefit the care of those we're really concerned about. I appreciate the work that both Martin and Allan both have done on really pointing out how we can do that in a great manor.

Carolyn: Thank you, all of you, for joining us today. I mean, it's been such an enlightening conversation. I'm sure the listeners have enjoyed it and thank you listeners for tuning in. Don't forget to tune in again next week.

Circulation November 8, 2016 Issue

7 november 2016 | 25 min

Dr. Carolyn Lam:

Welcome to circulation on the run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam associate editor for the National heart center and Duke National University of Singapore. Our podcast is really going around the world, and today's feature interview comes to you live from China. Where we will be discussing the prediction of ten year risks of cardiovascular disease in the Chinese population. So now to all our Chinese colleagues out there: Chinese dialect

First here's your summary of this week's journal. The first study challenges the assumption that all patients with vascular disease are at high risk of recurrent vascular events. First author Dr. Kasenbrud corresponding author Dr. Viceren and colleagues form the University Medical center Utric in the Netherlands, provide new data on the estimation of ten year risk of recurrent vascular events and a secondary prevention population. In other words, in patients with established cardiovascular disease they applied the second manifestations of arterial disease or 'smart' score for the ten year risk prediction of myocardial infarction, stoke or vascular death in more than six thousand-nine hundred Dutch patients with vascular diseases ranging for coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm and poly-vascular disease. Predictors included in the SMART risk score included age, sex, current smoking, diabetes, systolic blood pressure, total cholesterol, HGL cholesterol, presence of coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm, estimated glomariaol fruition rate, high sensitivity CRP and years since the first manifestation of vascular disease. They further externally validated the risk score in more than eighteen thousand four hundred patients with various types of vascular disease fro the TNT ideals Sparkle and Capri trials.

The overall findings was that the external performance of the SMART risk score was reasonable apart from over-estimation of risk in patients which a ten year risk of more than forty percent. What was striking was the substantial variation in the estimated ten year risk. The median ten year risk of a reoccurring major vascular event was 17 percent but this varied for less than 10 percent in 18 percent to more than 30 percent in 22 percent of patients.

The authors further estimated residual risk at guideline recommend targets by applying the relative risk reductions form meta-analysis to estimated risks for targets for systolic pressure, LDL, smoking, physical activity and use of anti-thrombotic agents. They found that if all modifiable risk factors were at guideline recommend targets only half of the patients would have ten year risk of less than 10 percent. Even with optimal treatment many patients with vascular disease appear to remain at more than a 20 percent or even more than 30 percent of a ten year risk.

The take home message is that a single secondary prevention strategy for all patients with vascular disease may not be appropriate. Instead novel risk stratification approaches may be helpful to individualize secondary prevention by identifying high risk patient which may derive the greatest benefit from novel interventions.

The next study provides experimental evidence that an indigenous-gastro transmitter hydrogen sulfide may potentially be a therapeutic target in diabetic patients with cardiovascular diseases. In this paper by first author Dr. Chen, corresponding author Dr.Kisher and Colleagues from the Louis Cat's school of medicine Temple University in Philadelphia. Authors aim to evaluate the role of hydrogen sulfide deficiency in diabetes induced bone marrow cell dysfunction and to examine the therapeutic effects of restoring hydrogen sulfide production in diabetic bone marrow cells on ischemic high limb injury in diabetic DBDB mice. They further specifically investigated the effects of hydrogen sulfide deficiency on the nitric oxide pathways under conditions of high glucose. They found that bone marrow cells for diabetic DBDB mice had decreased hydrogen sulfide production and lower levels cystathonine gamma lyaze which is the primary enzyme that produces hydrogen sulfide in the cardiovascular system. Administration of a stable hydrogen sulfide donor and over expression of cystathonine gamma lyaze in diabetic bone marrow cells restore their functional and restorative properties. Further more they demonstrated that the therapeutic actions of hydrogen sulfide were mediated by nitric oxide pathway involving endothelial nitric oxide synthase PT495.

In summary these results support the hypothesis that hydrogen sulfide deficiency plays critical role in diabetes induced bone marrow cell dysfunction and suggests that modulating hydrogen sulfide production in diabetic bone marrow cells may have transformational value in treating critical limbs ischemia.

The next study reinforces the importance of hypertension as a critical risk factor for inter-cerebral hemorrhage, and suggests that Blacks and Hispanics may be a particularly high risk. In this study by DR. Walsh and colleagues for the University of Cincinnati, authors conducted the largest case controlled study to date on treated and untreated hypertension as a risk factor for inter-cerebral hemorrhage. They also investigated whether there was variation by ethnicity. The ethnic racial variations of inter-cerebral hemorrhage or eriche study is a prospective multi-center case controlled study of inter-cerebral hemorrhage among Whites, Blacks and Hispanics. Cases were enrolled from 42 recruitment cites, controls were matched cases one to one by age, sex, ethnicity and metropolitan area. A total of 958 white, 880 black and 766 Hispanic cases of inter-cerebral hemorrhage were enrolled. Untreated hypertension was more highly prevalent in Blacks at almost 44 percent and Hispanics at almost 47 percent compared to whites at 33 percent. Treated hypertension was a significant independent risk factor and untreated hypertension was substantially greater risk factor for all three ethnic groups and across all locations. There was a striking interaction between ethnicity and risk of inter-cerebral hemorrhage, such that untreated hypertension conferred a greater risk of inter-cerebral hemorrhage in Blacks and Hispanics relative to Whites.

The nest study provides the first prospective multi-centered data on mortality and morbidity in rheumatic heart disease from low and middle income countries. First author Dr. Zulky, corresponding author Dr. Mayoci and authors from Gertrude hospital and University of Cape Town in South Africa present the results of two year follow up of the global rheumatic heart disease registry or remedy study in 3343 children and adults with rheumatic heart disease from 14 low and middle income countries. They found that although patients were young with a median age of only 28 years the 2 year case fatality rate was high at almost 17 percent. The median age at death was 28.7 years. Mortality was higher in low income and low middle income regions compared to upper middle income countries. Independent predictors of death was severe valve disease, more advanced functional class, atrial fibrillation and older age. Where as post primary education and female sex were associated with a lower risk of death. The authors carefully noted that apart from age and gender the independent risk factors for mortality such as severity of valve disease heart failure, atrial fibrillation and low education were all modifiable and thus they called for programs focused on the early detection and treatment on clinical rheumatic heart disease.

Well that's it for the summaries, now lets go over to China

For our feature interview today we are going all the way to Beijing at the great Wall meeting where we will be meeting authors as well as editors. So here we have first and corresponding author Professor {Dong Fen Gu} and co-author Professor {Sherliang} both from {Fu Y} hospital Chinese academy of medical sciences in Beijing. Welcome

Dr.Gu: Welcome we are so delighted to be interviewed by you

Dr. Carolyn Lam:

Thank you so much we are so excited to be talking about your paper predicting the ten year risks of cardiovascular disease in the Chinese population. And here we have as well editor in chief Dr. Joe Hill as well as Dr. Amid Kira digital strategies editor and associate editor. Gentlemen how is it in Beijing? And I hear that you have a Chinese greeting for everyone as well.

Joe Hill: {Ni how} and {nuchme and senchmen}

Amid Kira: I can't top that but I agree with what Joe said

Dr. Carolyn Lam: Dr. Gu, could you please tell us what is it that is so different about cardiovascular disease in China compared to what we heard about in the western world.

Dr.Gu: Okay cardiovascular disease is both leading cause of death in China and in United States as well in European countries. However the patterns for components of cardiovascular disease including coronary arteries and stroke are still quite different in the Chinese populations compared united states. For example there are coronary arteries mortality rate in the united states is along the 100 thousand per year and this is the first leading cause of death in the united states. And for stroke the annual mortality rate is along 36 per 100 thousand in the united states populations. However in china the stroke mortality rate among Chinese populations is around the 160 per 100 thousand, so that almost 3.5 to 4 as high as in untied states. Obviously for our lifestyle in including battery behavior quite different you can easily identify one kind of difference in the united states and the Europe restaurants from Chinese restaurants and some western style restaurants you can figure it out.

And another example, smoking rate is major component for risk of cardiovascular disease it is very high in Chinese adult men. It over 50 percent right now but in the united states in the past 50 years it declined immensely. And around maybe less than around 20 percent and from the previous experiment from studies by Dr. Liu Chin from and my colleague Dr.WU they used the questions for predictions of coronary arteries compared to equations and also use the similar prediction model compares that its chemical cardiovascular disease from the united states population and the Chinese population. That to over estimation if we use the united states produced this kind of equation. So based on this kind of scenario we based on Chinese long term larger scales cohort to precede and study our own prediction model.

Dr. Carolyn Lam: Wow that is really fascinating Dr. Gu and I really could not agree with you more because I sort of trained in the united states for quite some time and then I moved back to Singapore and saw for myself in Asia the tremendously high rates of stroke. I was also very struck by the relative youth of the patients suffering cardiovascular disease and the differences in risk factors, the smoking but not just that, obesity is almost defined on a different scale in our relatively sized smaller Chinese population compared to that in the western. Congratulations to you and your team for a successful amazing effort. Could you or Dr. Yang now just let us know what are your main findings.

Dr. Yang:

Well I think there are 2 major finding for our work. First we developed a new prediction risk model you know after analysis is for high risk score or equations released by AJ and ACC and is some other risk scores. We included 6 conditional risk factors in combination with our previous knowledge that included age, treated or untreated ISBP, total classical, HDLC current smoking and diabetes. So this traditional risk factors were set up as a base model and then we use the predefined statistical to include new additional variables they were Chinese special elements. Finally in our model there were rates as constraints and geographic region which means northern part versus the southern part in China and also organization is rural or urban area. And finally the forth one is family history as a CVD so this for additional variables in our model suggest that we maybe as a Chinese prediction and equations has something special. For example we feel more attention for central obesity in primary prevention in Chinese populations and also you know the norther part and the southern part there are large differences in the risk profiles. And so maybe according to our risk prediction model we pay more attentions for the residence living in northern part in China.

And then for the second points I think we found that PCE equation which shows for equations was not appropriate to predict ten year risk of in Chinese populations. For example in our revelation cohort we found that our model just slightly over predicts severity risk by 17 percent in Chinese man but when we use the PCE models released form AHA the over-estimation come to 50 percent so maybe equations from western populations are not appropriate to Chinese populations.

Dr. Carolyn Lam: Thank you so much Dr. Yang I mean those are just such important findings applicable to a huge population in china, like you said. And just as important as the second point that the pooled equations derived from western populations may not be the most appropriate for certain other ethnic populations. I think that a very important message and that why we are so proud to be publishing this in Circulation. Could I ask then are you applying these new equations in your personal clinical practice?

Dr.Gu:

Risk assessment is a fundamental components for prevention of ASSVD. In Chinese we question {turn the PA on} provide a valuable to identify high risk individuals in Chinese populations. And not with just complicated [inaudible 00:18:02] for further analysis. And propose three levels of groups of risk stratification could be identified by cut off 5 percent and 10 percent. So lower risk individuals with predicted activity risk of less than 5 percent should be offered lifestyle wise to maintain the lower risk status. While the moderate risk individual is predicted risk of 5 to 10 percentage for intensive therapeutic lifestyle change wit drug therapy if necessary. For the high individual risk high or large 10 percent teheraph of clinical aliment taken account for physicians recommendation should be required with therapy for the lifestyle modification. Then annually clinic up, including an echocardiographic information for carotid artery back and even for outer [inaudible 00:19:09] CT examinations for coronary artery are recommended. Also blood pressure, lipids, glucose measurement if necessary are suggest according to Chinese guideline. While cardiovascular disease prevention as well as for the epidemic of this kind a lines. For ACVD patients those are different kinds of risk assessment we could know whether their risk profile had been improved or be progressed so that appropriate clinical elements should be taken in clinical practice.

Dr. Carolyn Lam: Thank you very much Dr. Gu so that just show that these findings are immediately clinically applicable and I trust that means you're suing it in your clinics too, and once again were so happy to be publishing this in Circulation so in the rest of the time in going to now direct questions at Joe and Amid.

How's China been? How are your chopstick skills and any word on how Circulation is being received there?

Joe Hill: Well Carolyn its a delight to be here this is a bustling media that get better and better every year. In about 2 hours we have our first ever Circulation session, we brought several editors here to discuss the types of content that we are looking to publish, the type of work across prevention and population and electrophysiology of heart failure. This is an extraordinary media that is now internationally acclaimed and as we've heard here, the face of cardiovascular disease in Asia is changing. And as you pointed out 60percent of the human race lives in Asia and we want to do everything we can to be here on the ground, in Asia trying to address this curve that is already present and is worsening by the day.

Dr. Carolyn Lam: Amid, you know you've seen the latest statistic on our podcasts and you highlighted that we have quite a number of listeners over there as well. Would you like to tell me how this is all blending it to the digital strategies and anything else you might want to highlight?

Amid Kira: Sure its been an incredible meeting and we get to meet great colleagues like our colleagues today on this podcast and learning so much from this meeting. Our podcast as you pointed out quite a sizable and growing cadre of people in Asia and Japan and China who are listening and we truly want to enhance that as Joe mentioned with the large splurge of cardiovascular disease and the great science that is going on here. Want to make sure that we are able to be apart of that conversation and interact with researcher and clinitions here. In addition to podcast, we are exploring some other options involving social media, specifically in China so stayed tuned in how those develop but we certainly appreciate the importance of being her and interacting where so much of cardiovascular disease and cardiovascular science is occurring.

Dr. Carolyn Lam: That's so great. Joe or Amid now there's a specific we would like to highlight to our listeners the doodle, either of you want to pick that up a bit about blipping the doodle?

Amid Kira: So there is as you know Circulation now has this doodle where we change it periodically and its sort of a fun themed thing. Right now I think it Halloween and we've had several other ones that people have designed to sort of keep thing fresh and light and interesting. There's a new app called blippar which you can download from iTunes or android stores and you can essentially scroll that over with your phone with the doodle and that will take you to new content either table of contents of videos, different kinds of content that it can navigate you to. So I hope people will not only enjoy the doodle kind of anticipate what's next in terms of seasons but will take the time t blip the doodle when they get a chance.

Dr. Carolyn Lam: That great and that blippar- B l I P P A R. You really c should check it out, anyone who is listening to this really check it out you'll be floored. Joe could I just turn the mic to you for any last words about the global outreach of Circulation, I mean its just so amazing that you're there in China

Joe Hill: Well heart disease Carolyn knows no boundaries nor does Circulation. There was a day when cardiovascular disease was largely an issue in the developed world that is long since gone and that's why the study that we are talking about today with these authors is so important because the face of cardiovascular disease is different than in the west, the ways in which it is evolving id different here than in the west and I like many others foresee an increase a significant increase in the types and prevalence of heart disease here in Asia. for all the reasons that we have been talking about, hypertension, obesity, type two diabetes, smoking the environment all of these challenges I fear are going to lead to a substantial increase in the prevalence of heart disease in Asia and that why we're here on the ground with Circulation in Asia that's why we have one of our major leaders Chong Shong Ma who is here in Beijing. Circulation is in China everyday, it’s in Beijing everyday to try and address this problem.

Dr. Carolyn Lam: And you heard it from our editor and chief, so thank you everyone for listening to this episode of Circulation on run. Tune in next week.

Circulation November 1, 2016 Issue

31 oktober 2016 | 25 min

Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Our interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:

The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.

In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].

These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.

In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.

The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.

During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.

In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.

The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.

They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.

The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.

Well, those were your summaries! Now, let's on to Rome.

Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]

Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.

Dr. Eric M. : Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.

What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.

With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.

Dr. Carolyn Lam: That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.

Dr. Mark P: Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.

When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.

What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.

We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.

Dr. Carolyn Lam: OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?

Dr. Mark P: Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.

Dr. Carolyn Lam: With bypass compared to medical, yes.

Dr. Mark P: Exactly.

Dr. Eric M. : I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.

Dr. Carolyn Lam: That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?

Dr. Eric M. : I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.

Dr. Mark P: Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.

Dr. Carolyn Lam: You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.

Dr. Mark P: I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.

Dr. Carolyn Lam: Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.

Dr. Nancy S.: So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.

I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.

Dr. Carolyn Lam: Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?

Dr. Mark P: So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".

Dr. Carolyn Lam: Kudos to you, Nancy! And from your point of view, was it fun?

Dr. Nancy S.: It actually was fun.

Dr. Carolyn Lam: (laughs)

Dr. Nancy S.: You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.

Dr. Carolyn Lam: [inaudible 00:21:34] how long?

Dr. Nancy S.: We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.

Dr. Eric M. : First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.

A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.

Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in next week for more.

Circulation October 25, 2016 Issue

24 oktober 2016 | 23 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. We have such a special podcast for you today. The entire podcast is going to be a conversation with two very special guests, Dr. Marc Ruel from The University of Ottawa Heart Institute, the guest editor of the surgery themed issue this week. Hi Marc.

Marc: Hello Carolyn. How are you?

Carolyn: Very good. Especially because we also have Dr. Timothy Gardner, Surgeon, Associate Editor from Christiana Care Health System. Welcome back again, Tim.

Timothy: Thank you, Carolyn. Glad to be here.

Carolyn: Marc, could you first give us an overview of the surgery themed issue from your perspective.

Marc: This year as we have had on previous years, we are having a surgery themed issue which comprises what I would argue which is some of the very best cardiac surgical science can offer to the wide readership in the cardiovascular community that served by circulation. This year, we will have a total of ten articles that would be published in circulation, as a section of one of our regular issues and out of those ten, there are five original papers. There's one research letter which is an original research article but in a shorter format and we'll also have one invited perspective paper namely about coronary artery bypass grafting and its future with respect to multi-arterial grafts and the themed issue will be completed by three state of the art papers that deal in a very in depth comprehensive way with some important problems that the cardiovascular community faces from a clinical point of view.

Carolyn: Thanks Marc. That was a beautiful summary of the issue. I couldn't help but notice that there was a theme of coronary artery bypass surgery covering at least four of the papers and I really like your thoughts on that. You covered everything from medical therapy, CABG versus PCI, on versus off-pump, emergency surgery in the setting of shock. Could you go through each of these four papers a little and tell us what was your take home message from each?

Marc: As you said, there are three original research articles and one invited perspective that relate to coronary artery bypass grafting surgery and these encompass the number of clinical problems that are still controversial and certainly I believe they contribute a very, very significant [inaudible 00:02:31] with the wealth of knowledge that the cardiovascular community is looking for at this point. If I may go one by one, just with a very high level overview, if you will. The first one is a paper from the Leipzig Heart Center with first author, [Pieroz Adewalla 00:02:45], which looked at surgery for acute myocardial infarction but accompanied with cardiogenic shock. As you know, many patients undergo surgery in an acute MI context, but surgery for cardiogenic shock is often a very gruesome difficult decision.

Leipzig Heart Center looked at over 3,000 patients who had an acute MI prior to cardiac surgery for bypass surgery and of these, there were 508 patients who actually had cardiogenic shock due to [valve 00:03:15] failure with myocardial dysfunction and to give you an idea, these patients were quite sick. There's about 40% of the patients who were ventilated prior to surgery or very close to 40%. The timing was quite urgent, those patients were on inotrophes and on vasopressors to support their blood pressure prior to operation. Essentially, what they found is that first the outcomes got better over the last number of years, this is a series that dates back to about the 2000's, so the early 2000's.

They also favor an approach where they tried to avoid a cardioplegic arrest of the heart. Their favored overall approach is to do what we call on-pump beating heart type of surgery which would be a surgery where the cardioplegia would not be administered to stop the heart but the hemodynamics would be supported for the cardio coronary bypass. They also have over the years since the beginning of this year, is in 2000 ranging up to 2014 of increasing the use of the off-pump bypass surgery and certainly the outcomes have been better and the mortality although high has decreased significantly. It was as high as 40% in the early parts of the cohort if you will and in the latest third of the experience, therefore from 2010 to 2014, the mortality has been down to about 25%.

Again, these are patients who present with cardiogenic shock. What's also interesting to note is that patients who survive out of hospital still have a significant mortality burden and about 50% of them survive long term. What was interesting is the Leipzig group is looking at some predictors of bad outcomes in those patients and they found that the serum lactate over four minimal per liter was actually a very robust and multi-variative predictor of a poor outcome after surgery.

Carolyn: That was a great summary of that first paper. You mentioned beating heart surgery and so on. Would you like to comment on next paper that I think was the largest single institution European study comparing on versus off-pump bypass surgery?

Marc: You're absolutely right. This is a paper from England, [inaudible 00:05:25] from Liverpool, where the patients were gathered from and with some contribution from Oxford as well from a statistical and methodological point of view and it's a retrospective cohort study of all isolated CABG patients in Liverpool between 2001 and 2015. These are bypass surgery patients and in total, there were over 13,000 patients who had CABG. About 6,000 patients had off CAB which is off-pump bypass surgery and more than 7,000 had bypass with cardiopulmonary bypass. The median follow up was 6.2 years. What's interesting in this paper is that they essentially found equivalent long term outcomes. As you know, there has been some debate regarding the completions of myocardial revascularization and the long term graft patency with off-pump surgery versus on-pump surgery. Also named conventional CABG.

What's interesting here is that the benefits of off-pump CABG appear to be seen early on with regards to antiemetic release as stroke rates, etc. Which does correspond to some of what has seen in the randomized controlled studies. However, the long term data is interesting. There's a a nice editorial about this paper written from a group from the Cleveland Clinic with Dr. Joe Sabik as the senior author and essentially it raised a number of good points, although this is an important series, it also shows that the surgeons who are very good at off-pump bypass surgery may overall be slightly technically more skilled at doing bypass surgery in itself and for instance, use more often arterial grafts and have more advanced techniques in their completion of bypass surgeries for their patients.

Carolyn: Right. I'm so glad you mentioned the editorial. I was about to bring that up as well. Switching gears to you very kindly included a paper that talked about medications and the impact of here is the medical therapy on the comparative outcomes between CABG and PCI. Would you like to discuss that paper?

Marc: This is a paper from the Care Registry which has generated some interesting publications in the past. The lead author is Dr. Paul Polinski and there's co-authors, Dr. Herbert Prince and Michael Mack from Dallas as well. This was presented at the science sessions in Orlando last November and it's an interesting paper. Essentially they have looked at large databases, again the Care Registry which comprises eight community hospitals and they look at six month period of performance of CABG and those eight community hospitals. They ended up with over 2,700 patients who were then systematically followed on a regular basis up to 2009 at which time the database was locked.

They look at various outcomes but also medication use in great detail over that period of time and the interesting perspective that this paper brings is that first, most patients at least in that period were not on optimal medical therapy. The authors used their own predefined definitions of what constitutes optimal medical therapy and this is with regards to adherence to aspirin use, lipid lowering agents, beta blockers and indicates of PCI, dual anti-platelet therapy. As expected but nicely documented in this paper, the outcomes of patients who were not on optimal medical therapy were much worse than those who were and CABG proved to be more robust in patients who were not on optimal medical therapy compared to PCI.

The differences between CABG and PCI in patients who were on optimal medical therapy tended to vanish. However, a number of caveats here is that only 25% of patients in fact in this cohort were on optimal medical therapy. The vast majority of patients were not considered to be on optimal medical therapy. Therefore, there are considerations of definitions that one has to be aware of and also considerations of statistical power because the group that was on optimal medical therapy was much smaller than the other group. Therefore, the effects, the superiority of CABG over PCI could only be firmly demonstrated in the group was not on optimal therapy, again comprising 75% of patients in this cohort.

Carolyn: I love your summaries and they really show that these are true significant original contributions to that knowledge gaps in coronary artery bypass surgery. To round it all up, you also invited a perspective on novel concepts. Would you like to comment on that paper?

Marc: This is an invited perspective in the view classifications that circulation has which is entitled, "The evolution of coronary bypass surgery will determine relevance as a standard of care for the treatment of multi-vessel CABG." It is authored by three leaders in the field, Dr. Gener, Dr. Gudino, and Dr. Grouw. Dr. Gener has been leading several of what I would call the advanced multi-vessel coronary re-vascularization trials looking for instance at multi-arterial grafts doing numerous anastomosis with two ventral mammary arteries in a wide fashion. He's been a leader of this movement certainly. Dr. Gudino recently published [inaudible 00:10:43] the 20 years of outcome of the radial artery graft and certainly has been one of the pioneers which use of this arterial graft for coronary artery bypass surgery. What the authors provide here is a very nice summary of what the trials have shown so far and they also report as many know that their rate of multi-arterial grafts use in SYNTAX, FREEDOM and I think we will soon see in EXCEL and NOBLE that will be presented this fall, has not been as high as it should have been.

In the US, it is estimated right now that the rate of use of more than one mammary artery is less than 10% across the nation, and other countries have not performed better than this either. This perspective is a call to improving the quality of multi-vessel coronary artery bypass mainly through the use of multiple arterial re-vascularization. There is also considerations around the hybrid coronary re-vascularization and as well as the use of off-pump versus on-pump surgery.

Carolyn: I am really proud and privileged to have helped to manage one of the papers as associate editors in this issue as well and that is the paper from the group with corresponding author, Dr. Veselik, from Boston Children's Hospital and it centers around patients with congenitally corrected transposition of the great arteries but a management problem that is really increasingly encountered and really needs to be reviewed properly and that is the management of systemic right ventricular failure in these patients. Tim, you were so helpful in looking at this paper as well. Could you share some of your thoughts?

Timothy: Well, this is a somewhat unique situation where a patient with this condition, congenitally corrected transposition of the great arteries may go through early life, in fact may end up as a young adult before this particular condition is identified because if there is no shunting or no cause for cyanosis and heart murmurs and so on early on, the circulations seem to work pretty well until the poorly prepared right ventricle which is the systemic ventricle, starts to fail after years of work carrying the systemic circulation and that is really the focus of the paper. There's been a lot of work and publications and attention to transposition syndromes but this particular one is a condition that may be first encountered by adult heart failure cardiologist who have not had this kind of exposure to congenital heart disease. It's a particularly apt paper to bring this condition to our attention and to demonstrate that really it's the adult heart failure cardiologist who may be managing these patients in their late 20's or 30's, when that systemic right ventricle fails because of a lack of formation to manage the systemic circulation.

Carolyn: Exactly. Written by a group that has one of the most robust experiences in this field, so that also brings to mind another state of the art article in the issue that refers to the hypoplastic left heart syndrome and though it's entitled that and people may think it's rare, I think it's increasingly being seen in the adult cardiology world as well. You want to comment on that one?

Timothy: That actually is one of the main points of this paper that this very, very difficult condition of hypoplastic left heart syndrome that requires staged operations beginning in the neonatal period has now reached the state of surgical accomplishment in medical management where many of these young children are surviving into young adulthood. Albeit, with having had two, or three, or four operations. In a community like ours here in Delaware, where pediatric patients transition to adult services and adult cardiologist sometime around their 20's, it's really important for the entire cardiology community to be aware of what has happened in terms of the successful staged treatment of children with hypoplastic left heart syndrome and that is brought out very nicely by the three authors who look at various accomplishments and different techniques for managing these staged repairs. It is very amazing to someone who has been observing this field for sometime as I have, that many of these children are in fact surviving into young adulthood and will require comprehensive cardiovascular treatment, not just by neonatal specialist but by specialist in adult congenital heart disease.

Carolyn: Exactly, which is why such a timely state of the art articles both of them for this issue. There is another state of the art article that you were handling, Tim, "The Surgical Management of Infective Endocarditis Complicated by Embolic Stroke", now that's an important topic.

Timothy: Absolutely, as we know up to a half or more of patients with infective endocarditis primarily on their left sided heart valves will have cerebral embolic problems and it has really been a dilemma for many of us in terms of optimal timing for the cardiac surgery with respect to the existence of cerebral injury from the embolism, from hemorrhage that may occur, from hemorrhage that may be exacerbated by placing the patient on the heart-lung machine, etc, and this paper really takes an extremely comprehensive, careful and judicious look at all of the evidence that has emerged and it has been a confusing field of evidence as to how to best optimally manage these patients with cerebral involvement from infective endocarditis.

I think this paper is going to have a big impact. It appears that there are a couple of messages that I took away from this paper. Number one, we really need to use the full panoply of diagnostic opportunities or diagnostic test for characterizing the nature and the extent of the cerebral involvement in these patients and then perhaps even more important, we need to convene what the authors called the infective endocarditis team and that has to include not just the surgeon, the cardiologist and the infectious disease specialist but also the neurologist, the neuro-interventional specialist, the neurosurgeon and so on because all of these specialist need to contribute to the assessment and choosing the optimal timing for these patients.

That is the central message of the paper. The authors also suggest that we may be getting to the point where we need to update and make sure that the guidelines that we're using are in fact current. Current in the sense that the experience now with advance imaging and with more aggressive management of the neurological or cerebral issues really need to be factored into how best to handle these patients, but I think this paper is going to have a big impact, it's very well written and very thorough.

Carolyn: I agree. In fact all the content we just discussed is just so rich. Congratulations on such a beautiful issue. Marc, do you have any last highlights you'd like our audience to hear about?

Marc: I'd like to also mention two other original research papers that will be featured in the surgery themed issue. One, in keeping with the congenital theme that we had talked about is about the modified [Straun's 00:19:08] procedure for palliation of severe Ebstein's anomaly and this is a series actually from Professor [Straun 00:19:16] himself mostly originating from Children's Hospital Los Angeles and essentially, the series here is that of 27 patients about equal in gender distribution who were operated at seven days of life, between 1989 and 2015.

It's very interesting that patients did well, the survival at ten years is 76% and most of them have undergone successful Fontan completion. I think this is a very important paper not only because it is an extremely vexing and difficult problem to deal with Esbtein's anomaly but it comes from the innovator of the operation himself with his team and it provides much needed data regarding the long term outcomes of these children with this very difficult solution. I think this will be of great interest and also as we commented before veering into the world of adult cardiology as well, because fortunately most of these patients survive into adulthood.

The other paper I wanted to touch upon which is also an original research paper that will be in this themed issue, is a paper from the CTSN Group looking at the impact of left ventricular to mitral valve are being mismatched on recurrent ischemic MR after ring annuloplasty and this paper used the free innovative and interesting methods. As some of you may know, there were two large files recently that were conducted by the CTSN looking at either moderate MR at the time of coronary artery bypass grafting or at severe ischemic mitral regurgitation. The randomizations were different when the moderate MR was CABG lone versus CABG post mitral valve repair and the severe MR was mitral valve repair versus mitral valve replacement.

These studies have led to interesting conclusions that several will know about but what's been interesting in the current study is that they have gathered all patients who underwent mitral valve repair from both studies, original randomized trials and they ended up with about 214 patients who underwent mitral valve repair. The others had moderate or severe MR and basically the point of this study is to look at predictors of failure of mitral valve repair and this is an extremely relevant problem, not only for the cardiac surgical community I would venture, but also for heart failure community and for JV General cardiology community. What the others found is that the most important predictor of recurrent mitral regurgitation after mitral valve repair was something called the left ventricular and systolic diameter to ring size ratio and they provide an algorithm which will have to be tested clinically with regards to whether it is applicable and indeed changes outcome, but this is a very important discovery in the field of ischemic MR and enabling us to hopefully better understand and improve outcomes for patients with this very difficult problem.

Carolyn: I agree. Thank you so much, Marc and Tim for this most insightful discussion. Thank you very much and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next next week for more highlights and features.

Circulation October 18, 2016 Issue

17 oktober 2016 | 17 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore. Have you ever wondered what the clinical implications of very brief episodes of device-detected atrial tachyarrhythmias are? Well, we will be discussing this with novel data from the RATE registry in just a moment. First, here's your summary of this week's journal.

The first study provides the first evaluation of the Sweden nationwide abdominal aortic aneurysm screening program. Of almost 303,000 men invited for screening, 84% attended. The prevalence of screening detected abdominal aortic aneurysm was 1.5%. After a mean of 4.5 years, 29% of patients with aneurysms had been operated upon with a 30-day mortality rate of 0.9%. The introduction of screening was associated with a significant reduction in aneurysm-specific mortality. The number needed to screen to prevent 1 premature death was 667, while the number needed to operate on to prevent 1 premature death was 1.5.

Furthermore, the authors showed that their screening program was highly cost-effective in the contemporary setting in Sweden. These findings confirm results from earlier randomized controlled trials in a large population-based setting, and may be important for future healthcare decision-making. This and the diverse requirements for efficient population screening for abdominal aortic aneurysm, from program management to maintaining skills in open repair are discussed in an excellent accompanying editorial by Dr. Cole from Imperial College London.

The next study looks at thoracic epidural anesthesia and suggests that caution may be needed in patients with or at risk for right ventricular dysfunction. You see, thoracic epidural anesthesia involves blockade of cardiac sympathetic fibers, which may affect right ventricular function and interfere with the coupling between the right ventricle and right ventricular afterload. Dr. Wink and colleagues from the Leiden University Medical Center therefore used combined pressure volume conductance catheters to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular pulmonary artery coupling in 10 patients scheduled for lung resection.

Thoracic epidural anesthesia resulted in a significant reduction in right ventricular contractility, stroke work, dP/dt max and ejection fraction. This was accompanied by a reduction in effective arterial elastance such that ventricular pulmonary coupling remain unchanged. Clamping of the pulmonary artery increased right ventricular contractility but decreased ventricular pulmonary coupling. These effects of increased afterload were the same before and after thoracic epidural anesthesia. In conclusion, therefore, thoracic epidural anesthesia impaired right ventricular contractility but did not inhibit the native positive ionotropic response of the right ventricle to increase afterload. These findings are clinically relevant for daily practice in cardiothoracic surgery because pulmonary hypertension is frequently encountered, and right ventricular function is an important determinant of early and late outcomes.

The next study suggests that the use of point of care hemostatic testing may have a place in the management of patients undergoing cardiac surgery. Dr. Karkouti and colleagues of the Toronto General Hospital hypothesized that point of care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery, thereby reducing blood transfusion. They therefore conducted a pragmatic multi-center stepped-wedge cluster randomized controlled trial of a point of care based transfusion algorithm in 7,402 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They found that the trial intervention reduced rate of red cell transfusion with an adjusted relative risk of 0.91 and a number needed to treat of 24.7.

The intervention also reduced rates of platelet transfusion and major bleeding but had no effect on other blood product transfusions or major complications. These findings that point of care testing improved management of coagulopathy in cardiac surgery support the consideration of their broader adoption in clinical practice.

The next study provides experimental evidence that brings us one step closer to therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis. In this study from first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein and colleagues from LMU Munich, authors focus on cathepsin G, which is stored in neutrophil and azurophil granules and discharged upon neutrophil activation. They studied site-specific myeloid cell behavior after high-fat diet feeding or TNF stimulation in the carotid artery, the jugular vein, and cremasteric arterioles and venules in APOE E and Cathepsin G-deficient mice.

Their studies revealed a crucial role for Cathepsin G in arterial leukocyte adhesion, an effect that was specific for the arteries and not found during venular adhesion. Consequently, Cathepsin G deficiency attenuated atherosclerosis but not acute lung inflammation. Mechanistically, Cathepsin G was immobilized on arterial endothelium, where it activated leukocytes to firmly adhere, engaging endocrine clustering, a process of crucial importance to achieve effective adherence under high-sheer flow.

Therapeutic neutralization of Cathepsin G specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of Cathepsin G-neutralizing antibodies really allowed the inhibition of atherogenesis in the mice. Taken together, these findings presented evidence of an arterial-specific recruitment pattern centered on Cathepsin G adhesion, thus representing a potential novel strategy and target for the treatment of arterial inflammation. Well, that wraps it up for the summary of this week's journal. Now, for our featured discussion.

Our feature paper for today discusses the clinical implications of brief device-detected atrial tachycardias and really novel findings from the RATE registry. I'm so happy to be here with the first and corresponding author, Dr. Steven Swiryn from Feinberg School of Medicine, Northwestern University. Hi, Steven.

Steven: Good morning.

Carolyn: We also have with us Dr. Mark Link, associate editor from UT Southwestern. We all know that prolonged episodes of atrial tachycardia or atrial fibrillation are associated with increased risk and that if we anticoagulate those with a high CHA2DS2–VASc score, we can lower the risk of stroke. Now, the European Society of Cardiology guidelines also say that recent data reinforced the assumption that even brief episodes of silent atrial fibrillation may convey an increased risk of stroke. We also know that prior studies have looked at device-detected atrial fibrillation. Steven, I'd really love if you could start by telling us what makes your study different. What was the main thing you were trying to look at?

Steven: Well, one reason it's attractive to use the device population, patients with pacemakers or defibrillators, to look at these issues is because devices have a very high likelihood of detecting episodes of atrial fibrillation whereas symptoms or single 12 EKGs miss a lot of atrial fibrillation, so the sensitivity is much higher, although not perfect. The problem is that very brief episodes of atrial fibrillation are very poorly detected by devices. The specificity of automatic detection is very low, such that all previous studies until the RATE registry have excluded any episode of atrial fibrillation detected by a device less than 5 minutes in duration because they're unreliable. A lot of them turn out to be false positive detections. Our study was designed to evaluate whether even very brief episodes of an atrial tachyarrhythmia might also be associated with risk of clinical events and might or might not warrant anti-coagulation.

Carolyn: Ah, that's interesting, so you really helped to answer how brief is "brief" when we need to talk about device-detected atrial fibrillation. Could you expand on how you actually defined "short episodes" here?

Steven: Right. A short episode for the purpose of the RATE registry was defined as an episode where the electrogram that we scrutinized had both the onset and the offset of the episode within the same electrogram tracing, so although we can't put a specific time duration on it because that wasn't part of the criterion, it's typically less than 20 seconds or so, although not always, whereas a long episode was defined as an electrogram where either the onset and/or the offset was not captured by the device memory and therefore we don't know the duration. Some of those may not have been very long, and some of those may have been extremely prolonged episodes. That allows us to actually scrutinize the electrogram. We looked at 37,530 individual electrograms using 8 teams of adjudicators, each with a physician and a field clinical engineer from the device company so that we could actually say definitively, "Yes, this was atrial fibrillation," or, "No, it wasn't."

Carolyn: This is the first study to really look under that 5-minute limit of atrial tachycardias. What did you find?

Steven: Well, we found that in contrast to prolonged episodes, short episodes of atrial tachyarrhythmias were not associated with an increased risk compared to those without atrial fibrillation of pre-defined clinical events, including death from any cause, heart failure, stroke, hospitalization for atrial fibrillation, and a few other smaller events.

Carolyn: This was over a 2-year follow-up period, is that right?

Steven: The median follow-up was slightly less than 2 years, that's right.

Carolyn: What I really was struck with was also the second finding, the propensity to develop longer episodes. Could you expand on that?

Steven: We reasoned that in the clinic, one might be faced with a short episode was we defined them, and then you don't know what's going to happen for the next 2 years to bring to bear the results of our study. We looked at if your first episode was short, what was your likelihood over the full follow-up of the study of progressing to longer episodes. About 50% of patients who had their first episode as only a short episode progressed to a longer episode over the full follow-up and therefore were in the long category for the rest of the results. Half of them never got a longer episode.

It was, as one might imagine, if you had your first short episode very early in the study and had a longer follow-up, you were more likely to end up in the long category, and if you had very frequent short episodes, you were also more likely to end up in the long category by the time the full follow-up was over with. Having an initial short episode is not a guarantee that you're never going to get a long episode and that you'll never acquire a consideration of anti-coagulation.

Carolyn: That was a very important message to me as well because it meant that although I can be secure or reassured by these data for very short episodes, I needed to look out for the development of longer episodes, at least that's what your registry showed over 2 years of follow-up. I'm curious, Mark, what were your take-home messages because that leaves us with a bit of a conundrum. What do we do about anti-coagulation in these patients?

Mark: I think this study is a big help to the practicing electrophysiologist and practicing cardiologists. It's a very ledger number of patients with a lot of episodes of afib. It's reassuring to me that the shorter episodes of afib as defined by the study, the individuals did not have a higher incidence of stroke compared to those with no episodes, so it's reassuring and very important clinically as I go through my practice.

I do look forward to more analyses and more data from this study because although now we know that episodes less than 20 seconds are in all likelihood not going to need anti-coagulation, we still don't know about those from 20 seconds to 5 minutes. Hopefully with more analysis of this study we'll get that answer also.

Carolyn: Steven, do you agree with that?

Steven: We would love to have that. At first glance, you would think that devices would give you all of the data you needed because after all, they're monitoring the patient 100% of the time, but there are difficulties with that because device memory is limited, and you don't get electrograms that go on until the termination of atrial fibrillation even if the device were accurate in determining when that termination was because depending on how the device was programmed and depending on whether it was a more modern device later in the trial or earlier and had more or less memory, it cuts off after a limited amount of time, and you don't see necessarily how long the duration is.

Now, you can use device-based data. The device gives you its estimate of how long the episode is, but those are not as reliable as adjudicating the electrograms and actually looking at them. Those data would be a little softer than the main results if we get there.

Mark: That was the data that was used for all of the other studies, was [transassert 00:14:51]. It would be comparable to those other studies. I still think it would be very important data that I'd love to see.

Steven: Okay, well, I agree. I think it would be very interesting to look at that and a number of other things. We have a number of other things we could do with this database. There are a number of substudies that are in progress. For example, one interesting one is there were some instances we found, because we actually looked at these electrograms, there's something that we termed "competitive atrial pacing," where the device will pace at times when we as clinicians would not want to pace. For example, pacemaker-mediated tachycardia would be an instance of that, but then you can pace in the atrium inappropriately. There's a rhythm called repetitive non-reentrant ventricular atrial systole, which, although it's exotic to all of us, actually turned out to be fairly common where there's pacing in the atrium that occurs for various reasons when we want it to.

We actually saw instances where the device itself induced atrial fibrillation. It wasn't that common, but we did see it. We have a substudy that we're working on about the subjective competitive atrial pacing to see how much of that there was and of what, if any, consequence that was. That's one of the things that's been done. Because we scrutinized these so carefully, we tracked morphology and atrial rate at least as a crude estimate, and we have those data, so we could actually evaluate whether if something looks very, very rapid and disorganized as opposed to more organized electrograms at a slower rate, did that make any difference. We don't have any results for those analyses yet. I agree with Mark that the intermediate durations would be interesting to look at.

Carolyn: I agree too, and I'm really grateful for you sharing those thoughts. Very grateful for both of you for your time today. I just have to congratulate you. I completely agree this paper fills an important knowledge gap, and congratulations once again.

Steven: Thank you very much.

Mark: Thank you.

Carolyn: Thank you for listening. You've been listening to Circulation on the Run. Please tune in next week.

Circulation October 11, 2016 Issue

10 oktober 2016 | 21 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Today's featured discussion deals with the perspective piece entitled, What I Wish Clinicians Knew About Industry and Vice Versa. Intriguing, isn't it? I can tell you it is one of the best papers I have ever read, so stay tuned. First, here's your summary of this week's journal.

The first study takes a step towards understanding atrial fibrillation on a more fundamental level by demonstrating that some patients have altered left ventricular myocardial energetics even in the absence of other comorbid diseases. First author, Dr. [Veejay Surendra 00:00:50], corresponding author, Dr. [Cassidy 00:00:53] and colleagues from the University of Oxford studied 53 patients with lone atrial fibrillation undergoing catheter ablation and compared them to 25 matched controls without atrial fibrillation. They did this using sequential studies of cardiac function with magnetic resonance imaging as well as energetics with phosphorus-31 magnetic resonance spectroscopy.

At baseline, there was subtle but significant left ventricular dysfunction and abnormalities in ventricular energetics in patients relative to controls. Following ablation of atrial fibrillation, left ventricular function measured by ejection fraction and peak systolic circumferential strain improved rapidly with a switch to sinus rhythm but remained at normal at 6 to 9 months. Although pulmonary vein isolation effectively eliminated atrial fibrillation in all the patients in the study, the hearts continued to express an energetic profile consistent with a myopathic phenotype meaning that the ratio of phosphocreatine to adenosine triphosphate was lower in the atrial fibrillation compared to controls irrespective of recovery of sinus rhythm and freedom from recurring atrial fibrillation.

The clinical implications of these findings are that apparently lone atrial fibrillation may actually be a consequence rather than a cause of an occult cardiomyopathy and that this cardiomyopathy is unaffected by ablation. Of course, future studies are needed to prove this and to examine whether therapeutic strategies that target the adverse cardiometabolic phenotype could reduce atrial fibrillation recurrence. These important issues are discussed in an accompanying editorial by Doctors Hyman and Callans.

The next study provides experimental evidence that suggests we may finally have an answer to heart failure preserved ejection fraction or HFpEF, and that is the modification of titin. Titin is a sarcomeric protein that functions as a molecular spring and contributes greatly to left ventricular passive stiffness. The spring properties can be tuned through post-transcriptional and post-translational processes and their derangement has been shown to contribute to diastolic dysfunction in patients with HFpEF. The current paper by first author, Dr. Methawasin, corresponding author, Dr. Granzier and colleagues from University of Arizona provide important proof of principal investigation of the effects of manipulation of titin isoforms as a treatment for a transverse aortic constriction murine model of progressive left ventricular hypertrophy leading to HFpEF.

Conditional expression of a transgene with deletion of the RNA recognition motif for one of the splicing factor, RBM20 alleles, resulted in reduced splicing and a substantial increase in larger more compliant titins that were named super compliant titin. The result was normalization of passive stiffness of isolated muscle strips as well as normalization of left ventricular diastolic function and chamber stiffness as assessed by echocardiography and pressure volume analyses. There were no effects on extracellular matrix stiffness. The authors also showed that other spliced targets of RBM20 did not contribute to the results and thus, the beneficial effects were almost certainly entirely related to the changes in titin isoforms.

Furthermore, treadmill exercise was used to show that treated animals displayed improved exercise tolerance. In summary, the study showed that increasing titin compliance in this murine model resulted in marked improvement in multiple measures of diastolic function and performance, thus suggesting that titin holds promise as a therapeutic target in HFpEF. This is the discussed in an excellent accompanying editorial by Dr. LeWinter and Dr. Zile.

The next study adds importantly to evidence that heavy physical exertion and anger or emotional upset may act as triggers of first myocardial infarction. In this paper by first author, Dr. Smith, corresponding author, Dr. Yusuf, and colleagues from the Population Health Research Institute Hamilton Health Sciences and Master University, authors explored the triggering association of acute physical activity, anger, and emotional upset with acute myocardial infarction. They did this in the inter-heart study which was a case control study of first acute myocardial infarction in 52 countries. In the current analysis, the authors used a case crossover approach to estimate odds ratios for acute myocardial infarction occurring within 1 hour of triggers.

Of 12,461 cases, 13.6% engaged in physical activity and 14.4% were angry or emotionally upset in the case period referring to the 1 hour before symptom onset. Physical activity in the case period was associated with an increased odds of acute myocardial infarction with an odds ratio of 2.3 and a population attributable risk of 7.7%. Anger or emotional upset in the case period was associated with an increased odds of acute myocardial infarction of more than 2.4 odds ratio and a population attributable risk of 8.5%. Importantly, there was no effect modification by geographic region, prior cardiovascular disease, cardiovascular risk factor burden, prevention medications, time of day, or day of onset of acute myocardial infarction.

Interestingly, the authors did find an interaction between heavy physical exertion and anger or emotional upset with an additive association in participants with exposure to both in the 1 hour prior to the acute myocardial infarction. The take home message, these findings suggest that clinicians should advice patients to minimize exposure to extremes of anger or emotional upset due to the potential risk of triggering an acute myocardial infarction. While heavy or vigorous physical exertion may also be a trigger, this did not refer to just any physical activity and the authors cautioned that this must be balanced against the known well-established benefits of regular physical activity over the long term and clinicians should continue to advice patients about the life-long benefits of exercise.

The last study provides insights in the molecular mechanism in pulmonary hypertension. First author, Dr. Lee, corresponding author, Dr. Stenmark, and colleagues from the Pediatric Critical Care Meds and CVP Research University of Colorado Denver hypothesized that metabolic reprogramming to aerobic glycolysis may be a critical adaptation of fibroblast in the hypertensive vessel wall, an adaptation that drives proliferative and pro-inflammatory activation through a mechanism specifically involving increased activity of the NADH sensitive transcriptional corepressor, C-terminal-binding protein 1.

The authors assessed glycolytic reprogramming and measured NADH to NAD+ ratio in bovine and human adventitial fibroblast as well as mouse lung tissues. They found that expression of the C-terminal-binding protein 1 was increased in fibroblast within the primary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with pulmonary hypertension. Furthermore, treatment of fibroblast from the pulmonary hypertensive vessels of hypoxic mice with a pharmacological inhibitor of C-terminal-binding protein 1 led to a normalization of proliferation inflammation and the aberrant metabolic signaling.

In summary, these result showed that C-terminal-binding protein 1, a transcription factor that is activated by increased free NADH acts as a molecular linker to drive the proliferative and pro-inflammatory phenotype of adventitial fibroblast within the hypertensive vessel wall. Thus, this metabolic sensor may be a more specific target for treating metabolic abnormalities in pulmonary hypertension. Those were your summaries. Now for our feature paper. Our feature today is special on so many levels, and because it's so special, I actually have Dr. Joe Hill, editor-in-chief of circulation from UT Southwestern here today with me. Hi Joe.

Joe: Sure. As always, it's a pleasure to be here with you. This is a new type of content where we solicit thought leaders from a variety of vantage points around the cardiovascular space to provide their perspective on the future of cardiovascular Science in medicine. Rob Califf, the FDA Commissioner, provided his perspective on the regulatory role interfacing with cardiovascular medicine and Science. Victor Dzau who presides over the National Academy of Medicine in the United States did the same, provided a very insightful perspective from his vantage point now, formerly in academia, but now overseeing this advisory board to the policy makers in Congress. Today, we're going to talk about a perspective that emerges from industry, from someone who also has a strong and long history in academia.

Carolyn: That is a perfect lead up. The title of the paper; What I Wish Clinicians Knew About Industry and Vice Versa. Here is the amazing guest that we have today, it's Dr. Ken Stein, Chief Medical Office of Rhythm Management at Boston Scientific. Hi Ken. It is a very, very intriguing title and I'd like you to first describe to us what makes you the person who can talk about being a clinician and going over to the dark side of industry and vice versa?

Ken: Thanks Carolyn and Joe. I think right now just get over my embarrassment at being called a thought leader and being mentioned in the same as Rob Califf and Victor Dzau. I met both of them but I don't think I've ever been mentioned in the same sentence as either them and probably never will be again. Why me to do this? Again very gracious of Joe to invite the submission. My history, I've been in industry now at Boston Scientific for 7 years, and prior to that was an unreformed academic faculty at Cornell. Ever since I did my training, eventually becoming co-director of the EP Lab there for many years. Then 7 years ago, the opportunity came up to leave the cloistered ivory towers of academia and to join industry. It's been a very interesting and I think very productive ride ever since.

Carolyn: I have to tell you that your article is just one of the most well-written pieces I have ever read and I mean that sincerely. You began with the story that everybody asked you this question. Why did you do it? What did you learn? I'm going to ask that of you today. Tell us.

Ken: In the 7 years, I get 2 questions all the time. One is, do you miss practice? The answer is, there are things about practice that I miss very deeply and that is really the engagement that you get with patients and families. I think we always have to remember as caregivers, we're privileged to be able to do what we do. On the other hand is, but I do get an opportunity to participate in decisions now that rather than affect one patient at a time, for better or for worse, affect hundreds of thousands of patients at a time.

The other question is, what surprised you? What have you learned? What didn't you know about industry? As I thought about it, it's 2 things. It's one that I think in retrospect I was and I think many of us are way too cynical about the motivations of industry, how industry operates. The other shock, if you will, was that it goes 2 ways and there's a lot of cynicism in industry about physician motivations and how physicians operate on a day to day basis.

Carolyn: Really? Do you have any examples of that?

Ken: I'll give you a couple of examples. First, from the point of view of how does industry work and what are the motivations in industry. One of the first decisions that I had to make 7 years ago after joining the company was to issue a recall on one of our products. It actually was a recall that had not yet failed in the field but we had some bench testing that suggested that there was a particular risk to some patients and novel to the industry and the whole thing. This is not go over well with the CEO, but in fact, really the only question people ask is, is this the right decision for patients? That was a really gratifying piece of education to me.

The flip side of the coin, we did introduce a new battery technology in our fibrillators and CRT devices just before I joined the company that basically doubled the amount of battery capacity that we have in the devices. It's one of the funny things. There are still editorials being written in journals other than circulation, I'll say, that still say that industry will never increase battery longevity of their devices but cost us money because we lose money on device replacements. We've done it and a lot of our competitors are in the process of doing it.

When I got to the company, what I found is there was a tremendous amount of angst within the leadership of the company. Do doctors do this or are they afraid in a fee-for-service environment to give up what they get doing battery replacements on short-lived devices. Of course that cynicism is unfounded. That doctors have embraced longer, better battery life technology.

Joe: Ken, to hear you say this is interesting and frankly inspiring. You can't pick up a copy of the New York Times right now and not read about some issue around drug pricing and some of the companies that have done the wrong thing with. They've increased prices hundreds of percentage, 400%, even more. To know from your perspective that those are perhaps the exceptional circumstances and that there are many, many companies who of course have to keep a business running but at the same time they truly have the patient at heart. You have said and you said in your piece that as the Chief Medical Officer, you're the voice of the patient at your organization.

Ken: I aim to be. That was the lesson I learned from Don Baim who really ... Don passed away very shortly after I joined the company, who's really a giant in cardiology. I wish that I had been able to spend more time with him as a mentor but that was very important statement he made. Say he's right, there are bad actors, there are bad actors in industry, there are bad actors among physicians, there are bad actors among academics, but that's not generally true. I also want to be careful not to be misconstrued. Skepticism and doubt are important. Cogito ergo sum, it's not just I think, therefore I am, it's probably better understood that I doubt, therefore I think, therefore I am. Skepticism is fundamental to scientific process, but there's this border that you cross over where constructive skepticism turns into destructive cynicism. I'm afraid gets in the way of our ability to work together to better the outcomes, better welfare of patients.

Carolyn: Do you think we've swung from the United States maybe you could give me your opinion to the wrong end of that balance between constructive skepticism and destructive cynicism? Joe, what do you think?

Joe: As someone who has not worked in my own research closely with industry, sometimes I think that we have. I mean, there are certainly many examples. We all know where people have crossed the line and that is profoundly unacceptable, but at the same time, I worry that we've thrown the baby out with the bathwater and some of the things that are uniquely done in academia and some of the things that are uniquely done in industry, a synergy between them across the divide is essential to move this field forward. I think sometimes the boundaries and the bright lines separating them are so distinct and defined that it prevents those source of synergies.

Carolyn: Thank you for that paper that really provides that balanced perspective. The beautiful thing, it's just so personal almost. It feels like we're sitting with you, having a conversation when we're reading that paper. Like now, it's just been an amazing experience having you on this podcast. Do you have any last messages?

Ken: My last words. I again just want to thank you and thank Joe. Has the pendulum swung too far? Thing about pendulums are that they oscillate and I think what's needed is a willingness to watch out that it doesn't swing too far. Is there cynicism? I'll admit, I was flabbergasted and I still flabbergasted that you allowed me to write this piece but I think the fact that you welcomed the piece from someone in industry within the intent of bringing this out, that is the pendulum not going too far. As long as there are voices, editors, journals who are willing to help us articulate points like this, I think that's at least what keeps us in a reasonable balance.

Joe: As Carolyn said, you brought a uniquely human conversational element to this piece. Not everybody would publish a piece in circulation and acknowledge that you are intimated and embarrassed walking into Don Baim's office. That brought us right into your living room and that was powerful.

Ken: Honestly, I wasn't looking for the job. I was more interviewing them to find out what I can about the company, but I did not want to make an ass of myself in front of them. I felt like I was [pieing 00:19:53] for fellowship. I walked in the door and honestly I'm still standing with my hand on the doorknob and he looks up at me and I have to remember his voice, he had that deep sort of growly voice. He said, "Stein, you have no idea what Chief Medical Officer does, do you?" I'm just thinking, do I try to BS my way out of this or do I just give him the God honest truth and turn around and go back to work. I said, "No, Dr. Baim." I couldn't call him [inaudible 00:20:22] and to the end, I told him, "Dr. Baim," I said, "I had no idea." That's when he said, "Your job is to be the voice of the patient within Boston Scientific." He said after that, "You don't need to know anything about business. We know you don't know anything about business. We've got a lot of MBAs and hopefully they do."

Carolyn: Thank you once again for the paper, for this discussion. Thank you both for being here. For all of you who are listening, thank you for joining us again on Circulation on the Run.

Circulation October 4, 2016 Issue

3 oktober 2016 | 20 min

Today, we will be discussing an interesting Danish nationwide cohort study on the return to the workforce following first hospitalization for heart failure, but first here's your summary of this week's journal.

The first paper addresses a common question asked by patients who have survived an aortic dissection. Will this happen to me again? First author, Dr. Isselbacher, and corresponding author, Dr. Lindsay, and investigators of the International Registry of Aortic Dissection investigated this in the largest systematic analysis to date of patients presenting to hospital with a recurrent aortic dissection.

In this large registry, the authors identified 204 patients with recurrent aortic dissection and compared these to 3624 patients in the registry with an initial aortic dissection. They found that patients with recurrent dissection were more likely to have Marfan syndrome, but not bicuspid aortic valve. Descending aortic dimensions were greater in those with recurrent dissections than those with only an initial dissection, and this was independent of the sentinel dissection type. In multivariable analysis, the diagnosis of Marfan syndrome was independently predictive of a recurrent aortic dissection with a hazards ratio of 8.6.

Furthermore, they found that the patient's age at the time of first dissection correlated with the anatomic pattern of aortic involvement. In younger patients, dissection of the proximal aorta tended to be followed by dissection of the distal aorta, whereas the reverse was true among older patients suggesting divergent mechanisms of disease.

In summary, therefore, this study shows that recurrent aortic dissection while in common does occur and in fact affected 5% of those in this registry. The data really illustrate the importance of syndromic forms of aortic dissection and suggest that occurrence of a recurrent dissection should raise suspicion of a genetic etiology of aortic disease.

The next study provides pre-clinical data suggesting that counteracting increased hepcidin may be a therapeutic target for treatment of intracerebral hemorrhage. In this study from first author, Dr. Xiong, corresponding author, Dr. Yang, and colleagues from Xinqiao Hospital, the Third Military Medical University in China, parabiosis and intracerebral hemorrhage mouse models were combined with in vitro and in vivo experiments to investigate the roles of hepcidin in brain iron metabolism after intracerebral hemorrhage. Hepcidin in an important iron regulatory peptide hormone that controls cellular iron efflux.

The authors found that increased hepcidin-25 was found in the serum and astrocytes after intracerebral hemorrhage. In hepcidin-deficient mice with intracerebral hemorrhage, there was improvement in brain iron efflux and protection from oxydative brain injury and cognitive impairment, whereas, the administration of human hepcidin-25 peptide in these mice aggravated the brain injury and cognitive impairment.

In vitro studies showed that increased hepcidin inhibited intracellular iron efflux in brain microvascular endothelial cells, but this phenomenon was rescued by a hepcidin antagonist. Additionally, toll-like receptor 4 signally pathway increased hepcidin expression, whereas, a toll-like receptor 4 antagonist decrease brain iron levels and improve cognition following intracerebral hemorrhage.

In summary, the study showed that increased hepcidin expression caused by inflammation prevented brain iron efflux and aggravated oxidative brain injury and cognitive impairment, thus, counteracting increased hepcidin maybe a mechanistic target to promote brain iron efflux and attenuate oxidative brain injury following intracerebral hemorrhage.

The next basic science paper provides fascinating insights into the similarities between advanced atherosclerotic lesions and tuberculous granulomas, both of which are characterized by a necrotic lipid core and a fibrous cap. First author Dr. Clement, corresponding author Dr. Mallat, and colleagues from the University of Cambridge Addenbrooke's Hospital in United Kingdom looked at the C-type lectin receptor 4E which has been implicated in the events leading to granuloma formation in tuberculosis.

The authors hypothesized that the same C-type lectin receptor 4E may be involved in the formation of atherosclerotic lesions as well. They addressed this hypothesis by examining the impact of receptor activation on macrophage functions in vitro and on the development of atherosclerosis in mice. They showed that C-type lectin receptor 4E was expressed within human and mouse atherosclerotic lesions and was activated by necrotic lesion extracts. The receptor signaling in macrophages inhibited cholesterol efflux and induced endoplasmic reticulum stress responses leading to the induction of proinflammatory mediators and growth factors.

Furthermore, repopulation of LDL receptor-deficient mice with C-type lectin 4E receptor-deficient bone marrow reduced lipid accumulation, endoplasmic reticulum stress, macrophage inflammation, and proliferation within developing arterial lesions that's significantly limiting atherosclerosis.

In summary, this paper shows that C-type lectin receptor 4E orchestrates major pathophysiologic events during pluck development and progression, and thus, provides a mechanistic explanation for the close association between necrotic lipid core formation and the development of inflammatory advanced atherosclerotic lesions.

The last paper examined the impact of optimal medical therapy in the dual antiplatelet therapy or DAPT study. In this paper from first author, Dr. Resor, corresponding author, Dr. Mauri, from the Brigham and Women's Hospital in Boston and colleagues, authors sought to assess the impact of optimal medical therapy use on long term patient outcomes and on the treatment benefit and risk of continued dual antiplatelet therapy, and they did this using data from the DAPT study which was a randomized placebo control trial comparing 30 versus 12 months of final prudent therapy on the background of aspirin after coronary stenting.

Optimal medical therapy was defined as a combination of statin, beta blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker used in patients with an ACC/AHA class 1 indication for each medication. Endpoints included myocardial infarction, major adverse cardiovascular and cerebral vascular events or MACE, and GUSTO moderate or severe bleeding events.

Of 11,643 randomized patients with complete medication data, 63% were on optimal medical therapy. Between 12 and 30 months, continued final prudent therapy reduced myocardial infarction compared to placebo in both groups and had consistent effects on the reduction in MACE, and an increased bleeding regardless of the optimal medical therapy status. In other words, the P for interaction was nonsignificant for these comparisons.

Importantly, patients on optimal medical therapy had lower rates of myocardial infarction, MACE, and bleeding compared to patients not on optimal medical therapy. Rates of stent thrombosis in death did not differ. The take home message is therefore, that more emphasis on the use of optimal medical therapy after coronary stenting is needed, but the decision to continue dual antiplatelet therapy beyond 12 months should be made irrespective of the optical medical therapy status.

Those were your summaries. Now, for our feature paper.

Our feature paper today discusses a really important, but frankly, often neglected outcome in heart failure, and that is return to the workforce following first hospitalization for heart failure, and I'm really pleased to have the first and last author of this really special Danish paper, Dr. Rasmus Rorth and Dr. Soren Kristensen, both from the University of Copenhagen, here to join me today. Hello, gentlemen.

Soren: Hello and thank you for having us, Carolyn.

Rasmus: Hello.

Carolyn: As a very special third guest, we actually have editorialist, Dr. Martin Cowie from Imperial College London as well. Hi, Martin.

Martin: Hi, Carolyn. Nice to be part of the conversation.

Carolyn: This is going to be so fun. Let's get straight into this. Rasmus, maybe you could start by telling us. This return to work concept is hardly addressed in guidelines, it's so important, and yet, you are one of the first if not the first to take a look at it. What inspired you to do this?

Rasmus: First of all, we are very inspired to work with heart failure because heart failure is a common costly, disabling, and deadly disease, and furthermore, information on young patients with heart failure is vast. We know that they have a high hospitalization rate and a low mortality rate compared to all the patients. We also know from some of the big trials that young heart failure patients report low quality of life. Therefore, we wanted in this study to examine return to work for a number of reasons.

First of all, it gives off some information of the patient's performance basis and we get some information of their quality of life and mental status, and one more reason that is not that common for us as clinicians to think about is also for society, the economic burden these patients play in the society, and all of these reasons inspired us to get into this exciting field.

Carolyn: I really appreciated that you did this because the patients that I see here in Asia are on average 10 years younger than the heart failure patients that have been seen in other European registries and so on, so it is a very, very important aspect because my heart failure patients are often the sole breadwinners of families here. Could you, maybe, Soren, share with us what are those unique resources that you manage to look at this in such detail in the Danish registries?

Soren: The unique quality in Denmark is that you have the unique identifying numbers for all the citizens of Denmark and these numbers are not only used in the health systems. They're also used for administrative registries for tax paying and for state funds and pensions. We were able to link information from the hospital discharge registries with information on tax paying and whether or not people are getting pensions. In that way, we could follow all patients who stayed in Denmark at least to see whether or not they were receiving any funds, any pension, or sick leave money, or things like this from the state, or whether they upheld a position. That's what makes the Danish system a bit unique, that we have this ability to track the patients across all the fields of society and also that we have a public health system which all patients are included in, and the private sector is negligible in Denmark.

Carolyn: Wow. Listening to that is making all epidemiologist everywhere really drool. That is such a precious system to look at this. What were your main findings, Rasmus?

Rasmus: Maybe I should explain a bit about the setting. This is a nationwide-based study starting where we identify the patient with the first heart failure hospitalization, 18 to 60 years in the period from 1997 to 2012, and we followed them onwards. In our primary analysis, we only included patients in the workforce, that means either employed or available for the labor market at time hospitalization. That is the setting of the study.

Carolyn: Could you share your main findings and your take home messages?

Rasmus: Our primary outcome of this study is that after one year, 25% of the patients did not return to the workforce and we had a low mortality, only 7% died.

Carolyn: Twenty-five percent didn't return to the workforce?

Rasmus: Yeah, and keeping in mind, Carolyn, these are patients in the workforce at their first hospitalization and also young patients. Our take home patient from this paper is that patient in the workforce at heart failure hospitalization had a low mortality for the high risk of [inaudible 00:13:41] from the workforce at one year of followup. Furthermore, we look at some association effect associated with returning to work, and we found that young age, male sex, and high level of education were associated with high likelihood of returning to work.

Carolyn: Martin, you wrote just a beautiful editorial. I have to say I was chuckling and enjoying it as I read it. I could hear your voice in it. What do you make of these results in the interpretation?

Martin: I was really pleased to see something published by this really important topic that is largely ignored, and as you said in your introduction, the guidelines, if you read them you'll think that nobody of working age ever develops heart failure. There's no mention at all about return to work. There's no mention of the kind of urgent need to be able to provide people with the counseling about the heart failure and how it might impact their work, and also, no interaction, no mention of interaction with employers to tell them, "Yes, this person have this condition, but actually, could do their job or stay in the same job," or "How we can help support them?"

I think this article which is so good to see graded publish in Circulation and I think we have to see it in the context of other occupational rehabilitation work which shows that if you don't get people back to work quite quickly after a major event in their lives, then you'll never get them back, and that's got huge consequences for them in their mental health, their economic, social, family, and never mind the healthcare system. It's really nice to see this work and I hope many people read it and quote it.

Carolyn: Martin, you've been to Asia. You know that our patients are strikingly young, but I wonder, do you think these results are extrapolatable outside of Denmark?

Martin: I think this comment and not an editorial, Denmark, of course, is a relatively small country. It's wealthy. It's different from the states, but it's very different from Asia as you say, so lots of heart failure patients in Asia are young, of working age, and quite often, their families depend on them.

I think the tactics may have to be different to different countries, but the general principles are the same that we, as a heart failure team, as heart failure doctors, have to think about the person not just in terms of the left atrium and left ventricle, or even of the whole body function, but actually, what is their role in their family, what are they trying to achieve in life, how can we support them about way, because otherwise, we're really failing our patient.

I think, in Asia even more than in some wealthy, rich countries where there's a lot of safety nets, it's really important. I'd be interested in your comment, Carolyn, on what you think we can do to improve right across the world in terms of occupational rehab.

Carolyn: First, I think it begins with awareness and that's why I just wanted to tell Soren and Rasmus how much I enjoyed this paper and I will be citing it because I think it's so important especially in the younger heart for the community, but can I ask you, Soren or Rasmus, have these findings changed your practice in any way or to be even more provocative, do you think that maybe return to work should be a benchmark to evaluate heart failure programs?

Rasmus: Martin also points out that, first of all, we need to shed light on this hidden fact of heart failure, and afterwards, I think it's also a very good policy metrics to use in the future to see how our patients do.

Carolyn: Are there efforts in Denmark to improve this as a yardstick?

Soren: I'm quite sure that, by large, it's not really registered who is working, who is not working there. There's not much attention to it. We're all focusing very much on the performance of the patient of the NYHA class and so on, so I think we should put more emphasis on this issue and we should, as Martin also added, that we should discuss with the patients if they could change their job or their positions in some ways to better cope if they lost some of their performance, because we're both think and we both agree with Martin that it's a huge quality of life to be able to maintain your job in one way or the other, and we should definitely put more focus on that, but I'm afraid to say that I don't think we put much focus on it in Denmark at this time, but hopefully, we will.

Martin: I think you're right, the attitude have to change across the world, don't they, and they start with the heart failure team and the patients because I think most doctors and nurses and patients assume diagnosis of heart failure, that means really nothing can be the same again, but we really should be trying to return people to their optimal function, and I'm sure we can do a lot more, but perhaps, we need to upscale the workforce and knowing about the key things about occupational counseling, and maybe also [inaudible 00:18:30] interact with employers a little bit more without patient's permission to give them the confidence to have this person re-enter the workforce in a supported way because I'm sure the employers value many of these people and would be pleased to see them still in the workforce.

Rasmus: Exactly. I even think that could be like a fair way of trying to help the patient by relieving them from their job, which is actually will be a big mistake for some patients [inaudible 00:18:54] as a physician to help them with making sure they don't have to return to their job and fill out the statements and everything, but this may not be the best for the patient.

Martin: Exactly.

Carolyn: Gentlemen, I have enjoyed this conversation so much. Thank you for taking the time to discuss this very important paper.

You've been listening to Circulation on the Run. Tune in next week for more.

Circulation September 27, 2016 Issue

26 september 2016 | 17 min

Dr. Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal.

The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School.

These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes.

Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock.

They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis.

The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal.

The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis.

Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients.

The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California.

These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique.

The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo.

These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality.

The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes.

The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction.

These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras.

This brings us to the end of our summaries. Now for our feature paper.

Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick.

Dr. Calvert: It's a great pleasure to be here, thank you for inviting me.

Dr. Lam: Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi.

Dr. Kumbhani: Hi Carolyn, thanks for having me.

Dr. Lam: Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks?

Dr. Calvert: You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation.

Dr. Lam: Could you tell us what makes your series special?

Dr. Calvert: Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different.

I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work.

Dr. Lam: Which types of perivalvular leak are you talking about here?

Dr. Calvert: We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves.

Dr. Lam: Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper?

Dr. Kumbhani: I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round.

Dr. Lam: As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings.

Dr. Calvert: Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups.

Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis.

Dr. Lam: Very important clinically. Take home message from your point?

Dr. Kumbhani: I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that?

Dr. Calvert: When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis.

Dr. Kumbhani: Exactly.

Dr. Calvert: We all have had personal experiences of that happening.

Dr. Kumbhani: Yes.

Dr. Calvert: The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis.

Dr. Kumbhani: After the closure?

Dr. Calvert: After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately.

Dr. Kumbhani: One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct?

Dr. Calvert: That's approximately correct, yes.

Dr. Kumbhani: You had 20 centers that were doing this?

Dr. Calvert: Yes.

Dr. Kumbhani: 1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone?

The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this?

Dr. Calvert: I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in.

One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great.

I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices.

I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices.

Dr. Kumbhani: It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis?

Dr. Calvert: We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers.

Dr. Kumbhani: I see.

Dr. Calvert: I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space.

Dr. Kumbhani: That's good.

Dr. Lam: That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation.

Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.

Circulation August 23, 2016 Issue

20 september 2016 | 18 min

In just a moment, we are going to be discussing the feature paper on results of the RE-LY trial in patients with valvular heart disease. Yes, you heard me right, this means dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. You need to listen to this discussion with first author Dr. Michael Ezekowitz, but first here is a summary of this week's issue.

In the first study, Dr. Norby and colleagues from the School of Public Heath University of Minnesota assessed trajectories of cardiovascular risk factors and the incidence of atrial fibrillation over 25 years in the ARIC study or the Atherosclerosis Risk in Communities Study. They first assessed the trajectories of cardiovascular risk factors in more than 2,400 individuals with incident atrial fibrillation and more than 6,400 matched controls. Next, they determined the association of those risk factor trajectories with the incidence of new atrial fibrillation among more than 10,500 individuals free of atrial fibrillation at baseline.

The main finding was that stroke, myocardial infarction and heart failure risk increase steeply during the time close to diagnosis of atrial fibrillation. All cardiovascular risk factors were elevated in atrial fibrillation cases compared to controls more than 15 years prior to the diagnosis. A trajectory analysis showed not only the presence of the risk factors such hypertension and obesity, but also their duration which was more informative in determining the risk of atrial fibrillation compared to a one time clinical measurement.

Finally, they identified diverse and distinct trajectories for the risk factors findings that carry implications for the different roles of different risk factors in the pathogenesis of atrial fibrillation. The findings of this very significant study also highlight the need to establish preventive strategies that address risk factors decades before atrial fibrillation diagnosis.

The next study is by first author Dr. van der Valk and corresponding author Dr. Strauss from the Academic Medical Center in Amsterdam. These authors aimed to better understand the underlying mechanisms responsible for atherogenicity of lipoprotein a or LPa. The authors achieved this aim by a combination of three approaches. First, in vivo magnetic resonance imaging using 18F-FDG PET/CT and SPECT to measure atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Secondly, ex vivo analysis of monocytes using facts analysis, inflammatory stimulation assays and trans endothelial migration assays. Third, in vitro studies on monocytes using an in vitro model for trained immunity.

Their main findings were that, firstly, individuals with elevated LPa had increased arterial wall inflammation in vivo. Secondly, that monocytes from these individual remain in a long lasting activated state ex vivo, and finally, that LPa elicited a pro-inflammatory response in healthy monocytes in vitro, an effect that was markedly attenuated by removing or inactivating oxidized phospholipids on LPa.

In summary, this study nicely shows that LPa induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its oxidized phospholipid content. The clinical implications are therefore, that oxidation's specific epitope targeted therapy using for example specific antibodies as single gene antibodies may bear clinical potential to modulate the arthrogenic impact of LPa.

The final study is from first author Dr. Mazen, and corresponding author Dr. Ouzounian from Toronto General Hospital and University of Toronto in Ontario, Canada. These authors sought to compare the long term outcomes of patients undergoing the Ross procedure compared to mechanical aortic valve replacement in a propensity match cohort study of 208 pairs followed for a mean of 14 years.

They found long term survival and freedom from re-intervention were comparable between the Ross procedure and mechanical aortic valve replacement. Of note however, the Ross procedure was associated with improved freedom from cardiac and valve related mortality, as well as a significant reduction in the incidence of stroke and major bleeding. This paper provides important evidence that supports continued used of the Ross procedure in properly selected young adult patients in specialized centers.

What this means is having experienced surgical teams dedicated to mastering the technique and committed to carefully following up the patients for possible late complications. This and more is discussed in a provocative editorial by Dr. Schaff from Mayo Clinic Rochester, Minnesota who provocatively entitled his editorial 'The Ross Procedure: Is it the Preferred Procedure or Double, Double Toil and Trouble?'

Those were all summaries, now for our featured paper.

I am so excited to be joined from all over the world to discuss the featured paper today, and that is on the comparison of dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. To discuss this first we have, first and corresponding author, Dr. Michael Ezekowitz from the Sidney Kimmel Medical College at Thomas Jefferson University and Lankenau Medical Center in Philadelphia, as well as from the Cardiovascular Research Foundation in New York. Welcome Michael.

Michael: Thank you very much.

Carolyn: Michael, you're calling from South Africa aren't you?

Michael: I am indeed.

Carolyn: That's wonderful. We're very honored to have Dr. Shinya Goto Sensei, Associate Editor of Circulation from Tokai University Japan. Hello Shinya.

Shinya: Hello Carolyn, thank you very much for your invitation to such an excited podcast. I enjoy podcast every week.

Carolyn: I love this and it is extremely exciting and the most global discussion that we have had so far, with calling in Japan and Singapore and South Africa. Indeed it's because we're discussing a very important problem globally. Michael first, when we talk about the RE-LY trial and the NOAC trials, we're always associating them with non-valvular atrial fibrillation, and yet your topic is discussing valvular heart disease from RE-LY. Can you please start by clarifying that?

Michael: I think the reason we wrote this paper is that there is a misunderstanding of the patient populations that was studied in all the NOAC trials because they were characterized as having non-valvular atrial fibrillation. That's only partially true because in all the trials, patients with mechanical heart valve and hemodynamically significant mitral stenosis were excluded, and yet there were many patients with valvular disease that were included. In the RE-LY trial which is the focus of this particular paper, 25% of the patients had some form of valvular disease that were recruited into the study. So the term non-valvular is misleading.

Carolyn: That is such an important clarification, and it's an issue that I see a lot in Singapore. Frankly, lots of patients with atrial fibrillation have some valve disease even if you exclude prosthetic valves, significant mitral stenosis or valvular heart disease requiring intervention. We're very clear not that this is the patient population you're referring to. Shinya, I want to bring you into this. I see lots of these patients, how about you?

Shinya: The same. Majority of patients have valvular heart disease, small mitral regurgitation is very common. We are excluding only clinically overt mitral stenosis and basically mechanical heart valve in all the newest trials. As Michael pointed out, it is very important to correct misunderstanding. Non-valvular atrial fibrillation, we used in the clinical trial is all atrial fibrillation except clinical overt mitral stenosis and prosthetic for mechanical heart valve.

Carolyn: Exactly. A great foundation for us to get our understand right before we discuss the findings. Michael, could you please give us the top line result and tell us what do the results mean for your own clinical practice?

Michael: Basically, it means that the patients with valvular heart disease that were included in the trial, and these included patients with mitral regurgitation with was the most common lesion, mixed aortic valve disease, tricuspid regurgitation, and also it turned out that there were 192 patients that had mild mitral stenosis. Those with mitral stenosis were presumed to be rheumatic in ideology, and they did have a profile of having rheumatic heart disease, that there were more females, they were younger, there was a high incidence of heart failure and a high incidence of TIA and stroke.

The bottom line here is whether the patients had mild mitral stenosis or the other forms of valvular disease that I just mentioned, that they benefited in an identical fashion from the 150 milligram BID dose of dabigatran and the one 110 milligram BID dose of dabigatran as those patients without any valvular disease. The bottom line is that clinicians can use dabigatran with equal confidence in these patients with valvular disease as in patients without valvular disease.

Carolyn: Thank you Michael, that was very reassuring and something that is very clinically important. Shinya, I'm going to ask a different question. First, maybe your take on the findings, and secondly, what was it like handling this paper across the globe as the Associate Editor Managing this?

Shinya: That is a very important point. The past as Michael pointed out, this paper is very important to remind the clinician of non-valvular atrial fibrillation is not really non-valvular atrial fibrillation, and there is no difference between valvular atrial fibrillation except mitral stenosis and prosthetic valve. The result is similar to non-valvular atrial fibrillation in regard to the effect of dabigatran or by warfarin. That is the one point I have to assure. As a part, it is very important. We are now including many patients not limited in that North America, Europe. We are participating a huge number of patients from Asia. The results is applicable to the global level. We are now leading in that global evidence-based world and RE-LY is one of the good example for the global trial testing the hypothesis with [inaudible 00:13:58] over warfarin.

Michael made a very good summary of that, not only limited to RE-LY, he talked about as our trial like ARISTOTLE and the ROCKET trial. All of the NOAC trial include patient who is valvular heard disease, and the exclusion criteria is a little bit different. Michael beautifully summarized that difference in the table, in his paper. There is a strong intention to publish this paper integration from all the editorial of old member. This is a very nice paper.

Michael: He's been very kind, that's very nice. That's true. In fact, the results in RE-LY were compared in an indirect fashion with the other trials, ROCKET and ARISTOTLE, through have published similar papers on patients with and without valvular heart disease. Just in summary, the bottom line is that this finding in RE-LY is highly reproducible in the other two trials so this is an important finding that is reproducible and true of the three novel agents that had looked at this in detail.

The other point that was raised is that there were differences in the exclusion criteria in these trials, but at the end of the day, the Europeans and the Americans in terms of guidelines, had fairly similar recommendation. For instance in the United States, it was felt that all patients with valvular disease could be anti-coagulated with the novel agent unless they had rheumatic mitral stenosis, mechanical or bioprosthetic heart valves, or patients that had undergone a prior mitral valve repair. The emphasis was that all other patients could be included.

The Europeans differed slightly and that they agreed that mechanical prosthetic valve and moderate to severe mitral stenosis should be excluded, but they were somewhat more global in recommending inclusions of all other valvular conditions. There is a slight difference then between the European and the American recommendations and guidelines.

Carolyn: On that note of looking across the world at the guidelines and what these results mean, it really leaves me to congratulate you Michael on such an excellent paper, and Shinya for just managing this paper so well.

Michael: Thank you.

Shinya: Thank you very much for your invitation. Bye-bye.

Carolyn: You've been listening to Circulation on the Run. Thank you for joining us today.

Circulation September 13, 2016 Issue

20 september 2016 | 18 min

Carolyn: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Have you wondered which anti-platelet agent you should use in your patients with diabetes and coronary artery disease? Well, our feature paper deals with just this topic, so stay tuned, I'll be write back with it's author and associate editor. First, here's your summary of this week's journal: The first paper unravels novel peptides involved in atrial extracellular matrix remodelling in atrial fibrillation. This is work from first author Dr. Barallobre-Barreiro, corresponding author Dr Mayr from King's College London, and colleagues. They used novel mass spectrometry methods to analyze extracellular matrix in human atrial appendages from patients undergoing coronary artery bypass surgery.

Now, previous proteomic studies have examined the cellular proteome, but this is the first study to comprehensively characterize extracellular matrix proteins in human cardiac tissues, including the identification of glycosylation sites. They found extensive cleavage in the protein core of decorin which is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis and a variety of other extracellular matrix cell signalling molecules. Decorin processing differed between human ventricles and atria and was altered in disease. It's C-terminus which is important for the interaction with connective tissue growth factor was predominantly detected in ventricles compared to atria. In contrast, atrial tissues from patients in persistent atrial fibrillation had higher levels of full length decorin, but also harbored a unique cleavage site that was not found in atrial appendages from patients in sinus rhythm. This unique cleavage site preceded the M-terminal domain of decorin and altered the binding capacity for myostatin, this altering muscle growth.

The cleaved decorin peptide antagonized myostatin, such that myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and in hearts of decorin-null mice. Furthermore, a synthetic peptide corresponding to this decorin region, those dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. This is clinically important because mystatin inhibition has been implicated as a substrate for atrial fibrillation. This study therefore provides first evidence that peptides generated from the cleavage of extracellular matric proteins such as decorin, constitutes a local regulatory mechanism for growth factors in human cardiac tissue.

The next study looked at therapeutic hypothermia in patients with out of hospital cardiac arrest, and questioned if it may be most effective when induced early during cardiopulmonary resuscitation or CPR, in contrast to prior trials that looked at therapeutic hypothermia induced only after return of spontaneous circulation and hospital admission. This is the RINSE trial from Professor Bernard and colleagues from Ambulance Victoria Australia, which was a multi center randomized controlled trial which assigned adults with out of hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to two liters of cold saline, or standard care. The primary outcome measure was survival at hospital discharge. Secondary end points included return of spontaneous circulation.

The trial was unfortunately closed early at forty-eight percent of the recruitment target, due to changes in temperature management protocols at the major receiving hospitals. Still, a total of one thousand, one hundred and ninety-eight patients were randomized. Six hundred and eighteen to therapeutic hypothermia during CPR, and five hundred and eighty to standard pre-hospital care. Overall there was no difference in outcomes at discharge. In patients with an initial shockable cardiac rhythm there was lower rate of return of spontaneous circulation in patients who received cold saline compared with standard care. Thus, although this trial was stopped early, the data suggests that induction of mild therapeutic hypothermia using a rapid infusion of large volume intravenous cold saline during CPR did not affect outcomes at hospital discharge and may in fact cause harm in the subset of out of hospital cardiac arrest patients who present with shockable rhythm.

The last study provides the first generalizable risk score for sudden cardiac death among American adults from the general population without a history of cardiovascular disease. This large study from Dr. Deo of University of Pennsylvania, and colleagues, derived a sudden cardiac death prediction model using the Atherosclerosis Risk in Communities or ARIC cohort, and validated it in the Cardiovascular Health Study or CHS cohort. They found that the twelve independent risk factors in the ARIC study included age, male sex, African American race, current smoking, systolic blood pressure, use of [anti-hypotensive 00:06:00] medication, diabetes, serum potassium, serum albumin, HDO, estimated GFR, and QTC interval. Over a ten year follow up period this model combining these risk factors showed good to excellent discrimination for sudden cardiac death risk. In fact the model slightly outperformed that of the 2013 ACC AHA pooled cohort risk equations.

Finally, they also showed in the echocardiographic sub-cohort that a left ventricular ejection fraction less than fifty percent was present in only 1.1 percent of these participants and did not enhance sudden cardiac death prediction. This study importantly contributes to the distinguishing of sudden cardiac death risk across the general population, and the results can help target future strategies aimed at sudden cardiac death prevention for the highest risk subgroups in the American general population. That does it for the summaries. Now for our feature paper.

For our feature paper today we are discussing the super important issue of anti-platelet therapy in type 2 diabetes with coronary artery disease. Joining me today are the corresponding author, Dr. Dominick Angiolillo from the University of Florida College of Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate Editor from Paris, France. Welcome gentlemen.

Dominick: Thanks for having us.

Gabriel: Hello.

Carolyn: Dominick, I'd really like to start with you. Your paper entitled the OPTIMUS-4 Study, is really a study of the pharmacodynamic comparison of Prasugrel versus Ticagrelor in these patients with type 2 diabetes and coronary artery disease. The whole question is, what was the rationale to look at the pharmacodynamics?

Dominick: As the title of the study says, OPTIMUS-4, it means that there was an OPTIMUS-1, 2 and 3 in the past, which means that there's a lot of thought that went into this and a lot of background information. The rationale for this specific study was that we're all well aware of the fact that patients with diabetes have high platelet reactivity, which may be one of the reasons why they have a higher risk of recurrent atherothrombotic events. Therefore, the need to define ways to optimize their anti-platelet effects, their levels of platelet inhibition. In this specific study we took an approach of looking at the novel, although we cannot call them novel nowadays, but the newer P2Y12 receptor inhibitors Prasugrel and Ticagrelor. Looking at them in a head to head comparison from a pharmacodynamic standpoint to see if one drug would be superior than the other, again, in terms of a platelet inhibitory effect.

This is the rationale, and just to expand a little bit on this, there's been a perception, again I want to underscore a 'perception' that based on subgroup analysis of the larger clinical trials, that Prasugrel is a superior drug for patients with diabetes. We do know that there's a benefit also with Ticagrelor compared with Clopidogrel, although the absolute risk reductions in the studies led to a perception that Prasugrel would be a better drug. We said to ourselves, "Well, we're never going to have a large scale head to head clinical comparison, why don't we do a head to head pharmacodynamic comparison to see if there are any differences?" This was the overall rationale for conducting this specific study.

Carolyn: That really sets a background perfectly. Tell us about the main findings.

Dominick: The main finding was as follows, we conducted a very detailed pharmacodynamic study, this was a prospective randomized double-blind double-dummy crossover study, with all patients on the background of aspirin therapy. We looked at platelet reactivity, using a variety of assays, I like to say it in every possible salsa that you can imagine. The primary end point which is platelet reactivity at one week into two drugs, using an [ADP 00:10:00] specific assay, actually showed that Ticagrelor was superior to Prasugrel in terms of platelet inhibitory effects. That was the only time point where it was shown, but the study was actually designed to show the opposite, so it was a very interesting finding, while with all the other time points there were no differences between the platelet inhibitory effects between the two drugs.

The other thing that we did look at, which gives a little bit of a novelty to this study is, we went beyond just looking at ADP induced effects, which is the target for these two drugs, we looked at other signalling pathways which one would not believe to be necessarily affected by P2Y12 inhibitors, and we found these also to be reduced by both drugs to a similar extent.

Carolyn: Fascinating. I'm going to get to your second point a bit later. First, that first finding that surprisingly Ticagrelor appeared to perform better using one of the specific assays and so on, I'd really like Gabriel's opinion there. What do you think is the overall clinical implications or what was the message that the editorial board was hoping to get across to the audience? Because I noticed you invited an editorial as well, a beautiful one written by Dr. [Star-ee-an 11:36] Parker. What was the thinking behind that?

Gabriel: I think this is really a very important paper and I'm delighted that Dominick Angiolillo and his team submitted it to Circulation, in fact to be frank, we invited that paper after seeing his presentation at the ACC earlier this year. The reason that paper caught everybody's attention in the editorial board was that it's addressing a frequent and deadly disease, diabetes, that kills really patients with cardiovascular disease. There's a critical issue in the treatment because of the limitations of Clopidogrel because of the increased platelet reactivity in diabetics, and there's tremendous interest in the novel P2Y12 inhibitors Prasugrel and Ticagrelor, and of course any hint of differences between these agents has major clinical implications. In addition, I think I can state that Dominick's team is really one of the premiere international teams looking at this exact issue, platelet reactivity in diabetics. What they did was really state of the art rigorous clinical investigation by a highly skilled team, looking rigorously at a double blind crossover designed four different assays looking at platelet function and platelet response, looking both at the effect of a loading dose and the maintenance dose.

To me, the message is not a minute difference between the treatments, in fact I think that even though it's the primary outcome and it does show a slightly greater response with Ticagrelor than with Prasugrel, the overall most of the other assays at the other time points show a consistent good response with both agents. To us, and to me, the message is that the novel agents are clearly superior to Clopidogrel as we've seen in the clinical trials, but they are fairly consistent in their benefit, and it's reassuring to see this not in healthy volunteers but in actual patients with stable coronary artery disease. I think it was really important to show that. Certainly platelet reactivity doesn't summarize entirely the effects of any drug, and there might be platelet independent effects of Ticagrelor mostly and possibly Prasugrel, but I think on the platelet side, I think that this paper really nails it.

Carolyn: I read that editorial and really agree that that puts everything in perspective really well. I particularly like the figure that accompanied the editorial. In case any of our listeners out there don't really remember all the different pathways and how Prasugrel and Ticagrelor and Clopidogrel are metabolized differently, I'd really refer everyone to that figure as well. Just want to pick up on one of the points that both of you mentioned, and that is the non ADP induced platelet reactivity that Prasugrel and Ticagrelor both seem to have an affect on and so on, and if they're so effective, Dominick, is there still a role for aspirin co-administration with these new anti-platelet agents?

Dominick: The study clearly puts a little bit more beef, let's put it this way, to some of the ongoing clinical studies looking at whether we need aspirin in the patients treated with one of these newer P2Y12 receptor inhibitors. There are a series of ongoing studies out there. There's a laundry list, so I'm not going to go into the details. It does highlight that maybe when you have ultimate P2Y12 blockade, which is a key signalling pathway and blocks other responses by virtue of the fact that there's an interplay between this pathway and others, maybe you do not need this additional anti-platelet agent such as aspirin, which we know there's associated with potential bleeding particularly gastrointestinal side effects.

Having said that, this is not something that I'm advocating at time, but what I am saying is that we'll need to look into the results of the clinical trials. I believe that this study is an additional piece of evidence from an ex vivo standpoint to prior in vitro studies showing that aspirin is not associated with additional platelet inhibitory effects, at least not substantial platelet inhibitory effects. One can say that you may get away with just one of these newer agents. Again, this is based on pharmacodynamic findings, let's just wait for the clinical trial results.

Carolyn: I think that's so fairly put, and I learnt so much just listening to this conversation. Thank you so much for joining me today. Any last words from Gabriel?

Gabriel: Yeah, I'd like to make a couple of points as an Associate editor for Circulation. The first one is, this paper was picked up when we saw Dominick's team's presentation at the ACC, and I think it exemplifies that we really want to pick up the best science from the meetings, either before the meetings and publish it simultaneously as much as possible, but sometimes also at the meetings, so expect to see Circulation Editors at your presentations and maybe you'll seduce them enough with your science that we'll get good science submitted to the journal. The other aspect to it is also that I think with the new editorial board there's really a focus on trying to make the journal very international in it's approach, and I think it's fitting that I am Associate Editor from Europe and I think there's no more international a scientist than Dominick Angiolillo who's not only a good friend but also has been trained in Italy, has practiced in Spain, and now works in the US. I think he embodies how science transcends boundaries and borders. I think there's a definite international outlook to Circulation, and we're looking for great science from anywhere in the world, not solely the US.

Carolyn: Thank you so much Gabriel. Thank you so much Dominick. Thank you listeners for listening today, you've been listening to Circulation on the Run. Don't forget to join us next week for more summaries and highlights.

Circulation September 20, 2016 Issue

19 september 2016 | 18 min

Carolyn: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Today we will be diving deep into issues of resistant hypertension, adherence to anti-hypertensive medication, and renal denervation. All this by looking closely at new data from the Renal Denervation for Hypertension trial. First, here are your summaries of this week's journal.

The first paper sought to answer these questions: How can we better re-stratify patients with long QT syndrome type 3? You will remember that as the type caused by a gain of function mutation in the SCN5A sodium channel, and the type that has a more lethal course than types 1 and 2. Another question is, are we sure that beta blockers are effective in type 3 long QT syndrome? Well the current study is by co-first-authors, Dr. Wilde of Academic Medical Center, Amsterdam, and Dr. Moss from University of Rochester School of Medicine and Dentistry, which is the largest multi-center long QT type 3 syndrome cohort described to date.

This study was designed to identify the risk and therapeutic factors associated with cardiac events in patients. The risk factors evaluated included clinical features such as age, gender, ECG measurements, the mutation type, and the therapeutic effects of beta blockers, other medications, and ICD. In almost four hundred patients with type 3 long QT syndrome, 30% experienced at least one cardiac event; that is syncope, aborted cardiac arrest, or sudden death. The risk of a first cardiac event was directly related to the degree of QT prolongation. Each 10 millisecond increase in QTC up to 500 milliseconds was associated with a 19% increase in cardiac events. Prior syncope doubled the risk of life threatening events. Beta blocker therapy was associated with an 83% percent reduction in cardiac events in females, however the efficacy in males could not be conclusively determined due to low number of events. The take-home message is, in your patients with long QT syndrome type 3, recognize the very high risk sub-population with prolonged QTC and a history of syncope.

The next paper is a basic science paper that reveals a novel way in which mitochondrial dysfunction may be targeted in heart failure. This paper is from first author Dr. Li, corresponding author Dr. Tian, and colleagues from the Mitochondria and Metabolism Center at University of Washington. These authors previously found that elevation in the NADH to NAD ratio induces mitochondrial protein hyperacetylation, and renders hearts highly susceptible to stresses, and they showed this in a mouse model of primary mitochondrial dysfunction caused by genetic defects. In the current study they defined the molecular intermediaries linking specific NAD sensitive hyperacetylation targets to the development of heart failure, and further demonstrated the relevance of these mechanisms in human heart failure. Specifically, they identified that hyperacetylation of the regulators of mitochondrial permeability transition poor and malate-aspartate shuttle, mediates the increased susceptibility to cardiac stresses. Further, expanding the cardiac NAD pool via pharmacological or genetic approaches normalized the NADH to NAD ratio, and thereby normalized protein acetylation in hypertrophied and failing hearts. Importantly, these measures improved cardiac function and reduced pathological hypertrophy in mice. Thus, the clinical implication is that restoring the NADH to NAD ratio may be an effective and translatable strategy to treat mitochondrial dysfunction in heart failure.

The next study broadens our considerations of the benefits versus risks of intensive anti-platelet therapy in patients with a prior myocardial infarction, and really suggests that more intensive anti-platelet therapy should be considered, not only to reduce the risks of coronary events, but also to reduce the risk of stroke. This is a paper from Dr. Bonaca and colleagues of the TIMI study group from Brigham and Women's Hospital in Boston, Massachusetts, who investigated the efficacy of ticagrelor, 60 milligrams twice a day, for reducing stroke in patients with a prior myocardial infarction from the Pegasus-TIMI 54 trial.

You will remember that in the Pegasus-TIMI 54 trial, ticagrelor was already shown to reduce the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior MI. Of more than 14,000 patients randomized to placebo or Ticagrelor, 213 experienced a stroke, 85% of which were ischemic. 18% of strokes were fatal, and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke, with a hazards ratio of 0.75, and this was driven by a reduction in ischemic stroke. Hemorrhagic stroke occurred in nine patients on placebo and eight patients on ticagrelor. Furthermore, a meta-analysis of four placebo-controlled trials of more intensive antiplatelet therapy in more than 44,800 patients with coronary disease confirmed a marked reduction in ischemic stroke, with a combined hazards ratio of 0.66. Thus this study really broadens our considerations of benefits versus risks of intensive antiplatelet regimens for the long-term secondary prevention in patients with patients with prior myocardial infarction. It really highlights the broader benefits in reducing ischemic stroke, and not just coronary events. In summary, overall, for 1,000 patients initiated on ticagrelor 60 milligrams twice daily for three years, 13 primary endpoint events would be prevented, including approximately five ischemic strokes. This benefit would come at a cost of nine TIMI major bleeds, but no hemorrhagic strokes or fatal bleeds.

That wraps it up for our summaries! Now for our feature paper. Our feature paper today discusses a really important issue that we face everywhere around the world, and that is the management of resistant hypertension. We're taking a very interesting look at the Renal Denervation for Hypertension trial, because we're actually looking at the adherence to anti-hypertensive therapy, and what we've learned in this trial. I'm so excited because I am sitting right here with first and corresponding author Dr. Michel Azizi, from Georges Pompidou hospital in Paris, France. Hello Michel, thank you!

Michel: Hello, Carolyn. Thank you also for the invitation to discuss about the paper.

Carolyn: We're also so lucky to have the associate editor who handled the paper, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome, Wanpen.

Wanpen: Hi, Carolyn.

Michel: Hi, Wanpen.

Carolyn: This whole issue of resistant hypertension, I'll tell you, to me that means someone who's adequately treated, and despite all the treatment that we can throw at them, they still have a blood pressure that is above a certain level, right?

Michel: Yes.

Carolyn: But your study seems to tell us that that assumption, that everyone's receiving treatment and still having high blood pressure, may need to be questioned, so please tell us a little bit more about what you found.

Michel: This is a clinical trial where we compared the effect of renal denervation to medical treatment, optimal medical treatment. We standardized the anti-hypertensive treatment in the cohort of patients with resistant hypertension, and then we followed them on a monthly basis with home blood pressure monitoring. We also increased the intensity of the treatment every month after randomization between renal denervation against nothing, because this is a probe trial, it is not a double blind trial. We gave them the same treatment in both arms. At the end of the many study we demonstrated that there was 6 millimeter of difference, in terms of ABPM, in favor of renal denervation, against the same medical treatment alone.

However, because this trial was an open trial, it was open to a Hawthorne effect, and the possibility that patients or doctors behave differently in each arm of the study. Those having renal denervation may be more adherent to the treatment, and those not being given the new therapy, not being really adherent to treatment. This was an issue, so we specified analysis. We also measured drug levels in urine after six months of followup, and also assessed the exposure to each individual using a peptide in urine, which is N-acetyl-serylaspartyl-lysyl-proline (AcSDKP)/creatinine.

What we found after six months of followup in patients who really participated to this trial, they were willing to participate to the study, they signed an informed consent where it was written that, indeed, we will monitor drug levels. They knew that we would do this. They also knew that we will follow them very carefully every month, et cetera, that we'll provide them home blood pressure monitor for free. They had access to the same doctor, same nurse, same everything. They could arrive at the time they wanted in the morning for being investigated. After six months of followup we found that more than half of these patients did not take correctly their treatment, and even 15% of them, in reality, took zero medication over seven medications. This was a major, major surprise for us in this trial.

Carolyn: I think that's one of the most significant findings, even in a trial setting, that is such a lot of non-adherents, anti-habitants, of therapy. It really makes us question when we say someone has resistant hypertension, is it really that, or do we have just a very non-compliant patient?

Michel: Yes.

Carolyn: Because it can only be worse in the real-world setting, isn't it? Congratulations, that was a very striking message to me as well. What was the other main finding that you wanted to ... ?

Michel: The other finding was that the rate of non-adherence was similar in both arms. That there was absolutely no influence of being randomized to the renal denervation group or the medical treatment group only. This means that the patients were not influenced, and other physicians behaved similarly in both arms. Because at the end you have exactly the same rate of non-adherence to treatment. This is also very important.

Carolyn: Yes, indeed. Wanpen, I was wondering what your thoughts were, and take-home messages from this paper. We definitely thought it was significant in the editorial board because you even commissioned a wonderful editorial by Dr. David Calhoun on this. What are your thoughts?

Wanpen: In the United States, using the same technique, we found as much non-adherence. I think there is a lot that we need to do and to understand what caused non-adherence. The patient should not be the only party that's to blame. I think that the doctor's as much of a culprit here to try to tease out what's the barrier to the treatment. Also, as pointed out by Dr. Calhoun, is that although the trials show improvement in blood pressure in both groups, at the end number of medications of patients in resistant hypertension, they require to take four to five drugs to get the blood pressure under control. I think this is going to be a lifelong continuing medication treatment that the physicians have to face, and to deal with the adherence problem as well. Just lastly, I think that although people believe that doing drug levels is only for research purpose, but many people don't realize that actually many drug levels for anti-hypertensive drugs actually is clinical available and can be ordered. It takes a little bit more effort to order it, but it can be done, and actually our center has been doing that already anyway.

Carolyn: Wow. I cannot say that my center has been doing that in Asia, but I really have to admit that this paper made me think about it. Especially the editorial when he highlights it, the very unique information that is provided by actually measuring the blood levels. Michel, you were nodding your head vigorously when Wanpen was saying that we should not just blame the patient. Tell me, what are your thoughts, and how does this affect your clinical practice?

Michel: I fully agree with Wanpen. We have to now integrate the fact that it's accessible, you can measure drug levels through technology, with mass spectrometry, et cetera. This is very important to integrate and to change our paradigm that we have to put in our brain. We have to monitor drug levels. Using this technology we have to establish a partnership with the patient.

I think the truth, also, is somewhere, as Wanpen said, we are also culprits. If patients do not take their treatment, okay, there may be some benefit and e have to look why they are not taking pill treatment, but also we are culprits because we don't listen to them, we don't take enough time, et cetera, et cetera. But I think patients should not be only blamed, so it opens a new possibility to discuss with the patient about the fact that we didn't find the drug in levels in their urine, et cetera.

However, taking into account that there will be this toothbrush effect, that is, "Patient, brush your teeth when you go to see the dentist," you'll take the pills when you go to see the doctor so you can be treated. This is one of the difficulties. However I think it's a new possibility to discuss with the patient of his or her difficulties in taking the pills. It gives us the opportunity to discuss, to take time with our patients.

Carolyn: It's really fascinating, you're talking from a system based in Europe. You're based in Paris.

Michel: Yes.

Carolyn: Wanpen just said that she's doing it, and she's based in the US. Do you now routinely, maybe, monitor these medication levels?

Michel: Yes, yes, yes.

Carolyn: Wow.

Michel: In the hospital we have these mass spectrometer platforms, so we have access to this, and we are working with the house authority to have the reimbursement. Because I think it's important, because if it's not reimbursed there is also a problem.

Carolyn: Of course.

Michel: We are working to see how it could be reimbursed for labs doing these measurements.

Carolyn: But this is for maybe selected resistant hypertensive patients that are difficult to ... ?

Michel: Yes, absolutely. Those very difficult to manage. I think, as a rule of thumb, that after four or five drugs given to the patient, if the patient-

Carolyn: Yeah, we should start questioning, are they taking it.

Michel: If the patients do not have secondary hypertension, we should really start questioning ourself whether they are taking or not the treatment, even if they are looking right in your eyes and telling you, "Yes, doctor, I'm taking all the pills."

Carolyn: Wanpen, how about the reimbursement issues and things like that in the United States? How are you getting it done in your institution?

Wanpen: Actually the coding for doing drug levels, it's actually generic. It's the same coding for Digoxin or Cyclosporine. They actually don't care about what the name of the drug. Strangely, they're coded by the technique, so that's how we go with it, but we have to put in miscellaneous "other" for, we wanted to test for this. That's how we get around it.

Carolyn: Do you do that again routinely, or in selected patients that are difficult to manage hypertensive?

Wanpen: Obviously we have to be selective, so we select from people who we would suspect are non-adherent, but they say they're taking it. But if they already came in and made that they're not taking the drug, there's no point doing that for the clinical purpose. We're doing it for people who we suspect it, and we use it the way ... Actually we shall describe very well, not only just to find what drug they're not taking, because when they're not taking, only about 30% are not taking everything, about 20% not taking one or two drugs. When we drill down to that drug they say, "I have side effects to beta blocker and I don't want to tell my physician that I have problems taking it, but I just not take it." I think that's what led us to pinpoint the problem a little bit better with this technique.

Carolyn: What a lot of practical advice, and congratulations once again for very, very meaningful findings. I learned a lot this time. I don't do this, and so I'm definitely going to think about this much more because of your work. Thank you very much Wanpen, Michel.

And thank you, listeners, for tuning in this time. Remember, you're listening to circulation on the run. Listen in again next week. Thanks.

Circulation September 6, 2016 Issue

5 september 2016 | 17 min

Carolyn: Welcome to Circulation On The Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, associate editor from the national heart center and Duke National University of Singapore.

In just a while, we will be discussing patients with familial hypercholesterolemia after acute coronary syndrome, and the new data in this week's issue that suggests we still need to pay special attention to this group of patients even in the current era of the widespread use of high intensity satins. First here's your summary of this weeks issue.

The first paper suggests that we may need to look at thyroid function in our risk assessment sudden cardiac death in the general population. This paper is from co primary authors Dr. Chacker in Van Der Burgh and corresponding author Dr. Strecker and colleagues from the Erasmus University medical center in water dom.

The authors studied the association of thyroid function with sudden cardiac death in more than 10,000 participants of the population based Water Dom study. They found the higher levels of 3T4 were associated with an increased risk of sudden cardiac death even in the normal range of thyroid function. The estimated hazard ratio was 2.28 per one nano-gram per deciliter of 3T4, and these risk estimates did not change substantially even after stratification by age or sex or sensitivity analysis excluding participants with an abnormal 3T4. The absolute 10 year risk of sudden cardiac death increased in youth thyroid participants from 1 to 4% within increasing 3T4 levels.

Thus this study suggests that 3T4 and additive marker in risk stratifications for sudden cardiac death in the general population. Further research is needed to assess the possible additional benefit of using 3T4 levels to re stratify and prevent sudden cardiac death.

The next study reminds us that therapies to reduce ischemic events in patients undergoing percutaneous coronary intervention are still really important even in the current era of changing definitions of periprocedural myocardial infarction. This study is from first author Dr. Cavender of University of North Carolina chapel hill and corresponding author Dr. Bach Brigham women's hospital and colleagues.

The authors looked at more than 11,000 patients randomized to cangrelor or clopidogrel int the champion phoenix trial.

Cangrelor is an intravenous P2Y-12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention who are not pretreated with with a P2Y-12 inhibitor.

The authors explored the effects of cangrelor on myocardial infarction using different definitions of myocardial infarction and perform sensitivity analysis on primary endpoint.

They found that 4.2 percent of patients had a myocardial infarction defined by the second universal definition within 48 hours after undergoing PCI. When the sky definition of periprocedural MI was used, there were fewer total myocardial infarction, but the effects of cangrelor remain significant.

Finally similar effects were seen when MI's were restricted to those defined with large bio marker elevations or by symptoms of ECG changes. Very importantly patients who had an MI regardless of the definition, were at increased risk of death at 30 days.

In summary changes in the definition of MI used in the primary endpoint did not affect the overall findings from the champion phoenix trial. This study also reminds us that periprocedural MI remains an important clinical event in the current era. Being associated with increased risks of death at 30 days, and therefore reducing ischemic events in patients undergoing PCI remains very important.

The final paper describes experimental evidence of a novel treatment approach to hypertension using micro RNA's. This paper is from first author Dr. Lee and corresponding authors Dr. Chinn and Wang from Tong G medical college and Whadrom University of Science and Technology in Wuhan China.

Micro RNA's are a class of small non-coding RNA's that regulate gene expression at a post transcriptional level. These authors compared the expression of key neucler genoman coded and mitochondrial genoman coded genes involved reactive oxygen species production in spontaneous hypertensive rats and wistar rats. They then used bioinformatics to predict the micro RNA targets followed by biochemical validation using real time PCR and immunial precipitation.

They first found that there was down regulation of mitochondrial DNA encoded sitoca B in the spontaneous hyper intensive rats, which appeared to directly contribute to the increased mitochondrial reactive oxygen species.

Next they found that mere 21 a key micro RNA induced into hyper spontaneous rats, was able to trans-locate into mitochondria to counteract the mitochondria pseudonym B down regulation. Finally, they showed that exogenous mere 21 delivered by recombinant adeno associated virus was able to lower blood pressure and attenuate cardiac hypertrophy in the spontaneously hypertensive rat model.

These findings are striking because they provide experimental support for developing micro RNA based treatments for hypertension.

Those were your summaries of original papers but before I go, I just have to highlight this in depth review paper in this week's issue, and it is regarding sodium glucose co transported to inhibitors or SLG2 inhibitors in the treatment of diabetes, discussing the cardiovascular and kidney affects potential mechanisms and clinical applications.

It is a beautiful review article written by first author Dr. Heresphink of the University Medical Center Groningen, corresponding author Dr. Churney from Toronto general hospital and colleagues. Truly a must read, but now here is our featured paper.

Our featured paper today is on patients with familial hypercholesterolemia after acute cornery syndromes. Today I have with us the first and corresponding author David Nan chin university of Lausanne in Switzerland.

Hi David, thanks for joining us.

David: Hi, I'm very happy to be here.

Carolyn: As the associate editor who managed this paper we have Dr. Amat Kira and you will recognise him as the digital strategies editor as well from UT Southwestern. Welcome back Amat.

Amat: Thank You Carolyn, happy to be here.

Carolyn: I am really curious about this paper because it speaks of familial hypercholesterolemia that most of us would assume is very rare.

Now David, I know that you actually published prevalence in a prior paper last year, but could you maybe start by telling us why we should, how common is this in our patients with acute coronary syndrome?

David: In fact we studied patients who is hospitalized with acute coronary syndrome in several university hospitals in Switzerland. Of course we try our best to include all classifications in the study in order to be very protective of the acute coronary syndrome population.

We found that among patients with acute coronary syndrome, familial hypercholesterolemia was not a rare disease. We found a prevalence of 2-5% which is in fact 10 times higher than what is thought to be in the general population.

The important point here is that we use very simple clinical catatonia to assist the prevalence of adage. This catatonia includes unbelievable[inaudible 00:08:50] and the family of Bethany of coronary heart disease. This criteria are very easy to use and implement in a clinical practice in the sitting in acute coronary syndrome to detect patients with familial hypercholesterolemia.

Carolyn: Exactly. You did not use molecular diagnosis in your paper, but yet, with these simple criteria there was a very important clinical take home message. Could you tell us about those findings?

David: The question we wanted to answer here is wanted to know what happened to this patient with familial hypercholesterolemia after hospital discharge. We found that patients with familial hypercholesterolemia were an increased risk of recurrence of cornea events within the year after discharge, and this is despite the use of idol science.

In fact, one year after the coronary syndrome, 7 people found a patient with adage were still using idle studies, which is very good we were quite impressed by these numbers, but they mean[inaudible 00:09:57] one year after the acute coronary syndrome, with one in twenty become affected later.

Most of these patients were not able to decrease their added cholesterol to lower evens.

I really think there is clear room for infestation of leamington therapy among these patients. In any of those drugs available from my seeing and very effective to decrease and [inaudible 00:10:25] to substance, but they are very expensive.

Maybe the best initial strategy, to prescot these drugs, is to target patients with familial hypercholesterolemia after acute coronary syndrome. Because these patients are at high risk of recurrence and most of them cannot achieve their cholesterol level with our studies.

Carolyn: Congratulations for being really the first to show that. This is common and it affects recurrent events. I think actually the first step is to recognize this in our patients which very few of us really do I think.

Amat from your point of view, knowing the results of this paper how has it changed your clinical practice?

Amat: Absolutely Carolyn. First I congratulate Dr. Nan chin and his colleagues. This was an incredibly important paper, and I think as you pointed out, one of the first to really show us why it is irrelevant to show us why it is relevant to identify FH at the time of an ACS.

Generally even when I work with my trainees when we talk about FH, everyone is thinking, "Well, we'll just put everyone on statins," and it's well appreciated. We can think about cascades swinging and why it's important to their offspring, but what Dr. Nan chin and his colleagues have certainly highlighted, is that these patients are at higher risks for recurrent ACS and recurrent events, and that's incredibly important as mentioned that tells us that maybe the routine treatment post ACS with high dose statins is not sufficient.

What's next is the tricky part, do we initiate PCS canine initially, do we add a zedemi upfront. Sort of the next step is the part that's a little bit more tricky, but I certainly see a potential for augmented therapy in these patients up front.

Carolyn: I like the way you said tricky, and that's usually when we call for an editorial isn't it?

Amat: That is correct as we will see with this article.

Carolyn: I really like the title of it, "Diagnosis and Management of Petra Zygas familial hypercholesterolemia too little and too late."

That was very interesting, but are there any other take home messages from your end David?

David: Maybe one thing we can add ... We are currently trying to change our practice regarding these reasons that we have now. We have now implemented in our casualty department a system that's explaining strategy to identify this patient, to identify patient with asage.

We have a prevention team that can provide very early during hospitalization additional information for this patient about asage. That's one very important point is to encourage family testing especially for the children of the patient and also to provide concerning for other cardiovascular risk factors. Because we also found that half of these patients with asage were smokers in fact and 40% of them had hypertension.

Certainly to address the other cardio risk factor in patients with asage so certainly very important. At the end part of what we are doing is we are assured of the patient will an appropriate medical follow up in the primary care setting because it's also very important for management of asage and circular prevention in the primary care setting after discharge.

Carolyn: Wow. Those are excellent points. Very practical advice on screening, management, and really just applying the results of what you found. Congratulations once again.

Amat I'm going to switch tracks a little bit now. Since we've got you online I really have to ask you a couple of things with your hat as a digital strategies editor.

Has it been two months since we first chatted even about this podcast which is part of the digital strategies. Let's take stock of it. How are things going?

Amat: Well, so far I think excellent and frankly one of the highlights of our digital strategies is your podcast. It's gotten rave reviews and certainly appreciate all your enthusiasm and your unique take on how to do this. We've also had some excellent work with our social media. We have a revised website which has a lot more real estate for some novel offerings, and I think we certainly can't rule out traditional print media, but those articles that come out online.

It's been really an exciting time and thinking of novel ways to share new information in a modern era.

Carolyn: Right. Thanks to you really Amat and I would really want to bring out one of the strategies that we may have not talked about so often yet, and that's the "on my mind" vlogs.

The reason I'm going to bring it up is because last week I was struck by the on my mind article by Milton Packer and it's entitled, "Heart Failure's Dark Secret. Does anyone really care about optimal medical therapy?" That's just awesome. Could you tell us a bit more about this vlog.

Amat: I think you hit the nail on the head there it certainly an edgy and controversial title, and if you think about it that's the purpose of this in most of our academic writing. It's a little bit stiff in following certain para dines, and more formal para view. The purpose here for the on my mind was literally that for someone who is a thought leader to free associate various ideas they have that would be controversial or edgy or may not be accepted down the main stream.

That's a bit on purpose because we hope to create a dialog around that. If you look on our webpage, there's actually a place where people can add comments or start a dialog saying whether they agree or disagree, or begin an important conversation around these edgy topics.

Carolyn: I think that's the really cool part when we can actually start interacting with our readers and listeners online that way.

Thank you to my wonderful guests and thank you listeners for listening this week. Don't forget to tune in next week for more highlights and features.

Circulation August 30, 2016 Issue

29 augusti 2016 | 16 min

Carolyn: Welcome to "Circulation on the Run", your weekly podcast summary and backstage pass to the journal and its editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment, we will be discussing the very topical subject of wearable cardioverter defibrillators in patients at high risk of sudden cardiac death. Yes, this is the topic of our feature paper which really builds on prior US data using these devices and extends it, now, to a healthcare system outside the United States. First, here's the summary of this week's journal.

The first paper describes a novel class of mediators that may revolutionize the nonsurgical treatment of limb ischemia. This paper from first author Doctor Jung from University of Louisville School of Medicine and corresponding author Doctor Spite from Harvard Institute of Medicine and colleagues looked at resolvents. Resolvents are a family of lipid mediators synthesized from Omega-3 polyunsaturated fatty acids that promote the resolution of inflammation and have been shown to regulate the transition from inflammation to repair. Now, this is very relevant to limb ischemia because most other mediators that promote revascularization also exacerbate inflammation, thus potentially limiting their therapeutic use in chronic inflammatory diseases such as diabetes.

To assess the role of resolvents in revascularization and resolution of inflammation, the authors using a Murine model of hindlimb ischemia coupled with Laser Doppler profusion imaging, micro-computed tomography and targeted mass spectrometry. They identified that resolvent D2 is produced in the skeletal muscles of their Murine model of limb ischemia as well as in skeletal muscle biopsies of patients with peripheral artery disease. They showed that resolvent D2 increases tissue profusion by promoting arterial genesis that is collateral artery growth and, importantly, that it rescues defective revascularization in diabetic mice. These findings are important because they could inform the development of novel strategies for the clinical management of limb ischemia.

The next paper addresses food fortification with folic acid, which we all know prevents neural tube defects but may now even prevent congenital heart defects. This paper is from Doctor [Mule 00:02:53] and colleagues from The Center for Chronic Disease Prevention, Public Health Agency of Canada who studied approximately six million Canadian births from 1990 to 2011 and compared the prevalence rates and temporal trends in congenital heart disease sub-types before and after 1998 when folic acid fortification was mandated in Canada. They quantified the effects of folic acid fortification on the birth prevalence of specific non-chromosomal congenital heart disease sub-types, after controlling for concomitant changes in maternal age, pre-pregnancy diabetes, preterm pre-eclampsia, multiple birth and pregnancy termination. They found that there was an eleven percent reduction in non-chromosomal congenital heart defects following folic acid fortification. Specifically, folic acid fortification was associated with a twenty-seven percent reduction in conotruncal defects, a twenty-three percent reduction in coarctation of the aorta, a fifteen percent reduction in ventricular septal defects and an eighteen percent reduction in atrial septal defects. This large ecological study, therefore, provides evidence of a modest protective effect of folic acid fortification on congenital heart defects.

The last study suggests that in patients with ischemic cardiomyopathy and right ventricular systolic dysfunction, we should perhaps be taking a look at the mitral valve. This is work from first author Doctor Seib from the Beth Israel Deaconess Hospital and Harvard Medical School, corresponding author Doctor Kwon from the Heart and Vascular Institute of Cleveland Clinic Foundation and colleagues, who looked at over five hundred and fifty patients with ischemic cardiomyopathy, all of whom underwent cardiac MRI. They found that mitral regurgitation, as measured by effective orifice area, was a significant independent predictor of right ventricular ejection fraction. They further found that the relationship between right ventricular ejection fraction and mortality may be affected by mitral valve surgery in that a reduction in right ventricular ejection fraction was associated with increased mortality in non-repaired patients but not in patients who had undergone mitral valve repair.

The clinical take-home messages are that right ventricular function should be carefully assessed in patients with ischemic cardiomyopathy and if systolic dysfunction is found, patients should be assessed carefully for significant mitral regurgitation as well as other known risk factors such as right bundle branch block, right ventricular scar or a decreased left ventricular ejection fraction. The study suggests that mitral valve surgery may mitigate the relationship between right ventricular rejection fraction and mortality, however further studies are clearly needed.

Those were the summaries. Now, for our feature paper discussion.

I am thrilled to be joined by three guests today to discuss the feature paper on wearable cardio defibrillators in patients at high risk of sudden cardiac death. This is a real world experience all the way from Germany. Joining us today we have two authors of the paper, the first and corresponding author Doctor Nadine Visnic as well as author Doctor Ruth Strasser, both from the University of Dresden and Heart Center Dresden in Germany. Welcome, ladies.

Ruth: Hello, how are you?

Carolyn: Very good, thank you.

We have Doctor Mark Link, Associate Editor from UT Southwestern. Thank you for joining us, Mark.

Mark: You're very welcome.

Carolyn: Mark, let's start with a behind the scenes look. We have data from the United States describing the wearable cardio defibrillator. We have ample data on the implantable cardio defibrillators. What made the editorial board decide that this particular paper from Germany was so important?

Mark: There are a number of aspects that we looked at for this paper. This is exciting new technology that is beginning to impact the daily lives of all the physicians in the states, the wearable defibrillator. This is a very nice prospective study from Germany that looked at a very large group of patients with this wearable defibrillator, gave us real world experience and it also fits in with the circulation mission of becoming a world wide cardiac journal, not just United States journal. We were very interested in the topic. We're very interested in the international collaboration and we're very excited to publish this paper.

Carolyn: I love that. Practicing in a non US system, as well, I found this particularly special about this paper.

Nadiene, we're all wondering, could you describe the patient population, just so we know the kind of patients that your results are applicable to.

Nadine: The patients included in the register were regular patients we meet in clinic in every day life. No specific selection was made. For legal reason, of course, to analyze the data, they signed informed consent for the register. From April 2010 through October 2013, in total six thousand forty-three patients were using the wearable cardioverter defibrillator in Germany. All of these patients were registered into the life vest network, the registry to record demographic such as gender and age. Also, the cardiovascular indications and defibrillation treatments and daily wear time. The German population consisted of seventy-eight male and twenty-two female patients with median age of fifty-seven years.

Carolyn: Great. What were the indications for the wearable defibrillators?

Nadine: Most of the patients had to reduce the ejection faction by below thirty-five percent or even had experienced ventricular tachycardia as an indication. The largest group we had in our analysis was thirty-seven percent where those with newly diagnosed dilatative cardiomyopathy and ischemic cardiomyopathy accounted for twenty-seven of patients, especially forty days after myocardial infarction or after a high risk PCI or cabbage. Also, in total, we had twelve percent of patients that had an ICD explantation mostly due to infection situation. What is very special on that paper is that ten percent of all our patients had myocardidas as a diagnosis and was reason to use the WCD.

Carolyn: Wow. That does sound very representative of the real world patients that we would put wearable defibrillators on, as well.

Ruth, could you tell us, what were the main results? Were there any differences by sub-groups?

Ruth: Perhaps, we should first go on the compliance because this is very important to the daily wear time. This was more than twenty-two hours in ninety-four percent of the patients. Many patients who complained about the inconvenience but understanding that this life vest is a potentially life saving and only temporary treatment strategy made it acceptable to ninety-eight percent of the patients. As to the [inaudible 10:52] there is a difference, the younger patients, patients younger than forty-eight years of age or younger, they wear the life vest longer, sixty-six days. While the older patients, older than sixty-eight patients, this was statistically significant, wore it only forty-nine days. This difference was not used to compliance, because you do the description based on the cardiac diagnosis.

We also observed that the longer the cumulative wear of the life vest was, the longer day hours the patient had the life vest on. They were somewhat accustomed to it. One thing which is very, very important is, that in more than twenty-five percent of the patients, we could save the implantation of a permanent ICD due to the recovery of the ejection fraction. This was especially important for those patients who had the life vest, for example after myocardidas or after myocardial infarction, which is a very large population.

Also, which is important is that [full 12:06] shock treatment for reasons other then VT occurred only in point four percent, of less than one percent. Whereas those patients were successfully treated, this was one point six percent. They were treated in response to VT and VF. This means the incidence rate was eight point four per hundred patient years. This was even higher in those patients who had the life vest for the explantation. The life vest is very effective. It's a very effective strategy for general patient population with above indications. It can save the implantation, as I said already, in more than twenty-five percent in the population in Dresden itself. We could observe even a reduction of the need of implantation of permanent ICD more than thirty-five percent due to the recovery of the ejection. This is a very important treatment, especially for those patients who have an acute illness.

The German cohort is the first large cohort outside the US healthcare system. It confirms the overall value of the life vest and treatment pathways in Germany. Also, the cohorts analysis uncovered over two hundred forty-two sustained but self-terminated episodes of VT among seventy life vest patients, so that you have safely not treated because they were still conscious and could still press the response button. We found out that some of the self terminated VT episodes were even longer than eight minutes in duration time. All in all, we could see that the life vest is a device which is safe and which can prohibit shocks, as well.

Carolyn: Thanks, Nadine. [Ruth 14:12]

Mark, though, for the readers, I'm sure we need to put in perspective, as well, because there are still patients where perhaps an implantable cardio defibrillator is still more important. Could you share some thoughts about that?

Mark: Yeah. I think this is a very interesting, important study, for a number of regards.

One, is that there was a very high rate of compliance with using the life vest. To leave it on for twenty-three hours a day, for a mean of sixty days, is really quite impressive patient compliance. The data showed that it did recognize and treat VF in a small percentage, but in a important percentage, of people. This data does need to be put in perspective and the randomized trial is currently ongoing. The vest trial, which will randomize people, probably similar population to what the German study did, and look at the life vest performs in that population.

We look forward to further data from the vest trial and from other trials, that are looking at what the place of the wearable defibrillator will be in the future.

Carolyn: Thank you, Mark and that's perfect take home message for all us out there.

Thank you, once again, Nadine, Ruth, Mark. It has been wonderful chatting with you.

To all of you out there, you've been listening to Circulation on the Run.

Thank you for joining us.

Circulation August 16, 2016 Issue

15 augusti 2016 | 18 min

Carolyn: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. I am so pleased to be joined this week by Dr. Judd Hollander and Dr. Deborah Diercks to discuss a problem that all of us, as cardiologists and emergency department physicians will recognize. This is a feature paper on the state of the art approach to the patient presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome, but first here are the highlights of this weeks issue.

The first study is from first author's Dr. Wing and Dr. August from Grand Valley State University in Michigan who investigated whether social and physical neighborhood characteristics are related to progression of sub clinical atherosclerosis measured by coronary artery calcium. They studied this in almost six thousand adult participants of Mesa, a multi-ethnic study of atherosclerosis, followed over twelve years. The main result was that increases in density of neighborhood healthy food stores were associated with decreases in coronary artery calcium. This was significant even after adjusting for time varying demographic confiders, time varying behavioral risk factors and depression.

The next study from Dr. Hess and colleagues from the University of Colorado School of Medicine characterized rates of implantable cardioverter defibrillator or ICD counseling and ICD use among more than twenty-one thousand potentially ICD eligible hospitalized heart failure patients in the Get With the Guidelines heart failure program. This study had several notable findings. First, only twenty-two point six percent of patients received ICD counseling. This means that up to four out of five hospitalized heart failure patients, eligible for ICD counseling, did not receive it. Women were counselled less often than men and racial or ethnic minorities were counseled less frequently than white patients.

Among counseled patients, a totally of sixty-two point six percent of patients received an ICD or had a documented plan for ICD placement. Women were just as likely as men to receive an ICD, however, ICD used differences by race and ethnicity persisted. The clinical implications of this study are that future quality improvement initiatives should incorporate culturally competent ICD counseling and elevating ICD counseling to a full performance measure and publicly reporting it by sex or race or ethnicity may need to be considered.

The next paper is from first author Dr. Resconey and corresponding author, Dr. Catalucci and colleagues from the Institute of Genetic and BioMedical Research in Milan, Italy. These authors looked at the voltage dependent [inaudible 00:03:31] calcium channel which is a key mediator of interest [inaudible 00:03:34] calcium entry associated with various cardiovascular conditions such as hypertrophy, atrial fibrillation, hypertension and diabetic cardio myopathy. The author's aim to address the problem that [inaudible 00:03:47] approaches aimed at enhancing calcium current and inotropism in heart failure have also frequently been found to favor arrhythmogenesis and diastolic dysfunction. Thus, limiting their clinical use.

The novel hypothesis addressed in this study is that a peptidome emetic therapeutic approach may overcome the arrhythmogenic limitations of current channel activator inotropes. To test this hypothesis, the author's used a whole host of methods to dissect new regulatory pathways modulating the [inaudible 00:04:24] tight calcium channel life cycle. This included yeast, two hybrid screenings, biochemical and molecular evaluations, protein interaction essays, fluorescence, microscopy, and structural molecular modeling and functional studies. Having uncovered a novel mechanism involving the [inaudible 00:04:44] tight calcium channel, calcium beta two chaperon, the author's then generated a mimetic peptide that specifically targets this calcium beta two chaperon. Thereby controlling the channel assembly and density of the plasma membrane while preserving its physiological channel function.

Finally, they showed that delivery of this mimetic peptide into a mouse model of diabetic cardiomyopathy restored calcium balance and recovered cardiac function. This study is so significant because it provides the proof of concept for the exploitation of novel therapy based on mimetic peptide technology. Really opens the field to mimetic peptides being used as innovative therapeutic tools for the treatment of cardiac disease.

The last study is from Dr. Cammel from the Feil Family Brain and Mind Research Institute in New York and colleagues who studied the association between pregnancy and aortic complications such as dissection or rupture. They used data on all emergency department visits and acute care hospitalizations at nonfederal health care facilities in California and New York between the period of 2005 to 2013. This was a cohort crossover study where they authors defined the period of risk as six months before delivery until three months after delivery. Compared each patient's likelihood of aortic complications during this high risk period to an equivalent control period of two hundred and seventy days exactly one year later.

Among more than six and a half million pregnancies in almost five million women, they identify thirty-six cases of aortic dissectional rupture during the high risk pregnancy period and nine cases during the control period. This gives the rate of aortic complications a five point five per million patients during pregnancy compared to one point four per million during the equivalent period one year later. Thus, pregnancy was associated with a significantly increased risk of aortic dissectional rupture with an incidence rate ratio of four compared to the control period one year later.

Furthermore, absolute risks were particularly elevated in those with a documented diagnosis of hypertension or a connective tissue disease. These findings have clinical implications for the counseling of patients at high base line risk of aortic complications and they also further suggest that clinicians may need to have a lower threshold for initiating diagnostic testing for symptoms of a possible aortic dissection or rupture in pregnant or postpartum patients and especially in those with connective tissue disorders or hypertension.

Our feature paper this week discusses a problem that impacts twenty million patients in North America and Europe every year. What am I talking about? These are patients presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome. Who am I talking with? Well, today we have first author Dr. Judd Hollander from Thomas Jefferson University and Dr. Deborah Diercks associate editor from UT Southwestern. Welcome Judd and Deborah.

Dr. Deborah: Thank you.

Dr. Judd: Thank you.

Carolyn: Let's start with a behind the scenes look at this paper. It's an in depth review that was invited by the editorial team. Deborah, can you tell us how this idea came about?

Dr. Deborah: I think one of the goals of the editorial board of circulation is really to provide great clinical reviews that really could benefit the members. I have a unique aspect in that I'm an emergency physician. This idea was really brought about by discussion of really what can we merge cardiology and emergency medicine with. What would be the most clinically issue we're challenged with right now? You can't get two emergency physicians in a cardiologist's room together without some discussion and challenge around the [inaudible 00:09:11].

There's been so many changes in the last decade and so much more information about how we can use these in a clinically relevant way. It really fit nicely into a really great review article and I am really happy that we are able to invite Judd who's well known to the US and one of the leaders in the United States in this area and also an international group inviting a cardiologist from Europe and also an emergency physician from New Zealand to participate in it.

Carolyn: Judd, what is the take home message of this in depth review from your point of view?

Dr. Judd: I think the biggest take home message is we have known for decades and decades that if we rely on our clinical judgement we miss too many patients. We send home people that will be having acute coronary syndromes and acute myocardial infraction and the challenge over the last decades of trying to find ways where we're not going to spend a ton of money over admitting people to the hospital because of a fear of missing an event that may happen five percent of the time.

The beauty of the advances in troponins is we now have troponins that now have increasing sensitivity whether they be the non high sensitivity troponins used in the US or the high sensitivity troponins that are actually used in Europe and the rest of the world. We can use those better [inaudible 00:10:29] and combine them with clinical decision rules to create accelerated diagnostic pathways which is a big term. For now, if we put a blood test together with a structured clinical decision rule, we can, with more than ninety-nine percent negative predictor value, find patients who are safe to send home.

Carolyn: Judd, I really have to congratulate you on such a beautiful paper. You really did cover all of that but what I love most is the way that you've managed to summarize very clearly a whole wealth of information because when you talk about biomarkers, there's so many out there and there's zero hour, one hour, two hours, this score and that score. I'm actually looking at table one now where you show a summary of the biomarkers strategies and then, in table two, you show a summary of the risk scores and then the performance measures of each of these scores. That must have taken quite a lot to put together.

Dr. Judd: I think that's why Deb was very smart and invited authors from around the world. We have Christian Muller from Switzerland and Martin Tann from New Zealand which, literally, means we're all on different time zones and we were able to work around the clock to do that. There as always somebody awake. Getting more series, the nice thing is that my colleagues on this paper are some of the leaders in doing this kind of research. In fact, they are the leaders in doing this kind of research.

What I think is very challenging for the average cardiologist or the average emergency physician is there have been so many different approaches and many of them actually work. The challenge for us was to try and make it relatively simple so you can choose the approach at your institution and put it into a structured pathway and pick the one that works best for you. You can get a ninety-nine percent negative predicted value using the right essays with samples that the time of presentation and one hour later, you can get a ninety-nine percent negative predictor value at zero and two hours. You can combine it with an accelerated diagnostic pathway and do that at zero and two hours and zero and three hours.

I think the important thing is you need to figure out what will your clinicians use? Certain clinicians may be very comfortable with one risk score and not another and then they need to combine the timing of testing with the risk score their comfortable with in order for us to achieve the great possibilities we have with these new tasks. I think when you try and do a one size fits all, there are going to be people who push back because they don't like one component of the risk score. Really what we're trying to do and we didn't say everybody should do A, B or C but we present the data on five or six different options and let people choose what is most feasible for them.

Carolyn: How wonderful. Deborah, what were you thinking when you were reviewing this paper and trying to structure it for the clinician out there who wants to use this information?

Dr. Deborah: I think that, overall, we were really impressed by the clarity and the ease that a reader can take this information home. There is so much information out there and there are so many different ways to apply it that we're really impressed how the authors put it in a really pretty clear manner so you can actually see the risk stratification tools that are out there, what they're used with and what type of troponins. Think about your own clinical practice and what you can adapt really based on the evidence that is out there.

Carolyn: I couldn't agree more. Judd, how about this issue of the coronary CT angiogram and where that falls?

Dr. Judd: That's really an interesting question because there's been a lot of publicity and a lot of editorializing in recent years that maybe you can make a decision with your two troponins and your biomarkers and decrease the number of people that need downstream testing. One of the dilemma with this, like I said before, is we know we're not really good at predicting who has acute coronary syndrome based on clinical things and for that reason the European Society guidelines as well as the American AHAACC guidelines have always said you need to do two things. You need to rule out acute myocardial infraction and you need to risk stratify patients for underlying coronary disease. When a patient comes into the emergency department, if I'm going to be guideline compliant with the recommendations in the world, I need to do both things.

The paper, we summarize really clearly ways you can get out of the woods with biomarket testing and clinical pathways but then you still want to risk strategy for coronary disease. There are sometimes where you might not need that downstream testing but what coronary CTA really lets us do is it makes us more efficient than a stress test. A stress test I like to say is a next day test; although there is data that you can do it when the patient's in the emergency department rapidly. It certainly is not the standard practice.

There are people afraid of putting people on the treadmill too soon in case they have unstable angina but a coronary CTA lets me look at the coronary arteries, immediately, when they're in the emergency department. There's very few areas in emergency medicine where there are three large randomized control trials that all give the same results. It doesn't say coronary CTA is better than a next day stress test but it does say you can avoid admission and, hence, save some dollars. It says you can send patients home sooner and, hence, save some angst that the patients may feel while they're in that diagnostic indecision area.

Carolyn: That's such a practical summary and, in fact, it really reflects the entire paper which is really so clearly presenting the information. Judd, one last thing, could I check is this correct, in my understanding, that the main difference between this and say the guidelines that you just measured is that what you do here is really give the readers all the information? As you say, allow the readers to choose what suits them best. This is not making recommendations, it's summarizing all the information. Is that right?

Dr. Judd: Yeah, that's exactly right. If you look, I think it's table number four, where we go through each one of the decision aids and how many or what percent of patients actually fit into that decision aid and what the negative predictive value is for that decision aid combined with troponin. Then what type of troponin was used to achieve those results, you'll see that about half the studies are done with, what we call, the contemporary troponin or just the regular sensitivity troponin that we use in the United States. The other half of the data we show is with high sensitivity troponins. It would not be a good idea for somebody creating their quality program in their emergency department to take something that was tested with a high sensitivity troponin and validate it there and then apply it in an emergency department in the United States where we don't have those [inaudible 00:17:18].

We thought it was critically important to lay out the data and as the high sensitivity troponins come on the market, hopefully in the next year in the US, people can begin with something now and switch to something else later if they want. If we made a recommendation that was firm, the world changes too fast. I don't think we would be doing the best for our patients.

Carolyn: That is such a great statement to end this on. Thank you so much Judd and Deborah. This was an excellent discussion.

Dr. Judd: Thank you.

Dr. Deborah: Thank you.

Carolyn: You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week for more exciting cardiology needs from all over the world.

Circulation August 9, 2016, Issue

8 augusti 2016 | 15 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from National Heart Center and Duke National University in Singapore. Joining me today will be Dr. Katherine Mills and Dr. Andrew Moran to discuss the very striking findings of a new study on global disparities of hypertension prevalence and control, but first, here's the summary of this week's original papers.

In a study by first author, Dr. [Lu 00:00:42], corresponding author, Dr. Denny, from the Harvard TH Chan School of Public Health in Boston, Massachusetts and colleagues, authors aimed to investigate how the risk of cardiovascular disease is distributed among whites and blacks in the United States and how interventions on cardiovascular risk factors would reduce these racial disparities. To achieve these aims, the authors used a nationally representative sample of more than 6,000 adults, age 50-69 years of age, in the United States and developed a risk prediction model that was calibrated separately for blacks and whites.

The main results were that were substantial disparities in the risk of fatal cardiovascular disease; 25% of black men and 12% of black women were at high risk of fatal cardiovascular disease compared to only 10% of white men and 3% of white women, respectively. A large proportion of these fatal cardiovascular events among blacks were concentrated among this small proportion of the population. Now, whereas, population wide and interventions focused on single risk factors did not reduce black/white disparities in fatal cardiovascular risk and intervention that focused on high-risk individuals and reduced multiple risk factors simultaneously could indeed reduce black/white disparities in fatal cardiovascular disease by a quarter in men and a third in women.

These results really emphasize that focusing preventative interventions on the high-risk individuals has a large potential to improve overall cardiovascular health and reduce racial disparities in the United States.

The next paper is from first author, Dr. Lee, corresponding author, Dr. Federer, from Ohio State University Wexner Medical Center in Columbus Ohio and colleagues who looked at the issue of adenosine-induced atrial fibrillation and aimed to elucidate the molecular and functional mechanisms that may underlie this problem. To achieve this aim they integrated panoramic optical mapping and regional immunoblotting to allow them to resolve the protein expression of the two main components of the adenosine signaling pathway, mainly the A1R and GIRK4. They found that these signaling pathways were 2-3 times higher in the human right atrium compared to the left atrium leading to a greater right atrial action potential duration shortening in response to adenosine.

Furthermore, they showed that sustained adenosine-induced atrial fibrillation is maintained by re-entrant drivers localized in the lateral right atrial regions with the highest A1R and GIRK4 expression. Finally, the authors demonstrated that selective GIRK channel blockade successfully terminated and prevented atrial fibrillation. Thus, suggesting that the arrhythmogenic effect of adenosine in human atria may be mediated by activating GIRK channels. The take-home message, therefore, is that specific blockade of the GIRK channels may offer a novel mechanism to prevent adenosine mediated atrial fibrillation in patients.

The next study is from Dr. Nielsen and colleagues from the Copenhagen University Hospital of Bispebjerg in Copenhagen, Denmark, who aimed to assess the optimal blood pressure in patients with asymptomatic aortic valve stenosis. To achieve this aim, the authors used data from the simvastatin, ezetimibe in aortic stenosis or SEAS trial of 1,767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease. Outcomes that were studied included all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. The main findings were that an average diastolic blood pressure above 90 and a systolic blood pressure above 160 millimeters mercury were associated with a poor outcome.

Furthermore, low systolic blood pressure was also related to adverse outcomes while low average diastolic blood pressure was harmful in moderate aortic stenosis. In summary, the optimal blood pressure, which was associated with the lowest risk of adverse outcomes, were the systolic blood pressure between 130 and 139 and a diastolic blood pressure between 70 and 90 millimeters mercury. The clinical take-home message is that in the scarcity of randomized controlled evidence, these results may assist clinicians in their decisions in blood pressure measurements in patients with aortic stenosis, meaning that a blood pressure above 149D may be treated while a blood pressure lower than 120 systolic or 60 diastolic may be recognized as a warning signal for poor outcomes.

That was the summary of this week's original papers. Now for a discussion of our feature paper.

I am so excited to be joined by two guests today to discuss our feature paper entitled Global Disparities of Hypertension Prevalence and Control, a systematic analysis of population-based studies from 90 countries. We are so pleased to have the first author, Dr. Katherine Mills, from Tulane University School of Public Health and Tropical Medicine in New Orleans. Welcome, Katherine.

Katherine: Thank you. Good morning.

Carolyn: And a very special occasion indeed, we have an editorialist joining us, as well, in none other than Dr. Andrew Moran from Columbia University Medical Center in New York. Welcome, Andrew.

Andrew: Good morning. Thank you, Carolyn.

Carolyn: It's wonderful to have you discuss this. This paper has so many key findings that really struck me. If you don't mind, I am just going to summarize some of these. For example, Katherine, you reported globally more than 30% of the adult population, amounting to almost 1.4 billion people have hypertension in 2010, and the prevalence of hypertension was higher in low and middle income countries than in the high income countries, making it, therefore, that approximately 75% of people living with hypertension live in the low and the middle income countries. Yet, hypertension awareness, treatment, and control were much lower in the low and middle income countries compared to the high income countries. That is really striking. Katherine, I'd really love for you to share with us what was the inspiration to look at this and what do you think was the most striking finding?

Katherine: We know that hypertension is a very important risk factor for cardiovascular and kidney disease. It's the leading cause of cardiovascular disease in the world and for premature death. A previous study in our research group found that about 26% of the world's adult population had hypertension in 2000, but since then there really hasn't been any global estimate made. Basically, since 2000, a lot of studies from individual countries and high income countries have shown a leveling off or decrease of hypertension prevalence, but studies from individual low and middle income countries have actually shown an increase in hypertension prevalence.

Given these trends in individual countries and the importance of hypertension prevalence and treatment and control, to prevent cardiovascular disease, we really wanted to look and see what the disparities were in high income compared to low and middle income countries. I think the most striking findings to me was that we found that over 75% of adults with hypertension globally are in low and middle income countries, and that's over a billion people. We also found that only 7.7% of those people with hypertension and low and middle income countries have controlled hypertension. That represents a huge global public health problem that could lead down the road to a large burden of cardiovascular and kidney disease if it's not effectively addressed.

Carolyn: Katherine, I could not agree with you more because it's actually a living reality that I'm seeing where I come from in Asia. We have just so much hypertension, and what struck me was that from 2000 to 2010, while the prevalence increased here, it decreased in high income countries. Yet, this is where the greatest need is and where the control is the lowest. That was striking. Can you just articulate a bit further how your data now add to the knowledge that was there before your paper?

Katherine: Basically, this is the first paper to show that the prevalence of hypertension is higher in low an middle income countries compared to high income countries. It's the first paper since 2000 to quantify the global burden of hypertension, and it's the first paper to really compare rates of awareness, treatment, and control comparing high income to low and middle income countries.

Carolyn: That is fantastic and really striking. I think that's why the Circulation Editorial Board to invite an editorial by Andrew to discuss this. Andrew, your editorial was entitled Still on the Road to Worldwide Hypertension Control, and even in the first sentence of your editorial, you mention that hypertension is a preventable risk factor, and that's why this is so important. I really like that your first subheading has this big word, action. Maybe you could tell us a bit more. What are the implications of these findings for worldwide hypertension control and actions that we can take?

Andrew: There's a growing attention to noncommunicable diseases worldwide as a lot of maternal and fetal deaths, those rates have improved worldwide, and so really as the world population ages, problems like hypertension and related noncommunicable diseases are becoming a bigger and bigger health problem for people around the world, not just in high income countries. As a matter of fact, recently the World Health Organization set a 25 by 25 goal, meaning to reduce deaths from noncommunicable diseases by 25% by the year 2025. A big part of that effort is going to be an effort to control hypertension. The World Heart Federation has set a goal of improving hypertension control by 25% as part of that overall effort.

Carolyn: Yes. You mentioned that I think in the editorial, as well, but are there some action steps that we could take globally as a community?

Andrew: Yes. It's striking to me as a practicing physician that something so basic as measuring blood pressure and recommending treatment for people with elevated blood pressure, which is so integral to our daily practice in medicine, that we still have so far to go in achieving control both in high income settings and low and middle income country settings. One of the most basic cornerstones of achieving control is proper measurement of blood pressure. I think one of the goal efforts has to involve making sure that primary care settings and even community centers have available well-calibrated and validated blood pressure measurement devices and that people know how to measure blood pressure accurately.

The other problems that come up with controlling hypertension are for people who have a diagnosis that is accurately made, are they able to follow up with a primary care provider to monitor their blood pressure, and do they have medications available to them that are affordable? It's important to note that especially in low and middle income countries, most people have to pay for their medications out of their own pockets, so the affordability and availability of medications is a really important part of achieving our goals. I think it's important to see that low and middle income countries, even though it can seem like a daunting setting in which to implement improvements in the quality of healthcare delivery, there also important places to experiment with improving the quality of care delivery worldwide.

For example, the concept of having a community health worker make home visits and reach out into the community was something that was developed in low and middle income countries and now is becoming a popular and effective method of delivering care in all countries worldwide.

Katherine: One thing I would add is that I think we really need collaborations from the international level because so many of these low and middle income countries have very limited healthcare resources, and there still dealing with a lot of infectious diseases, so I think it really is going to take an international effort to address this problem in low and middle income countries.

Carolyn: Thank you so much for joining us for another episode of Circulation on the Run. Tune in next week for more summaries and highlights.

Circulation August 2, 2016, Issue

1 augusti 2016 | 19 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Joining on me in just a moment are two guests to discuss a very exciting new category of papers, known as the white paper. The topic for today is an evolution within the field of current day percutaneous coronary intervention that of the treatment of higher risk patients with an indication for revascularization. But first, here is your summary of this week's journal.

The first study is from first author doctor Jolis and corresponding author doctor Grainger, from the duke clinical research institute in Durham, North Carolina. These authors describe the American Heart Association Mission: Lifeline, STEMI Systems Accelerator. This exciting project represents the largest effort ever attempted in the United States to organize ST segment elevation myocardial infarction care across multiple regions, including 484 hospitals, 1,253 emergency medical services across sixteen regions and involving more than 23,800 patients.

Indeed, this project aims to organize coordinated regional reperfusion plans so as to increase the proportion of patients treated within guideline goals, that is a first medical contact to devise time of less than 90 minutes for STEMI patients directly presenting to PCI capable hospitals and less than 120 minutes for transferred patients.

The authors observed that during the study period of July 2012 to December 2013, there was a significant increase in the proportion of patients meeting these guideline goals, including an increase from 50% to 55% of STEMI patients directly presenting via emergency services and from 44% to 48% of those transfer patients. The authors concluded that these improvements, while modest, suggest the potential for reductions in total ischemic time and happily observe corresponding trends towards lower in-hospital mortality compared with the national data towards the end of the measurement period. Indeed, the tickle message is that the findings support continued efforts to implement regional STEMI networks.

The next study is by first author doctor Hidari and corresponding author doctor Kuang from the Brigham and Women's Hospital in Boston, Massachusetts. They describe the OMEGA-REMODEL randomized clinical trial. This is a multi-center, double-blinded, placebo control trial of 358 participants presenting within acute myocardial infarction who are randomized to six months of high dose omega-3 fatty acids at four grams daily versus placebo.

Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and following therapy with the primary study in point being a change in left ventricular systolic volume index. Indeed, the authors reported that compared to placebo, patients who received four grams daily omega-3 fatty acids experienced significant improvements in both left ventricular and systolic volume and surrogate measures of non-infarct myocardial fibrosis during the six months of treatment.

These remodeling benefits further followed a dose response relationship with the rise in the in vivo omega-3 fatty acid levels as quantified by your red blood cell index. They concluded that four grams daily of omega-3 fatty acid is a safe and effective treatment in improving cardiac remodeling in patients receiving current guideline based post-myocardial infarction therapies. Indeed, this does warrant perspective clinical studies.

The third study is by first author doctor Liu and corresponding author doctor Sia from University of Texas, Houston Medical School and Colleagues, who sought to understand the molecular basis underlying adaption to high altitude hypoxia. By conducting both human high altitude and most genetic studies, the authors identified a novel functional role of CD73-dependent elevations in extracellular adenosin signolin in response to high altitude hypoxia.

This led to sequential activation of a readthrough site AMP-activated protein kinase, which in turn resulted in increased 2,3-bisphosphoglyceric production and enhanced oxygen release capacity to peripheral tissues. Thus, reducing tissue hypoxia, inflammation and pulmonary injury. These findings have significantly added to our understanding of the molecular mechanisms underlying adaption to hypoxia. Thereby, opened novel therapeutic possibilities for the prevention and treatment of hypoxia related conditions.

The final study is from first author doctor Yen and corresponding author doctor Chen from the National Taiwan University and Colleagues, who aimed to determine the effect of betel nut chewing and paternal smoking on the risks of early metabolic syndrome in human offspring. The author studied more than 13,000 parent-child trios identified from more than 238,000 Taiwanese aged 20 years or older screened in two large community based screening cohorts.

The main finding was that pre-fatherhood habits of both betel nut chewing and cigarette smoking led to a 77% and 27% increase in risk of early metabolic syndrome in their offspring respectively. In fact, they even observed a dose-response relationship where the risk was higher with an increase in duration of exposure as well as with earlier age of starting exposure. These findings interestingly suggest that genetic or epigenetic changes due to exposure to both betel nut and cigarette smoking before birth can contribute to early occurrence of metabolic syndrome in offspring. In fact, these findings really support education for avoidance of these habits or cessation of these habits.

That was your weekly summary. Now, for our feature paper. Our feature paper this week is a white paper regarding the treatment of higher risk patients with an indication for revascularization and evolution within the field current-day percutaneous coronary intervention. To join me in this discussion, I'll have the first and corresponding author doctor Ajay Kirtane from Colombia University Medical Center, New York Presbyterian hospital, as well as doctor [Manus Brelaques 00:08:22], associate editor from UT Southwestern. Welcome, Ajay and Manus.

Ajay: Thanks so much for having us.

Manus: Thanks Carolyn.

Carolyn: Great. Manus, I would love if we could start by talking about the concept of the white paper and what circulation is looking in these white papers.

Manus: Of course. It is a very exciting part of the new circulation which is for topics that are very timely and important, but at the same time there's not enough populous data and populous literature to be able to address it in a more formal systematic review way. The concept is that establish the leaders in the field. I'm going to provide their perspectives which have derived through their clinical practice and be able to inform us of what the current issues are, how can they best be addressed and what are the next steps forward.

Carolyn: That's great, and what a great example to start with with this paper by Ajay. Ajay, maybe I could just start by asking you to make it crystal clear to us the kind of patients you're referring to in this higher risk and the context and the scope of the problem that you're talking about in your paper.

Ajay: Absolutely. First of all, I'm honored that you would consider that's both timely and important and that this will be one of the new papers in the series on behalf of all the [cohorts 00:09:44] is we're really pleased to be able to discuss it. I think the reason that we find this really critical at this juncture is because what we're sort of saying is an evolution in current-day [catlab 00:09:53] practice. There are many patients now who were seen that have either been turned down for cardiac surgery of have highly complex disease that we know merit revascularization.

In other words, medical therapy has failed for them either from the symptomatic standpoint or because it puts them at too high risk given the complexity of their coronary anatomy and where these lesions are located. Yet at the same time, in order to be able to treat these patients effectively, we need to grasp not only advanced techniques in terms of how to do it, but also need to be able to select the patients appropriately so that they can undergo these procedures safely and to drag the benefit that we'd like to be able to offer them.

Just one brief thing to mention is that we certainly know that over the past 10 years or so, there's been a lot of criticism of the PCI procedures they could perform, particularly here in the United states. Some of them were perhaps unnecessary or some of them were not necessarily benefiting patients. The good news is we've curtailed a lot of that, but yet at the same with that curtail we've sort of seen a decline in these types of cases that we refer to in the paper where patients really could benefit from revascularization, but for whatever reason or not being offered it.

Carolyn: Listeners might be wondering though, what is the difference between what you're talking about high risk, and we read a lot of papers about complex procedures and complex PCI, you want to make that differentiation just slightly clearer?

Ajay: Sure. I think that complex PCI has been something that carries the historical definition and usually involves lesion subsets like the left main, chronic total occlusion, bifurcations, that require more than just a simple predilatation stent implantation. The concept of procedural risk though while it overlaps with complexity, to some extent actually has other inputs. For instance, the ventricular function of the patient whether or not the other circulation is also compromised, so it's a larger ischemic territory, and similarly some things that were previously complex with an evolution of techniques actually don't offer or confer that much greater risk on patients.

I would say when I did my fellowship training, left main was something that my heart rate got up for and we were worried about the patient in that respect. Now when we do left mains, it's actually something where we view it as one of the more simple things that we do relative to for instance the retrograde approach to a CTO revascularization. There's been an evolution and there's an overlap of what's complex and what's high risk.

Carolyn: Very nicely put. Could you tell us a little bit about how your paper is structured? I really like for example the way your tables are laid out and so on, but maybe just give an overview?

Ajay: Absolutely. I think we start off with just setting the scope of the problem. Basically, looking at coronary heart disease and the fact that there are subsets of coronary diseases for which has prognosticked the importance to revascularize. For instance, the publication of this ten-year result for the first trial [inaudible 00:12:45] revascularization as a whole. We talk a little bit about the assessment of procedural risk and then we sort of move on in the end to the various areas that interventionalists need to become better trained in order to deal with these types of patients. I have to give credit where credit is due. The tables that you like so much were actually the suggestion of the editors.

Because of the new theory, Manus had a lot to do with this. I think it's very important for people to understand, at least for this paper the role, the back-and-forth conversation between not only us, but also the editors and the reviewers play in bringing this manuscript to its final form. I really give them credit for it. What's in the tables are not only descriptions of the types of multidisciplinary teams that are needed in order to [affect 00:13:27] that we take of these patients. Also, the techniques that would be useful for interventionalists to know how to use and be [inaudible 00:13:33] to take care of these patients. Finally, a table looking at future directions because it's all good and fine for us to say this is a new area and we're moving into it, but we need to sort of generate the research and the evidence base to really support the treatment that we're trying offer or saying we can offer in the manuscript.

Carolyn: Manus, you have to this describe some of this back-and-forth conversation that went on.

Manus: Ajay, I wish that every author took the comments as well as you did because that's definitely not the case. I must admit that it was a pleasure working with you because again you were so open to all the comments and suggestions even though some were tough ones. I think the interaction and being so open I think made the paper better and we're very, very appreciative for your response to those.

Ajay: I think at the end of the day when you have a new editor team taking over, there are going to be changes and some changes you learn how to grow through and other changes you basically adopt what the previous editors were doing. At least my experience, not to [despair 00:14:29], is the prior circulation editors at all, I actually had a great experience with them as well, but this was novel, and I think it's something that for many authors will find quite nice to experience because there was a lot of back and forth. Some parts were contemptuous, but these were all resolved. I wrote in my response back to the reviewers I really do feel the paper was better as a result.

Manus: I think that's the idea that [inaudible 00:14:51] the language and the whole editorial team is trying to enforce and we're very happy with it and enjoyed.

Carolyn: I couldn't agree more. Actually, Manus I was also going to ask the title is provocative. It says this is an evolution and even in the conclusion of the paper that this could be a new field of coronary interventional procedures. I really love your thoughts. Is this a beginning of a whole new field?

Manus: I personally do believe and many people I think do believe that there's a tremendous evolution that is going on right now, continue to go on in the field compared to the early days of [inaudible 00:15:26] where we did simple angioplasty I think it has come a long way. But I think there is gap between what can be done right now in terms of technical possibilities, in terms of equipment we'll have and improved patients' quality and quantity of life.

Actually, what is being done because as you heard from Ajay, many of those patients who could benefit do not. Within the environment of trying to stop in a [inaudible 00:15:51] procedure, which is very appropriate, what happened exactly is that those more complex and high risk cases because of the fear of complications or sub-optimal outcomes led to offering less treatment to those complex patients.

I do believe it's an evolution in the field. I do believe that having access to these techniques, equipment and offering options to the patients and explaining there is benefit ratio can bring the patient's life, make them better and bring the field forward to the next step.

Carolyn: Ajay, do you think you could elaborate a little bit more then on what those next steps you think are and what are the future areas of research?

Ajay: Yeah, I'd certainly be happy to do so. I couldn't agree with Manus more. I know he and I share a lot of beliefs in terms of this. One of the things that's important to recognize is while we can all assess procedural risk, some of these advanced techniques are not commonly shared by all interventionalists here in the United States, particularly if you look at the overall case volumes of many interventionalists in the United States, there are folks who are just not going to have the requisite volume to be able to do complex CTO revascularization with a retrograde approach. For instance, they would bring procedural success rates up around 90%.

I think that some of this is education. You have to sort of understand what can and cannot be done, what can and cannot be done [faithfully 00:17:08] and what techniques you use or are necessary in order to be able to improve this rate of success. If for instance I can't do the procedure myself, then I need to be familiar with somebody who actually can because if the patient merits revascularization, in other words they could benefit from having a procedure done, they're not a surgical candidate and they could be helped by PCI, then rather than saying, "We should just do medical therapy because I can't do the procedure." The appropriate thing to do is to actually refer the patient to somebody who actually could do the procedure in a safe way and therefore ensure benefit for the patient.

That's an educational aspect. Some of it relates to training, but I think conceptually we do need to start understanding now that there is a sub-specialization within coronary intervention of interventionalists who are able to offer things that many interventionalists cannot. That's somewhat of a fundamental step many people have to take, but I think it's time to take that step and that was the whole point in writing this paper.

Carolyn: I think that is a very effective first step that now you've brought it to light and we're so proud and privileged to be publishing this paper. Thank you so much Ajay, thank you so much Manus.

Ajay: Thanks so much for having us.

Manus: Thanks Carolyn.

Carolyn: And thank you listeners. You've been listening to Circulation on the Run. Please tune in next week for more highlights and discussions.

Circulation July 26, 2016, Issue

25 juli 2016 | 18 min

Carolyn: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. I am so excited to be joined in just a moment by Dr. Andrea [inaudible 00:00:21] and Dr. Wendy Post to discuss the feature paper this week about leisure-time physical activity and the risk of coronary heart disease in young women. First, here's the summary of this week's issue.

The first paper, by Dr. Bohula and colleagues at the TIMI Study Group at Brigham and Women's Hospital in Boston, Massachusetts, aim to test the hypothesis that an atherothrombotic risk stratification tool may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventive therapy such as treatment with Vorapaxar following a myocardial infarction. As a reminder, Vorapaxar is a first-in-class anti-platelet agent that inhibits thrombin-mediated activation of platelets via the protease activator receptor 1. The authors studied almost 8,600 stable patients with a prior myocardial infarction followed for a median of two and a half years.

In the thrombin receptor antagonist and secondary prevention of athrothrombotic ischemic events, TIMI 50 trial. They identified nine independent risk predictors which were age, diabetes, hypertension, smoking, peripheral artery disease, prior stroke, prior coronary bypass grafting, heart failure and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rates of cardiovascular death, myocardial infarction or ischemic stroke. Moreover, the net clinical outcome was increasingly favorable with Vorapaxar across the risk groups.

In summary, this paper provides a practical strategy that could be used by clinicians to assist with risk stratification and therapeutic decision-making regarding Veropaxar use for secondary prevention after myocardial infarction.

The next paper is by first author Dr. [inaudible 00:02:40] and corresponding authors, Dr. [Gerstein 00:02:43] from the Beth Israel Deaconess Medical Center and Dr. [Carr 00:02:47] from the Broad Institute of Harvard and MIT, who look at aptamer-based proteomic profiling. Now DNA aptamers are [alu 00:02:57] nucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. They therefore holds considerable promise for biomarker and pathway discovery in cardiovascular diseases.

These authors applied a novel technology that uses single-stranded DNA aptamers to measure over 1,100 proteins in a single blood sample. They applied this to a model of planned myocardial injury and that is patients undergoing septal ablation for hypertrophic cardiomyopathy, and they found that 217 proteins were significantly changed in the peripheral vein blood after planned myocardial injury in this derivation cohort. They validated 79 of these proteins in an independent cohort. Furthermore, among 40 validated proteins that increase within one hour after myocardial injury, 23 were also elevated in patients with spontaneous myocardial infarction.

Finally, the authors applied this to archive samples from the Framingham heart study and showed 156 significant protein associations with the Framingham risk score. This study is so exciting because it highlights any merging proteomics tool that captures a large number of low abundance analytes with high sensitivity and precision, thus providing important proof of principle for future clinical applications and this is discussed in an excellent editorial that accompanies this paper by doctors Graham [Malini 00:04:37], [Lau Enleui 00:04:39] from the University of Ottawa Heart Institute.

The next paper is by Dr. [Anter 00:04:51] and colleagues from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, who looked at post infarction, reentrant ventricular tachycardia and addressed the problem that in vivo descriptions of ventricular tachycardia circuits are currently limited by insufficient spatiotemporal resolution. The authors therefore utilize a novel, high resolution mapping technology to characterize the electrophysiological properties of these reentrant circuits in 15 swine.

The main finding was that the zones of slow conduction within the reentrant circuits with the inward and outward curvatures while conduction velocity in the comment channel isthmus itself was nearly normal. The authors further demonstrated that entrainment mapping over estimated the true size of the isthmus. Thus, the conclusion was that high resolution activation mapping of ventricular tachycardia may better guide ablation therapy and ablation at zones of high curvature may be an attractive target for ablation.

The final papers from first author, Dr. [Tang 00:06:08] and corresponding author Dr. [Fitzgerald 00:06:10] from the University of Pennsylvania Perlman School of Medicine in Philadelphia. These authors studied the cardiovascular consequences of prostanoid I-receptor deletion in microsomal prostaglandin E synthase-1 deficient hyperlipidemic mice. The clinical background to this research question is that inhibitors of cyclooxygenase-2 or Cox-2 are well-known to relieve pain, fever and inflammation by suppressing biosynthesis of prostacyclin and prostaglandin E2.

However, suppression of these prostaglandins particularly prostacyclin by Cox-2 inhibitors or deletion of the I-prostanoid receptor for prostacyclin is known to accelerate atherogenesis and enhance thrombogenesis in mice. In contrast, deletion of the microsomal prostaglandin E synthase1 has been shown to suppress PGE2 but increase biosynthesis of prostacyclin. It therefore confers analgesia while attenuating atherogenesis and does not predispose mice to thrombogenesis. Therefore, possibly contributing to cardiovascular efficacy.

In this particular study, therefore, the authors sought to determine the relative contribution of suppressing PGE2 versus augmenting prostacyclin to the impact of depletion of microsomal prostaglandin E synthase-1 in hyperlipidemic mice. The main findings were that augmentation of prostacyclin is the dominant contributor to the favorable thrombogenic profile of microsomal prostaglandin E synthase-1 depletion in these atherosclerotic mice while suppression of PGE2 accounted for the protective effects in atherosclerosis and the exciting clinical take-home message is that inhibitors of the microsomal prostaglandin E synthase-1 may be less likely to cause cardiovascular adverse effects than NSAIDS or specific inhibition of Cox-2. Those were the highlights of this week. Now for our feature paper.

Our feature paper today is entitled "The frequency, [type 00:08:41] and volume of leisure time physical activity and risk of coronary heart disease in young women" and I am so excited to be joined by two lovely ladies today to discuss this paper. First, the first and corresponding author Dr. Andrea [Comastick 00:08:58] from the School of Public Health of Indiana University Bloomington and Dr. Wendy Post, associate editor from the Johns Hopkins University. Welcome Andrea and Wendy.

Andrea: Hi. Thanks.

Wendy: Thank you so much for having us.

Carolyn: I am just so excited that we are talking about a paper about women being discussed by women. What more could you ask for? I have to say this is a first for Circulation on the Run, which is why I’m just so excited, so let’s get straight into it.

Andrea, maybe I could just ask you to start by sharing the story of how you and your team came up with some new questions and new data because I’m sure a lot of listeners are thinking there’s a lot of data on exercise and how good it is for cardiovascular health in women already.

Andrea: Yeah, that's a great question. When we started talking about conceptualizing this paper, the first thing was to focus on younger women. Most of the previous work on physical activity and heart disease has been in older adults and that's primarily because it's older adults that have heart attacks. It’s hard to get a large enough study of young women that has enough coronary heart disease events to be able to study this. We were fortunate where we had a large cohort in the nurses health study too of women and because it’s been followed for over 20 years, we had enough events to be able to examine this association.

We did want to think about, "Okay, what can we add?" because there’s a lot of information about just overall physical activity and health, so what can we do differently? I’m pretty familiar with the physical activity guidelines and really tried to look at what in the guidelines currently and then what could we add? What could be of interest when they start revising the guidelines which is actually going to happen very soon.

That was when we started focusing on, "Okay, instead of looking at just overall activity, look at intensity, comparing moderate and vigorous." We also wanted to look at frequency of physical activity and looking at frequency but also adjusted for a total time or total amount of physical activity that somebody does. Then we are also, the third thing was that we thought was important was looking at adolescent physical activity.

We know that kids, unfortunately as they get older and get into their teenage years, their activity declines quite a bit. Looking at how this physical activity during adolescence earlier life impact coronary heart disease risk in adulthood. Those were the three main things that we were focusing on when we first conceptualized the paper.

Carolyn: Nice. Tell us, what did you find?

Andrea: We did find that exercise is just as beneficial in younger woman as it is in older adults, which is great. We also found that moderate intensity exercise is just as beneficial as vigorous intensity exercise, which I think is a really important message to get out there. I think a lot of people, especially those that are really inactive to begin with are completely intimidated about the fact of trying to think about going to a gym or trying to jog or run a marathon or something like that.

I think really emphasizing that moderate intensity activity is beneficial and we found that walking was actually the most beneficial activity that we looked at in our study, that brisk walking was really really good for everybody and really lowered risk of coronary heart disease.

Carolyn: Hooray.

Andrea: Yeah, and the other thing we found which might be of interest for those that are also extremely busy, especially this target population where a lot of people are moms and working was that frequency didn't seem to matter, that as long as people were exercising for a couple hours a week that they should be that they could accumulate it in a couple times a week or they could do it more frequently, four or five times a week. It didn't seem to matter.

Carolyn: That’s cool. You know what? I think a lot of these things we'll also discuss at the Editorial Board when we're looking at this paper. Wendy, we promised that we would give a backstage pass to the Editorial Board and The Journal, so could you share a little bit about what we talked about there?

Wendy: Well, the Editorial Board was really excited about this paper. We loved the emphasis on young women and the important public health message about how we need to get out there and move and exercise to reduce our risk for cardiovascular disease. As was mentioned, there have been previous studies that also show the benefit of exercise but the Editorial Board especially liked the large sample size, the long duration of follow-up, the number of events that had been accrued that allowed for sophisticated analyses, adjustment for confounders and the very rigorous study design and excellent statistical methods that have been used in this study and so many other studies from the nurses health study, but I think we particularly just loved the message. The message was great.

We need to get out there and move. We need to tell our patients, especially young women, that now we have data that if you start exercising now, it will help in the future but also the study showed that if you hadn't exercised much in early life that’s starting to exercise more proximal to the event was also important as well.

Carolyn: Thank you Wendy. I also remember that we talked about the lack of interaction with body mass index, and I thought that was a great message. Andrea, could you maybe share a little bit about that?

Andrea: Yeah, this is something that previous investigators have looked at the interaction between body mass index and exercise. Unfortunately, we’ve all found the same thing so it doesn’t seem to matter whether women are normal weight or overweight or obese that they still get benefit when they exercise, and I think that’s really encouraging. I know a lot of people might start to exercise because they really want to drop some weight but just trying to emphasize even if the numbers on the scale aren't changing, that exercise still has all these really great benefits for heart disease and also for many other diseases.

Carolyn: Exactly. Can I just ask both of you and maybe I’ll start with Andrea, what will you do different now both as a woman and as a clinician seeing women now that you know what you do from your data?

Andrea: Well, I’m not a clinician. I’m an epidemiologist so unfortunately I don’t get to see patients and counsel them although I do try to talk to community members as a public health person and really get in the community on board with what we’re talking about. I just try to tell people, I actually talked to a group of people last week, and just trying to say, "Anything is better than nothing and just trying to even start with some short walks." Again, just emphasizing you don’t have to go to a gym or you don’t have to be doing anything that's super strenuous but just do stuff that feels good and just try to get your heart rate up a little bit like going out for a brisk walk. I think that's my main message that I try to tell everybody is at least start with something and get moving a little bit.

Carolyn: I love that. Wendy?

Wendy: I like to emphasize the data about brisk walking. I thought that was great because many of our patients don’t want to join a gym, don’t have the time to join a gym so just getting out and walking is fabulous exercise and now we have the data here that in young women that after 20 years of follow-up, brisk walking was associated with I think it was a 35% reduction in risk for cardiovascular disease during follow-up.

In addition, I liked the message about the total amount of time that you spend exercising in a week is what’s important. It doesn’t matter whether you divide that into seven days a week to get to that same amount of time or whether you do it in bursts of three days a week, and I think that’s particularly important for the many women who have so many different responsibilities and may not have time every day to go out and exercise. The days that you do have time, just exercise a little bit more those days, so lots of really important messages for our patients and for ourselves.

Carolyn: I really couldn’t agree more and just from my point of view, because I see a lot of patients in Asia and I do acknowledge just like you did, Andrea, in your paper that your data are predominantly in white populations. Still one of the messages I like to get out to the women I see is we have very skinny women and when I see younger women, and I really like emphasizing that, "Hey, just because you’re not struggling with an obesity issue or just because you’re young, it doesn’t mean you don’t need to exercise and that we all should just get moving." Thank you very, very much for that Andrea.

Andrea: Oh, no. It's my pleasure and thank you for having me come on today and talk about this.

Carolyn: Thank you too, Wendy. Do you have any other comments?

Wendy: No, but congratulations on your publication, Andrea.

Andrea: Oh, thank you so much, Wendy. I was really happy to get the message that guys were excited about it. Thank you so much.

Carolyn: You’ve been listening to Circulation on the Run. Thank you for joining us this week and please tune in next week.

Circulation July 19, 2016 Issue

18 juli 2016 | 18 min

Speaker 1: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Joining me in just a moment are Dr. James Gammie and Dr. Timothy Gardner to discuss our feature paper this week describing the first-in-human clinical experience with a novel transapical beating heart mitral valve repair.

First, here are the highlights of this week's journal. The first paper is from co-primary authors doctors Yoon, [Tsue 00:00:49], and [Cha 00:00:50] as well as corresponding authors Dr. [Che 00:00:55] and Dr. Kim from the Seoul National University College of Medicine. These authors examine mechanisms underlying diabetes-induced microvasculopathy, testing the hypothesis that Notch signaling in endothelial cells may play an important role in this condition.

The authors tested this hypothesis by inducing diabetes in eight-week-old adult mice using intravenous streptozotocin. They then modulated endothelial Notch signaling using chemical inhibitors in both wild type and transgenic mice. Results showed that the Notch ligand called Jagged-1 was markedly increased in endothelial cells of diabetic mice. Using endothelial specific Jagged-1 knocked down mice, they found that blocking Jagged-1 prevented diabetic microvaculopathy. Furthermore, using the induceable endothelium-specific Jagged-1 knocked down mice, blocking Jagged-1 even at four weeks after the establishment of diabetic microvaculopathy could reverse the condition.

In summary, these findings show that diabetes induces Jagged-1 over expression and suppresses Notch signalling in endothelial cells leading to diabetic microvaculopathy in adult mice. The clinical implications are that dysregulated intercellular Notch signalling may therefore represent a novel molecular target in the treatment of diabetic retinopathy.

The next study by Dr. Smith and colleagues at the Leiden University Medical Center in the Netherlands evaluated the association between LDL cholesterol variability and four cognitive domains at 30 months in the 4428 participants of the prosper study.

Results showed that a higher LDL cholesterol variability was associated with lower cognitive test performance for intermediate and delayed memory-related tasks, selective attention, and processing speed. Higher LDL cholesterol variability was also associated with lower cerebral blood flow and greater white matter hyperintensity load in an MRI substudy of 535 patients.

In addition to being independent of the mean LDL cholesterol levels and of clinically overt cardiovascular diseases, these associations were present both in the placebo and pravastatin treatment [inaudible 00:03:43] of the prosper trial suggesting that the findings did not mearly reflect pleiotropic effects of statins or of nonadherence.

The study importantly provides the first observational evidence that lipid variability, not just absolute or mean values, but the variability, maybe of importance to neurocognitive function and thus contributes while understanding potential pathways of neurocogniticve decline.

The next study is by first author, Dr. [Huh 00:04:19], and corresponding author, Dr. Ralph, from the Menzies School of Health Research Charles Darwin University in Australia. These authors aimed to investigate the long term outcomes from acute rheumatic fever and rheumatic heart disease.

They achieved this aim by using linked data between the rheumatic heart disease register, hospital data, and death register for residents of the northern territory of Australia, and examined 1248 patients with rheumatic heart disease as well as 572 patients with acute rheumatic fever in the period 1997 to 2013.

The main findings were that in the first year after an acute rheumatic fever episode, the incidents of progression to rheumatic heart disease was 10 times higher than acute rheumatic fever recurrence; 10% of rheumatic heart disease patients had severe disease at diagnosis. The presence of comorbidities was associated with higher incidence of rheumatic heart disease complications and mortality. In particular, comorbid renal failure and hazardous alcohol use accounted for 28% of the access indigenous mortality.

These findings have global relevance for settings with high acute rheumatic fever, rheumatic heart disease rates and really emphasized the need for integrated chronic disease management strategies for these patients.

The final paper is by first author Dr Bettencourt, corresponding author Dr. Blankstein, and colleagues from Brigman and Women's Hospital in Boston, Massachusetts. These authors sought to answer the question what is the most appropriate score for evaluating the pretest probability of obstructive coronary artery disease?

To answer the question, the authors compared the Diamond-Forrester score with the two CAD consortium scores recently recommended by the European Society of Cardiology, and they did this in 2274 consecutive patients without prior CAD referred for coronary CT angiography. CT angiography findings were used to determine the presence or absence of obstructive CAD defined as 50% or more stenosis.

Here's a refresher of the different probability scores. The Diamond-Forrester score is calculated based on chest pain type such as non-anginal, atypical or typical angina, gender, and age. The first CAD consortium model score called CAD consortium basic is also based on these factors, but was developed using more advanced statistical modeling strategies which were not available when the Diamond-Forrester model was derived. Additionally, the population had a lower prevalence of disease than the original Diamond-Forrester derivation cohort.

The second CAD consortium score called CAD consortium clinical included the same characteristics as CAD basic, but also included the following clinical risk factors; diabetes, smoking status, hypertension, and dyslipidemia. Moreover, the presence of typical chest pain was weighted less in diabetics compared to nondiabetics in the CAD clinical score. Results showed that among symptomatic individuals referred for coronary CT angiography, the CAD consortium clinical pretest probability score demonstrated improved calibration and discrimination for the prediction of obstructive CAD compared to the Diamond-Forrester classification.

Driving home the clinical implications of this, the authors applied these observed differences in pretest probability of obstructive CAD to guidelines-based patient management algorithms and projected that the use of the newest score could decrease the proportion of individuals in whom testing would be recommended and increase the yield of diagnosing obstructive CAD.

Those were the highlights of these weeks issue. Now, for our feature paper. Our feature paper today is about the first-in-human clinical experience with the transapical beating heart mitral valve repair using a expanded polytetrafluoroethylene chordal insertion device. We're really lucky today to have the first and corresponding author, Dr. James Gammie from the University of Maryland Medical Center as well as Dr. Timothy Gardner, associate editor from Christiana Care Health System to discuss this exciting paper. Welcome, both of you.

Tim: Thank you.

James: Thank you.

Speaker 1: James, may I start with you? What an exciting title, a first-in-human experience, and this is really sounding very reminiscent of our experience with TAVR and aortic stenosis valves. Could I ask you, with so many exciting things, what is it about the results that excited you most?

James: This is an exciting project in that we believe it affords a new treatment option for patients with degenerative mitral regurgitation. We believe that this is a less invasive way of achieving surgical grade reduction of mitral regurgitation. This is a project which has involved a great number of people on our team both within the university and then within Harpoon Medical, as well as our colleagues in Europe to bring this device from an idea which was asked more than a decade ago into a clinical experience.

It really rose out of our recognition in particularly my own practice that virtually, every patient with degenerative mitral regurgitation could be fixed with ePTFE or Gore-Tex neo-chords, and the question became how can we place neo chords on a prolapsed mitral leaflets without doing open heart surgery?

We begin working on that in the laboratory a number of years ago and went through a variety of prototypes, and ultimately, came up with this idea where we could use a 3 millimeter shafted instrument with a specially designed wrap of Gore-Tex on a 21-gauge needle such that we could land on the underside of the mitral leaflet, deploy device, and create a specially designed knot on the atrial surface of the leaflet, and that would anchor the ePTFE on the leaflet. We could repeat that a few times transapically and then adjust the length of those chords in real time using transesophageal echo guidance.

We got this to work in the laboratory and we had hoped that we would have some modest success in humans, but we've been quite pleasantly surprised that it has just worked and we've outlines this initial clinical experience in the manuscript.

Speaker 1: First of all, I'd just like to pick up on the point that this is degenerative mitral regurgitation, so this is limited to the primary mitral regurgitation, not secondary?

James: That's correct and we know that right now, at least in North America, that two-thirds of mitral valve operations are done for degenerative disease. That's correct.

Speaker 1: I think a lot of the audience out there is going to be wondering how this new technique compares to the MitraClip. Could you tell us a little bit more about that?

James: I do MitraClip as well, so I think I'm well positioned to comment on the differences. The Harpoon device right now is still in operation. It does require a small one or two-inch incision. We anticipate it's going to be a thoracoscopic approach in the very near future and then, beyond that, we would hope to extend it to a transcatheter approach. That's one difference.

The MitraClip now is certainly across the world. It's used predominantly for functional mitral regurgitation. In our own experience, it seems to work best for functional mitral regurgitation and as you know, there are anatomic limitations for MitraClip in degenerative disease. The MiraClip replicates the LCRA surgical approach and I think what we've learned from all the less invasive approaches to treat mitral valve disease is that we have to respect what we've learned from our surgical experience, and we know that the LCRA approach works best when it's combined with an annuplasty ring, and certainly, the MitraClip, again, is mostly this perfunctional MR.

Another point I'd bring up is that the experience with MitraClip has been that when you place a MitraClip, you get a fairly strong fibrous reaction and in most of the series, it's not been possible to then go back and surgical repair the valve, but you have to do a replacement because you've compromised the leaflets. Our own approach were simply putting Gore-Tex sutures in the leaflets and we believe that one advantage is that we're not burning any bridges, and that you can go back and do an open repair of you had to.

In our experience, you asked about our results, we had great results in 10 out of 11 of our patients. One patient did require a reoperation. Actually, one of the chords had come untied on the surface in that patient. We were able to go ahead and do a repair and we saw as we had anticipated it based on our animal experience, there was not much compromised to the leaflets.

One of the advantages of our approach is that we can titrate the length to the Gore-Tex chords to optimize the amount of coaptation and maximize the quality of the repair, and that's something that we can't do an open cardiac surgery, and one of the challenges of mitral valve repair is that you have to figure out how long to make those chords while the heart is arrested and placid, and that's one of the challenges in why mitral valve repair is certainly some degree of an art to doing that.

What we've found is that the imager is incredibly important, and so we've teamed up with our echocardiography colleagues, and they really provide essential input into the procedure, and it's done not looking directly at the valve, but looking up at the screens. I think as surgeons, with this procedure, we're moving more into almost becoming interventionalists.

Speaker 1: Thank you, James. That was so exciting. Tim, I have to bring you into this now. Now that James has said they're becoming like the interventionalist. Back to my original comment of TAVR and aortic stenosis, are we witnessing history in the making now? You invited an editorial by Dr. Michael Mack and his title was very provocative, Transcatheter Treatment of Mitral Valve Disease. Is it deja vu all over again? What are your thoughts?

Tim: I think this is an exciting report and I think that this is the wave of the future. I agree completely with Michael Mack that we are beginning to see interventions for mitral valve disease that are effective, less invasive, in some instances catheter based, but this is just the beginning. In fact, mitral valve disease is somewhat more complex even than aortic stenosis, but this type of experience and the ingenuity and the technical prowess, and the ability to do this minimally, invasively, and so on really portend a whole new era.

I agree with Jim. This is sort of the common ground between the interventional structural cardiologist and the surgeon, and we're becoming even more entwined, more collaborative, and more mutually supportive. We are in a new era and I think over those next decade or so, we're going to see this and similar, and even different procedures tried and proven to be useful for the variety of mitral valve disorders that we encounter. Perhaps the era of the full sternotomy for fairly straightforward, single, focused operations will become something of a thing of the past.

Speaker 1: That's beautifully put. James, with that comment, what are the next steps?

James: As we said in the manuscript, this isn't barely experience and we're continuing to learn as we move [inaudible 00:17:07] to the clinical arena. We are currently in the midst of a CE Mark trial in Europe. We rolled it out to eight separate centers. As we approve clinical experience, we will learn more about precisely which patients work best with this approach and we will accrue longer term data. We now have a number of patient out to a year with stable results and so, as the numbers go up, we'll do that, and then we anticipate a randomized trial in the United States in the early to mid portion of 2017 where we'll compare this approach to conventional open cardiac surgery.

Speaker 1: That's fantastic. Thank you so much to both of you, gentlemen, for joining me on our podcast today.

Tim: Thank you.

James: Thank you.

Speaker 1: You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week.

Circulation July 12, 2016 Issue

14 juli 2016 | 23 min

Dr. Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. Dr. Sanjay Kaul and Darren McGuire will be joining me in just a moment to share their perspectives on the EMPA-REG OUTCOME trials. Are the results with empagliflozin in diabetic patients at high risk, are they too good to be true. First, here are the highlights from five original papers in this week's issue.

The first paper is from Dr. Gilboa, from the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention in Atlanta, Georgia, and Dr. Marelli from the McGill Adult Unit for congenital heart diseases in Montreal, Quebec, and colleagues. These authors recognize that because of advancements in care there has been a decline in mortality from congenital heart defects over the last several decades. However, there are still no current empirical data documenting the number of people living with congenital heart defects in the United States.

These authors address this gap in knowledge by using prevalence data from Quebec, Canada, in the year 2010, as a foundation for a mathematical model, and estimated that in the United States in the year 2010, approximately 2.4 million people, including 1.4 million adults, and 1 million children were living with congenital heart defects. This estimate is significant, because it corresponds to a 63% increase in the estimated size of the adult population with congenital heart defects in the United States since the year 2000. This has significant implications for resource allocation for health services delivery that will need to account for this growing population of adults with congenital heart defects.

The second paper is from first author Dr. Tabot, and corresponding author Dr. Liao, from the University of Chicago, and colleagues who aim to understand better the common complication of angiodysplasia leading to nonsurgical bleeding in patients with left ventricular assist devices. The authors studied 101 patients with heart failure, left ventricular assist devices, or orthotopic heart transplants. They found that compared to patients with heart failure, or transplant patients, patients with left ventricular assist devices had elevated serum levels, and endothelial expression of angiopoietin-2, which is a potent angiogenic mediator.

Elevated levels of angiopoietin-2 in these patients increase angiogenesis in vitro, and were associated with bleeding events. Furthermore, they found that increased thrombin levels in left ventricular assist device patients were associated with elevated angiopoietin-2 levels. In aggregate, therefore, the results indicate that high levels of thrombin induced endothelial angiopoietin-2 expression, which may then contribute to angiodysplasia and non-surgical bleeding in patients with left ventricular assist devices. The clinical implications are that clinical studies angiopoietin-2, and factor 12 inhibitors may therefore be indicated to prevent nonsurgical bleeding in patients with left ventricular assist devices.

The third paper is Dr. Gordon from Hasbro Children's Hospital in Rhode Island, and Dr. Kieran from the Dana Farber Cancer Institute in Boston, Massachusetts, and colleagues who addressed the Hutchinson Gilford Progeria Syndrome. An extremely rare, fatal segmental premature aging syndrome, where without specific treatment, death usually occurs at an average age of 14 1/2 years from an accelerated atherosclerosis.

A PRIA single arm clinical trial has demonstrated that the protein farnesyltransferase inhibitor, Lonafarnib, ameliorates some aspects of cardiovascular and bone disease in this syndrome. The current trial sought to further disease outcomes by additionally inhibiting progerin prenylation using pravastatin and zoledronic acid on top of Lonafarnib in 37 participants with the Progeria syndrome. Results showed that the composite primary study outcome of increased rate weight gain and decreased carotid artery echodensity was achieved. Overall, participants experienced increased bone density, size, and structural properties. However, unlike the PRIA single arm Lonafarnib monotherapy trial, mean carotid-femoral pulse wave velocity and mean carotid artery adventitial echodensity were not improved. In addition, rates of carotid and femoral artery plaques and extraskeletal calcifications all increased.

In summary, compared PRIA Lonafarnib monotherapy treatment, additional bone mineral density benefit, but likely no additional additional cardiovascular benefit was obtained with the addition of pravastatin and zoledronic acid. The authors concluded that since increased bone fracture is not a disease feature, the addition of a combination of statin and biphosphonate to Lonafarnib therapy is not recommended for clinical treatment of Progeria syndrome. However, it is reasonable to consider statins if concurrent lipid abnormalities need to be treated.

This paper is accompanied by an excellent editorial by Dr. Francis Collins, who describes our journey in seeking a cure for this rare disease of Progeria. The fourth paper is by first author, Dr. Grisenti and corresponding author Dr. Tilley from Lewis Katz School of Medicine, Temple University in Philadelphia, and colleagues who aimed to better understand the role of leukocyte expressed beta-2 adrenergic receptors in regulating immune cell responses to acute cardiac injury. The authors achieved this aim by studying wild type mice who were irradiated, and then transplanted either with isoform specific beta adrenergic receptor knock out bone marrow, or wild type bone marrow. These chimeric mice, after full reconstitution then underwent myocardial infarction surgery.

Results showed that immune cell specific beta-2 adrenergic receptor expression was essential to the repair process following myocardial infarction. In the absence of beta-2 adrenergic receptors, vascular cell adhesion molecule-1 expression was increased in leukocytes, inducing their splenic retention following injury, and leading to impaired scar formation, followed by rupture and death. Splenectomy partially restored the beta-2 adrenergic receptor deficient leukocyte infiltration into the heart, but gene therapy to rescue the leukocyte beta-2 adrenergic receptor expression completely restored all injury responses back to normality.

This study is clinically important because it highlights a bit of a tension that we're facing. On the one had, beta adrenergic receptors are known to regulate cardiac function and remodeling following myocardial injury, by their effects through cardiomyocytes. That's why we use beta blockers to prevent, at first, cardiac remodeling. However, the current studies now indicate that inhibition or deletion of the immune cell expressed beta-2 adrenergic receptor causes leukocyte dysfunction, and impaired immunomodulatory responses to myocardial injury. These results may, therefore, have implications on the use of beta blockers around the time of acute myocardial injury, such as myocardial infarction, or perioperatively. This is really an area that needs further research and understanding.

The fifth paper is by Dr. Herman, from the hospital of the University of Pennsylvania, and colleagues who report on the one year clinical outcomes of SAPIEN 3 transcatheter aortic valve replacement in high risk and inoperable patients with severe aortic stenosis. Now, as a refresher, in the initial partner trial of transcatheter aortic valve replacement for high risk and inoperable patients with severe symptomatic aortic stenosis, there was a demonstration of marked survival advantage compared to medical management ... But a high one year mortality of 24% in the high risk, and 31% in inoperable patients.

More recently, the lower profile SAPIEN 3 prosthesis system has become available. Which has a balloon expandable cobalt chromium frame, with bovine pericardial leaflets, and an external fabric seal. The early 30 day outcomes of this system have been reported, and show a very low rate of adverse events.

The current study now reports the one year survival, and showed that all cause survival was more than 85% for all patients, above 87% in the high risk, and above 82% in the inoperable subgroups. Furthermore, there was a high rate of transfemoral access at 84%, and a high all cause and cardiovascular one year survival in the high risk transfemoral subgroup of 89% and 93%, respectively. Between 30 and 365 days, the incidence of moderate perivalvular aortic regurgitation did not increase. There was no association between mild perivalvular leak and one year mortality. Although, a small increase in disabling stroke occurred.

These results, which likely reflect device iteration and procedural evolution, support the use of Taver as a therapy to consider in high risk and inoperable patients with aortic stenosis.

Those were the highlights from this week's issues, and now for our feature paper. We will be discussing the perspective paper entitled "Is the Mortality Benefit With Empagliflozin in Type 2 Diabetes Too Good to be True?". To discuss this, we have two very special guests. First, Dr. Sanjay Kaul, writer of this paper, and from Cedars-Sinai Medical Center. Second, Dr. Darren McGuire, deputy editor of circulation from UT Southwestern. Welcome, Sanjay and Darren.

Dr. McGuire: Thanks, Carolyn.

Dr. Kaul: Thank you, Carolyn.

Dr. Lam: To start us off, I'd really love if Darren could please introduce this new content category of circulation. Frame of reference section, of which this is one of the papers, a perspective article.

Dr. McGuire: Sure, so we envisioned, as we're evolving circulation to our new editorship, an opportunity for authors, luminaries in the field, to give us in a very encapsulated form, a laser focus perspective on a specific topic. These come in two flavors, the perspectives piece, which this is, is a little more evidence and scientific quantitatively based. Then we'll also have a section called on my mind, which is more of a free-flowing opinion editorial targeting possibly a contentious or controversial issue. These are going to be very short, and hopefully very entertaining, and kind of teasers for the readership of the Journal.

Dr. Lam: Sanjay, you made it very personal, and I like that, too. Share with us how this idea came about.

Dr. Kaul: Well, I was very impressed at the reception that the results of the EMPA-REG outcome trial received at the EAST meeting at Starcom last year. While I was witnessing the applause, I had polar reactions. On one hand, I thought that after nearly five decades of trials with checkered history, with regards to cardiovascular outcomes, here we have for the first time a trial demonstrating not only cardiovascular benefit, but a mortality benefit. I thought maybe it's time to take the trumpets out and sort of herald this holy grail, which we had failed to achieve. On the other hand, realizing that we had been fooled before many times by trials, yielding implausibly large treatments actually, that were never replicated at subsequent trials.

I had a skeptical response to it, and sort of asked this question rather tongue-in-cheek, or maybe used as a rhetorical tool to address whether this mortality benefit was too good to be true.

Dr. Lam: You know, you didn't just question it. You examined the data, and provided even more evidence. That's what I was impressed with in your paper. That table where you provided base factor, as well as a Bayesian analysis. Could you break that down for us, and explain what you found?

Dr. Kaul: Yes, I was trying to sort of examine the strength of the evidence, in terms of the quantitative aspect. Yes, the effect size for the cardiovascular benefit was quite impressive. For the primary endpoint, which was a compositive cardiovascular, death, non-fatal MI, and non-fatal stroke, the p-value was not very robust. It was .04. The p-value tends to overestimate the strength of evidence. I utilized base factor, which basically is a metric that allows the two competing hypotheses to predict the data. Using the base factor, I was able to demonstrate that the alternative hypothesis was stronger than the null hypothesis by eight-fold. The p-value of .04 translated into a base factor of .13. Which is not strong evidence against the null hypothesis. It requires independent confirmation and subsequent trials.

A p-value of .04, while meeting the superiority criteria, would not be sufficient enough to meet the FDA's requirement of substantial effectiveness. Substantial effectiveness just basically means that the FDA requires two trials, each with a p-value less than .05. In 1998, they modified their regulatory requirement, and accepted that one single trial would be sufficient, provided that there would be a persuasive p-value. Persuasive basically is defined as a p-value less than .001. The base factor allows us to sort of interpret the strength of the evidence, with respect to the primary composite endpoint was not strong enough to meet this requirement. With respect to cardiovascular mortality, as well as all cause mortality, which trumps all other endpoints, it was persuasive enough.

Dr. Lam: What's your conclusion on that?

Dr. Kaul: What is controversial about that was that in the three specified statistical plan, the so-called hierarchical testing strategy, the non-inferiority for three point MACE, followed by non-inferiority for four point MACE, and followed by superiority of three point MACE, and lastly, superiority of four point MACE. Because the p-value of four point MACE superiority was .08, one can argue purely from a statistical perspective that you stop your testing strategy, and any analysis beyond that would be deemed exploratory. Even though cardiovascular mortality and all cause mortality was prespecified, the purist would argue that since you failed superiority for four point MACE, you really can't proceed further. You can analyze, but it will be considered an exploratory analysis.

I sort of wept and said that because Christopher Columbus had prespecified that he will be discovering the route to India, the fact that he stumbled upon America does not mean it doesn't exist because he had not prespecified it. I think all cause mortality is the most meaningful endpoint, and the least subjective measurement error. It meets the key attributes of regulatory decision making. Which it's prespecified, it's highly persuasive, therefore, it meets the replication criteria, and the p-value is so robust that even if you adjust for nearly 100 multiple comparisons, the p-value would still hold. It meets all the regulatory criteria for approval.

Dr. McGuire: Sanjay, let me just chime in here. I think it's also important, not only were these prespecified, but it's important, I think, for readers of these diabetes programs to realize that hospitalization for heart failure ... Although it's not part of the primary outcome ... In virtually every one of these trials, it is prospectively collected, chartered to find, and essentially adjudicated by blind endpoint adjudicators. You know, death is death. Cardiovascular death in these programs are all adjudicated, as well. I think the prospective collection and central adjudication also adds legitimacy to the hospitalization for heart failure are above and beyond the analytic issues.

Dr. Lam: Darren and Sanjay, I hear both of you kind of saying it does look like, even looking at it from different angles, the data do look strong. At the end of the day, Sanjay, you concluded that it does need another trial. Results do need to be replicated. That was your conclusion. I'd love to hear Darren's take on this.

Dr. McGuire: I think what Sanjay is saying there, and I think what we all believe, was we would really love to see this observation with another member or members of the class. We're learning a lot in hindsight based on these observations, and people are exploring potential mechanistic underpinnings. We're learning a lot about the mechanisms of these medications, above and beyond their glucose uric effects. There's a lot of implication about renal physiology and hemodynamics, and altered myocardial metabolism. I think as Sanjay points out in the paper, some of this looks like a possible arrhythmic effect. We have a lot to learn about this mechanism of action, and whether or not this will be unique to impact gliflozin. It has been publicly announced, Boehringer Ingelheim is planning, they're in the planning phases for heart failure trials with empagliflozin to further explore this signal. I think they will address Sanjay's desire to have some replication in a different patient population. Still, we would love to see these extended into other patient populations. To both extend the use of the medications if they're found, but also provide further confirmation of the observations from EMPA-REG outcome.

Dr. Kaul: Carolyn, let me also add, I used the title as a rhetorical tool, as I stated earlier. I do conclude that the mortality data is not likely to be spurious. In the back of my mind, I still have that 1% skepticism that I would like to eliminate, because the findings were totally unexpected, and unprecedented, as we discussed earlier. If all the pathways, including the mechanistic pathways are aligned, I would have substantial reassurance, beyond any reasonable doubt that the findings are true. That's why I'm asking for replication. Not necessarily by empagliflozin in other trials, but by another molecule within the same class. I think that would be sufficient.

Dr. McGuire: Yeah, and I think it's really interesting to note there, is that I was involved in the early days of some of these drugs as they're being developed. When the other two members of this class went to the FDA, dapagliflozin and canagliflozin, they provided FDA's requirement and meta analysis from all of the phase 2B and 3 trials that had been completed to date. The meta analysis of the cardiovascular outcomes. Both dapagliflozin and canagliflozin had point estimates of cardiovascular death reduction of 30%, and 35%, respectively. When we saw those data, they were based on 25 to 40 total events. We chuckled, thinking this is spurious, from small events being analyzed. That there's no way they would prevent cardiovascular death. Sure enough, you know, you could almost superimpose those point estimate plots from the phase 2B-3 meta analysis, with the ultimate outcomes from EMPA-REG. There's some promising, although again, very statistically imprecise estimates that this may well be a class effect. As many of the listeners will know, there are ongoing cardiovascular outcomes trials for all of these medications. That will come some time in the next year or two.

Dr. Lam: That's fantastic. Thank you both for sharing those perspectives. I mean, I learned so much. I really think, Sanjay, your paper achieved exactly what you had meant for it to achieve, and exactly what circulation was hoping to create the discussion, as well.

Dr. McGuire: Thank you, Carolyn.

Dr. Kaul: Thank you very much.

Dr. Lam: You've been listening to Circulation on the Run. Thank you for listening. Don't forget to join us next week for more highlights and discussions.

Circulation July 5, 2016 Issue

29 juni 2016 | 22 min

Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

I am excited to be joined today by 2 guests and we will be discussing the feature paper on phenotype specific treatment of heart failure with preserve ejection fraction but first here are the highlights from 5 original papers in this week's issue.

(0:42) The first paper by first author doctor Haas, corresponding author Dr. Bidinger and colleagues from Boston Children's Hospital aim to investigate the role of PCSK9 in nephrotic syndrome associated hypercholesterolemia. The authors did this by first looking at 50 patients with nephrotic syndrome and showing that resolution of nephrotic syndrome was associated with a decrease in their plasma cholesterol, as well as a decrease in their plasma PCSK9 levels. They then looked at two mouse models of nephrotic syndrome. One using nephrotoxic serum to induce immune mediated damage of the kidney podocytes. The second, a model of genetic ablation of the kidney podocyte.

In both these models nephrotic syndrome produced hypercholesterolemia and a 7 to 24 fold induction of plasma PCSK9 levels. The authors then went on to look at the effect of knocking out PCSK9 both in the whole body as well as specifically in the liver in these mice. They showed that mice lacking PCSK9 no longer showed the increase in LDL cholesterol with nephrotic syndrome induced by nephrotoxic serum. Thus in summary, podocyte damage triggered mocked inductions in plasma PCSK9 and conversely knocking out PCSK9 in ameliorated this lepodimia in a mouse model of nephrotic syndrome. The cool thing about this data is that they now opened the door to the consideration of PCSK9 inhibitors in patients with nephrotic syndromes associated hypercholesterolemia.

(2:45) The second paper by Dr. Fortis and colleagues from Duke Clinical Research Institute aimed to address an important knowledge gap that has not yet been addressed in the pivotal noac trials or large registries. Which is whether outcomes differ among atrial fibrillation papers with worsening renal function compared with those with stable renal function while taking a noac versus warfarin. The authors looked a this by studying more than 12,600 patients who were treated with rivaroxaban compared to warfarin in the ROCKET AF trial. On treatment worsening renal function was defined as a decrease of more than 20% from screening creatinine clearance measurement any time point during the study.

The main finding was that among patients with on treatment worsening renal function, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin without an increase in the composite leading end point. This is really encouraging to all of us who treat these patients, knowing that it is possible to safely anti-coagulate patients with worsening renal function without excessive bleeding and to know that rivaroxaban may be an alternative to warfarin in these patients. This paper is accompanied by a beautiful editorial on the multifaceted dilemma of renal function and atrial fibrillation by doctors Hijazi and Wellington.

(4:30) The third paper by doctor [inaudible 00:04:32] and colleagues from Massachusetts Journal Hospital describes a randomized controlled trial of an advanced care planing video decision support tool in 246 patients with advanced heart failure. Patients were randomized to an intervention arm which consisted of a six minute video as well as an advanced care planning checklist or to a control arm where patients received only a verbal description of the goals of care. This video began by first introducing to the patient the concept of advanced care planning and then using images to depict the three part goals of care namely, life prolonging care, limited medical care and comfort care. Patients in the intervention arm who were showed the video, were more likely to be informed, to select a focus on comfort and less likely to desire CPR and intubation compared to patients receiving the verbal information only. The clinical application of this finding is that advanced care planning video decision needs can stimulate and supplement patient decision communication. Indeed we need such tools to enhance patients understanding of their goals of care options and to ensure that our patients get care that reflects their well-informed wishes.

(6:10) The fourth paper is by first author Dr. [inaudible 00:06:12] and corresponding author Dr. Lloyd Jones and colleagues from the Northwestern University Feinburg school of medicine in Chicago. These authors provided the first prospective evaluation of atherosclerotic cardiovascular disease outcomes in adults with heterozygous familial hypercholesterolemia in the US population. They did this by using individual pool data from 6 epidemiologic cohorts including more than 68,500 baseline person exams and 1.2 million person years of follow up. They confirmed substantially elevated long term, meaning up to 30 year risks of coronary heart disease and total atherosclerotic cardiovascular disease including stroke in US adults with a familial hypercholesterolemia phenotype defined as LDL cholesterol above 190 milligrams per deciliter. This was associated with an acceleration of coronary heart disease risk by up to 20 to 30 years. These findings were independent of other risk factors and were consistent using various definitions of the familial hypercholesterolemia phenotype.

What are the clinical implications of these findings? This was discussed by Dr. Rodriguez and Dr. [inaudible 00:07:47] in an editorial, the take home message is that there is likely an important long term burden of atherosclerotic cardiovascular disease in phenotypic but unrecognized familial hypercholesterolemia patients in the United States. Current efforts to identify patterns and gaps in the diagnosis and management are well justified. The findings also have implications for risk communication to patients.

(8:20) Finally, the fifth paper is by Dr. [inaudible 00:08:25] and colleagues of the TIMI study group from Brigham and Women's Hospital. These authors looked at the impact of renal function on outcomes with edoxaban and oral factor 10 A inhibitor with 50% renal clearance compared to warfarin in the ENGAGE AF-TIMI 48 trial. In the pre-specified subgroups of granting clearance 30 to 50 and more than 50 ml per minute. The higher dose edoxaban regiment was comparable to warfarin for preventing stroke or systemic embolism and resulted in significantly less major bleeding. In further exploratory analysis, there was a suggestion of lower relative efficacy for prevention of stroke or systemic embolism with the high dose edoxaban regiment, compared to warfarin in the upper range of creatinine clearance beyond 95 ml per minute. Due to lower rates of major bleeding, the net clinical benefit was more favorable with the higher dose edoxaban regiment across the range of creatinine clearance.

In summary, edoxaban demonstrated superior safety and comparable efficacy to warfarin for the prevention of thromboembolic events in many patients with atrial fibrillation. However the authors were careful to note that there was insufficient evidence to allow definitive conclusions to be drawn in patients with normal renal clearance above 95 ml per minute. The authors called for further investigation of optimal dosing of edoxaban in the higher range of creatinine clearance.

(10:14) Those were our highlights now for our feature paper of the week. Phenotype specific treatment of heart failure with preserved ejection fraction, a multi-organ road map. The first author is Dr. [inaudible 00:10:31] from Northwestern University Feinberg School of Medicine in Chicago and colleagues. To discuss this very special paper today I have two guests, one is a corresponding author, Dr. Walter Paulus from the VU, University medical center in Amsterdam as well as Dr. Jarett Berry, associate editor from UT Southwestern. Welcome Walter and Jarett.

Jarett Berry: Thanks Carolyn.

Walter Paulus: Thank you very much Carolyn.

Carolyn Lam: To start us off this is an in depth review paper and it is a really very special type of paper that it's new to Circulation. Jarett could you tell us a little bit about these reviews and how this paper came to be?

Jarett Berry: As we think about the new Circulation and our goals to really make the content of Circulation as clinically relevant as possible, as we think of the different circumstances and clinically challenges faced by practicing physicians, many different topics come to mind and one in particular, therapeutic area heart failure with preserved ejection fraction is one particular type of cardiovascular disorder that has been very difficult to find novel treatments for. As we all know there has been a number of large scale clinical trials that have failed to improve clinical outcomes in these patients, in situations like this what we really need is wisdom and a guide from those with expertise in this area so we can take that wisdom and that perspective and incorporate it into our approach to caring for these patients in a way that can provide a road map moving forward.

This particular review addressing heart failure with preserved ejection fraction was timely in that sense and the choice of author, of course, Walter and his colleagues are leaders in the field in terms of the research and our understanding of HFpEF. With that goal, we're really trying to reach out to these types of investigators for these types of reviews to provide us with a framework to help us think about charging our way forward and we couldn't think of a more appropriate choice to lead that effort other than Walter Paulus.

Carolyn Lam: Thank you so much Jarett, that's so well put and I couldn't agree more. I mean HFpEF is one of those disease syndromes were guidelines haven't changed in years and basically the first sentence is that we don't have outcome improving treatments available. Walter this must have been particularly challenging and I really congratulate you because one of the central figures that I'm so impressed with in this review is actually a clinical application figure and I'm referring to figure 2. Do you think you could tell the readers a little bit more about this?

Walter Paulus: I would like to thank first the editors of Circulation for having given us the opportunity to write this in-depth review. I must admit before answering Carolyn's question that I really enjoy this [inaudible 00:13:37]. We have a very challenging team of co-authors and the most difficult part of the enterprise was to have all the noses directed in the same direction. You have to align very many ideas and it has been a very challenging in-depth but I think it will be teamed out with a, not a compromise but something, a paper where everybody is still happy with its content. This is somehow also reflected in the figure 2 to which Carolyn is alluding.

When we start speaking about the phenotypic diversity, it's very difficult to [inaudible 00:14:13] with a conceptual theme on how we're going to organize therapy when there are many different phenotypes around. I think this is what this figure is all about, it tries to organize the phenotypic diversity and come up with a type of personalized medicine for each phenotype in a very comprehensive way. This figure, in fact, orders the phenotypes, presentation phenotypes and pre-disposition phenotypes with presentation phenotypes on the abscissa and the pre-disposition phenotypes on the ordinate. Then you get a matrix configuration, you start out in the matrix in the left hand corner for the most common phenotype which is metabolic risk combined with [inaudible 00:14:59] congestion. Then you go on and you see that you can have [inaudible 00:15:04] hypertension, then you have additional measures that need to be taken. You can go downwards in the graph and then you'll find out that it might be renal dysfunction and then you find specific measures that have to be taken when renal dysfunction is present.

By combining the ordinate and the abscissa in the matrix, you find a very personalized type of therapy for the individual phenotype. I think this to me what makes the figure that feeling is that it's structured, it's organized, it's something very complex in something which is easily comprehensible.

Carolyn Lam: Walter, I have not seen a figure like this that it's so novel and I know that clinicians will really welcome this because as Jarett so nicely put, it's wisdom and some sort of simplification and yet with in-depth understanding that we so need in the management of this syndrome. Another thing that I thought was very special about your paper is that you tackled head on the divergent results of several recent trials. You described the low nitric oxide, low cyclic guanosine monophosphate cycle that's present in HFpEF but also try to put into context the need trial, the relax trial, top cat and even mention Socrates preserved in all of this. Do you have any quick top line comments, not to give the whole story away because I'm sure readers are now encouraged to look at the paper but on how all of this actually falls into place in your schema.

Walter Paulus: I think how everything falls into place is illustrated in the figure 1. Figure 1 shows a very broad perspective on the problems of HFpEF as it shows HFpEF to be the result of systemic inflammatory state but so far we have focused only on the project manifestations of the systemic inflammatory state [inaudible 00:17:08] cardiac manifestations, which is the stiffness of the myocardium, and the [inaudible 00:17:12] of the myocardium. There are also things going in the pulmonary [inaudible 00:17:16], there are things going on in the skeletal muscle and there are things going on in the kidney. I think that if you do not take these other organs into perspective, then the image you will have from the results of your trials is getting blurred. For instance, we have so many trials about look at the exercise [inaudible 00:17:35] in terms of elevation of [inaudible 00:17:37].

It's my feeling that many patients with HFpEF just get treated diabetic. You see them afterwards again in your [inaudible 00:17:46] patient clinic and they have symptoms of nasal fatigue. They no longer being hindered by the elevation of [inaudible 00:17:52] probably because of the administration of the diabetic but they're still highly symptomatic and they have moved over to another board and that limits the [inaudible 00:18:01] mainly the skeletal muscle. It's of course nicely illustrated already for years by the work of Dalane Kitzman which is one of the co-authors, but still these issues, the same goes for the hypertension, a field in which Carolyn has been very active. There are some patients who are persistent [inaudible 00:18:18] hypertension, I'm intrigued by our classification.

It's clear that these patients have moved to a [three catalyst 00:18:24] type of hypertension and we should pay attention to this and we should try to treat it in a very specific way. Again [inaudible 00:18:33] the failure of our trials is also comprehensible. He have two, [inaudible 00:18:38] focus on the myocardium and we should try to keep a very broad perspective and look at [inaudible 00:18:43] in major broader way. Just to support this point is the result of the Socrates reserve trial which I was very intrigued by it, just listen to the results couple of days ago at the European Heart Failure Society meeting in Florence. Turns out if you give this very [inaudible 00:19:01] patients that there is no change in nature at [inaudible 00:19:05], no change in left atrial dimension, there's no single argument that something is changing in the myocardium. Nevertheless the effort tolerance of the patients was greatly increased and the question is in quality of life, how that has drastically improved? What I think is going on, is that maybe on the dose of the [inaudible 00:19:23] you are using this very [inaudible 00:19:24].

The main effect might be going on the [inaudible 00:19:27] and you just took the wrong end point, you are again focusing very narrowly on the myocardium. I think most of the patients have entered such a trial are relatively stable. You're not going to put in a trial a patient who is unstable, they must be all be treated with diabetics and you shift symptoms from the myocardium to the other organs. I think that the index review which we provide, I think has 2 main issues, that you should have a broad perspective on HFpEF with inclusion of the other organs and secondly, that we provide a matrix configuration for phenotypes specific treatment.

Carolyn Lam: Walter that is beautifully put and Jarett I think I'm speaking on behalf of you too that this paper has really accomplished what our in-depth reviews were aiming to do, which is to provide a clinical perspective and really insightful comments regarding the syndrome. Is there anything else you'd like to add Jarett?

Jarett Berry: Yeah, I just wanted to echo your congratulations and just to really highlight the importance of this figure 2. I think it is an important step for us to begin to take the concept of the heterogeneity the phenotype, whether it's something happening centrally or peripherally and take that heterogeneity and try to incorporate that into our practice pattern. I think that's obviously been discussed in length in literature before but has not been put together in a practical way for practicing clinicians. I just want to echo your comments that Walter and his coauthors have done an important service for all of us as we think about how to take care of our patients with HFpEF.

Carolyn Lam: That's awesome, I think anyone listening is really going to want to take hold of that journal and have a look at both figures, 1 and 2 and read this beautiful paper. Thank you very much Jarett and Walter for your time, today.

Jarett Berry: Thanks Carolyn.

Walter Paulus: Thank you very much Carolyn, [good night 00:21:20].

Carolyn Lam: You've been listening to Circulation on the Run, thank you for listening and don't forget to join us next week for more highlights.

Introduction to the Show

27 april 2016 | 12 min

Carolyn: Welcome to Circulation on the Run. You're weekly podcast summary and backstage pass to the journal. I'm Dr. Carolyn Lam from the National Heart Center in Duke National University of Singapore. I am thrilled to be your host every week. Joining me today to introduce our podcast are two very very special guests. Dr. Joseph Hill from UT Southwestern is editor and chief of Circulation. Hi Joe.

Joe: Pleasure to be here, Carolyn. Carolyn: Thanks, and your second guest, Dr Amit Kara is also from UT Southwestern and the associate editor for digital strategies of Circulation. Hi Amit.

Amit: Hi, Carolyn. Happy to be here. Carolyn: No Joe and Amit, if you don't mind I'm going to start the ball rolling by sharing my little story of how these podcasts came to be. Now do you guys remember when we first talked about this? All right well I do. Joe: Absolutely. Carolyn: Ha ha because frankly, and I don't know if you know this Joe, it wasn't a very good day for me. I had just landed very early in the morning from a long trip and I was battling jet lag while trying to get a million things done such as unpack, clear my mail, get ready for work. You know, the usual. Of course the thing I needed most was to learn that I also needed to do weekly podcasts for Circulation right. So after our chat I did I suppose what a lot of us do when things seem a little bit overwhelming. I dropped everything and I headed for a run in the gym. But in the gym as always I was trying to multitask as well, so I brought my mobile device for my jog so that I could read my mail at the same time, you know. I can already see the smiles of everyone listening because I know you've done this before. Anyone who's done it will know what a pain it is trying to read while you're bouncing up and down on the treadmill. It was just at this point when I was about to go cross-eyed that the radio in the gym started to play the morning news and the news headlines. I remember thinking to myself, oh wow, how I wish I could have someone read my mail or at least the headlines of the mail to me so that I could get the gist of everything even while I was literally on the run. That's how the Circulation podcast idea came to me and hence it's name, Circulation on the Run. To me it's an audio summary of the headlines of the journal so that you the listener can in 15 minutes get caught up literally on the run or drive or whatever it is you're doing when you'd rather listen than read. Just so you know you haven't missed the big things. But in addition to getting an overview of the issues contents every week, you get main take home messages as a clinician. Because it will be dull to talk to myself every week I will be inviting an author, an editor, of a featured article of particular clinical significance so that we can give you a behind the scenes look of the paper. That is the idea of the Circulation podcast. Joe, how does this fit with your vision of the journal? Joe: Carolyn, I love your story behind the scenes on how this all got started and I really, truly appreciate your energy and leadership here. This is such an important endeavor for where we want to take the journal. In fact, your leadership here illustrates one of the major initiatives that we have started and that is a global footprint of editorial oversight for Circulation. We are afforded an extraordinary privilege here to see the best science as it emerges from all around the world and we want to do everything we can to make sure that the journal meets the needs of the clinicians, the practitioners, and the investigators everywhere in the world. Here you are leading this important initiative from your home base in Singapore. That's exactly what we're looking to foster and develop going forward. Carolyn: Oh Joe thanks so much for that. I really so appreciate this privilege of doing this and it's true that I'm a living example of the journal going global so to speak. I also really like the way you say that with this overwhelming knowledge that we're facing, we do need help to synthesize and synergize that information. Especially in the clinically oriented way. I think you made that very clear to us in your leadership of our editorial board. Thanks for that. Maybe speaking of trying to reach the world, social media and digital strategies play a big roll. Amit maybe you could tell us a little bit more about how the podcasts fit in your larger scheme for the journal. Amit: Absolutely and I just want to echo Joe's comments and thank you, Carolyn, for taking the lead of this important endeavor. We couldn't think of a better person to do so. When we look digital strategies we have to remember that the journal is producing so much valuable content. The authors are working very hard and creating such an immense amount of new knowledge. We have to appreciate that people consume knowledge in different ways. In the current era there's so many different ways to do that. One hand we still have the traditional print journal which is incredibly valuable and important. Has depth of information that certainly many and most people would want to investigate. But the other end of the spectrum we have our bite sized information which is Twitter and Facebook and so forth which certainly helps people sort of prioritize or are able to glean what's exciting that week and then they can go back and do a deeper dive. The podcast fits somewhere in between. I love what you said, Circulation on the Run, you're example was a great one for people who are wanting to consume this information but perhaps in a different way. The audio component and also a time component where they have 10 to 15 minutes to take in this information. Your vision for this is a great one. We'll have a brief component where you will review the weekly articles and people can then learn what's in the journal and what's the most important findings and content that week. Similarly they have the opportunity to really get to know an author and get to know some editors and to really get behind the scenes. This backstage pass if you will. We finally have to remember that we're appealing to a broad audience. People of different ages and around the world. People like to consume information in different ways. We really like to have this as an important part of our offering towards helping people consume this information. Carolyn: Oh Amit. I couldn't have said it better. Thank you so much. Just to be true to ethos. Let me remind everyone that it's going to be a 15 minute podcast and we're going to do our very best to compress all that you need to know into those 15 minutes. I just want to echo what you said that this is only part of the broader strategy and it doesn't mean that the print journal is dead in any way. In fact I am so excited to see the new journal. I don't know about you. It's got a whole new look. It is really really quite good looking, if I might say so. Everyone out there, you're going to expect this new journal on June 29th, 2016. Look out for it. Trust me. You won't be disappointed because there's also a very special little part of the cover that I'd like to discuss before we sign off. That is the doodle. Joe could you tell us a little bit more about the doodle? Joe: As you say the journal look I think is fantastic. It has a clean and modern look to it. The judicious use of color to highlight the different types of content, which as before spans a spectrum of basic science, the definition going forward is vertebrate models, pre clinical models, and disease oriented questions. Starting there, traversing through clinical science, population sciences, health services research, the entire spectrum. Again we are afforded an extraordinary privilege here to help frankly shape the future of cardiovascular medicine. We take that responsibility very seriously. That's why we've recruited an extraordinary team of editors from literally around the world. At the same time, we want to have a little fun. We want to make it fun and engaging as well as very very serious. As part of that, we've launched something that we're calling the Circulation Doodle. That is an idea that leverages the google.com website where I think everyone is familiar with. They, based on an event that occurred that day or week or month, they play around with the visual depiction of the word Google. We're going to do the same thing with Circulation. Every month we will reach out and solicit doodles from artists all around the world. Everyone who's listening to this podcast, I encourage you to think about this. Every month there will be a doodle theme. The first one for July will be Texas. Commemorating the fact that the journal headquarters is moving back to Texas after having been in Boston for 12 years. Previous to that it was under the leadership of Jim Willerson. It's coming back to Texas and the first Circulation doodle depicts a Texas theme. In fact, if you're interested you can find this in the April 25th issue of the journal where in the third of four notes from the incoming editor in that third one on April 25th, we show the first doodle. We're asking people to submit doodles according to monthly themes. The month of August will be vacation. I can tell you start thinking about ways in which you might incorporate a vacation theme in the depiction of the world Circulation for August and the one that comes in that's the best, that the editors like the most, it will be placed on the cover of the print journal and on the website for a full month. We've also conceived themes for the rest of the year all the way through to June of 2017, and in the first issue that comes out from our team, we will list those themes and you'll have plenty of time to start thinking about what you would like to submit. Then in subsequent years, those monthly themes will also evolve. We'd like to get people's ideas about issues that come up related to holidays or national heritage months. Things that we might not know about from our base in the US. We want to do that around the world. It's an opportunity to be creative at the level of themes, and again artistic depiction of the word circulation. Carolyn: I love that. Thank you so much Joe and that just exemplifies that we are all about science and all about having fun at the same time. That was a brilliant introduction to what our podcasts are going to be like as well. Thank you so much Joe and Amit for joining me today. Again, everyone, this was Circulation on the Run. Don't forget, first issue coming out 29th June, 2016.

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Circulation on the Run

Each 15-minute podcast begins with an overview of the issue’s contents and main take-home messages for busy clinicians on the run.

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